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Prof. Dr. Sabine Dittrich

Faculty of European Campus Rottal-Inn

Professors

Professor

Dean of Studies @ECRI

Study coordinator: Master in Global Public Health

AA 239

0991/3615-8875

publications

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Journal article

Sabine Dittrich
B. Schwöbel
S. Jordan
V. Vanisaveth
P. Rattanaxay
E.-M. Christophel
S. Phompida
T. Jelinek

Distribution of the two forms of Plasmodium falciparum erythrocyte binding antigen-175 (eba-175) gene in Lao PDR.

In: Malaria Journal vol. 2 pg. 23

22.07.2003 (2003)

DOI: 10.1186/1475-2875-2-23

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BACKGROUND The erythrocyte binding antigen 175 (EBA-175) is a 175 kDa antigen of Plasmodium falciparum and plays a major role in erythrocyte recognition by the parasite. The antigen is also supposed to be partly responsible for the invasion of erythrocytes by merozoites. EBA-175 has been sequenced from the FCR-3 and CAMP strains of P. falciparum. The sequences were identical in most parts of the gene. Differences were apparent in a 423 bp segment in the FCR-3 strain, the F-Fragment, that is not found in the CAMP-strain and a 342 bp segment, the C-Fragment, which is present in the CAMP-strain but not in the FCR-3-strain. The aim of this study was to assess the distribution of the two EBA-175-alleles in the Lao PDR. MATERIALS & METHODS Altogether, 240 blood-samples were collected in two areas of the country: Attapeu in the south and Lung Namtha in the north. Subsequently, the material was scanned for the F-and C-fragments. RESULTS In the whole study population, 52% carried the F-fragment, and 41% the C-fragment while seven percent of the patients were infected with at least two parasite strains and showed both alleles. CONCLUSION Distribution of the alleles showed significant differences between the north and the south province. Reasons for this include possible importation of different parasite strains from neighbouring countries.

Journal article

J. Cramer
F. Mockenhaupt
I. Möhl
Sabine Dittrich
E. Dietz
R. Otchwemah
S. Ehrhardt
U. Bienzle
T. Jelinek

Allelic dimorphism of the erythrocyte binding antigen-175 (eba-175) gene of Plasmodium falciparum and severe malaria: Significant association of the C-segment with fatal outcome in Ghanaian children.

In: Malaria Journal vol. 3 pg. 11

12.05.2004 (2004)

DOI: 10.1186/1475-2875-3-11

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BACKGROUND The erythrocyte binding antigen-175 (EBA-175) on Plasmodium falciparum merozoites mediates sialic acid dependent binding to glycophorin A on host erythrocytes and, therefore, plays a crucial role in cell invasion. Dimorphic allele segments have been found in its encoding gene with a 342 bp segment present in FCR-3 strains (F-segment) and a 423 bp segment in CAMP strains (C-segment). Possible associations of the dimorphism with severe malaria have been analysed in a case-control study in northern Ghana. METHODS Blood samples of 289 children with severe malaria and 289 matched parasitaemic but asymptomatic controls were screened for eba-175 F- and C-segments by nested polymerase chain reaction. RESULTS In children with severe malaria, prevalences of F-, C- and mixed F-/C-segments were 70%, 19%, and 11%, respectively. The C-segment was found more frequently in severe malaria cases whereas mixed infections were more common in controls. Infection with strains harbouring the C-segment significantly increased the risk of fatal outcome. CONCLUSION The results show that the C-segment is associated with fatal outcome in children with severe malaria in northern Ghana, suggesting that it may contribute to the virulence of the parasite.

Journal article

J. Stohrer
Sabine Dittrich
V. Thongpaseuth
V. Vanisaveth
R. Phetsouvanh
S. Phompida
F. Monti
E.-M. Christophel
N. Lindegardh
A. Annerberg
T. Jelinek

Therapeutic efficacy of artemether-lumefantrine and artesunate-mefloquine for treatment of uncomplicated Plasmodium falciparum malaria in Luang Namtha Province, Lao People's Democratic Republic.

In: Tropical Medicine & International Health (TM & IH) vol. 9 pg. 1175-83

(2004)

DOI: 10.1111/j.1365-3156.2004.01320.x

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The efficacy of the six-dose regimen of artemether-lumefantrine was compared with the combination of artesunate and mefloquine in a randomised, comparative trial in Luang Namtha Province, Northern Laos. Of 1033 screened patients, 201 were positive for Plasmodium falciparum; 108 patients of all age groups (2-66 years) with acute, uncomplicated P. falciparum malaria were enrolled in the study, 100 of whom were followed-up for 42 days. Fifty-three patients received artemether-lumefantrine and 55 received artesunante-mefloquine. Both drug combinations induced rapid clearance of parasites and malaria symptoms; there was no significant difference in the initial therapeutic response parameters. Both regimes were well tolerated. After 42 days, cure rates were 93.6% (95% CI = 82.5-98.7%; 44 of 47 patients) for artemether-lumefantrine and 100% (95% CI = 93.3-100.0%; 53 of 53 patients) for artesunate-mefloquine. The results show the excellent efficacy and tolerability of both artemether-lumefantrine and artesunate-mefloquine in Northern Laos.

Journal article

K. Stoeter
Sabine Dittrich
M. Alifrangis
N. Muehlberger
T. Jelinek
M. Grobusch
T. Weitzel
et al.

Molecular surveillance for malaria drug resistance in imported Plasmodium falciparum isolates: sentinel data from TropNetEurop.

In: American Journal of Tropical Medicine and Hygiene vol. 73 pg. 273

(2005)

Journal article

Sabine Dittrich
M. Alifrangis
J. Stohrer
V. Thongpaseuth
V. Vanisaveth
R. Phetsouvanh
S. Phompida
I. Khalil
T. Jelinek

Falciparum malaria in the north of Laos: the occurrence and implications of the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene haplotype SVMNT.

In: Tropical Medicine & International Health (TM & IH) vol. 10 pg. 1267-70

(2005)

DOI: 10.1111/j.1365-3156.2005.01514.x

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OBJECTIVE The Pfcrt-gene encodes a transmembrane protein located in the Plasmodium falciparum digestive vacuole. Chloroquine resistant (CQR) strains of African and Southeast Asian origin carry the Pfcrt-haplotype (c72-76) CVIET, whereas most South American and Papua New Guinean CQR stains carry the SVMNT haplotype. METHOD Eighty-eight samples from an area with reported in vivo Chloroquine and in vitro Amodiaquine-resistance were screened for the K76T mutation and their Pfcrt-haplotype (c72-76) using a new SSOP-ELISA. RESULTS Hundred percent of the analysed samples showed the K76T mutation which is highly associated with in vivo drug failure. This very high rate of a CQR-marker is alarming in an area were CQ is still used as first line drug. The distribution of the three main Pfcrt-haplotypes was as follows: 68% CVIET, 31% SVMNT, 0% CVMNT. CONCLUSIONS These data show, for the first time, the South American/PNG -haplotype (SVMNT) on mainland Southeast Asia. SVMNT-haplotype and others might be associated with a decreased efficacy of Amodiaquine and could therefore be potential markers for of amodiaquine resistance (AQR). If there is a correlation between AQR and the SVMNT-haplotype as suggested, 31% prevalence of a potential resistance marker is cause for concern.

Journal article

T. Weitzel
Sabine Dittrich
I. Möhl
E. Adusu
T. Jelinek

Evaluation of seven commercial antigen detection tests for Giardia and Cryptosporidium in stool samples.

In: Clinical Microbiology and Infection vol. 12 pg. 656-9

(2006)

DOI: 10.1111/j.1469-0691.2006.01457.x

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Stool samples from patients with abdominal symptoms were used to evaluate different copro-diagnostic assays for the detection of Giardia and Cryptosporidium. Results from microscopical examination following conventional stool concentration and direct fluorescent-antibody methods were compared with various commercially available immunochromatographic and enzyme immunoassays. Of 220 samples, 45 were positive for Giardia and 17 for Cryptosporidium. For Giardia, the sensitivities obtained by Ridascreen Giardia, Rida Quick Giardia, Rida Quick Combi and Giardia-Strip were 82%, 80%, 80% and 44%, respectively. For Cryptosporidium, the sensitivities obtained by Rida Quick Cryptosporidium, Ridascreen Cryptosporidium, Rida Quick Combi and Cryptosporidium-Strip were 88%, 82%, 82% and 75%, respectively. The specificity of all tests was > or = 98%. Other intestinal parasites were present in 68 samples, but cross-reactions with other protozoan or helminthic parasites were not observed. Overall, the copro-antigen assays were less time-consuming and easier to perform, but were less sensitive than conventional microscopical methods. Thus, these tests might be a useful addition to, but not a substitute for microscopical methods in the diagnosis of travel-associated giardiasis and cryptosporidiosis.

Journal article

A. Heidari
H. Keshavarz
M. Assmar
M. Razavi
M. Nateghpour
Sabine Dittrich
T. Jelinek

Genetic diversity in the circumspordzoite protein gene of Plasmodium falciparum from major endemic regions of Iran.

In: Iranian Journal of Public Health vol. 35

(2006)

Journal article

A. Heidari
H. Keshavarz
Sabine Dittrich
A. Ebrahimzad
T. Jelinek

Genotyping of Plasmodium falciparum Field Isolates in Major Endemic Region of Iran and Potential Uses in Identification of Field Strains.

In: Journal of Medical Sciences vol. 7 pg. 228-232

(2007)

DOI: 10.3923/jms.2007.228.232

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A number of the stage specific antigens were used to develop the vaccines and to differentiate the strains of Plasmodium falciparum. Polymerase chain reaction amplification was used to determine polymorphisms of the genes of Merozoite Surface Protein 1 (MSP-1) and merozoite surface protein 2 (MSP-2) and as well as Circum Sporozoite Protein (CSP). A total of 67-microscopically positive Plasmodium falciparum infected individuals from a major endemic region, Southeast Iran, were included in this trial. Five fragments of MSP-1, 8 of MSP-2 and 3 of CSP were identified. The results showed that amplified products from these surface antigens varied in size and there was a specific pattern for each strain, besides, regarding this pattern 10 multiple infections with at least two clones were observed. Fragment 320 bp MSP-1 loci demonstrated high frequency in patients of more severe clinical manifestations. While the malaria endemic region of Iran is classified as low to moderate group but extensive polymorphisms was observed for each marker and the MSP-2 central repeat was the most diverse one.

Journal article

A. Heidari
Sabine Dittrich
T. Jelinek
A. Kheirandish
K. Banihashemi
H. Keshavarz

Genotypes and in vivo resistance of Plasmodium falciparum isolates in an endemic region of Iran.

In: Parasitology Research vol. 100 pg. 589-92

26.09.2006 (2007)

DOI: 10.1007/s00436-006-0291-z

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Mutations in the dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genes of Plasmodium falciparum have been correlated with and used to detect antifolate treatment failure, such as sulfadoxine-pyrimethamine (SP), in regions endemic for malaria. To determine the association between molecular markers of SP resistance and in vivo drug resistance, a quick and simple technique that detects single nucleotide polymorphisms in the DHFR and DHPS genes, using PCR-ELISA and sequence-specific oligonucleotide probes, was applied to 53 isolates obtained from an in vivo study in Sistan and Baluchistan Province, in southeastern Iran. Overall, 11.3% of these isolates were obtained from patients with SP treatment failure. Four DHFR polymorphisms (codons 51, 59, 108, and 164) and five DHPS polymorphisms (codons 436, 437, 540, 581, and 613) were investigated. Mutations DHFR Asn-108, DHFR Arg-59, and DHPS 436-Ala/Phe were very common (100, 81.1, and 85%, respectively). Plasmodium falciparum was isolated from 96% of patients with at least two DHFR/DHPS mutations. All resistant isolates had at least three mutations. The high prevalence of mutation associated with antifolate resistance may point toward low drug efficacy in the future.

Journal article

J. Hyde
Sabine Dittrich
P. Wang
P. Sims
V. Crécy-Lagard
A. Hanson

Plasmodium falciparum: a paradigm for alternative folate biosynthesis in diverse microorganisms?.

In: Trends in Parasitology vol. 24 pg. 502-8

19.09.2008 (2008)

DOI: 10.1016/j.pt.2008.08.004

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Folates have a key role in metabolism, and the folate-dependent generation of DNA precursors in the form of deoxythymidine 5'-phosphate is particularly important for the replication of malaria parasites. Although Plasmodium falciparum can synthesize folate derivatives de novo, a long-standing mystery has been the apparent absence of a key enzyme, dihydroneopterin aldolase, in the classical folate biosynthetic pathway of this organism. The discovery that a different enzyme, pyruvoyltetrahydropterin synthase, can produce the necessary substrate for the subsequent step in folate synthesis raises the question of whether this solution is unique to P. falciparum. Bioinformatic analyses suggest otherwise and indicate that an alternative route to folate could be widespread among diverse microorganisms and could be a target for novel drugs.

Journal article

Sabine Dittrich
S. Mitchell
A. Blagborough
Q. Wang
P. Wang
S. Sims
J. Hyde

An atypical orthologue of 6-pyruvoyltetrahydropterin synthase can provide the missing link in the folate biosynthesis pathway of malaria parasites.

In: Molecular Microbiology vol. 67 pg. 609-18

18.12.2007 (2008)

DOI: 10.1111/j.1365-2958.2007.06073.x

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Folate metabolism in malaria parasites is a long-standing, clinical target for chemotherapy and prophylaxis. However, despite determination of the complete genome sequence of the lethal species Plasmodium falciparum, the pathway of de novo folate biosynthesis remains incomplete, as no candidate gene for dihydroneopterin aldolase (DHNA) could be identified. This enzyme catalyses the third step in the well-characterized pathway of plants, bacteria, and those eukaryotic microorganisms capable of synthesizing their own folate. Utilizing bioinformatics searches based on both primary and higher protein structures, together with biochemical assays, we demonstrate that P. falciparum cell extracts lack detectable DHNA activity, but that the parasite possesses an unusual orthologue of 6-pyruvoyltetrahydropterin synthase (PTPS), which simultaneously gives rise to two products in comparable amounts, the predominant of which is 6-hydroxymethyl-7,8-dihydropterin, the substrate for the fourth step in folate biosynthesis (catalysed by 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase; PPPK). This can provide a bypass for the missing DHNA activity and thus a means of completing the biosynthetic pathway from GTP to dihydrofolate. Supported by site-directed mutagenesis experiments, we ascribe the novel catalytic activity of the malarial PTPS to a Cys to Glu change at its active site relative to all previously characterized PTPS molecules, including that of the human host.

Journal article

A. Nerlich
B. Schraut
Sabine Dittrich
T. Jelinek
A. Zink

Plasmodium falciparum in Ancient Egypt.

In: Emerging Infectious Diseases vol. 14 pg. 1317-9

(2008)

DOI: 10.3201/eid1408.080235

Journal article

Sabine Dittrich
S. Mitchell
A. Blackborough
P. Wang
P. Sims
J. Hyde

An atypical ortholog of 6-pyruvoyltetrahydropterin synthase provides the missing link in the folate biosynthesis of malaria parasites.

In: International Journal for Parasitology vol. 38 pg. S42-S43

(2008)

Journal article

A. Timen
M. Koopmans
Vossen, A. C. T. M.
G. Doornum
S. Günther
F. van den Berkmortel
K. Verduin
Sabine Dittrich
P. Emmerich
Osterhaus, A. D. M. E.
J. van Dissel
R. Coutinho

Response to Imported Case of Marburg Hemorrhagic Fever, the Netherlands.

In: Emerging Infectious Diseases vol. 15 pg. 1171-1175

(2009)

DOI: 10.3201/eid1508.090051

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On July 10, 2008, Marburg hemorrhagic fever was confirmed in a Dutch patient who had vacationed recently in Uganda. Exposure most likely occurred in the Python Cave (Maramagambo Forest), which harbors bat species that elsewhere in Africa have been found positive for Marburg virus. A multidisciplinary response team was convened to perform a structured risk assessment, perform risk classification of contacts, issue guidelines for follow-up, provide information, and monitor the crisis response. In total, 130 contacts were identified (66 classified as high risk and 64 as low risk) and monitored for 21 days after their last possible exposure. The case raised questions specific to international travel, postexposure prophylaxis for Marburg virus, and laboratory testing of contacts with fever. We present lessons learned and results of the follow-up serosurvey of contacts and focus on factors that prevented overreaction during an event with a high public health impact.

Journal article

A. Heidari
H. Keshavarz
Sabine Dittrich
T. Jelinek

Allelic Dimorphism of the Plasmodium falciparum Erythrocyte Binding Antigen-175 (EBA-175) Gene in the Southeast of Iran.

In: Iranian Journal of Parasitology vol. 4 pg. 17-22

(2009)

Journal article

E. Fanoy
J. Cremer
J. Ferreira
Sabine Dittrich
van Lier, A.: Hahné, S. J. H.
H. Boot
R. van Binnendijk

Transmission of mumps virus from mumps-vaccinated individuals to close contacts.

In: Vaccine vol. 29 pg. 9551-6

05.10.2011 (2011)

DOI: 10.1016/j.vaccine.2011.09.100

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During a recent mumps epidemic in the Netherlands caused by a genotype D mumps virus strain, we investigated the potential of vaccinated people to spread mumps disease to close contacts. We compared mumps viral titers of oral fluid specimens obtained by quantitative PCR from vaccinated (n=60) and unvaccinated (n=111) mumps patients. We also investigated the occurrence of mumps infection among the household contacts of vaccinated mumps patients. We found that viral titers are higher for unvaccinated patients than for vaccinated patients during the 1st 3 days after onset of disease. While no symptomatic cases were reported among the household contacts (n=164) of vaccinated mumps patients (n=36), there were cases with serological evidence of asymptomatic infection among vaccinated household contacts (9 of 66 vaccinated siblings). For two of these siblings, the vaccinated index patient was the most probable source of infection. We conclude that, in this particular outbreak, the risk of a close contact becoming infected by vaccinated patients was small, but present.

Journal article

Sabine Dittrich
S. Hahné
A. van Lier
R. Kohl
H. Boot
M. Koopmans
R. van Binnendijk

Assessment of serological evidence for mumps virus infection in vaccinated children.

In: Vaccine vol. 29 pg. 9271-5

06.10.2011 (2011)

DOI: 10.1016/j.vaccine.2011.09.072

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It is estimated that at least one-third of mumps virus infections in non-vaccinated individuals are asymptomatic. Little information is available whether this proportion is the same among those vaccinated. We validated a commercial oral fluid mumps IgG-specific Enzyme Immunoassays (EIA) with vaccinated control groups to identify symptomatic and asymptomatic mumps virus infections in vaccinated individuals during a mumps outbreak in The Netherlands. A vaccinated control group was required to define a new cutoff value for the assay, because of the presence of low but significant levels of IgG antibodies in oral fluid as a result of mumps vaccination in the past. With a new cutoff, calculated using receiver operator characteristic analysis, we identified an attack rate of 7-10% compared to 2.7% based on clinical symptoms among vaccinated children. This finding has important implications when studying transmission patterns, strain virulence, as well as mumps vaccine effectiveness to protect from infection rather than disease.

Journal article

H.-F. Kinkel
Sabine Dittrich
B. Bäumer
T. Weitzel

Evaluation of eight serological tests for diagnosis of imported schistosomiasis.

In: Clinical and Vaccine Immunology (CVI) vol. 19 pg. 948-53

21.03.2012 (2012)

DOI: 10.1128/cvi.05680-11

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The diagnosis of schistosomiasis in individuals from countries where the disease is not endemic is challenging, and few data are available on the accuracy of serological diagnosis in those patients. We evaluated the performance of eight serological assays, including four commercial kits, in the diagnosis of imported schistosomiasis in individuals from areas where the disease is not endemic, including six enzyme-linked immunosorbent assays using three different antigens, an indirect hemagglutination assay, and an indirect immunofluorescent-antibody test. To analyze the assays, we used a total of 141 serum samples, with 121 derived from patients with various parasitic infections (among which were 37 cases of schistosomiasis) and 20 taken from healthy volunteers. The sensitivity values for detection of schistosomiasis cases ranged from 41% to 78% and were higher for Schistosoma mansoni than for S. haematobium infections. Specificity values ranged from 76% to 100%; false-positive results were most frequent for samples from patients with cestode infections. By combining two or more tests, sensitivity improved markedly and specificity decreased only moderately. Serological tests are useful instruments for diagnosing imported schistosomiasis in countries where the disease is not endemic, but due to limitations in test sensitivities, we recommend the use of two or more assays in parallel.

Journal article

Sabine Dittrich

Online-Only Abstract.

In: Clinical Microbiology and Infection vol. 19 pg. 969

(2013)

DOI: 10.1111/1469-0691.12357

show abstract

We investigated whether dried cerebrospinal fluid (CSF) conserved on filter paper can be used as a substrate for accurate PCR diagnosis of important causes of bacterial meningitis in the Lao PDR. Using mock CSF, we investigated and optimized filter paper varieties, paper punch sizes, elution volumes and quantities of DNA template to achieve sensitive and reliable detection of bacterial DNA from filter paper specimens. FTA Elute Micro CardTM (Whatman, Maidstone, UK) was the most sensitive, consistent and practical variety of filter paper. Following optimization, the lower limit of detection for Streptococcus pneumoniae from dried mock CSF spots was 14 genomic equivalents (GE)/μL (interquartile range 5.5 GE/μL) or 230 (IQR 65) colony forming units/mL. A prospective clinical evaluation for S. pneumoniae, S. suis and Neisseria meningitidis was performed. Culture and PCR performed on fresh liquid CSF from patients admitted with a clinical diagnosis of meningitis (n = 73) were compared with results derived from dried CSF spots. Four of five fresh PCR-positive CSF samples also tested PCR positive from dried CSF spots, with one patient under the limit of detection. In a retrospective study of S. pneumoniae samples (n = 20), the median (IQR; range) CSF S. pneumoniae bacterial load was 1.1 × 104 GE/μL (1.2 × 105; 1 to 6.1 × 106 DNA GE/μL). Utilizing the optimized methodology, we estimate an extrapolated sensitivity of 90%, based on the range of CSF genome counts found in Laos. Dried CSF filter paper spots could potentially help us to better understand the epidemiology of bacterial meningitis in resource-poor settings and guide empirical treatments and vaccination policies.

Journal article

A. Bonačić Marinović
M. Koopmans
Sabine Dittrich
P. Teunis
C. Swaan
J. van Steenbergen
M. Kretzschmar

Speed versus coverage trade off in targeted interventions during an outbreak.

In: Epidemics vol. 8 pg. 28-40

15.08.2014 (2014)

DOI: 10.1016/j.epidem.2014.05.003

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Which case-based intervention measures should be applied during an epidemic outbreak depends on how timely they can be applied and how effective they are. During the course of each individual's infection, the earlier control measures are applied on him/her the more effectively further disease spread can be prevented. However, quick implementation can lead to loss of efficacy or coverage, e.g., when individuals are targeted based on rapid but poorly sensitive diagnostic tests in place of slower but accurate PCR tests. To analyse this trade off between speed and coverage we used stochastic models considering how the individual reproduction density is modified by interventions. We took as example the case-based intervention strategy employed in the Netherlands during the beginning of the H1N1 pandemic. Suspected cases were isolated and samples were collected for PCR diagnosis. In case of positive diagnosis, antiviral drugs were provided to contacts as post-exposure prophylaxis. At the time there were also rapid influenza diagnostic tests (RIDTs) available which provided results within an hour after sample collection compared to a median of 2.7 days for PCR tests, but they were less sensitive. We studied how interventions based on RIDTs with various sensitivities affect the outbreak size and how these compare to PCR diagnosis based interventions. Using an intervention based on a bedside RIDT with 60% detection ratio or a laboratory RIDT with 70% detection ratio is as effective as the most effective PCR-diagnosis based intervention. Relative performances of interventions are not dependent on the basic reproduction number R0 but only on distributions of individual reproduction density and of delay periods. The individual reproduction density combines R0 and infection time distribution, both crucial in determining the impact of case-based interventions during epidemic outbreaks.

Journal article

Sabine Dittrich
J. Castonguay-Vanier
C. Moore
N. Thongyoo
P. Newton
D. Paris

Loop-mediated isothermal amplification for Rickettsia typhi (the causal agent of murine typhus): problems with diagnosis at the limit of detection.

In: Journal of Clinical Microbiology vol. 52 pg. 832-8

26.12.2013 (2014)

DOI: 10.1128/jcm.02786-13

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Murine typhus is a flea-borne disease of worldwide distribution caused by Rickettsia typhi. Although treatment with tetracycline antibiotics is effective, treatment is often misguided or delayed due to diagnostic difficulties. As the gold standard immunofluorescence assay is imperfect, we aimed to develop and evaluate a loop-mediated isothermal amplification (LAMP) assay. LAMP assays have the potential to fulfill the WHO ASSURED criteria (affordable, sensitive, specific, user friendly, robust and rapid, equipment free, deliverable to those who need them) for diagnostic methodologies, as they can detect pathogen-derived nucleic acid with low technical expenditure. The LAMP assay was developed using samples of bacterial isolates (n=41), buffy coat specimens from R. typhi PCR-positive Lao patients (n=42), and diverse negative controls (n=47). The method was then evaluated prospectively using consecutive patients with suspected scrub typhus or murine typhus (n=266). The limit of detection was ∼40 DNA copies/LAMP reaction, with an analytical sensitivity of <10 DNA copies/reaction based on isolate dilutions. Despite these low cutoffs, the clinical sensitivity was disappointing, with 48% (95% confidence interval [95% CI], 32.5 to 62.7%) (specificity, 100% [95% CI, 100 to 100%]) in the developmental phase and 33% (95% CI, 9.2 to 56.8%) (specificity, 98.5% [95% CI, 97.0% to 100%]) in the prospective study. This low diagnostic accuracy was attributed to low patient R. typhi bacterial loads (median, 210 DNA copies/ml blood; interquartile range, 130 to 500). PCR-positive but LAMP-negative samples demonstrated significantly lower bacterial loads than LAMP-positive samples. Our findings highlight the diagnostic challenges for diseases with low pathogen burdens and emphasize the need to integrate pathogen biology with improved template production for assay development strategies.

Journal article

Sabine Dittrich
K. Phommasone
T. Anantatat
P. Panyanivong
G. Slesak
S. Blacksell
A. Dubot-Pérès
J. Castonguay-Vanier
J. Stenos
P. Newton
D. Paris

Rickettsia felis Infections and comorbid conditions, Laos, 2003-2011.

In: Emerging Infectious Diseases vol. 20 pg. 1402-4

(2014)

DOI: 10.3201/eid2008.131308

Journal article

A. Heidari
H. Keshavarz
S. Shojaee
A. Raesi
Sabine Dittrich

In vivo Susceptibility of Plasmodium vivax to Chloroquine in Southeastern Iran..

In: Iranian Journal of Parasitology vol. 7 pg. 8-14

(2014)

show abstract

Plasmodium vivax is the predominant species causes of malaria with about 90% total annual reported malaria in Iran. This study conducted to determine the susceptibility of Plasmodium vivax isolates to chloroquine in Sistan and Balochistan Province, southeastern Iran.MethodsA total 270 subjects with symptomatic malaria and confirmed P. vivax infection completed the designed 28-day in vivo study. The thick and thin film blood smears were screened for malaria parasites by microscopy. The nested PCR was applied using the Plasmodium 18 subunit ribosomal ribonucleic (Ssr RNA) genes for detecting mixed infections and diagnosis of parasites in the samples with low parasite on days 0, 5, 6, 7, and 28.ResultsP. vivax was cleared in 15%, 50%, 95%, and 100% of patients on days 1, 2, 3, 4 respectively by microscopy assessment. Six patients were exhibited specific P. vivax band in nested PCR on day 5. No recurrence was observed on days 7, 14 and 28. Mean (±standard deviation) parasite clearance time was 2.41 (±0.8) days.ConclusionP. vivax is still susceptible to chloroquine in Southeatern Iran. This finding is compatible with results of neighboring countries Pakistan and Afghanistan.

Contribution

Sabine Dittrich
P. Sunyakumthorn
S. Rattanavong
R. Phetsouvanh
P. Panyanivong
A. Sengduangphachanh
P. Phouminh
T. Anantatat
A. Chanthongthip
S. Lee
A. Dubot-Pérès
N. Day
et al.

Blood–Brain Barrier Function and Biomarkers of Central Nervous System Injury in Rickettsial Versus Other Neurological Infections in Laos.

In: ASTMH 64th Annual Meeting. pg. 232-237

Eds.:
The American Society of Tropical Medicine and Hygiene
American Journal of Tropical Medicine and Hygiene

(2015)

Journal article

Günther Slesak
Saythong Inthalath
Sabine Dittrich
Daniel Paris
Paul Newton

Leeches as further potential vectors for rickettsial infections.

In: Proceedings of the National Academy of Sciences of the United States of America vol. 112 pg. E6593-4

23.11.2015 (2015)

DOI: 10.1073/pnas.1515229112

show abstract

We were very interested in the discovery and comprehensive investigation by Dieme et al. (1) of mosquitos as potential vectors for Rickettisa felis. We would like to draw attention to another ectoparasite that we encountered as a possibly overlooked potential vector for rickettsial infections: the leech. In 2008, a 39-y-old diabetic woman was admitted to a hospital in Northern Laos with a 7-d history of fever, headaches, limb pains, chills, and 2 d of nausea and vomiting. She had a typical eschar on her right anteromedial thigh (7 × 4 mm) (Fig. 1). She remembered being bitten by a terrestrial leech (Haemadipsida spp.), while working in a rice field, exactly at the eschar site 5 d before onset of fever. No tick or other ectoparasite was observed at this site until eschar manifestation. Molecular characterization of eschar biopsy revealed amplicons of 100% identity to the Rickettsia felis-URRWXCal2 strain (2). The patient responded promptly to treatment with oral doxycycline.

Journal article

I. Vongphoumy
D. Dance
Sabine Dittrich
J. Logan
V. Davong
S. Rattanavong
J. Blessmann

Case report: Actinomycetoma caused by Nocardia aobensis from Lao PDR with favourable outcome after short-term antibiotic treatment.

In: PLoS Neglected Tropical Diseases vol. 9 pg. e0003729

16.04.2015 (2015)

DOI: 10.1371/journal.pntd.0003729

show abstract

BACKGROUND Mycetoma is a neglected, chronic, localized, progressively destructive, granulomatous infection caused either by fungi (eumycetoma) or by aerobic actinomycetes (actinomycetoma). It is characterized by a triad of painless subcutaneous mass, multiple sinuses and discharge containing grains. Mycetoma commonly affects young men aged between 20 and 40 years with low socioeconomic status, particularly farmers and herdsmen. METHODOLOGY/PRINCIPAL FINDINGS A 30 year-old male farmer from an ethnic minority in Phin District, Savannakhet Province, Lao PDR (Laos) developed a painless swelling with multiple draining sinuses of his right foot over a period of approximately 3 years. X-ray of the right foot showed osteolysis of tarsals and metatarsals. Aerobic culture of sinus discharge yielded large numbers of Staphylococcus aureus and a slow growing Gram-positive rod. The organism was subsequently identified as Nocardia aobensis by 16S ribosomal RNA gene sequencing. The patient received antimicrobial treatment with amikacin and trimethoprim-sulfamethoxazole according to consensus treatment guidelines. Although slight improvement was noted the patient left the hospital after 14 days and did not take any more antibiotics. Over the following 22 weeks the swelling of his foot subsequently diminished together with healing of discharging sinuses. CONCLUSION This is the first published case of Actinomycetoma caused by Nocardia aobensis and the second case of Actinomycetoma from Laos. A treatment course of only 14 days with amikacin and trimethoprim-sulfamethoxazole was apparently sufficient to cure the infection, although long-term treatment up to one year is currently recommended. Treatment trials or prospective descriptions of outcome for actinomycetoma should investigate treatment efficacy for the different members of Actinomycetales, particularly Nocardia spp., with short-term and long-term treatment courses.

Contribution

Sabine Dittrich
P. Panyanivong
S. Thongpaseuth
D. Paris
S. Blacksell
R. Phetsouvanh
P. Newton

How to Optimally Diagnose Orientia Tsutsugamushi or Rickettsia Typhi Infections in Patients With Central Nervous System Disease?.

In: ASTMH 64th Annual Meeting. pg. 162-163

Eds.:
The American Society of Tropical Medicine and Hygiene
American Journal of Tropical Medicine and Hygiene

(2015)

Journal article

Sabine Dittrich
Sayaphet Rattanavong
Sue Lee
Phonepasith Panyanivong
Scott Craig
Suhella Tulsiani
Stuart Blacksell
David Dance
Audrey Dubot-Pérès
Amphone Sengduangphachanh
Phonelavanh Phoumin
Daniel Paris
Paul Newton

Orientia, rickettsia, and leptospira pathogens as causes of CNS infections in Laos: a prospective study.

In: The Lancet Global Health vol. 3 pg. e104-12

(2015)

DOI: 10.1016/s2214-109x(14)70289-x

show abstract

BACKGROUND Scrub typhus (caused by Orientia tsutsugamushi), murine typhus (caused by Rickettsia typhi), and leptospirosis are common causes of febrile illness in Asia; meningitis and meningoencephalitis are severe complications. However, scarce data exist for the burden of these pathogens in patients with CNS disease in endemic countries. Laos is representative of vast economically poor rural areas in Asia with little medical information to guide public health policy. We assessed whether these pathogens are important causes of CNS infections in Laos. METHODS Between Jan 10, 2003, and Nov 25, 2011, we enrolled 1112 consecutive patients of all ages admitted with CNS symptoms or signs requiring a lumbar puncture at Mahosot Hospital, Vientiane, Laos. Microbiological examinations (culture, PCR, and serology) targeted so-called conventional bacterial infections (Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, S suis) and O tsutsugamushi, Rickettsia typhi/Rickettsia spp, and Leptospira spp infections in blood or cerebrospinal fluid (CSF). We analysed and compared causes and clinical and CSF characteristics between patient groups. FINDINGS 1051 (95%) of 1112 patients who presented had CSF available for analysis, of whom 254 (24%) had a CNS infection attributable to a bacterial or fungal pathogen. 90 (35%) of these 254 infections were caused by O tsutsugamushi, R typhi/Rickettsia spp, or Leptospira spp. These pathogens were significantly more frequent than conventional bacterial infections (90/1051 [9%] vs 42/1051 [4%]; p<0·0001) by use of conservative diagnostic definitions. CNS infections had a high mortality (236/876 [27%]), with 18% (13/71) for R typhi/Rickettsia spp, O tsutsugamushi, and Leptospira spp combined, and 33% (13/39) for conventional bacterial infections (p=0·076). INTERPRETATION Our data suggest that R typhi/Rickettsia spp, O tsutsugamushi, and Leptospira spp infections are important causes of CNS infections in Laos. Antibiotics, such as tetracyclines, needed for the treatment of murine typhus and scrub typhus, are not routinely advised for empirical treatment of CNS infections. These severely neglected infections represent a potentially large proportion of treatable CNS disease burden across vast endemic areas and need more attention. FUNDING Wellcome Trust UK.

Journal article

Sabine Dittrich
W. Phuklia
G. Turner
S. Rattanavong
V.ilada Chansamouth
et al.

Neorickettsia sennetsu as a Neglected Cause of Fever in South-East Asia.

In: PLoS Neglected Tropical Diseases vol. 9 pg. e0003908

09.07.2015 (2015)

DOI: 10.1371/journal.pntd.0003908

show abstract

Neorickettsia sennetsu infection is rarely recognized, with less than 100 globally reported patients over the last 50 years. The disease is thought to be contracted by eating raw fish, a staple of many South-East Asian cuisines. In 2009, the first patient with sennetsu was identified in the Lao PDR (Laos), raising the question as to how common this organism and related species are in patients presenting with fever. We investigated the frequency of N. sennetsu infection at hospitals in diverse areas of Laos. Consenting febrile hospital inpatients from central (Vientiane: n = 1,013), northern (Luang Namtha: n = 453) and southern (Salavan: n = 171) Laos were screened by PCR for N. sennetsu, if no previous positive direct diagnostic test was available. A PCR-restriction fragment length polymorphism assay was developed to differentiate between N. sennetsu, Ehrlichia chaffeensis and Anaplasma phagocytophilum. To allow more detailed studies of N. sennetsu, culture was successfully established using a reference strain (ATCC VR-367), identifying a canine-macrophage cell line (DH82) to be most suitable to visually identify infection. After screening, N. sennetsu was identified and sequence confirmed in four (4/1,637; 0.2%) Lao patients. Despite the previously identified high seroprevalence of N. sennetsu antibodies in the Lao population (~17%), acute N. sennetsu infection with sufficient clinical signs to prompt hospitalization appears to be rare. The reservoir, zoonotic cycle and pathogenicity of N. sennetsu remain unclear and require further investigations.

Journal article

C. Nic Fhogartaigh
D. Dance
V. Davong
P. Tann
R. Phetsouvanh
P. Turner
Sabine Dittrich
P. Newton

A novel technique for detecting antibiotic-resistant typhoid from rapid diagnostic tests.

In: Journal of Clinical Microbiology vol. 53 pg. 1758-60

11.03.2015 (2015)

DOI: 10.1128/jcm.00531-15

show abstract

Fluoroquinolone-resistant typhoid is increasing. An antigen-detecting rapid diagnostic test (RDT) can rapidly diagnose typhoid from blood cultures. A simple, inexpensive molecular technique performed with DNA from positive RDTs accurately identified gyrA mutations consistent with phenotypic susceptibility testing results. Field diagnosis combined with centralized molecular resistance testing could improve typhoid management and surveillance in low-resource settings.

Contribution

M. Mayxay
O. Sengvilaipaseuth
A. Chanthongthip
A. Dubot-Pérès
J.-M. Rolain
P. Parola
S. Craig
S. Tulsiani
M.-A. Burns
M. Khanthavong
S. Keola
T. Pongvongsa
D. Raoult
Sabine Dittrich
P. Newton

Causes of Fever in Rural Southern Laos.

In: ASTMH 64th Annual Meeting. pg. 517-520

Eds.:
The American Society of Tropical Medicine and Hygiene
American Journal of Tropical Medicine and Hygiene

(2015)

Journal article

M. Knappik
D. Dance
S. Rattanavong
A. Pierret
O. Ribolzi
V. Davong
J. Silisouk
M. Vongsouvath
P. Newton
Sabine Dittrich

Evaluation of Molecular Methods To Improve the Detection of Burkholderia pseudomallei in Soil and Water Samples from Laos.

In: Applied and Environmental Microbiology vol. 81 pg. 3722-7

27.03.2015 (2015)

DOI: 10.1128/aem.04204-14

show abstract

Burkholderia pseudomallei is the cause of melioidosis, a severe and potentially fatal disease of humans and animals. It is endemic in northern Australia and Southeast Asia and is found in soil and surface water. The environmental distribution of B. pseudomallei worldwide and within countries where it is endemic, such as the Lao People's Democratic Republic (Laos), remains unclear. However, this knowledge is important to our understanding of the ecology and epidemiology of B. pseudomallei and to facilitate public health interventions. Sensitive and specific methods to detect B. pseudomallei in environmental samples are therefore needed. The aim of this study was to compare molecular and culture-based methods for the detection of B. pseudomallei in soil and surface water in order to identify the optimal approach for future environmental studies in Laos. Molecular detection by quantitative real-time PCR (qPCR) was attempted after DNA extraction directly from soil or water samples or after an overnight enrichment step. The positivity rates obtained by qPCR were compared to those obtained by different culture techniques. The rate of detection from soil samples by qPCR following culture enrichment was significantly higher (84/100) than that by individual culture methods and all culture methods combined (44/100; P < 0.001). Similarly, qPCR following enrichment was the most sensitive method for filtered river water compared with the sensitivity of the individual methods and all individual methods combined. In conclusion, molecular detection following an enrichment step has proven to be a sensitive and reliable approach for B. pseudomallei detection in Lao environmental samples and is recommended as the preferred method for future surveys.

Journal article

A. Taylor
K. Vongphayloth
M. Vongsouvath
M. Grandadam
P. Brey
P. Newton
I. Sutherland
Sabine Dittrich

Large-Scale Survey for Tickborne Bacteria, Khammouan Province, Laos.

In: Emerging Infectious Diseases vol. 22 pg. 1635-9

(2016)

DOI: 10.3201/eid2209.151969

show abstract

We screened 768 tick pools containing 6,962 ticks from Khammouan Province, Laos, by using quantitative real-time PCR and identified Rickettsia spp., Ehrlichia spp., and Borrelia spp. Sequencing of Rickettsia spp.-positive and Borrelia spp.-positive pools provided evidence for distinct genotypes. Our results identified bacteria with human disease potential in ticks in Laos.

Journal article

Sabine Dittrich
Elizabeth Card
Weerawat Phuklia
Williams Rudgard
Joy Silousok
Phonelavanh Phoumin
Latsaniphone Bouthasavong
Sarah Azarian
Viengmon Davong
David Dance
Manivanh Vongsouvath
Rattanaphone Phetsouvanh
Paul Newton

Survival and Growth of Orientia tsutsugamushi in Conventional Hemocultures.

In: Emerging Infectious Diseases vol. 22 pg. 1460-3

(2016)

DOI: 10.3201/eid2208.151259

show abstract

Orientia tsutsugamushi, which requires specialized facilities for culture, is a substantial cause of disease in Asia. We demonstrate that O. tsutsugamushi numbers increased for up to 5 days in conventional hemocultures. Performing such a culture step before molecular testing could increase the sensitivity of O. tsutsugamushi molecular diagnosis.

Journal article

Sabrina Weiss
Angela Menezes
Kate Woods
Anisone Chanthongthip
Sabine Dittrich
Agatha Opoku-Boateng
Maimuna Kimuli
Victoria Chalker

An Extended Multilocus Sequence Typing (MLST) Scheme for Rapid Direct Typing of Leptospira from Clinical Samples.

In: PLoS Neglected Tropical Diseases vol. 10 pg. e0004996

21.09.2016 (2016)

DOI: 10.1371/journal.pntd.0004996

show abstract

BACKGROUND Rapid typing of Leptospira is currently impaired by requiring time consuming culture of leptospires. The objective of this study was to develop an assay that provides multilocus sequence typing (MLST) data direct from patient specimens while minimising costs for subsequent sequencing. METHODOLOGY AND FINDINGS An existing PCR based MLST scheme was modified by designing nested primers including anchors for facilitated subsequent sequencing. The assay was applied to various specimen types from patients diagnosed with leptospirosis between 2014 and 2015 in the United Kingdom (UK) and the Lao Peoples Democratic Republic (Lao PDR). Of 44 clinical samples (23 serum, 6 whole blood, 3 buffy coat, 12 urine) PCR positive for pathogenic Leptospira spp. at least one allele was amplified in 22 samples (50%) and used for phylogenetic inference. Full allelic profiles were obtained from ten specimens, representing all sample types (23%). No nonspecific amplicons were observed in any of the samples. Of twelve PCR positive urine specimens three gave full allelic profiles (25%) and two a partial profile. Phylogenetic analysis allowed for species assignment. The predominant species detected was L. interrogans (10/14 and 7/8 from UK and Lao PDR, respectively). All other species were detected in samples from only one country (Lao PDR: L. borgpetersenii [1/8]; UK: L. kirschneri [1/14], L. santarosai [1/14], L. weilii [2/14]). CONCLUSION Typing information of pathogenic Leptospira spp. was obtained directly from a variety of clinical samples using a modified MLST assay. This assay negates the need for time-consuming culture of Leptospira prior to typing and will be of use both in surveillance, as single alleles enable species determination, and outbreaks for the rapid identification of clusters.

Journal article

A. Rachlin
Sabine Dittrich
K. Phommasone
A. Douangnouvong
R. Phetsouvanh
P. Newton
D. Dance

Investigation of Recurrent Melioidosis in Lao People's Democratic Republic by Multilocus Sequence Typing.

In: The American Journal of Tropical Medicine and Hygiene vol. 94 pg. 1208-1211

21.03.2016 (2016)

DOI: 10.4269/ajtmh.15-0909

show abstract

Melioidosis is an infectious disease caused by the saprophytic bacterium Burkholderia pseudomallei In northeast Thailand and northern Australia, where the disease is highly endemic, a range of molecular tools have been used to study its epidemiology and pathogenesis. In the Lao People's Democratic Republic (Laos) where melioidosis has been recognized as endemic since 1999, no such studies have been undertaken. We used a multilocus sequence typing scheme specific for B. pseudomallei to investigate nine cases of culture-positive recurrence occurring in 514 patients with melioidosis between 2010 and 2015: four were suspected to be relapses while the other five represented reinfections. In addition, two novel sequence types of the bacterium were identified. The low overall recurrence rates (2.4%) and proportions of relapse and reinfection in the Laos are consistent with those described in the recent literature, reflecting the effective use of appropriate antimicrobial therapy.

Journal article

Patpong Rongkard
Viriya Hantrakun
Sabine Dittrich
Prapaporn Srilohasin
Premjit Amornchai
Sayan Langla
Cherry Lim
Nicholas Day
David AuCoin
Vanaporn Wuthiekanun
Direk Limmathurotsakul

Utility of a Lateral Flow Immunoassay (LFI) to Detect Burkholderia pseudomallei in Soil Samples.

In: PLoS Neglected Tropical Diseases vol. 10 pg. e0005204

14.12.2016 (2016)

DOI: 10.1371/journal.pntd.0005204

show abstract

BACKGROUND Culture is the gold standard for the detection of environmental B. pseudomallei. In general, soil specimens are cultured in enrichment broth for 2 days, and then the culture broth is streaked on an agar plate and incubated further for 7 days. However, identifying B. pseudomallei on the agar plates among other soil microbes requires expertise and experience. Here, we evaluate a lateral flow immunoassay (LFI) developed to detect B. pseudomallei capsular polysaccharide (CPS) in clinical samples as a tool to detect B. pseudomallei in environmental samples. METHODOLOGY/PRINCIPAL FINDINGS First, we determined the limit of detection (LOD) of LFI for enrichment broth of the soil specimens. Soil specimens (10 grams/specimen) culture negative for B. pseudomallei were spiked with B. pseudomallei ranging from 10 to 105 CFU, and incubated in 10 ml of enrichment broth in air at 40°C. Then, on day 2, 4 and 7 of incubation, 50 μL of the upper layer of the broth were tested on the LFI, and colony counts to determine quantity of B. pseudomallei in the broth were performed. We found that all five soil specimens inoculated at 10 CFU were negative by LFI on day 2, but four of those five specimens were LFI positive on day 7. The LOD of the LFI was estimated to be roughly 3.8x106 CFU/ml, and culture broth on day 7 was selected as the optimal sample for LFI testing. Second, we evaluated the utility of the LFI by testing 105 soil samples from Northeast Thailand. All samples were also tested by standard culture and quantitative PCR (qPCR) targeting orf2. Of 105 soil samples, 35 (33%) were LFI positive, 25 (24%) were culture positive for B. pseudomallei, and 79 (75%) were qPCR positive. Of 11 LFI positive but standard culture negative specimens, six were confirmed by having the enrichment broth on day 7 culture positive for B. pseudomallei, and an additional three by qPCR. The LFI had 97% (30/31) sensitivity to detect soil specimens culture positive for B. pseudomallei. CONCLUSIONS/SIGNIFICANCE The LFI can be used to detect B. pseudomallei in soil samples, and to select which samples should be sent to reference laboratories or proceed further for bacterial isolation and confirmation. This could considerably decrease laboratory workload and assist the development of a risk map for melioidosis in resource-limited settings.

Journal article

Sabine Dittrich
Birkneh Tadesse
Francis Moussy
Arlene Chua
Anna Zorzet
Thomas Tängdén
David Dolinger
Anne-Laure Page
John Crump
Valerie DAcremont
Quique Bassat
Yoel Lubell
Paul Newton
Norbert Heinrich
Timothy Rodwell
Iveth González

Target Product Profile for a Diagnostic Assay to Differentiate between Bacterial and Non-Bacterial Infections and Reduce Antimicrobial Overuse in Resource-Limited Settings: An Expert Consensus.

In: PLoS One vol. 11 pg. e0161721

25.08.2016 (2016)

DOI: 10.1371/journal.pone.0161721

show abstract

Acute fever is one of the most common presenting symptoms globally. In order to reduce the empiric use of antimicrobial drugs and improve outcomes, it is essential to improve diagnostic capabilities. In the absence of microbiology facilities in low-income settings, an assay to distinguish bacterial from non-bacterial causes would be a critical first step. To ensure that patient and market needs are met, the requirements of such a test should be specified in a target product profile (TPP). To identify minimal/optimal characteristics for a bacterial vs. non-bacterial fever test, experts from academia and international organizations with expertise in infectious diseases, diagnostic test development, laboratory medicine, global health, and health economics were convened. Proposed TPPs were reviewed by this working group, and consensus characteristics were defined. The working group defined non-severely ill, non-malaria infected children as the target population for the desired assay. To provide access to the most patients, the test should be deployable to community health centers and informal health settings, and staff should require <2 days of training to perform the assay. Further, given that the aim is to reduce inappropriate antimicrobial use as well as to deliver appropriate treatment for patients with bacterial infections, the group agreed on minimal diagnostic performance requirements of >90% and >80% for sensitivity and specificity, respectively. Other key characteristics, to account for the challenging environment at which the test is targeted, included: i) time-to-result <10 min (but maximally <2 hrs); ii) storage conditions at 0-40°C, ≤90% non-condensing humidity with a minimal shelf life of 12 months; iii) operational conditions of 5-40°C, ≤90% non-condensing humidity; and iv) minimal sample collection needs (50-100μL, capillary blood). This expert approach to define assay requirements for a bacterial vs. non-bacterial assay should guide product development, and enable targeted and timely efforts by industry partners and academic institutions.

Journal article

T. Weitzel
Sabine Dittrich
J. López
W. Phuklia
C. Martinez-Valdebenito
et al.

Endemic Scrub Typhus in South America.

In: The New England Journal of Medicine vol. 375 pg. 954-61

(2016)

DOI: 10.1056/nejmoa1603657

show abstract

Scrub typhus is a life-threatening zoonosis caused by Orientia tsutsugamushi organisms that are transmitted by the larvae of trombiculid mites. Endemic scrub typhus was originally thought to be confined to the so called "tsutsugamushi triangle" within the Asia-Pacific region. In 2006, however, two individual cases were detected in the Middle East and South America, which suggested that the pathogen was present farther afield. Here, we report three autochthonous cases of scrub typhus caused by O. tsutsugamushi acquired on Chiloé Island in southern Chile, which suggests the existence of an endemic focus in South America. (Funded by the Chilean Comisión Nacional de Investigación Científica y Tecnológica and the Wellcome Trust.).

Journal article

A. Kapasi
Sabine Dittrich
I. González
T. Rodwell

Host Biomarkers for Distinguishing Bacterial from Non-Bacterial Causes of Acute Febrile Illness: A Comprehensive Review.

In: PLoS One vol. 11 pg. e0160278

03.08.2016 (2016)

DOI: 10.1371/journal.pone.0160278

show abstract

BACKGROUND In resource limited settings acute febrile illnesses are often treated empirically due to a lack of reliable, rapid point-of-care diagnostics. This contributes to the indiscriminate use of antimicrobial drugs and poor treatment outcomes. The aim of this comprehensive review was to summarize the diagnostic performance of host biomarkers capable of differentiating bacterial from non-bacterial infections to guide the use of antibiotics. METHODS Online databases of published literature were searched from January 2010 through April 2015. English language studies that evaluated the performance of one or more host biomarker in differentiating bacterial from non-bacterial infection in patients were included. Key information extracted included author information, study methods, population, pathogens, clinical information, and biomarker performance data. Study quality was assessed using a combination of validated criteria from the QUADAS and Lijmer checklists. Biomarkers were categorized as hematologic factors, inflammatory molecules, cytokines, cell surface or metabolic markers, other host biomarkers, host transcripts, clinical biometrics, and combinations of markers. FINDINGS Of the 193 citations identified, 59 studies that evaluated over 112 host biomarkers were selected. Most studies involved patient populations from high-income countries, while 19% involved populations from low- and middle-income countries. The most frequently evaluated host biomarkers were C-reactive protein (61%), white blood cell count (44%) and procalcitonin (34%). Study quality scores ranged from 23.1% to 92.3%. There were 9 high performance host biomarkers or combinations, with sensitivity and specificity of ≥85% or either sensitivity or specificity was reported to be 100%. Five host biomarkers were considered weak markers as they lacked statistically significant performance in discriminating between bacterial and non-bacterial infections. DISCUSSION This manuscript provides a summary of host biomarkers to differentiate bacterial from non-bacterial infections in patients with acute febrile illness. Findings provide a basis for prioritizing efforts for further research, assay development and eventual commercialization of rapid point-of-care tests to guide use of antimicrobials. This review also highlights gaps in current knowledge that should be addressed to further improve management of febrile patients.

Journal article

Sabine Dittrich
William Rudgard
Kate Woods
Joy Silisouk
Weerawat Phuklia
Viengmon Davong
Manivanh Vongsouvath
Koukeo Phommasone
Sayaphet Rattanavong
Michael Knappik
Scott Craig
Steven Weier
Suhella Tulsiani
David Dance
Paul Newton

The Utility of Blood Culture Fluid for the Molecular Diagnosis of Leptospira: A Prospective Evaluation.

In: The American Journal of Tropical Medicine and Hygiene vol. 94 pg. 736-740

15.02.2016 (2016)

DOI: 10.4269/ajtmh.15-0674

show abstract

Leptospirosis is an important zoonosis worldwide, with infections occurring after exposure to contaminated water. Despite being a global problem, laboratory diagnosis remains difficult with culture results taking up to 3 months, serology being retrospective by nature, and polymerase chain reaction showing limited sensitivity. Leptospira have been shown to survive and multiply in blood culture media, and we hypothesized that extracting DNA from incubated blood culture fluid (BCF), followed by quantitative real-time polymerase chain reaction (qPCR) could improve the accuracy and speed of leptospira diagnosis. We assessed this retrospectively, using preincubated BCF of Leptospira spp. positive (N= 109) and negative (N= 63) febrile patients in Vientiane, Lao PDR. The final method showed promising sensitivities of 66% (95% confidence interval [CI]: 55-76) and 59% (95% CI: 49-68) compared with direct or direct and indirect testing combined, as the respective reference standards (specificities > 95%). Despite these promising diagnostic parameters, a subsequent prospective evaluation in a Lao hospital population (N= 352) showed that the sensitivity was very low (∼30%) compared with qPCR on venous blood samples. The disappointingly low sensitivity does suggest that venous blood samples are preferable for the clinical microbiology laboratory, although BCF might be an alternative if leptospirosis is only suspected postadmission after antibiotics have been used.

Journal article

Olivier Ribolzi
Emma Rochelle-Newall
Sabine Dittrich
Yves Auda
Paul Newton
Sayaphet Rattanavong
Michael Knappik
Bounsamai Soulileuth
Oloth Sengtaheuanghoung
David Dance
Alain Pierret

Land use and soil type determine the presence of the pathogen Burkholderia pseudomallei in tropical rivers.

In: Environmental science and pollution research international vol. 23 pg. 7828-39

13.01.2016 (2016)

DOI: 10.1007/s11356-015-5943-z

show abstract

Burkholderia pseudomallei is the bacterium that causes melioidosis in humans. While B. pseudomallei is known to be endemic in South East Asia (SEA), the occurrence of the disease in other parts of the tropics points towards a potentially large global distribution. We investigated the environmental factors that influence the presence (and absence) of B. pseudomallei in a tropical watershed in SEA. Our main objective was to determine whether there is a link between the presence of the organism in the hydrographic network and the upstream soil and land-use type. The presence of B. pseudomallei was determined using a specific quantitative real-time PCR assay following enrichment culture. Land use, soil, geomorphology, and environmental data were then analyzed using partial least squares discriminant analysis (PLSDA) to compare the B. pseudomallei positive and negative sites. Soil type in the surrounding catchment and turbidity had a strong positive influence on the presence (acrisols and luvisols) or absence (ferralsols) of B. pseudomallei. Given the strong apparent links between soil characteristics, water turbidity, and the presence/absence of B. pseudomallei, actions to raise public awareness about factors increasing the risk of exposure should be undertaken in order to reduce the incidence of melioidosis in regions of endemicity.

Contribution

C. Escadafal
C. Nzansabana
J. Archer
V. Chihota
W. Rodriguez
Sabine Dittrich

From New Biomarkers to Diagnostic Tools for the Management of Fever in Low- and Middle-Income Countries: An Overview of the Challenges.

In: ASTMH 66th Annual Meeting - Abstract Book. pg. 286

Eds.:
The American Society of Tropical Medicine and Hygiene
American Journal of Tropical Medicine and Hygiene

(2017)

Journal article

B. Tadesse
E. Ashley
S. Ongarello
J. Havumaki
M. Wijegoonewardena
I. González
Sabine Dittrich

Antimicrobial resistance in Africa: a systematic review.

In: BMC Infectious Diseases vol. 17 pg. 616

11.09.2017 (2017)

DOI: 10.1186/s12879-017-2713-1

show abstract

BACKGROUND Antimicrobial resistance (AMR) is widely acknowledged as a global problem, yet in many parts of the world its magnitude is still not well understood. This review, using a public health focused approach, aimed to understand and describe the current status of AMR in Africa in relation to common causes of infections and drugs recommended in WHO treatment guidelines. METHODS PubMed, EMBASE and other relevant databases were searched for recent articles (2013-2016) in accordance with the PRISMA guidelines. Article retrieval and screening were done using a structured search string and strict inclusion/exclusion criteria. Median and interquartile ranges of percent resistance were calculated for each antibiotic-bacterium combination. RESULTS AMR data was not available for 42.6% of the countries in the African continent. A total of 144 articles were included in the final analysis. 13 Gram negative and 5 Gram positive bacteria were tested against 37 different antibiotics. Penicillin resistance in Streptococcus pneumoniae was reported in 14/144studies (median resistance (MR): 26.7%). Further 18/53 (34.0%) of Haemophilus influenza isolates were resistant to amoxicillin. MR of Escherichia coli to amoxicillin, trimethoprim and gentamicin was 88.1%, 80.7% and 29.8% respectively. Ciprofloxacin resistance in Salmonella Typhi was rare. No documented ceftriaxone resistance in Neisseria gonorrhoeae was reported, while the MR for quinolone was 37.5%. Carbapenem resistance was common in Acinetobacter spp. and Pseudomonas aeruginosa but uncommon in Enterobacteriaceae. CONCLUSION Our review highlights three important findings. First, recent AMR data is not available for more than 40% of the countries. Second, the level of resistance to commonly prescribed antibiotics was significant. Third, the quality of microbiological data is of serious concern. Our findings underline that to conserve our current arsenal of antibiotics it is imperative to address the gaps in AMR diagnostic standardization and reporting and use available information to optimize treatment guidelines.

Journal article

C. Escadafal
C. Nsanzabana
J. Archer
V. Chihota
W. Rodriguez
Sabine Dittrich

New Biomarkers and Diagnostic Tools for the Management of Fever in Low- and Middle-Income Countries: An Overview of the Challenges.

In: Diagnostics (Basel, Switzerland) vol. 7 pg. 44

21.07.2017 (2017)

DOI: 10.3390/diagnostics7030044

show abstract

A lack of simple, inexpensive, and rapid diagnostic tests for febrile illnesses other than malaria leads to overtreatment with antibiotics for those who test negative for malaria, and contributes to the global rise in antimicrobial resistance. New tests for the detection of host biomarkers provide promising tools to differentiate bacterial from non-bacterial infections in febrile patients. However, most available biomarker tests are not currently used in resource-limited settings, and very few evaluations have been performed in low- and middle-income country populations with non-severe febrile illness. As a result, our knowledge of the performance of these tests in settings with high prevalence of infectious and poverty-related diseases such as malaria, HIV, malnutrition and intestinal parasites is poor. This paper describes challenges faced during the process of getting to an approved test, including difficulties in selecting the most appropriate fever biomarkers; suitable study designs and sites for test evaluations; lack of available reference tests to evaluate the performance of new tests; and lack of clear regulatory pathways to introduce such tests. As many new biomarker assays are in development, understanding these challenges will better enable those working in this area to address them during product development.

Contribution

J. Osborn
T. Roberts
M. Murtahg
C. Kelly-Cirino
Sabine Dittrich
O. Bernal
F. Moussy
E. Guillen

Designing a Novel Multiplex Multi-Analyte Diagnostic Platform (MAPDx) to Address Severe Febrile Illness.

In: ASTMH 67th Annual Meeting - Abstract Book. pg. 383

Eds.:
The American Society of Tropical Medicine and Hygiene
American Journal of Tropical Medicine and Hygiene

(2018)

Journal article

K. Woods
C. Nic-Fhogartaigh
C. Arnold
L. Boutthasavong
W. Phuklia
C. Lim
A. Chanthongthip
S. Tulsiani
S. Craig
M-A Burns
S. Weier
V. Davong
S. Sihalath
D. Limmathurotsakul
D. Dance
N. Shetty
M. Zambon
P. Newton
Sabine Dittrich

A comparison of two molecular methods for diagnosing leptospirosis from three different sample types in patients presenting with fever in Laos.

In: Clinical Microbiology and Infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases vol. 24 pg. 1017.e1-1017.e7

26.10.2017 (2018)

DOI: 10.1016/j.cmi.2017.10.017

show abstract

OBJECTIVES To compare two molecular assays (rrs quantitative PCR (qPCR) versus a combined 16SrRNA and LipL32 qPCR) on different sample types for diagnosing leptospirosis in febrile patients presenting to Mahosot Hospital, Vientiane, Laos. METHODS Serum, buffy coat and urine samples were collected on admission, and follow-up serum ∼10 days later. Leptospira spp. culture and microscopic agglutination tests (MAT) were performed as reference standards. Bayesian latent class modelling was performed to estimate sensitivity and specificity of each diagnostic test. RESULTS In all, 787 patients were included in the analysis: 4/787 (0.5%) were Leptospira culture positive, 30/787 (3.8%) were MAT positive, 76/787 (9.7%) were rrs qPCR positive and 20/787 (2.5%) were 16SrRNA/LipL32 qPCR positive for pathogenic Leptospira spp. in at least one sample. Estimated sensitivity and specificity (with 95% CI) of 16SrRNA/LipL32 qPCR on serum (53.9% (33.3%-81.8%); 99.6% (99.2%-100%)), buffy coat (58.8% (34.4%-90.9%); 99.9% (99.6%-100%)) and urine samples (45.0% (27.0%-66.7%); 99.6% (99.3%-100%)) were comparable with those of rrs qPCR, except specificity of 16SrRNA/LipL32 qPCR on urine samples was significantly higher (99.6% (99.3%-100%) vs. 92.5% (92.3%-92.8%), p <0.001). Sensitivities of MAT (16% (95% CI 6.3%-29.4%)) and culture (25% (95% CI 13.3%-44.4%)) were low. Mean positive Cq values showed that buffy coat samples were more frequently inhibitory to qPCR than either serum or urine (p <0.001). CONCLUSIONS Serum and urine are better samples for qPCR than buffy coat, and 16SrRNA/LipL32 qPCR performs better than rrs qPCR on urine. Quantitative PCR on admission is a reliable rapid diagnostic tool, performing better than MAT or culture, with significant implications for clinical and epidemiological investigations of this global neglected disease.

Journal article

A. Fleshman
K. Mullins
J. Sahl
C. Hepp
N. Nieto
K. Wiggins
H. Hornstra
D. Kelly
T.-C. Chan
R. Phetsouvanh
Sabine Dittrich
et al.

Comparative pan-genomic analyses of Orientia tsutsugamushi reveal an exceptional model of bacterial evolution driving genomic diversity.

In: Microbial Genomics vol. 4

23.07.2018 (2018)

DOI: 10.1099/mgen.0.000199

show abstract

Orientia tsutsugamushi, formerly Rickettsia tsutsugamushi, is an obligate intracellular pathogen that causes scrub typhus, an underdiagnosed acute febrile disease with high morbidity. Scrub typhus is transmitted by the larval stage (chigger) of Leptotrombidium mites and is irregularly distributed across endemic regions of Asia, Australia and islands of the western Pacific Ocean. Previous work to understand population genetics in O. tsutsugamushi has been based on sub-genomic sampling methods and whole-genome characterization of two genomes. In this study, we compared 40 genomes from geographically dispersed areas and confirmed patterns of extensive homologous recombination likely driven by transposons, conjugative elements and repetitive sequences. High rates of lateral gene transfer (LGT) among O. tsutsugamushi genomes appear to have effectively eliminated a detectable clonal frame, but not our ability to infer evolutionary relationships and phylogeographical clustering. Pan-genomic comparisons using 31 082 high-quality bacterial genomes from 253 species suggests that genomic duplication in O. tsutsugamushi is almost unparalleled. Unlike other highly recombinant species where the uptake of exogenous DNA largely drives genomic diversity, the pan-genome of O. tsutsugamushi is driven by duplication and divergence. Extensive gene innovation by duplication is most commonly attributed to plants and animals and, in contrast with LGT, is thought to be only a minor evolutionary mechanism for bacteria. The near unprecedented evolutionary characteristics of O. tsutsugamushi, coupled with extensive intra-specific LGT, expand our present understanding of rapid bacterial evolutionary adaptive mechanisms.

Contribution

C. Escadafal
S. Geis
J. Malava
L. Banda
H. Mvula
J. Saul
A. Mace
V. Harris
Sabine Dittrich

Preliminary Data from a Biomarker Evaluation Trial among Non-Severe Febrile Patients in a Malaria Endemic Setting in Malawi.

In: ASTMH 67th Annual Meeting - Abstract Book. pg. 427

Eds.:
The American Society of Tropical Medicine and Hygiene
American Journal of Tropical Medicine and Hygiene

(2018)

Contribution

S. Incardona
K. Torres
W. Oyibo
S. Ongarello
A. Mace
F. Alava
Sabine Dittrich
et al.

Performance of a New Multiplex Fever Pathogen Rapid Test to Detect Malaria When Used by Health Workers in Peru and Nigeria.

In: ASTMH 67th Annual Meeting - Abstract Book. pg. 539-540

Eds.:
The American Society of Tropical Medicine and Hygiene
American Journal of Tropical Medicine and Hygiene

(2018)

Journal article

D.A.B. Dance
M. Knappik
Sabine Dittrich
V. Davong
J. Silisouk
M. Vongsouvath
S. Rattanavong
A. Pierret
P. Newton
et al.

Evaluation of consensus method for the culture of Burkholderia pseudomallei in soil samples from Laos.

In: Wellcome Open Research vol. 3 pg. 132

(2018)

DOI: 10.12688/wellcomeopenres.14851.1

Contribution

M. Robinson
P. Nawtaisong
M. Vongsouvath
K. Khammavong
P. Milavong
A. Rachlin
Sabine Dittrich
A. Dubot-Pérès
M. Pruvot
P. Newton

Molecular Diagnostics of Potential Pathogens in the Wildlife Trade in Lao PDR.

In: ASTMH 67th Annual Meeting - Abstract Book. pg. 220

Eds.:
The American Society of Tropical Medicine and Hygiene
American Journal of Tropical Medicine and Hygiene

(2018)

Contribution

J. Barber
J. Osborn
O. Bernal
E. Guillen
C. Kelly-Cirino
Sabine Dittrich

Febrile Patient Management Worldwide: Analysis of Existing Guidelines and Algorithms to Inform Novel Diagnostic and Algorithmic Solutions. Barber J., Osborn J., Bernal O., Guillen E., Kelly-Cirino C., Dittrich S..

In: ASTMH 67th Annual Meeting - Abstract Book. pg. 604-605

Eds.:
The American Society of Tropical Medicine and Hygiene
American Journal of Tropical Medicine and Hygiene

(2018)

Contribution

P. Roddy
J. Osborn
T. Roberts
E. Guillen
O. Bernal
S. Ongarello
A. Sprecher
A.-L. Page
I. Ribeiro
E. Piriou
A. Tamrat
R. La Tour
B. Rao
L. Flevaud
T. Jensen
L. McIver
C. Kelly
Sabine Dittrich

Prioritizing Pathogens to Support Diagnostic Product Development for Febrile Illness Management: A Novel Yet Pragmatic Approach.

In: ASTMH 67th Annual Meeting - Abstract Book. pg. 386

Eds.:
The American Society of Tropical Medicine and Hygiene
American Journal of Tropical Medicine and Hygiene

(2018)

Journal article

Sabine Dittrich
L. Boutthasavong
D. Keokhamhoung
W. Phuklia
et al.

A Prospective Hospital Study to Evaluate the Diagnostic Accuracy of Rapid Diagnostic Tests for the Early Detection of Leptospirosis in Laos.

In: The American Journal of Tropical Medicine and Hygiene vol. 98 pg. 1056-1060

22.02.2018 (2018)

DOI: 10.4269/ajtmh.17-0702

show abstract

Leptospirosis is a globally important cause of acute febrile illness, and a common cause of non-malarial fever in Asia, Africa, and Latin America. Simple rapid diagnostic tests (RDTs) are needed to enable health-care workers, particularly in low resource settings, to diagnose leptospirosis early and give timely targeted treatment. This study compared four commercially available RDTs to detect human IgM against Leptospira spp. in a head-to-head prospective evaluation in Mahosot Hospital, Lao PDR. Patients with an acute febrile illness consistent with leptospirosis (N = 695) were included in the study during the 2014 rainy season. Samples were tested with four RDTs: ("Test-it" [Life Assay, Cape Town, South Africa; N = 418]; "Leptorapide" [Linnodee, Ballyclare, Northern Ireland; N = 492]; "Dual Path Platform" [DPP] [Chembio, Medford, NY; N = 530]; and "SD-IgM" [Standard Diagnostics, Yongin, South Korea; N = 481]). Diagnostic performance characteristics were calculated and compared with a composite reference standard combining polymerase chain reaction (PCR) (rrs), microscopic agglutination tests (MATs), and culture. Of all patients investigated, 39/695 (5.6%) were positive by culture, PCR, or MAT. The sensitivity and specificity of the RDTs ranged greatly from 17.9% to 63.6% and 62.1% to 96.8%, respectively. None of the investigated RDTs reached a sensitivity or specificity of > 90% for detecting Leptospira infections on admission. In conclusion, our investigation highlights the challenges associated with Leptospira diagnostics, particularly in populations with multiple exposures. These findings emphasize the need for extensive prospective evaluations in multiple endemic settings to establish the value of rapid tools for diagnosing fevers to allow targeting of antibiotics.

Journal article

A. Dubot-Pérès
M. Mayxay
R. Phetsouvanh
Sue Lee
S. Rattanavong
M. Vongsouvath
V. Davong
V. C.hansamouth
Koukeo Phommasone
C. Moore
Sabine Dittrich
O. Lattana
J. Sirisouk
P. Phoumin
P. Panyanivong
A. Sengduangphachanh
B. Sibounheuang
A. Chanthongthip
M. Simmalavong
D. Sengdatka
A. Seubsanith
V. Keoluangkot
P. Phimmasone
K. Sisout
K. Detleuxay
K. Luangxay
I. Phouangsouvanh
S. Craig
S. Tulsiani
M.-A. Burns
D. Dance
S. Blacksell
X. Lamballerie
P. Newton

Management of Central Nervous System Infections, Vientiane, Laos, 2003-2011.

In: Emerging Infectious Diseases vol. 25 pg. 898-910

(2019)

DOI: 10.3201/eid2505.180914

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During 2003-2011, we recruited 1,065 patients of all ages admitted to Mahosot Hospital (Vientiane, Laos) with suspected central nervous system (CNS) infection. Etiologies were laboratory confirmed for 42.3% of patients, who mostly had infections with emerging pathogens: viruses in 16.2% (mainly Japanese encephalitis virus [8.8%]); bacteria in 16.4% (including Orientia tsutsugamushi [2.9%], Leptospira spp. [2.3%], and Rickettsia spp. [2.3%]); and Cryptococcus spp. fungi in 6.6%. We observed no significant differences in distribution of clinical encephalitis and meningitis by bacterial or viral etiology. However, patients with bacterial CNS infection were more likely to have a history of diabetes than others. Death (26.3%) was associated with low Glasgow Coma Scale score, and the mortality rate was higher for patients with bacterial than viral infections. No clinical or laboratory variables could guide antibiotic selection. We conclude that high-dependency units and first-line treatment with ceftriaxone and doxycycline for suspected CNS infections could improve patient survival in Laos.

Contribution

S. Arafah
S. Blacksell
M. Mayo
B. Currie
A. Macé
S. Ongarello
A. Gunasekera
J. Esfandiari
Sabine Dittrich

Performance evaluation of a novel multiplexed lateral flow assay to identify common causes of fever in Asia and inform treatment decisions (Session 131 - Poster Session C: Presentations and Light Lunch).

In: ASTMH 68th Annual Meeting - Abstract Book. pg. 482-483

Eds.:
The American Society of Tropical Medicine and Hygiene
American Journal of Tropical Medicine and Hygiene

(2019)

Journal article

W. Phuklia
P. Panyanivong
D. Sengdetka
P. Sonthayanon
P. Newton
D. Paris
N. Day
Sabine Dittrich

Novel high-throughput screening method using quantitative PCR to determine the antimicrobial susceptibility of Orientia tsutsugamushi clinical isolates.

In: The Journal of Antimicrobial Chemotherapy vol. 74 pg. 74-81

(2019)

DOI: 10.1093/jac/dky402

show abstract

OBJECTIVES To develop a method to enable the large-scale antimicrobial susceptibility screening of Orientia tsutsugamushi clinical isolates, using one timepoint and one concentration of antibiotics to considerably speed up the time to result. METHODS Growth, harvesting, multiplicity of infection (moi) and the day to determine the MICs were optimized using five O. tsutsugamushi reference strains [susceptible (Karp, Kato and Gilliam) and putatively resistant (AFC-3 and AFSC-4)], one clinical isolate (UT76) and one rodent isolate (TA763). Subsequently, the MICs of azithromycin, chloramphenicol and doxycycline for these strains and 51 clinical isolates including AFSC-7 were determined. An optimal concentration was calculated using the epidemiological cut-off value. RESULTS The conditions for O. tsutsugamushi infection, growth and harvesting were determined to be an moi of 100:1 and trypsinization with the peak growth on day 10. The resulting MICs were in line with previously published susceptibility data for all reference strains, except for Karp and AFSC-4, which showed azithromycin MICs of 0.0156 and 0.0313 mg/L, compared with 0.0078 and 0.0156 mg/L, respectively, in previous reports. The MIC of doxycycline for AFC-3 was 0.125 mg/L compared with >4 mg/L in earlier reports. The final single screening concentrations were identified as: azithromycin, 0.125 mg/L; chloramphenicol, 8 mg/L; and doxycycline, 1 mg/L. CONCLUSIONS This simplified procedure facilitates the simultaneous screening of 48 isolates for actively monitoring potential resistance of this important fever pathogen, with an 8-fold throughput improvement over early methods. The data do not support the existence of doxycycline- and chloramphenicol-resistant scrub typhus.

Contribution

A. Devine
S. Incardona
R. Price
Sabine Dittrich
X. Ding

Treatment algorithms with radical cure of vivax malaria based on sex: a cost-effectiveness analysis to support roll out strategies.

In: ASTMH 68th Annual Meeting - Abstract Book. pg. 112

Eds.:
The American Society of Tropical Medicine and Hygiene
American Journal of Tropical Medicine and Hygiene

(2019)

Journal article

G. Bancone
D. Menard
N. Khim
S. Kim
L. Canier
C. Nguong
K. Phommasone
M. Mayxay
Sabine Dittrich
M. Vongsouvath
N. Fievet
J.-Y. Le Hesran
V. Briand
S. Keomany
P. Newton
G. Gorsawun
K. Tardy
C. Chu
O. Rattanapalroj
T. Le Dong
H. Quang
N. Tam-Uyen
N. Thuy-Nhien
T. Hien
M. Kalnoky
F. Nosten

Molecular characterization and mapping of glucose-6-phosphate dehydrogenase (G6PD) mutations in the Greater Mekong Subregion.

In: Malaria Journal vol. 18 pg. 20

23.01.2019 (2019)

DOI: 10.1186/s12936-019-2652-y

show abstract

BACKGROUND Plasmodium vivax malaria elimination can only be achieved by the deployment of 8-aminoquinolines (primaquine and tafenoquine) in combination with ACT to kill both blood and liver-stage parasites. However, primaquine and the other 8-aminoquinolines cause dose-dependent haemolysis in subjects with G6PD deficiency, an X-linked disorder of red blood cells that is very common in populations living in tropical and subtropical areas. In order to inform safer use of 8-aminoquinolines in the Greater Mekong Subregion, a multi-centre study was carried out to assess the prevalence of G6PD deficiency and to identify the main G6PD variants in samples collected in Cambodia, Lao PDR, Myanmar, Thailand and Vietnam. METHODS Blood samples were collected in the five countries during National Malaria Surveys or during Population Surveys. During Population Surveys samples were characterized for G6PD phenotype using the Fluorescent Spot Test. Samples were then genotyped for a panel of G6PD mutations. RESULTS G6PD deficiency was found to be common in the region with an overall mean prevalence of deficient or mutated hemizygous males of 14.0%, ranging from a mean 7.3% in Thailand, 8.1% in Lao PDR, 8.9% in Vietnam, 15.8% in Myanmar and 18.8% in Cambodia. Mahidol and Viangchan mutations were the most common and widespread variants found among the nine investigated. CONCLUSIONS Owing to the high prevalence of G6PD deficiency in the Greater Mekong Subregion, strategies for vivax malaria elimination should include point-of-care G6PD testing (both qualitative and quantitative) to allow safe and wide treatment with 8-aminoquinolines.

Journal article

P. Dailey
J. Osborn
E. Ashley
E. Baron
D. Dance
D. Fusco
C. Fanello
Y. Manabe
M. Mokomane
P. Newton
B. Tessema
C. Isaacs
Sabine Dittrich

Defining System Requirements for Simplified Blood Culture to Enable Widespread Use in Resource-Limited Settings.

In: Diagnostics (Basel, Switzerland) vol. 9

11.01.2019 (2019)

DOI: 10.3390/diagnostics9010010

show abstract

Bacterial blood stream infections (BSI) are a common cause of mortality and morbidity globally. As the causative agents and the resulting treatment decisions vary, near-patient testing and surveillance tools are necessary to monitor bacterial causes and resistance to antimicrobial agents. The gold standard to identify BSIs is blood culture (BC), a methodology not widely available in resource-limited settings. The aim of the study was to map out a target product profile of a simplified BC system (SBCS) to inform product development efforts. To identify the desired characteristics of a SBCS, we enlisted a small group of specialists working in Africa and Asia. Questions were used to understand challenges and how these constraints inform system requirements. The specialists were infectious disease physicians, public health/clinical microbiologists, clinical researchers, and technology experts with different geographical backgrounds. All suggested that BC should ideally be available at the district hospital level. Many of the same operational challenges, such as limited availability of culture bottles, electricity and internet connectivity, profuse dust, the lack of ambient temperature control, and human capacity constraints were identified across the different regions. BCs, although the accepted gold standard for diagnosis of BSIs, are not widely available outside of reference/research centers in Africa and Asia. To extend the reach of this important tool, it is crucial to engage product developers and academic research partners to develop accessible alternatives.

Journal article

D. Bhaskaran
S. Chadha
S. Sarin
R. Sen
S. Arafah
Sabine Dittrich

Diagnostic tools used in the evaluation of acute febrile illness in South India: a scoping review.

In: BMC Infectious Diseases vol. 19 pg. 970

13.11.2019 (2019)

DOI: 10.1186/s12879-019-4589-8

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BACKGROUND Acute febrile illness (AFI) is characterized by malaise, myalgia and a raised temperature that is a nonspecific manifestation of infectious diseases in the tropics. The lack of appropriate diagnostics for the evaluation of AFI leads to increased morbidity and mortality in resource-limited settings, specifically low-income countries like India. The review aimed to identify the number, type and quality of diagnostics used for AFI evaluation during passive case detection at health care centres in South India. METHODS A scoping review of peer-reviewed English language original research articles published between 1946-July 2018 from four databases was undertaken to assess the type and number of diagnostics used in AFI evaluation in South India. Results were stratified according to types of pathogen-specific tests used in AFI management. RESULTS The review included a total of 40 studies, all conducted in tertiary care centres (80% in private settings). The studies demonstrated the use of 5-22 tests per patient for the evaluation of AFI. Among 25 studies evaluating possible causes of AFI, 96% tested for malaria followed by 80% for dengue, 72% for scrub typhus, 68% for typhoid and 60% for leptospirosis identifying these as commonly suspected causes of AFI. 54% studies diagnosed malaria with smear microscopy while others diagnosed dengue, scrub typhus, typhoid and leptospirosis using antibody or antigen detection assays. 39% studies used the Weil-Felix test (WFT) for scrub typhus diagnosis and 82% studies used the Widal test for diagnosing typhoid. CONCLUSIONS The review demonstrated the use of five or more pathogen-specific tests in evaluating AFI as well as described the widespread use of suboptimal tests like the WFT and Widal in fever evaluation. It identified the need for the development of better-quality tests for aetiological diagnosis and improved standardised testing guidelines for AFI.

Contribution

R. Mather
P. Dailey
H. Hopkins
Sabine Dittrich

Redefining Typhoid Diagnosis: What should a better test look like, and what innovations are available to meet the needs?.

In: ASTMH 68th Annual Meeting - Abstract Book. pg. 536-537

Eds.:
The American Society of Tropical Medicine and Hygiene
American Journal of Tropical Medicine and Hygiene

(2019)

Contribution

N. Struck
Sabine Dittrich

From Biomarker Discovery to Differential Diagnosis in Malaria Endemic Settings.

In: ASTMH 68th Annual Meeting - Abstract Book. pg. 261

Eds.:
The American Society of Tropical Medicine and Hygiene
American Journal of Tropical Medicine and Hygiene

(2019)

Journal article

P. Newton
V. Keolouangkhot
S. Lee
K. Choumlivong
S. Sisouphone
M. Vongsouvath
M. Mayxay
V. Chansamouth
V. Davong
K. Phommasone
J. Sirisouk
S. Blacksell
P. Nawtaisong
C. Moore
J. Castonguay-Vanier
Sabine Dittrich
S. Rattanavong
K. Chang
C. Darasavath
O. Rattanavong
D. Paris
R. Phetsouvanh

A Prospective, Open-label, Randomized Trial of Doxycycline Versus Azithromycin for the Treatment of Uncomplicated Murine Typhus.

In: Clinical Infectious Diseases (an official publication of the Infectious Diseases Society of America) vol. 68 pg. 738-747

(2019)

DOI: 10.1093/cid/ciy563

show abstract

BACKGROUND Murine typhus, or infection with Rickettsia typhi, is a global but neglected disease without randomized clinical trials to guide antibiotic therapy. METHODS A prospective, open, randomized trial was conducted in nonpregnant, consenting inpatient adults with rapid diagnostic test evidence of uncomplicated murine typhus at 2 hospitals in Vientiane, Laos. Patients were randomized to 7 days (D7) or 3 days (D3) of oral doxycycline or 3 days of oral azithromycin (A3). Primary outcome measures were fever clearance time and frequencies of treatment failure and relapse. RESULTS Between 2004 and 2009, the study enrolled 216 patients (72 per arm); 158 (73.2%) had serology/polymerase chain reaction (PCR)-confirmed murine typhus, and 52 (24.1%) were R. typhi PCR positive. The risk of treatment failure was greater for regimen A3 (22.5%; 16 of 71 patients) than for D3 (4.2%; 3 of 71) or D7 (1.4%; 1 of 71) (P < .001). Among R. typhi PCR-positive patients, the area under the time-temperature curve and the fever clearance time were significantly higher for A3 than for D3 (1.8- and 1.9-fold higher, respectively; P = .005) and D7 (1.5- and 1.6-fold higher; P = .02). No patients returned with PCR-confirmed R. typhi relapse. CONCLUSION In Lao adults, azithromycin is inferior to doxycycline as oral therapy for uncomplicated murine typhus. For doxycycline, 3- and 7-day regimens have similar efficacy. Azithromycin use in murine typhus should be reconsidered. Investigation of genomic and phenotypic markers of R. typhi azithromycin resistance is needed. CLINICAL TRIAL REGISTRATION ISRCTN47812566.

Journal article

R. Mather
H. Hopkins
C. Parry
Sabine Dittrich

Redefining typhoid diagnosis: what would an improved test need to look like?.

In: BMJ Global Health vol. 4 pg. e001831

31.10.2019 (2019)

DOI: 10.1136/bmjgh-2019-001831

show abstract

INTRODUCTION Typhoid fever is one of the most common bacterial causes of acute febrile illness in the developing world, with an estimated 10.9 million new cases and 116.8 thousand deaths in 2017. Typhoid point-of-care (POC) diagnostic tests are widely used but have poor sensitivity and specificity, resulting in antibiotic overuse that has led to the emergence and spread of multidrug-resistant strains. With recent advances in typhoid surveillance and detection, this is the ideal time to produce a target product profile (TPP) that guides product development and ensure that a next-generation test meets the needs of users in the resource-limited settings where typhoid is endemic. METHODS A structured literature review was conducted to develop a draft TPP for a next-generation typhoid diagnostic test with minimal and optimal desired characteristics for 36 test parameters. The TPP was refined using feedback collected from a Delphi survey of key stakeholders in clinical medicine, microbiology, diagnostics and public and global health. RESULTS A next-generation typhoid diagnostic test should improve patient management through the diagnosis and treatment of infection with acute Salmonella enterica serovars Typhi or Paratyphi with a sensitivity ≥90% and specificity ≥95%. The test would ideally be used at the lowest level of the healthcare system in settings without a reliable power or water supply and provide results in <15 min at a cost of

Journal article

T. Althaus
R. Greer
M. Swe
J. Cohen
N. Tun
J. Heaton
S. Nedsuwan
D. Intralawan
N. Sumpradit
Sabine Dittrich
Z. Doran
N. Waithira
H. Thu
H. Win
J. Thaipadungpanit
P. Srilohasin
M. Mukaka
P. Smit
E. Charoenboon
M. Haenssgen
T. Wangrangsimakul
S. Blacksell
D. Limmathurotsakul
N. Day
F. Smithuis
Y. Lubell

Effect of point-of-care C-reactive protein testing on antibiotic prescription in febrile patients attending primary care in Thailand and Myanmar: an open-label, randomised, controlled trial.

In: The Lancet Global Health vol. 7 pg. e119-e131

(2019)

DOI: 10.1016/s2214-109x(18)30444-3

Journal article

Y. Lubell
A. Chandna
F. Smithuis
L. White
H. Wertheim
M. Redard-Jacot
Z. Katz
A. Dondorp
N. Day
N. White
Sabine Dittrich

Economic considerations support C-reactive protein testing alongside malaria rapid diagnostic tests to guide antimicrobial therapy for patients with febrile illness in settings with low malaria endemicity.

In: Malaria Journal vol. 18 pg. 442

26.12.2019 (2019)

DOI: 10.1186/s12936-019-3059-5

show abstract

Malaria is no longer a common cause of febrile illness in many regions of the tropics. In part, this success is a result of improved access to accurate diagnosis and effective anti-malarial treatment, including in many hard-to-reach rural areas. However, in these settings, management of other causes of febrile illness remains challenging. Health systems are often weak and other than malaria rapid tests no other diagnostics are available. With millions of deaths occurring annually due to treatable bacterial infections and the ever increasing spread of antimicrobial resistance, improvement in the management of febrile illness is a global public health priority. Whilst numerous promising point-of-care diagnostics are in the pipeline, substantial progress can be made in the interim with existing tools: C-reactive protein (CRP) is a highly sensitive and moderately specific biomarker of bacterial infection and has been in clinical use for these purposes for decades, with dozens of low-cost devices commercially available. This paper takes a health-economics approach to consider the possible advantages of CRP point-of-care tests alongside rapid diagnostic tests for malaria, potentially in a single multiplex device, to guide antimicrobial therapy for patients with febrile illness. Three rudimentary assessments of the costs and benefits of this approach all indicate that this is likely to be cost-effective when considering the incremental costs of the CRP tests as compared with either (i) the improved health outcomes for patients with bacterial illnesses; (ii) the costs of antimicrobial resistance averted; or (iii) the economic benefits of better management of remaining malaria cases and shorter malaria elimination campaigns in areas of low transmission. While CRP-guided antibiotic therapy alone cannot resolve all challenges associated with management of febrile illness in remote tropical settings, in the short-term a multiplexed CRP and malaria RDT could be highly cost-effective and utilize the well-established funding and distribution systems already in place for malaria RDTs. These findings should spark further interest amongst industry, academics and policy-makers in the development and deployment of such diagnostics, and discussion on their geographically appropriate use.

Contribution

K. Pelle
M. McLaughlin
A. Giwa
E. Mount-Finette
S. Scarpino
N. Haidar
F. Adamu
T. Adeyoju
N. Ravi
A. Thompson
B. Finette
Sabine Dittrich

A Report on the Integration of a Malaria Rapid Diagnostic Test in a Point of Care Clinical Decision Support Platform, MEDSCINC, for Use in Primary Healthcare Settings in Kano State, Nigeria.

In: ASTMH 68th Annual Meeting - Abstract Book. pg. 481

Eds.:
The American Society of Tropical Medicine and Hygiene
American Journal of Tropical Medicine and Hygiene

(2019)

Journal article

P. Roddy
U. Dalrymple
T. Jensen
Sabine Dittrich
V. Rao
D. Pfeffer
K. Twohig
T. Roberts
O. Bernal
E. Guillen

Quantifying the incidence of severe-febrile-illness hospital admissions in sub-Saharan Africa.

In: PLoS One vol. 14 pg. e0220371

25.07.2019 (2019)

DOI: 10.1371/journal.pone.0220371

show abstract

Severe-febrile-illness (SFI) is a common cause of morbidity and mortality across sub-Saharan Africa (SSA). The burden of SFI in SSA is currently unknown and its estimation is fraught with challenges. This is due to a lack of diagnostic capacity for SFI in SSA, and thus a dearth of baseline data on the underlying etiology of SFI cases and scant SFI-specific causative-agent prevalence data. To highlight the public health significance of SFI in SSA, we developed a Bayesian model to quantify the incidence of SFI hospital admissions in SSA. Our estimates indicate a mean population-weighted SFI-inpatient-admission incidence rate of 18.4 (6.8-31.1, 68% CrI) per 1000 people for the year 2014, across all ages within areas of SSA with stable Plasmodium falciparum transmission. We further estimated a total of 16,200,337 (5,993,249-27,321,779, 68% CrI) SFI hospital admissions. This analysis reveals the significant burden of SFI in hospitals in SSA, but also highlights the paucity of pathogen-specific prevalence and incidence data for SFI in SSA. Future improvements in pathogen-specific diagnostics for causative agents of SFI will increase the abundance of SFI-specific prevalence and incidence data, aid future estimations of SFI burden, and enable clinicians to identify SFI-specific pathogens, administer appropriate treatment and management, and facilitate appropriate antibiotic use.

Contribution

S. Incardona
B. Srivastava
S. Sharma
S. Ongarello
Shenai, S. Loganathan, P.
S. Sarin
A. Anvikar
Sabine Dittrich

Prospective performance evaluation of a combined malaria/CRP rapid diagnostic test in India (Session 81 – Diagnosis of Malaria: Are the Available Tools Sufficient to Eliminate the Disease?).

In: ASTMH 68th Annual Meeting - Abstract Book. pg. 380

Eds.:
The American Society of Tropical Medicine and Hygiene
American Journal of Tropical Medicine and Hygiene

(2019)

Journal article

R Kadam
W. White
N. Banks
Z. Katz
Sabine Dittrich
C. Kelly-Cirino

Target Product Profile for a mobile app to read rapid diagnostic tests to strengthen infectious disease surveillance.

In: PLoS One vol. 15 pg. e0228311

29.01.2020 (2020)

DOI: 10.1371/journal.pone.0228311

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The essential role of rapid diagnostic tests (RDTs) in disease control is compromised every time a test is not performed correctly or its result is not reported accurately and promptly. A mobile app that utilizes the camera and connectivity of a common smartphone can fill this role of supporting the test's proper execution and the automatic transmission of results. In a consensus process with 51 expert participants representing the needs of clinical users, healthcare programs, health information systems, surveillance systems, and global public health stakeholders, we developed a Target Product Profile describing the minimal and optimal characteristics of such an app. We collected feedback over two rounds and refined the characteristics to arrive at a preferred agreement level of greater than 75%, with an average of 92% agreement (range: 79-100%). As per this feedback, such an app should be compatible with many RDTs and mobile devices without needing accessories. The app should assist the user with RDT-specific instructions, include checks to facilitate quality control of the testing process and suggest results with ≥ 95% accuracy across common lighting conditions while allowing the user to determine the final result. Data from the app must be under the control of the health program that operates it, and the app should support at least one of the common data exchange formats HL7, FHIR, ASTM or JSON. The Target Product Profile also lays out the minimum data security and privacy requirements for the app.

Journal article

K. Phakhounthong
M. Mukaka
Sabine Dittrich
A. Tanganuchitcharnchai
N. Day
L. White
P. Newton
S. Blacksell

The temporal dynamics of humoral immunity to Rickettsia typhi infection in murine typhus patients.

In: Clinical Microbiology and Infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases vol. 26 pg. 781.e9-781.e16

31.10.2019 (2020)

DOI: 10.1016/j.cmi.2019.10.022

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OBJECTIVES This study examined individuals with Rickettsia typhi infection in the Lao People's Democratic Republic (Lao PDR) to (a) investigate humoral immune dynamics; (b) determine the differences in reference diagnostic results and recommend appropriate cut-offs; (c) determine differences in immune response after different antibiotic treatments; and (d) determine appropriate diagnostic cut-off parameters for indirect immunofluorescence assay (IFA). METHODS Sequential serum samples from 90 non-pregnant, adults were collected at seven time-points (days 0, 7, 14, 28, 90, 180 and 365) as part of a clinical antibiotic treatment trial. Samples were tested using IFA to determine IgM and IgG antibody reciprocal end-point titres against R. typhi and PCR. RESULTS For all 90 individuals, reciprocal R. typhi IgM and IgG antibody titres ranged from <400 to ≥3200. The median half-life of R. typhi IgM was 126 days (interquartile range 36-204 days) and IgG was 177 days (interquartile range 134-355 days). Overall median patient titres for R. typhi IgM and IgG were significantly different (p < 0.0001) and at each temporal sample collection point (range p < 0.0001 to p 0.0411). Using Bayesian latent class model analysis, the optimal diagnostic cut-off reciprocal IFA titer on patient admission for IgM was 800 (78.6%, 95% CI 71.6%-85.2% sensitivity; 89.9%, 95% CI 62.5%-100% specificity), and for IFA IgG 1600 (77.3%; 95% CI 68.2%-87.6% sensitivity; 99%, 95% CI 95%-100% specificity). CONCLUSIONS This study suggests suitable diagnostic cut-offs for local diagnostic laboratories and other endemic settings and highlights antibody persistence following acute infection. Further studies are required to validate and define cut-offs in other geographically diverse locations.

Journal article

N. Thi Thuy Do
R. Greer
Y. Lubell
Sabine Dittrich
M. Vandendorpe
A. van Nguyen
P. Ngoc Thach
T. Thi Dieu Ngan
N. van Kinh
C. Hung Thai
T. Le Dung
T. Nguyen Thi Cam
T. Nguyen
B. Nadjm
H. van Doorn
S. Lewycka

Implementation of C-reactive protein point of care testing to improve antibiotic targeting in respiratory illness in Vietnamese primary care (ICAT): a study protocol for a cluster randomised controlled trial.

In: BMJ Open vol. 10 pg. e040977

23.12.2020 (2020)

DOI: 10.1136/bmjopen-2020-040977

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INTRODUCTION C-reactive protein (CRP), a biomarker of infection, has been used widely in high-income settings to guide antibiotic treatment in patients presenting with respiratory illnesses in primary care. Recent trials in low- and middle-income countries showed that CRP testing could safely reduce antibiotic use in patients with non-severe acute respiratory infections (ARIs) and fever in primary care. The studies, however, were conducted in a research-oriented context, with research staff closely monitoring healthcare behaviour thus potentially influencing healthcare workers' prescribing practices. For policy-makers to consider wide-scale roll-out, a pragmatic implementation study of the impact of CRP point of care (POC) testing in routine care is needed. METHODS AND ANALYSIS A pragmatic, cluster-randomised controlled trial, with two study arms, consisting of 24 commune health centres (CHC) in the intervention arm (provision of CRP tests with additional healthcare worker guidance) and 24 facilities acting as controls (routine care). Comparison between the treatment arms will be through logistic regression, with the treatment assignment as a fixed effect, and the CHC as a random effect. With 48 clusters, an average of 10 consultations per facility per week will result in approximately 520 over 1 year, and 24 960 in total (12 480 per arm). We will be able to detect a reduction of 12% to 23% or more in immediate antibiotic prescription as a result of the CRP POC intervention. The primary endpoint is the proportion of patient consultations for ARI resulting in immediate antibiotic prescription. Secondary endpoints include the proportion of all patients receiving an antibiotic prescription regardless of ARI diagnosis, frequency of re-consultation, subsequent antibiotic use when antibiotics are not prescribed, referral and hospitalisation. ETHICS AND DISSEMINATION The study protocol was approved by the Oxford University Tropical Research Ethics Committee (OxTREC, Reference: 53-18), and the ethical committee of the National Hospital for Tropical Diseases in Vietnam (Reference:07/HDDD-NDTW/2019). Results from this study will be disseminated via meetings with stakeholders, conferences and publications in peer-reviewed journals. Authorship and reporting of this work will follow international guidelines. TRIAL REGISTRATION DETAILS NCT03855215; Pre-results.

Journal article

Sabine Dittrich
M. Lamy
S. Acharya
H. Thu
R. Datta
S. Blacksell
P. Hein
C. Mercado
X. Ding
A. Chebbi

Diagnosing malaria and other febrile illnesses during the COVID-19 pandemic.

In: The Lancet Global Health vol. 8 pg. e879-e880

(2020)

DOI: 10.1016/s2214-109x(20)30210-2

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As the global malaria community observes World Malaria Day on April 25, 2020, we have plenty to celebrate. Yet this year, the coronavirus disease 2019 (COVID-19) outbreak is greatly dampening the spirits. While the Asia-Pacific region has made substantial progress against malaria, with a 42% reduction in confirmed cases between 2010 and 2018,1 the emergence of COVID-19 could undermine elimination efforts. Like malaria, one of the most common symptoms of COVID-19 is fever.2 Diagnosis of fever in the Asia-Pacific region has always been a challenge due to the large number of febrile diseases prevalent in the region, including malaria, dengue fever, scrub typhus, typhoid fever, and leptospirosis, among others, and to health systems' insufficient capacity to cope with them.3 With COVID-19 added to the mix, differentiation between these diseases becomes even more difficult. Furthermore, due to physical distancing measures and personal protective equipment (PPE) requirements, COVID-19 is limiting access to health care. To ensure that health emergencies such as COVID-19 do not impede progress towards elimination of malaria, health-care workers at the frontline must be better equipped to tackle such threats.

Journal article

I. Stegeman
E. Ochodo
F. Guleid
G. Holtman
B. Yang
C. Davenport
J. Deeks
J. Dinnes
Sabine Dittrich
D. Emperador
L. Hooft
R. Spijker
Y. Takwoingi
A. van den Bruel
Wang, J.
M. Langendam
J. Verbakel
M. Leeflang

Routine laboratory testing to determine if a patient has COVID-19.

In: The Cochrane Database of Systematic Reviews vol. 11 pg. CD013787

19.11.2020 (2020)

DOI: 10.1002/14651858.cd013787

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BACKGROUND Specific diagnostic tests to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and resulting COVID-19 disease are not always available and take time to obtain results. Routine laboratory markers such as white blood cell count, measures of anticoagulation, C-reactive protein (CRP) and procalcitonin, are used to assess the clinical status of a patient. These laboratory tests may be useful for the triage of people with potential COVID-19 to prioritize them for different levels of treatment, especially in situations where time and resources are limited. OBJECTIVES To assess the diagnostic accuracy of routine laboratory testing as a triage test to determine if a person has COVID-19. SEARCH METHODS On 4 May 2020 we undertook electronic searches in the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID-19 publications. We did not apply any language restrictions. SELECTION CRITERIA We included both case-control designs and consecutive series of patients that assessed the diagnostic accuracy of routine laboratory testing as a triage test to determine if a person has COVID-19. The reference standard could be reverse transcriptase polymerase chain reaction (RT-PCR) alone; RT-PCR plus clinical expertise or and imaging; repeated RT-PCR several days apart or from different samples; WHO and other case definitions; and any other reference standard used by the study authors. DATA COLLECTION AND ANALYSIS Two review authors independently extracted data from each included study. They also assessed the methodological quality of the studies, using QUADAS-2. We used the 'NLMIXED' procedure in SAS 9.4 for the hierarchical summary receiver operating characteristic (HSROC) meta-analyses of tests for which we included four or more studies. To facilitate interpretation of results, for each meta-analysis we estimated summary sensitivity at the points on the SROC curve that corresponded to the median and interquartile range boundaries of specificities in the included studies. MAIN RESULTS We included 21 studies in this review, including 14,126 COVID-19 patients and 56,585 non-COVID-19 patients in total. Studies evaluated a total of 67 different laboratory tests. Although we were interested in the diagnotic accuracy of routine tests for COVID-19, the included studies used detection of SARS-CoV-2 infection through RT-PCR as reference standard. There was considerable heterogeneity between tests, threshold values and the settings in which they were applied. For some tests a positive result was defined as a decrease compared to normal vaues, for other tests a positive result was defined as an increase, and for some tests both increase and decrease may have indicated test positivity. None of the studies had either low risk of bias on all domains or low concerns for applicability for all domains. Only three of the tests evaluated had a summary sensitivity and specificity over 50%. These were: increase in interleukin-6, increase in C-reactive protein and lymphocyte count decrease. Blood count Eleven studies evaluated a decrease in white blood cell count, with a median specificity of 93% and a summary sensitivity of 25% (95% CI 8.0% to 27%; very low-certainty evidence). The 15 studies that evaluated an increase in white blood cell count had a lower median specificity and a lower corresponding sensitivity. Four studies evaluated a decrease in neutrophil count. Their median specificity was 93%, corresponding to a summary sensitivity of 10% (95% CI 1.0% to 56%; low-certainty evidence). The 11 studies that evaluated an increase in neutrophil count had a lower median specificity and a lower corresponding sensitivity. The summary sensitivity of an increase in neutrophil percentage (4 studies) was 59% (95% CI 1.0% to 100%) at median specificity (38%; very low-certainty evidence). The summary sensitivity of an increase in monocyte count (4 studies) was 13% (95% CI 6.0% to 26%) at median specificity (73%; very low-certainty evidence). The summary sensitivity of a decrease in lymphocyte count (13 studies) was 64% (95% CI 28% to 89%) at median specificity (53%; low-certainty evidence). Four studies that evaluated a decrease in lymphocyte percentage showed a lower median specificity and lower corresponding sensitivity. The summary sensitivity of a decrease in platelets (4 studies) was 19% (95% CI 10% to 32%) at median specificity (88%; low-certainty evidence). Liver function tests The summary sensitivity of an increase in alanine aminotransferase (9 studies) was 12% (95% CI 3% to 34%) at median specificity (92%; low-certainty evidence). The summary sensitivity of an increase in aspartate aminotransferase (7 studies) was 29% (95% CI 17% to 45%) at median specificity (81%) (low-certainty evidence). The summary sensitivity of a decrease in albumin (4 studies) was 21% (95% CI 3% to 67%) at median specificity (66%; low-certainty evidence). The summary sensitivity of an increase in total bilirubin (4 studies) was 12% (95% CI 3.0% to 34%) at median specificity (92%; very low-certainty evidence). Markers of inflammation The summary sensitivity of an increase in CRP (14 studies) was 66% (95% CI 55% to 75%) at median specificity (44%; very low-certainty evidence). The summary sensitivity of an increase in procalcitonin (6 studies) was 3% (95% CI 1% to 19%) at median specificity (86%; very low-certainty evidence). The summary sensitivity of an increase in IL-6 (four studies) was 73% (95% CI 36% to 93%) at median specificity (58%) (very low-certainty evidence). Other biomarkers The summary sensitivity of an increase in creatine kinase (5 studies) was 11% (95% CI 6% to 19%) at median specificity (94%) (low-certainty evidence). The summary sensitivity of an increase in serum creatinine (four studies) was 7% (95% CI 1% to 37%) at median specificity (91%; low-certainty evidence). The summary sensitivity of an increase in lactate dehydrogenase (4 studies) was 25% (95% CI 15% to 38%) at median specificity (72%; very low-certainty evidence). AUTHORS' CONCLUSIONS Although these tests give an indication about the general health status of patients and some tests may be specific indicators for inflammatory processes, none of the tests we investigated are useful for accurately ruling in or ruling out COVID-19 on their own. Studies were done in specific hospitalized populations, and future studies should consider non-hospital settings to evaluate how these tests would perform in people with milder symptoms.

Journal article

J. Wongsantichon
Y. Jaiyen
Sabine Dittrich
J. Salje

Orientia tsutsugamushi.

In: Trends in Microbiology vol. 28 pg. 780-781

23.03.2020 (2020)

DOI: 10.1016/j.tim.2020.02.014

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Orientia tsutsugamushi is an obligate intracellular bacterial pathogen that causes the mite-borne human disease scrub typhus, one of the most widespread and severe rickettsial infections. Symptoms typically begin 7–14 days after inoculation and include headache, fever, rash, myalgia, and a painless eschar at the site of the mite’s bite. Untreated, the disease can escalate to cause multiple organ failure and death. Major challenges to disease control include slow and inaccurate diagnostic tests and low awareness amongst clinicians. O. tsutsugamushi infects a range of host cell types including endothelial cells, monocytes/macrophages, and dendritic cells, and it replicates directly in the host cell cytoplasm. Aspects of its infection cycle and biology differentiate it from other genera in the family Rickettsiaceae; these include a microtubule-driven mode of motility, a budding mechanism of host cell exit, a minimal peptidoglycan-like cell wall, and a highly repetitive genome.

Journal article

L. Porte
P. Legarraga
V. Vollrath
X. Aguilera
J. Munita
R. Araos
G. Pizarro
P. Vial
M. Iruretagoyena
Sabine Dittrich
T. Weitzel

Evaluation of a novel antigen-based rapid detection test for the diagnosis of SARS-CoV-2 in respiratory samples.

In: International Journal of Infectious Diseases vol. 99 pg. 328-333

01.06.2020 (2020)

DOI: 10.1016/j.ijid.2020.05.098

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OBJECTIVES In the context of the coronavirus disease 2019 (COVID-19) pandemic, the development and validation of rapid and easy-to-perform diagnostic methods are of high priority. This study was performed to evaluate a novel rapid antigen detection test (RDT) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory samples. METHODS The fluorescence immunochromatographic SARS-CoV-2 antigen test (Bioeasy Biotechnology Co., Shenzhen, China) was evaluated using universal transport medium with nasopharyngeal (NP) and oropharyngeal (OP) swabs from suspected COVID-19 cases. Diagnostic accuracy was determined in comparison to SARS-CoV-2 real-time (RT)-PCR. RESULTS A total of 127 samples were included; 82 were RT-PCR-positive. The median patient age was 38 years, 53.5% were male, and 93.7% were from the first week after symptom onset. Overall sensitivity and specificity were 93.9% (95% confidence interval 86.5-97.4%) and 100% (95% confidence interval 92.1-100%), respectively, with a diagnostic accuracy of 96.1% and Kappa coefficient of 0.9. Sensitivity was significantly higher in samples with high viral loads. CONCLUSIONS The RDT evaluated in this study showed a high sensitivity and specificity in samples mainly obtained during the first week of symptoms and with high viral loads, despite the use of a non-validated sample material. The assay has the potential to become an important tool for early diagnosis of SARS-CoV-2, particularly in situations with limited access to molecular methods.

Journal article

S. Pokharel
L. White
R. Aguas
O. Celhay
K. Pellé
Sabine Dittrich

Algorithm in the Diagnosis of Febrile Illness Using Pathogen-specific Rapid Diagnostic Tests.

In: Clinical Infectious Diseases (an official publication of the Infectious Diseases Society of America) vol. 70 pg. 2262-2269

(2020)

DOI: 10.1093/cid/ciz665

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BACKGROUND In the absence of proper guidelines and algorithms, available rapid diagnostic tests (RDTs) for common acute undifferentiated febrile illnesses are often used inappropriately. METHODS Using prevalence data of 5 common febrile illnesses from India and Cambodia, and performance characteristics (sensitivity and specificity) of relevant pathogen-specific RDTs, we used a mathematical model to predict the probability of correct identification of each disease when diagnostic testing occurs either simultaneously or sequentially in various algorithms. We developed a web-based application of the model so as to visualize and compare output diagnostic algorithms when different disease prevalence and test performance characteristics are introduced. RESULTS Diagnostic algorithms with appropriate sequential testing predicted correct identification of etiology in 74% and 89% of patients in India and Cambodia, respectively, compared with 46% and 49% with simultaneous testing. The optimally performing sequential diagnostic algorithms differed in India and Cambodia due to varying disease prevalence. CONCLUSIONS Simultaneous testing is not appropriate for the diagnosis of acute undifferentiated febrile illnesses with presently available tests, which should deter the unsupervised use of multiplex diagnostic tests. The implementation of adaptive algorithms can predict better diagnosis and add value to the available RDTs. The web application of the model can serve as a tool to identify the optimal diagnostic algorithm in different epidemiological settings, while taking into account the local epidemiological variables and accuracy of available tests.

Journal article

J. Schneider
C. Boehme
B. Borisch
Sabine Dittrich

Application of a simple point-of-care test to reduce UK healthcare costs and adverse events in outpatient acute respiratory infections.

In: Journal of Medical Economics vol. 23 pg. 673-682

07.04.2020 (2020)

DOI: 10.1080/13696998.2020.1736872

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Background: Acute respiratory infection (ARI) accounts for over two-thirds of total antibiotic prescriptions although most are caused by viruses that do not benefit from antibiotics. Most antibiotics are prescribed in the outpatients setting. Antibiotic overuse leads to antibiotic-related adverse events (AEs), inclusive of secondary infections, resistance, and increased costs. Point-of-care tests (POCT) may reduce unnecessary antibiotics. A cost analysis was performed to assess diagnostic POCT options to identify patients with an ARI that may benefit from antibiotics in a United Kingdom (UK) outpatient setting.Methods: Healthcare savings were estimated using a budget impact analysis based on UK National Institute for Health and Care Excellence (NICE) data and direct costs (antibiotics, AEs, POCTs) derived from published literature. Otitis media, sinusitis, pharyngitis and bronchitis were considered the most common ARIs. Antibiotic-related AE costs were calculated using re-consultation costs for anaphylaxis, Stevens-Johnson syndrome, allergies/diarrhea/nausea, C. difficile infection (CDI). Potential cost-savings from POCTs was assessed by evaluating NICE guideline-referenced POCTs (CRP, FebriDx, Sarasota, FL) as well as a target product profile (TPP).Results: Fifty-percent (7,718,283) of ARI consultations resulted in antibiotics while guideline-based prescribing suggest appropriate antibiotic prescriptions are warranted 9% (1,444,877) of ARI consultations. Direct antibiotic costs for actual ARI consultations associated with antibiotics was £24,003,866 vs. £4,493,568 for guideline-based, "appropriate" antibiotic prescriptions. Antibiotic-related AEs and re-consultations for actual vs. appropriate prescribing totaled £302,496,486 vs. £63,854,269. ARI prescribing plus AE costs totaled £326,729,943 annually without the use of delayed prescribing practices or POCT while the addition of delayed prescribing plus POCT totaled £60,114,564-£78,148,933 depending on the POCT.Conclusions: Adding POCT to outpatient triage of ARI can reduce unnecessary antibiotics and antibiotic-related AEs, resulting in substantial cost savings. Further, near patient diagnostic testing can benefit health systems and patients by avoiding exposure to unnecessary drugs, side effects and antibiotic resistant pathogens.Key points for decision makersMany patients are unnecessarily treated with antibiotics for respiratory infections.Antibiotic misuse leads to unnecessary adverse events, secondary infections, re-consultations, antimicrobial resistance and increased costs.Point-of-care diagnostic tests used to guide antibiotic prescriptions will avoid unnecessary adverse health effects and expenses.

Journal article

T. Struyf
J. Deeks
J. Dinnes
Y. Takwoingi
C. Davenport
M. Leeflang
R. Spijker
L. Hooft
D. Emperador
Sabine Dittrich
J. Domen
S. Horn
A. van den Bruel

Signs and symptoms to determine if a patient presenting in primary care or hospital outpatient settings has COVID-19 disease.

In: The Cochrane Database of Systematic Reviews vol. 7 pg. CD013665

07.07.2020 (2020)

DOI: 10.1002/14651858.cd013665

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BACKGROUND Some people with SARS-CoV-2 infection remain asymptomatic, whilst in others the infection can cause mild to moderate COVID-19 disease and COVID-19 pneumonia, leading some patients to require intensive care support and, in some cases, to death, especially in older adults. Symptoms such as fever or cough, and signs such as oxygen saturation or lung auscultation findings, are the first and most readily available diagnostic information. Such information could be used to either rule out COVID-19 disease, or select patients for further diagnostic testing. OBJECTIVES To assess the diagnostic accuracy of signs and symptoms to determine if a person presenting in primary care or to hospital outpatient settings, such as the emergency department or dedicated COVID-19 clinics, has COVID-19 disease or COVID-19 pneumonia. SEARCH METHODS On 27 April 2020, we undertook electronic searches in the Cochrane COVID-19 Study Register and the University of Bern living search database, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID-19 publications. We did not apply any language restrictions. SELECTION CRITERIA Studies were eligible if they included patients with suspected COVID-19 disease, or if they recruited known cases with COVID-19 disease and controls without COVID-19. Studies were eligible when they recruited patients presenting to primary care or hospital outpatient settings. Studies including patients who contracted SARS-CoV-2 infection while admitted to hospital were not eligible. The minimum eligible sample size of studies was 10 participants. All signs and symptoms were eligible for this review, including individual signs and symptoms or combinations. We accepted a range of reference standards including reverse transcription polymerase chain reaction (RT-PCR), clinical expertise, imaging, serology tests and World Health Organization (WHO) or other definitions of COVID-19. DATA COLLECTION AND ANALYSIS Pairs of review authors independently selected all studies, at both title and abstract stage and full-text stage. They resolved any disagreements by discussion with a third review author. Two review authors independently extracted data and resolved disagreements by discussion with a third review author. Two review authors independently assessed risk of bias using the QUADAS-2 checklist. Analyses were descriptive, presenting sensitivity and specificity in paired forest plots, in ROC (receiver operating characteristic) space and in dumbbell plots. We did not attempt meta-analysis due to the small number of studies, heterogeneity across studies and the high risk of bias. MAIN RESULTS We identified 16 studies including 7706 participants in total. Prevalence of COVID-19 disease varied from 5% to 38% with a median of 17%. There were no studies from primary care settings, although we did find seven studies in outpatient clinics (2172 participants), and four studies in the emergency department (1401 participants). We found data on 27 signs and symptoms, which fall into four different categories: systemic, respiratory, gastrointestinal and cardiovascular. No studies assessed combinations of different signs and symptoms and results were highly variable across studies. Most had very low sensitivity and high specificity; only six symptoms had a sensitivity of at least 50% in at least one study: cough, sore throat, fever, myalgia or arthralgia, fatigue, and headache. Of these, fever, myalgia or arthralgia, fatigue, and headache could be considered red flags (defined as having a positive likelihood ratio of at least 5) for COVID-19 as their specificity was above 90%, meaning that they substantially increase the likelihood of COVID-19 disease when present. Seven studies carried a high risk of bias for selection of participants because inclusion in the studies depended on the applicable testing and referral protocols, which included many of the signs and symptoms under study in this review. Five studies only included participants with pneumonia on imaging, suggesting that this is a highly selected population. In an additional four studies, we were unable to assess the risk for selection bias. These factors make it very difficult to determine the diagnostic properties of these signs and symptoms from the included studies. We also had concerns about the applicability of these results, since most studies included participants who were already admitted to hospital or presenting to hospital settings. This makes these findings less applicable to people presenting to primary care, who may have less severe illness and a lower prevalence of COVID-19 disease. None of the studies included any data on children, and only one focused specifically on older adults. We hope that future updates of this review will be able to provide more information about the diagnostic properties of signs and symptoms in different settings and age groups. AUTHORS' CONCLUSIONS The individual signs and symptoms included in this review appear to have very poor diagnostic properties, although this should be interpreted in the context of selection bias and heterogeneity between studies. Based on currently available data, neither absence nor presence of signs or symptoms are accurate enough to rule in or rule out disease. Prospective studies in an unselected population presenting to primary care or hospital outpatient settings, examining combinations of signs and symptoms to evaluate the syndromic presentation of COVID-19 disease, are urgently needed. Results from such studies could inform subsequent management decisions such as self-isolation or selecting patients for further diagnostic testing. We also need data on potentially more specific symptoms such as loss of sense of smell. Studies in older adults are especially important.

Journal article

C. Escadafal
S. Geis
A. Siqueira
S. Agnandji
T. Shimelis
B. Tadesse
M. Massinga Loembé
V. Harris
B. Fernandez-Carballo
A. Macé
S. Ongarello
W. Rodriguez
Sabine Dittrich

Bacterial versus non-bacterial infections: a methodology to support use-case-driven product development of diagnostics.

In: BMJ Global Health vol. 5

(2020)

DOI: 10.1136/bmjgh-2020-003141

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Acute febrile illness (AFI) is one of the most common reasons for seeking medical care in low-income and middle-income countries. Bacterial infections account for a relatively small proportion of AFIs; however, in the absence of a simple diagnostic test to guide clinical decisions, healthcare professionals often presume that a non-malarial febrile illness is bacterial in origin, potentially resulting in inappropriate antibiotic use. An accurate differential diagnostic tool for AFIs is thus essential, to both limit antibiotic use to bacterial infections and address the antimicrobial resistance crisis that is emerging globally, without resorting to multiple or complex pathogen-specific assays. The Biomarker for Fever-Diagnostic (BFF-Dx) study is one of the largest fever biomarker studies ever undertaken. We collected samples and classified disease aetiology in more than 1900 individuals, distributed among enrolment centres in three countries on two continents. Identical protocols were followed at each study site, and the same analyses were conducted in each setting, enabling like-with-like comparisons to be made among the large sample set generated. The BFF-Dx methodology can act as a model for other researchers, facilitating wider utility of the work in the future. The established sample collection is now accessible to researchers and companies and will facilitate the development of future fever-related diagnostic tests. Here, we outline the methodology used to determine the sample populations and to differentiate bacterial versus non-bacterial AFIs. Future publications will set out in more detail the study's demographics, the causes of fever identified and the performance of selected biomarkers.

Journal article

J. Moreira
C. Escadafal
Sabine Dittrich
P. Brasil
A. Siqueira

Antibiotic prescription and antipyretic use in febrile patients attending emergency departments in Rio de Janeiro, Brazil: A cross-sectional study.

In: International Journal of Infectious Diseases vol. 101 pg. 410-411

(2020)

DOI: 10.1016/j.ijid.2020.09.1077

show abstract

Background: Fever is a leading cause of a visit to Emergency Departments (ED), and few studies described the antibiotic prescription in this setting across Latin America. Antipyretics are commonly used home medications that result in a lowering of temperature when a patient comes seeking care. We aim to evaluate antibiotic prescription and antipyretic use at home among patients presenting to ED with a complaint of fever in Rio de Janeiro, Brazil. Methods & Materials: We did a cross-sectional study of patients who presented with fever to two urban ED between October 25, 2018, and March 29, 2019. Eligible subjects had a history of fever ≤7 days or had a measured temperature ≥37.5°C at the ED. Consented participants were interviewed and medical records were reviewed to extract information related to diagnosis and prescribed antibiotics. Results: Of 1551 triaged patients, 374 (24.1%) presented with fever. Among those, 248 (66.3%) had a temperature ≥37.5°C at arrival at the ED. The mean age was 30.6 [0–84] years, adults (82.5%) and females (54.8%) predominated. Suspicion of infection was attributed in 198/374 (53%), and upper respiratory tract infection 84/198 (42.4%) was the primary source of infection. Antibiotic was prescribed to 131/374 (35%) and varied accordingly to the foci of infection and the temperature recorded. Patients who had temperature ≥37.5°C at presentation were more likely to be diagnosed with an infection [OR: 2.2 (95% 1.4–3.5)] and were prescribed antibiotics most frequently [OR: 2 (95% 1.1–3.5)] compared to those with temperature <37.5°C. The antibiotic class most frequently prescribed was beta-lactam (57%), quinolone (17.5%), and macrolide (16.7%). A total of 249/374 (66.6%) received antipyretic at home and dipyrone (72.2%) was the antipyretic of choice. Conclusion: Antibiotic prescription in febrile patients presenting to the surveyed ED is common and respiratory infections accounted for the main indication for a prescription. These data highlight the need for more concerted interventions targeting the rational use of antibiotics. Antipyretics use is ubiquitous, and their use might influence clinical decisions in febrile patients.

Journal article

M. Cheng
J. Papenburg
M. Desjardins
S. Kanjilal
C. Quach
M. Libman
Sabine Dittrich
C. Yansouni

Diagnostic Testing for Severe Acute Respiratory Syndrome-Related Coronavirus 2: A Narrative Review.

In: Annals of Internal Medicine vol. 172 pg. 726-734

13.04.2020 (2020)

DOI: 10.7326/m20-1301

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Diagnostic testing to identify persons infected with severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection is central to control the global pandemic of COVID-19 that began in late 2019. In a few countries, the use of diagnostic testing on a massive scale has been a cornerstone of successful containment strategies. In contrast, the United States, hampered by limited testing capacity, has prioritized testing for specific groups of persons. Real-time reverse transcriptase polymerase chain reaction-based assays performed in a laboratory on respiratory specimens are the reference standard for COVID-19 diagnostics. However, point-of-care technologies and serologic immunoassays are rapidly emerging. Although excellent tools exist for the diagnosis of symptomatic patients in well-equipped laboratories, important gaps remain in screening asymptomatic persons in the incubation phase, as well as in the accurate determination of live viral shedding during convalescence to inform decisions to end isolation. Many affluent countries have encountered challenges in test delivery and specimen collection that have inhibited rapid increases in testing capacity. These challenges may be even greater in low-resource settings. Urgent clinical and public health needs currently drive an unprecedented global effort to increase testing capacity for SARS-CoV-2 infection. Here, the authors review the current array of tests for SARS-CoV-2, highlight gaps in current diagnostic capacity, and propose potential solutions.

Journal article

C. Escadafal
S. Incardona
B. Fernandez-Carballo
Sabine Dittrich

The good and the bad: using C reactive protein to distinguish bacterial from non-bacterial infection among febrile patients in low-resource settings.

In: BMJ Global Health vol. 5

(2020)

DOI: 10.1136/bmjgh-2020-002396

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C reactive protein (CRP), a marker for the presence of an inflammatory process, is the most extensively studied marker for distinguishing bacterial from non-bacterial infections in febrile patients. A point-of-care test for bacterial infections would be of particular use in low-resource settings where other laboratory diagnostics are not always available, antimicrobial resistance rates are high and bacterial infections such as pneumonia are a leading cause of death. This document summarises evidence on CRP testing for bacterial infections in low-income and middle-income countries (LMICs). With a push for universal health coverage and prevention of antimicrobial resistance, it is important to understand if CRP might be able to do the job. The use of CRP polarised the global health community and the aim of this document is to summarise the 'good and the bad' of CRP in multiple settings in LMICs. In brief, the literature that was reviewed suggests that CRP testing may be beneficial in low-resource settings to improve rational antibiotic use for febrile patients, but the positive predictive value is insufficient to allow it to be used alone as a single tool. CRP testing may be best used as part of a panel of diagnostic tests and algorithms. Further studies in low-resource settings, particularly with regard to impact on antibiotic prescribing and cost-effectiveness of CRP testing, are warranted.

Journal article

A. Devine
R. Howes
D. Price
K. Moore
B. Ley
J. Simpson
Sabine Dittrich
R. Price

Cost-Effectiveness Analysis of Sex-Stratified Plasmodium vivax Treatment Strategies Using Available G6PD Diagnostics to Accelerate Access to Radical Cure.

In: The American Journal of Tropical Medicine and Hygiene vol. 103 pg. 394-403

30.04.2020 (2020)

DOI: 10.4269/ajtmh.19-0943

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Tafenoquine has been licensed for the single-dose radical cure of Plasmodium vivax in adults; however, it is only recommended in patients with > 70% of normal glucose-6-phosphate dehydrogenase (G6PD) activity. Because this may hinder widespread use, we investigated sex-based treatment strategies in which all adult patients are tested with a qualitative G6PD rapid diagnostic test (RDT). Glucose-6-phosphate dehydrogenase normal males are prescribed tafenoquine in all three strategies, whereas G6PD normal females are prescribed either a low-dose 14-day primaquine regimen (PQ14, total dose 3.5 mg/kg) or a high-dose 7-day primaquine regimen (PQ7, total dose 7 mg/kg), or referred to a healthcare facility for quantitative G6PD testing before prescribing tafenoquine. Patients testing G6PD deficient are prescribed a weekly course of primaquine for 8 weeks. We compared the cost-effectiveness of these three strategies to usual care in four countries using a decision tree model. Usual care in Ethiopia does not include radical cure, whereas Afghanistan, Indonesia, and Vietnam prescribe PQ14 without G6PD screening. The cost per disability-adjusted life-year (DALY) averted was expressed through incremental cost-effectiveness ratios (ICERs). Compared with usual care, the ICERs for a sex-based treatment strategy with PQ7 for females from a healthcare provider perspective were $127 per DALY averted in Vietnam, $466 in Ethiopia, $1,089 in Afghanistan, and $4,443 in Indonesia. The PQ14 and referral options cost more while averting fewer DALYs than PQ7. This study provides an alternative cost-effective mode of rolling out tafenoquine in areas where initial testing with only a G6PD RDT is feasible.

Journal article

J. Deeks
J. Dinnes
Y. Takwoingi
C. Davenport
M. Leeflang
R. Spijker
L. Hooft
A. van den Bruel
D. Emperador
Sabine Dittrich

Diagnosis of SARS-CoV-2 infection and COVID-19: accuracy of signs and symptoms; molecular, antigen, and antibody tests; and routine laboratory markers.

In: Cochrane Database of Systematic Reviews

(2020)

DOI: 10.1002/14651858.CD013596

show abstract

Objectives This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows: To assess the diagnostic accuracy of laboratory real‐time polymerase chain reaction (RT‐PCR) and other laboratory molecular tests to determine if a person presenting in the community or in secondary care has SARS‐CoV‐2 infection. To assess the diagnostic accuracy of each rapid PCR and antigen test to determine if a person presenting in the community or in secondary care has SARS‐CoV‐2 infection. To assess the diagnostic accuracy of each antibody test to determine if a person presenting in the community or in secondary care has SARS‐CoV‐2 infection, or has previously had SARS‐CoV‐2 infection. To assess the diagnostic accuracy of signs and symptoms to determine if a person presenting in the community, general practice, or at the emergency department has SARS‐CoV‐2 infection, COVID‐19 pneumonia, or severe COVID‐19 pneumonia/ARDS requiring hospital admission. To assess the diagnostic accuracy of routine laboratory testing to determine if a person has COVID‐19 pneumonia or SARS‐CoV‐2 infection. Secondary objectives Where data are available, for reviews #1 to #5, we will investigate the accuracy (either by stratified analysis or meta‐regression) according to: laboratory method, days of symptoms, severity of symptoms, reference standard, sample type, study design, setting; test brand and version, days of symptoms, severity of symptoms, reference standard, sample type, study design, setting; current infection or past infection, test brand and version, days of symptoms or days since symptoms resolved, reference standard, study design, setting; days of symptoms, reference standard, study design, setting; specific measurement or biomarker, days of symptoms, severity of symptoms, reference standard, sample type, study design, setting.

Journal article

S. Incardona
D. Bell
A. Campillo
J. Cunningham
F. Ariey
T. Fandeur
J. Luchavez
C. Luna
D. Ménard
S. Nhem
J. Sornillo
B. Witkowski
Z. Katz
Sabine Dittrich
X. Ding

Keep the quality high: the benefits of lot testing for the quality control of malaria rapid diagnostic tests.

In: Malaria Journal vol. 19 pg. 247

13.07.2020 (2020)

DOI: 10.1186/s12936-020-03324-3

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BACKGROUND The production and use of malaria rapid diagnostic tests (RDTs) has risen dramatically over the past 20 years. In view of weak or non-existing in vitro diagnostics (IVD) regulations and post-marketing surveillance (PMS) systems in malaria endemic countries, the World Health Organization, later joined by the Foundation for Innovative New Diagnostics, established an independent, centralized performance evaluation and Lot Testing (LT) programme to safeguard against poor quality of RDTs being distributed through the public health sector of malaria endemic countries. RDT performances and manufacturer quality management systems have evolved over the past decade raising questions about the future need for a centralized LT programme. RESULTS Between 2007 and 2017, 6056 lots have been evaluated, representing approximately 1.6 Billion RDTs. A total of 69 lots (1.1%) failed the quality control. Of these failures, 26 were detected at receipt of the RDT lot in the LT laboratory, representing an estimated 7.9 million poor quality RDTs, and LT requesters were advised that RDTs were not of sufficient quality for use in patient management. Forty-three were detected after long-term storage in the laboratory, of which 24 (56%) were found to be due to a major issue with insufficient buffer volume in single use buffer vials, others predominantly showing loss of sensitivity. The annual cost of running the programme, based on expenses recorded in years 2014-2016, an estimated volume of 700 lots per year and including replenishment of quality control samples, was estimated at US$ 178,500 ($US 255 per lot tested). CONCLUSIONS Despite the clear benefits of the centralized LT programme and its low cost compared with the potential costs of each country establishing its own PMS system for RDTs, funding concerns have made its future beyond 2020 uncertain. In order to manage the risks of misdiagnosis due to low quality RDTs, and to ensure the continued safety and reliability of malaria case management, there is a need to ensure that an effective and implementable approach to RDT quality control continues to be available to programmes in endemic countries.

Journal article

T. Althaus
J. Thaipadungpanit
R. Greer
M. Swe
Sabine Dittrich
P. Peerawaranun
P. Smit
T. Wangrangsimakul
S. Blacksell
J. Winchell
M. Diaz
N. Day
F. Smithuis
P. Turner
Y. Lubell

Causes of fever in primary care in Southeast Asia and the performance of C-reactive protein in discriminating bacterial from viral pathogens.

In: International Journal of Infectious Diseases vol. 96 pg. 334-342

11.05.2020 (2020)

DOI: 10.1016/j.ijid.2020.05.016

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OBJECTIVES This study investigated causes of fever in the primary levels of care in Southeast Asia, and evaluated whether C-reactive protein (CRP) could distinguish bacterial from viral pathogens. METHODS Blood and nasopharyngeal swab specimens were taken from children and adults with fever (>37.5 °C) or history of fever (<14 days) in Thailand and Myanmar. RESULTS Of 773 patients with at least one blood or nasopharyngeal swab specimen collected, 227 (29.4%) had a target organism detected. Influenza virus type A was detected in 85/227 cases (37.5%), followed by dengue virus (30 cases, 13.2%), respiratory syncytial virus (24 cases, 10.6%) and Leptospira spp. (nine cases, 4.0%). Clinical outcomes were similar between patients with a bacterial or a viral organism, regardless of antibiotic prescription. CRP was higher among patients with a bacterial organism compared with those with a viral organism (median 18 mg/L, interquartile range [10-49] versus 10 mg/L [≤8-22], p = 0.003), with an area under the curve of 0.65 (95% CI 0.55-0.75). CONCLUSIONS Serious bacterial infections requiring antibiotics are an exception rather than the rule in the first line of care. CRP testing could assist in ruling out such cases in settings where diagnostic uncertainty is high and routine antibiotic prescription is common. The original CRP randomised controlled trial was registered with ClinicalTrials.gov, number NCT02758821.

Journal article

J. Moreira
J. Barros
O. Lapouble
M. Lacerda
I. Felger
P. Brasil
Sabine Dittrich
A. Siqueira

When fever is not malaria in Latin America: a systematic review.

In: BMC Medicine vol. 18 pg. 294

21.09.2020 (2020)

DOI: 10.1186/s12916-020-01746-z

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BACKGROUND In malaria-endemic countries, febrile episodes caused by diseases other than malaria are a growing concern. However, limited knowledge of the prevalent etiologic agents and their geographic distributions restrict the ability of health services to address non-malarial morbidity and mortality through effective case management. Here, we review the etiology of fever in Latin America (LA) between 1980 and 2015 and map significant pathogens commonly implicated in febrile infectious diseases. METHODS A literature search was conducted, without language restrictions, in three distinct databases in order to identify fever etiology studies that report laboratory-confirmed fever-causing pathogens that were isolated from usually sterile body sites. Data analyses and mapping was conducted with Tableau Desktop (version 2018.2.3). RESULTS Inclusion criteria were met by 625 publications corresponding to data relative to 34 countries. Studies using serology (n = 339) predominated for viral infections, culture (n = 131) for bacteria, and microscopy (n = 62) for fungi and parasites. The pathogen groups most frequently reported were viral infections (n = 277), bacterial infections (n = 265), parasitic infections (n = 59), fungal infections (n = 47), and more than one pathogen group (n = 24). The most frequently reported virus was dengue virus (n = 171), followed by other arboviruses (n = 55), and hantavirus (n = 18). For bacteria, Staphylococcus spp. (n = 82), Rickettsia spp. (n = 70), and Leptospira spp. (n = 55) were frequently reported. Areas with biggest gaps on etiology of fever were apparent. CONCLUSIONS This review provides a landscape of pathogens causing febrile illness other than malaria in LA for over 30 years. Our findings highlight the need to standardize protocols and report guidelines for fever etiology studies for better comparability of results and improved interpretation. Lastly, we should improve existing national laboratory surveillance systems, especially from low- to middle-income countries, to inform global fever policy priorities and timely identify emerging infections threats. STUDY REGISTRATION PROSPERO systematic review registration number: CRD42016049281.

Journal article

K. Pellé
C. Rambaud-Althaus
V. DAcremont
G. Moran
R. Sampath
Z. Katz
F. Moussy
G. Mehl
Sabine Dittrich

Electronic clinical decision support algorithms incorporating point-of-care diagnostic tests in low-resource settings: a target product profile.

In: BMJ Global Health vol. 5 pg. e002067

28.02.2020 (2020)

DOI: 10.1136/bmjgh-2019-002067

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Health workers in low-resource settings often lack the support and tools to follow evidence-based clinical recommendations for diagnosing, treating and managing sick patients. Digital technologies, by combining patient health information and point-of-care diagnostics with evidence-based clinical protocols, can help improve the quality of care and the rational use of resources, and save patient lives. A growing number of electronic clinical decision support algorithms (CDSAs) on mobile devices are being developed and piloted without evidence of safety or impact. Here, we present a target product profile (TPP) for CDSAs aimed at guiding preventive or curative consultations in low-resource settings. This document will help align developer and implementer processes and product specifications with the needs of end users, in terms of quality, safety, performance and operational functionality. To identify the characteristics of CDSAs, a multidisciplinary group of experts (academia, industry and policy makers) with expertise in diagnostic and CDSA development and implementation in low-income and middle-income countries were convened to discuss a draft TPP. The TPP was finalised through a Delphi process to facilitate consensus building. An agreement greater than 75% was reached for all 40 TPP characteristics. In general, experts were in overwhelming agreement that, given that CDSAs provide patient management recommendations, the underlying clinical algorithms should be human-interpretable and evidence-based. Whenever possible, the algorithm's patient management output should take into account pretest disease probabilities and likelihood ratios of clinical and diagnostic predictors. In addition, validation processes should at a minimum show that CDSAs are implementing faithfully the evidence they are based on, and ideally the impact on patient health outcomes. In terms of operational needs, CDSAs should be designed to fit within clinic workflows and function in connectivity-challenged and high-volume settings. Data collected through the tool should conform to local patient privacy regulations and international data standards.

Journal article

J. Osborn
T. Roberts
E. Guillen
O. Bernal
P. Roddy
S. Ongarello
A. Sprecher
A.-L. Page
I. Ribeiro
E. Piriou
A. Tamrat
R. La Tour
V. Rao
L. Flevaud
T. Jensen
L. McIver
C. Kelly
Sabine Dittrich

Prioritising pathogens for the management of severe febrile patients to improve clinical care in low- and middle-income countries.

In: BMC Infectious Diseases vol. 20 pg. 117

10.02.2020 (2020)

DOI: 10.1186/s12879-020-4834-1

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BACKGROUND Severe febrile illness without a known source (SFWS) is a challenge for clinicians when deciding how to manage a patient, particularly given the wide spectrum of potential aetiologies that contribute to fever. These infections are difficult to distinguish clinically, and accurate diagnosis requires a plethora of diagnostics including blood cultures, imaging techniques, molecular or serological tests, and more. When laboratory services are available, a limited test menu hinders clinical decision-making and antimicrobial stewardship, leading to empiric treatment and suboptimal patient outcomes. To specifically address SFWS, this work aimed to identify priority pathogens for a globally applicable panel for fever causing pathogens. METHOD A pragmatic two-pronged approach combining currently available scientific data in an analytical hierarchy process and systematically gathered expert input, was designed to address the lack of comprehensive global aetiology data. The expert re-ranked list was then further adapted for a specific use case to focus on community acquired infections in whole blood specimens. The resulting list was further analysed to address different geographical regions (Asia, Africa, and Latin America), and Cohen kappa scores of agreement were calculated. RESULTS The expert ranked prioritized pathogen list generated as part of this two-pronged approach included typhoidal Salmonella, Plasmodium species and Mycobacterium tuberculosis as the top 3 pathogens. This pathogen list was then further adapted for the SFWS use case to develop a final pathogen list to inform product development. Subsequent analysis comparing the relevance of the SFWS pathogen list to multiple populations and geographical regions showed that the SFWS prioritized list had considerable utility across Africa and Asia, but less so for Latin America. In addition, the list showed high levels of agreement across different patient sub-populations, but lower relevance for neonates and symptomatic HIV patients. CONCLUSION This work highlighted once again the challenges of prioritising in global health, but it also shows that taking a two-pronged approach, combining available prevalence data with expert input, can result in a broadly applicable priority list. This comprehensive utility is particularly important in the context of product development, where a sufficient market size is essential to achieve a sustainable commercialized diagnostic product to address SFWS.

Journal article

M. Cheng
C. Yansouni
N. Basta
M. Desjardins
S. Kanjilal
K. Paquette
C. Caya
M. Semret
C. Quach
M. Libman
L. Mazzola
J. Sacks
Sabine Dittrich
J. Papenburg

Serodiagnostics for Severe Acute Respiratory Syndrome-Related Coronavirus 2 : A Narrative Review.

In: Annals of Internal Medicine vol. 173 pg. 450-460

04.06.2020 (2020)

DOI: 10.7326/m20-2854

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Accurate serologic tests to detect host antibodies to severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) will be critical for the public health response to the coronavirus disease 2019 pandemic. Many use cases are envisaged, including complementing molecular methods for diagnosis of active disease and estimating immunity for individuals. At the population level, carefully designed seroepidemiologic studies will aid in the characterization of transmission dynamics and refinement of disease burden estimates and will provide insight into the kinetics of humoral immunity. Yet, despite an explosion in the number and availability of serologic assays to test for antibodies against SARS-CoV-2, most have undergone minimal external validation to date. This hinders assay selection and implementation, as well as interpretation of study results. In addition, critical knowledge gaps remain regarding serologic correlates of protection from infection or disease, and the degree to which these assays cross-react with antibodies against related coronaviruses. This article discusses key use cases for SARS-CoV-2 antibody detection tests and their application to serologic studies, reviews currently available assays, highlights key areas of ongoing research, and proposes potential strategies for test implementation.

Journal article

T. Shimelis
B. Tadesse
F. Gebriel
J. Crump
G. Schierhout
Sabine Dittrich
J. Kaldor
S. Vaz Nery

Aetiology of acute febrile illness among children attending a tertiary hospital in southern Ethiopia.

In: BMC Infectious Diseases vol. 20 pg. 903

30.11.2020 (2020)

DOI: 10.1186/s12879-020-05635-x

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BACKGROUND The diagnosis of non-malarial aetiologies, which now represent the majority of febrile illnesses, has remained problematic in settings with limited laboratory capacity. We aimed to describe common aetiologies of acute febrile illness among children in a setting where malaria transmission has declined. METHODS A prospective cross-sectional study was conducted among children aged at least 2 months and under 13 years presenting with fever (temperature of ≥37.5 °C or a history of fever in the past 48 h) to Hawassa Comprehensive Specialized Hospital, southern Ethiopia, from May 2018 through February 2019. Clinical and demographic data were gathered for consecutive participants, and malaria microscopy, HIV testing, and blood and urine cultures were performed regardless of clinical presentation. Additionally, stool analyses (culture and rotavirus/adenovirus RDT) and throat swab for group A Streptococcus (GAS) and urine Streptococcus pneumoniae were performed by RDTs for children with specific conditions. The antimicrobial susceptibility of bacterial isolates was determined using disc diffusion method. RESULTS During the study period 433 children were recruited, median age 20 months (range, 2 months - 12 years) and 178 (41.1%) female. Malaria was diagnosed in 14 (3.2%) of 431 children, and 3 (0.7%) had HIV infection. Bacteraemia or fungaemia was detected in 27 (6.4%) of 421 blood cultures, with Staphylococcus aureus isolated in 16 (3.8%). Urinary tract infections (UTIs) were detected in 74 (18.4%) of 402, with Escherichia coli isolated in 37 (9.2%). Among 56 children whose stool specimens were tested, 14 (25%) were positive for rotavirus, 1 (1.8%) for Salmonella Paratyphi A, and 1 (1.8%) for Shigella dysenteriae. Among those with respiratory symptoms, a throat swab test for GAS and urine test for S. pneumoniae were positive in 28 (15.8%) of 177 and 31 (17.0%) of 182, respectively. No test was positive for a pathogen in 266 (61.4%) of 433 participants. Bacterial isolates were frequently resistant to ampicillin, trimethoprim-sulfamethoxazole, tetracycline, and amoxicillin and clavulanic acid. CONCLUSION Our results showed low proportions of malaria and bacteraemia among febrile children. In contrast, the frequent detection of UTI emphasize the need to support enhanced diagnostic capacity to ensure appropriate antimicrobial intervention.

Journal article

J. Verbakel
L. Rop
I. Stegeman
G. Holtman
E. Ochodo
B. Yang
F. Guleid
C. Davenport
J. Deeks
J. Dinnes
Sabine Dittrich
D. Emperador
L. Hooft
R. Spijker
A. van den Bruel
Wang, J.
Y. Takwoingi
M. Langendam
M. Leeflang

Accuracy of routine laboratory tests to predict mortality and deterioration to severe or critical COVID-19 in people with SARS-CoV-2.

In: Cochrane Database of Systematic Reviews vol. 2021

(2021)

DOI: 10.1002/14651858.cd015050

show abstract

Objectives This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows: To assess the accuracy of routine blood‐based laboratory tests to predict mortality and deterioration to severe or critical (from mild or moderate) COVID‐19 in people with SARS‐CoV‐2 infection. Secondary objectives Where data are available, we will investigate whether prognostic accuracy varies according to a specific measurement or test, reference standard, timing of outcome verification, sample type, study design, and setting, including prevalence of the target condition (either by stratified analysis or meta‐regression).

Journal article

E. Kendall
N. Arinaminpathy
J. Sacks
Y. Manabe
Sabine Dittrich
S. Schumacher
D. Dowdy

Antigen-based Rapid Diagnostic Testing or Alternatives for Diagnosis of Symptomatic COVID-19: A Simulation-based Net Benefit Analysis.

In: Epidemiology vol. 32 pg. 811-819

(2021)

DOI: 10.1097/ede.0000000000001400

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BACKGROUND SARS-CoV-2 antigen-detection rapid diagnostic tests can diagnose COVID-19 rapidly and at low cost, but lower sensitivity compared with reverse-transcriptase polymerase chain reaction (PCR) has limited clinical adoption. METHODS We compared antigen testing, PCR testing, and clinical judgment alone for diagnosing symptomatic COVID-19 in an outpatient setting (10% COVID-19 prevalence among the patients tested, 3-day PCR turnaround) and a hospital setting (40% prevalence, 24-hour PCR turnaround). We simulated transmission from cases and contacts, and relationships between time, viral burden, transmission, and case detection. We compared diagnostic approaches using a measure of net benefit that incorporated both clinical and public health benefits and harms of the intervention. RESULTS In the outpatient setting, we estimated that using antigen testing instead of PCR to test 200 individuals could be equivalent to preventing all symptomatic transmission from one person with COVID-19 (one "transmission-equivalent"). In a hospital, net benefit analysis favored PCR and testing 25 patients with PCR instead of antigen testing achieved one transmission-equivalent of benefit. In both settings, antigen testing was preferable to PCR if PCR turnaround time exceeded 2 days. Both tests provided greater net benefit than management based on clinical judgment alone unless intervention carried minimal harm and was provided equally regardless of diagnostic approach. CONCLUSIONS For diagnosis of symptomatic COVID-19, we estimated that the speed of diagnosis with antigen testing is likely to outweigh its lower accuracy compared with PCR, wherever PCR turnaround time is 2 days or longer. This advantage may be even greater if antigen tests are also less expensive.

Journal article

M. McLaughlin
K. Pellé
S. Scarpino
A. Giwa
E. Mount-Finette
N. Haidar
F. Adamu
N. Ravi
A. Thompson
B. Heath
Sabine Dittrich
B. Finette

Development and Validation of Manually Modified and Supervised Machine Learning Clinical Assessment Algorithms for Malaria in Nigerian Children.

In: Frontiers in Artificial Intelligence vol. 4 pg. 554017

03.02.2022 (2021)

DOI: 10.3389/frai.2021.554017

show abstract

It is currently estimated that 67% of malaria deaths occur in children under-five years (WHO, 2020). To improve the identification of children at clinical risk for malaria, the WHO developed community (iCCM) and clinic-based (IMCI) protocols for frontline health workers using paper-based forms or digital mobile health (mHealth) platforms. To investigate improving the accuracy of these point-of-care clinical risk assessment protocols for malaria in febrile children, we embedded a malaria rapid diagnostic test (mRDT) workflow into THINKMD's (IMCI) mHealth clinical risk assessment platform. This allowed us to perform a comparative analysis of THINKMD-generated malaria risk assessments with mRDT truth data to guide modification of THINKMD algorithms, as well as develop new supervised machine learning (ML) malaria risk algorithms. We utilized paired clinical data and malaria risk assessments acquired from over 555 children presenting to five health clinics in Kano, Nigeria to train ML algorithms to identify malaria cases using symptom and location data, as well as confirmatory mRDT results. Supervised ML random forest algorithms were generated using 80% of our field-based data as the ML training set and 20% to test our new ML logic. New ML-based malaria algorithms showed an increased sensitivity and specificity of 60 and 79%, and PPV and NPV of 76 and 65%, respectively over THINKD initial IMCI-based algorithms. These results demonstrate that combining mRDT "truth" data with digital mHealth platform clinical assessments and clinical data can improve identification of children with malaria/non-malaria attributable febrile illnesses.

Journal article

B. Leticia Fernandez-Carballo
C. Escadafal
E. MacLean
A. Kapasi
Sabine Dittrich

Distinguishing bacterial versus non-bacterial causes of febrile illness - A systematic review of host biomarkers.

In: The Journal of Infection vol. 82 pg. 1-10

19.02.2021 (2021)

DOI: 10.1016/j.jinf.2021.01.028

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BACKGROUND Acute febrile illnesses (AFIs) represent a major disease burden globally; however, the paucity of reliable, rapid point-of-care testing makes their diagnosis difficult. A simple tool for distinguishing bacterial versus non-bacterial infections would radically improve patient management and reduce indiscriminate antibiotic use. Diagnostic tests based on host biomarkers can play an important role here, and a target product profile (TPP) was developed to guide development. OBJECTIVES To qualitatively evaluate host biomarkers that can distinguish bacterial from non-bacterial causes of AFI. DATA SOURCES The PubMed database was systematically searched for relevant studies published between 2015 and 2019. STUDY ELIGIBILITY CRITERIA Studies comparing diagnostic performances of host biomarkers in patients with bacterial versus non-bacterial infections were included. PARTICIPANTS Studies involving human participants and/or human samples were included. METHODS We collected information following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A risk of bias assessment was performed, based on a modified QUADAS-2 (Quality Assessment of Diagnostic Accuracy Score 2). RESULTS We identified 1107 publications. Following screening, 55 publications were included, with 265 biomarker entries. Entries mostly comprised protein biomarkers (58.9%), followed by haematological, RNA, and metabolite biomarkers (15.5%, 8.7%, 12.5%). Sensitivity/specificity was reported for 45.7% of biomarker entries. We assessed a high overall risk of bias for most entries (75.8%). In studies with low/medium risk of bias, four biomarker entries tested in blood samples had sensitivity/specificity of more than 0.90/0.80. Only 12 additional biomarker entries were identified with sensitivity/specificity of more than 0.65/0.65. CONCLUSIONS Most recently assessed biomarkers represent well-known biomarkers, e.g. C-reactive protein and procalcitonin. Some protein biomarkers with the highest reported performances include a combined biomarker signature (CRP, IP-10, and TRAIL) and human neutrophil lipocalin (HNL). Few new biomarkers are in the pipeline; however, some RNA signatures show promise. Further high-quality studies are needed to confirm these findings.

Journal article

A. Chandna
J. Osborn
Q. Bassat
D. Bell
S. Burza
V. DAcremont
B. Fernandez-Carballo
K. Kain
M. Mayxay
M. Wiens
Sabine Dittrich

Anticipating the future: prognostic tools as a complementary strategy to improve care for patients with febrile illnesses in resource-limited settings.

In: BMJ Global Health vol. 6

(2021)

DOI: 10.1136/bmjgh-2021-006057

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In low-income and middle-income countries, most patients with febrile illnesses present to peripheral levels of the health system where diagnostic capacity is very limited. In these contexts, accurate risk stratification can be particularly impactful, helping to guide allocation of scarce resources to ensure timely and tailored care. However, reporting of prognostic research is often imprecise and few prognostic tests or algorithms are translated into clinical practice.Here, we review the often-conflated concepts of prognosis and diagnosis, with a focus on patients with febrile illnesses. Drawing on a recent global stakeholder consultation, we apply these concepts to propose three use-cases for prognostic tools in the management of febrile illnesses in resource-limited settings: (1) guiding referrals from the community to higher-level care; (2) informing resource allocation for patients admitted to hospital and (3) identifying patients who may benefit from closer follow-up post-hospital discharge. We explore the practical implications for new technologies and reflect on the challenges and knowledge gaps that must be addressed before this approach could be incorporated into routine care settings.Our intention is that these use-cases, alongside other recent initiatives, will help to promote a harmonised yet contextualised approach for prognostic research in febrile illness. We argue that this is especially important given the heterogeneous settings in which care is often provided for patients with febrile illnesses living in low-income and middle-income countries.

Journal article

P. van Dorst
S. van der Pol
O. Salami
Sabine Dittrich
P. Olliaro
M. Postma
C. Boersma
A. van Asselt

Evaluations of training and education interventions for improved infectious disease management in low-income and middle-income countries: a systematic literature review.

In: BMJ Open vol. 12 pg. e053832

21.02.2022 (2022)

DOI: 10.1136/bmjopen-2021-053832

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OBJECTIVES To identify most vital input and outcome parameters required for evaluations of training and education interventions aimed at addressing infectious diseases in low-income and middle-income countries. DESIGN Systematic review. DATA SOURCES PubMed/Medline, Web of Science and Scopus were searched for eligible studies between January 2000 and November 2021. STUDY SELECTION Health economic and health-outcome studies on infectious diseases covering an education or training intervention in low-income and middle-income countries were included. RESULTS A total of 59 eligible studies covering training or education interventions for infectious diseases were found; infectious diseases were categorised as acute febrile infections (AFI), non-AFI and other non-acute infections. With regard to input parameters, the costs (direct and indirect) were most often reported. As outcome parameters, five categories were most often reported including final health outcomes, intermediate health outcomes, cost outcomes, prescription outcomes and health economic outcomes. Studies showed a wide range of per category variables included and a general lack of uniformity across studies. CONCLUSIONS Further standardisation is needed on the relevant input and outcome parameters in this field. A more standardised approach would improve generalisability and comparability of results and allow policy-makers to make better informed decisions on the most effective and cost-effective interventions.

Journal article

J. Moreira
P. Brasil
Sabine Dittrich
A. Siqueira

Mapping the global landscape of chikungunya rapid diagnostic tests: A scoping review.

In: PLoS Neglected Tropical Diseases vol. 16 pg. e0010067

25.07.2022 (2022)

DOI: 10.1371/journal.pntd.0010067

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BACKGROUND Chikungunya (CHIKV) is a reemerging arboviral disease and represents a global health threat because of the unprecedented magnitude of its spread. Diagnostics strategies rely heavily on reverse transcriptase-polymerase chain reaction (RT-PCR) and antibody detection by enzyme-linked Immunosorbent assay (ELISA). Rapid diagnostic tests (RDTs) are available and promise to decentralize testing and increase availability at lower healthcare system levels. OBJECTIVES We aim to identify the extent of research on CHIKV RDTs, map the global availability of CHIKV RDTs, and evaluate the accuracy of CHIKV RDTs for the diagnosis of CHIKV. ELIGIBILITY CRITERIA We included studies reporting symptomatic individuals suspected of CHIKV, tested with CHIKV RDTs, against the comparator being a validated laboratory-based RT-PCR or ELISA assay. The primary outcome was the accuracy of the CHIKV RDT when compared with reference assays. SOURCES OF EVIDENCE Medline, EMBASE, and Scopus were searched from inception to 13 October 2021. National regulatory agencies (European Medicines Agency, US Food and Drug Administration, and the Brazilian National Health Surveillance Agency) were also searched for registered CHIKV RDTs. RESULTS Seventeen studies were included and corresponded to 3,222 samples tested with RDTs between 2005 and 2018. The most development stage of CHIKV RDTs studies was Phase I (7/17 studies) and II (7/17 studies). No studies were in Phase IV. The countries that manufacturer the most CHIKV RDTs were Brazil (n = 17), followed by the United States of America (n = 7), and India (n = 6). Neither at EMA nor FDA-registered products were found. Conversely, the ANVISA has approved 23 CHIKV RDTs. Antibody RDTs (n = 43) predominated and demonstrated sensitivity between 20% and 100%. The sensitivity of the antigen RDTs ranged from 33.3% to 100%. CONCLUSIONS The landscape of CHIKV RDTs is fragmented and needs coordinated efforts to ensure that patients in CHIKV-endemic areas have access to appropriate RDTs. Further research is crucial to determine the impact of such tests on integrated fever case management and prescription practices for acute febrile patients.

Journal article

T. Shimelis
S. Vaz Nery
G. Schierhout
B. Tadesse
Sabine Dittrich
J. Crump
J. Kaldor

Differences in diagnosis, management, and outcomes of acute febrile illness by health facility level in southern Ethiopia.

In: Scientific Reports (Nature Publishing Group) vol. 12 pg. 19166

10.11.2022 (2022)

DOI: 10.1038/s41598-022-23641-8

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We assessed the diagnosis, management and outcomes of acute febrile illness in a cohort of febrile children aged under 5 years presenting at one urban and two rural health centres and one tertiary hospital between 11 August 2019 and 01 November 2019. Pneumonia was diagnosed in 104 (30.8%) of 338 children at health centres and 128 (65.0%) of 197 at the hospital (p < 0.001). Malaria was detected in 33 (24.3%) of 136 children at the urban health centre, and in 55 (55.6%) of 99 and 7 (7.4%) of 95 children at the rural health centres compared to 11 (11.6%) of 95 at the hospital. Antibacterials were prescribed to 20 (11.5%) of 174 children without guidelines-specified indications (overprescribing) at health centres and in 7 (33.3%) of 21 children at the hospital (p = 0.013). Antimalarials were overprescribed to 13 (7.0%) of 185 children with negative malaria microscopy at the hospital. The fever resolved by day 7 in 326 (99.7%) of 327 children at health centres compared to 177 (93.2%) of 190 at the hospital (p < 0.001). These results suggest that additional guidance to health workers is needed to optimise the use of antimicrobials across all levels of health facilities.

Journal article

T. Roberts
P. Dahal
P. Shrestha
W. Schilling
R. Shrestha
R. Ngu
V. Huong
H. van Doorn
Vilayouth Phimolsarnnousith
Thyl Miliya
John Crump
David Bell
Paul Newton
Sabine Dittrich
Heidi Hopkins
Kasia Stepniewska
Philippe Guerin
Elizabeth Ashley
Paul Turner

Antimicrobial resistance patterns in bacteria causing febrile illness in Africa, South Asia, and Southeast Asia: a systematic review of published etiological studies from 1980-2015.

In: International Journal of Infectious Diseases vol. 122 pg. 612-621

09.07.2022 (2022)

DOI: 10.1016/j.ijid.2022.07.018

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OBJECTIVE In this study, we aimed to conduct a systematic review to characterize antimicrobial resistance (AMR) patterns for bacterial causes of febrile illness in Africa and Asia. METHODS We included published literature from 1980-2015 based on data extracted from two recent systematic reviews of nonmalarial febrile illness from Africa, South Asia, and Southeast Asia. Selection criteria included articles with full bacterial identification and antimicrobial susceptibility testing (AST) results for key normally sterile site pathogen-drug combinations. Pooled proportions of resistant isolates were combined using random effects meta-analysis. Study data quality was graded using the Microbiology Investigation Criteria for Reporting Objectively (MICRO) framework. RESULTS Of 3475 unique articles included in the previous reviews, 371 included the target pathogen-drug combinations. Salmonella enterica tested against ceftriaxone and ciprofloxacin were the two highest reported combinations (30,509 and 22,056 isolates, respectively). Pooled proportions of resistant isolates were high for third-generation cephalosporins for Klebsiella pneumoniae and Escherichia coli in all regions. The MICRO grading showed an overall lack of standardization. CONCLUSION This review highlights a general increase in AMR reporting and in resistance over time. However, there were substantial problems with diagnostic microbiological data quality. Urgent strengthening of laboratory capacity, standardized testing, and reporting of AST results is required to improve AMR surveillance.

Journal article

J. Sapkota
R. Hasan
R. Onsare
S. Arafah
S. Kariuki
S. Shakoor
F. Qamar
S. Mundalo
F. Njeru
R. Too
E. Ndegwa
J. Andrews
Sabine Dittrich

Comparative Analysis of Commercially Available Typhoid Point-of-Care Tests: Results of a Prospective and Hybrid Retrospective Multicenter Diagnostic Accuracy Study in Kenya and Pakistan.

In: Journal of Clinical Microbiology vol. 60 pg. e0100022

30.11.2022 (2022)

DOI: 10.1128/jcm.01000-22

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Blood and bone marrow cultures are considered the gold standard for the diagnosis of typhoid, but these methods require infrastructure and skilled staff that are not always available in low- and middle-income countries where typhoid is endemic. The objective of the study is to evaluate the sensitivity and specificity of nine commercially available Salmonella Typhi rapid diagnostic tests (RDTs) using blood culture as a reference standard in a multicenter study. This was a prospective and retrospective multicenter diagnostic accuracy study conducted in two geographically distant areas where typhoid is endemic (Pakistan and Kenya; NCT04801602). Nine RDTs were evaluated, including the Widal test. Point estimates for sensitivity and specificity were calculated using the Wilson method. Latent class analyses were performed using R to address the imperfect gold standard. A total of 531 serum samples were evaluated (264 blood culture positive; 267 blood culture negative). The sensitivity of RDTs varied widely (range, 0 to 78.8%), with the best overall performance shown by Enterocheck WB (72.7% sensitivity, 86.5% specificity). In latent class modeling, CTK IgG was found to have the highest sensitivity (79.1%), while the highest overall accuracy was observed with Enterocheck (73.8% sensitivity, 94.5% specificity). All commercially available Salmonella Typhi RDTs evaluated in the study had sensitivity and specificity values that fell below the required levels to be recommended for an accurate diagnosis. There were minimal differences in RDT performances between regions of endemicity. These findings highlight the clear need for new and more-accurate Salmonella Typhi tests.

Journal article

H. Slater
X. Ding
S. Knudson
D. Bridges
H. Moonga
N. Saad
M. Smet
A. Bennett
Sabine Dittrich
L. Slutsker
G. Domingo

Performance and utility of more highly sensitive malaria rapid diagnostic tests.

In: BMC Infectious Diseases vol. 22 pg. 121

04.02.2022 (2022)

DOI: 10.1186/s12879-021-07023-5

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BACKGROUND A new more highly sensitive rapid diagnostic test (HS-RDT) for Plasmodium falciparum malaria (Alere™/Abbott Malaria Ag P.f RDT [05FK140], now called NxTek™ Eliminate Malaria Ag Pf) was launched in 2017. The test has already been used in many research studies in a wide range of geographies and use cases. METHODS In this study, we collate all published and available unpublished studies that use the HS-RDT and assess its performance in (i) prevalence surveys, (ii) clinical diagnosis, (iii) screening pregnant women, and (iv) active case detection. Two individual-level data sets from asymptomatic populations are used to fit logistic regression models to estimate the probability of HS-RDT positivity based on histidine-rich protein 2 (HRP2) concentration and parasite density. The performance of the HS-RDT in prevalence surveys is estimated by calculating the sensitivity and positive proportion in comparison to polymerase chain reaction (PCR) and conventional malaria RDTs. RESULTS We find that across 18 studies, in prevalence surveys, the mean sensitivity of the HS-RDT is estimated to be 56.1% (95% confidence interval [CI] 46.9-65.4%) compared to 44.3% (95% CI 32.6-56.0%) for a conventional RDT (co-RDT) when using nucleic acid amplification techniques as the reference standard. In studies where prevalence was estimated using both the HS-RDT and a co-RDT, we found that prevalence was on average 46% higher using a HS-RDT compared to a co-RDT. For use in clinical diagnosis and screening pregnant women, the HS-RDT was not significantly more sensitive than a co-RDT. CONCLUSIONS Overall, the evidence presented here suggests that the HS-RDT is more sensitive in asymptomatic populations and could provide a marginal improvement in clinical diagnosis and screening pregnant women. Although the HS-RDT has limited temperature stability and shelf-life claims compared to co-RDTs, there is no evidence to suggest, given this test has the same cost as current RDTs, it would have any negative impacts in terms of malaria misdiagnosis if it were widely used in all four population groups explored here.

Journal article

J. Dinnes
J. Deeks
S. Berhane
M. Taylor
A. Adriano
C. Davenport
Sabine Dittrich
D. Emperador
Y. Takwoingi
J. Cunningham
S. Beese
J. Domen
J. Dretzke
L. Di Ferrante Ruffano
I. Harris
M. Price
S. Taylor-Phillips
L. Hooft
M. Leeflang
M. McInnes
R. Spijker
A. van den Bruel

Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection.

In: The Cochrane Database of Systematic Reviews vol. 7 pg. CD013705

22.07.2022 (2022)

DOI: 10.1002/14651858.CD013705.pub3

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BACKGROUND Accurate rapid diagnostic tests for SARS-CoV-2 infection could contribute to clinical and public health strategies to manage the COVID-19 pandemic. Point-of-care antigen and molecular tests to detect current infection could increase access to testing and early confirmation of cases, and expediate clinical and public health management decisions that may reduce transmission. OBJECTIVES To assess the diagnostic accuracy of point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection. We consider accuracy separately in symptomatic and asymptomatic population groups. SEARCH METHODS Electronic searches of the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) were undertaken on 30 Sept 2020. We checked repositories of COVID-19 publications and included independent evaluations from national reference laboratories, the Foundation for Innovative New Diagnostics and the Diagnostics Global Health website to 16 Nov 2020. We did not apply language restrictions. SELECTION CRITERIA We included studies of people with either suspected SARS-CoV-2 infection, known SARS-CoV-2 infection or known absence of infection, or those who were being screened for infection. We included test accuracy studies of any design that evaluated commercially produced, rapid antigen or molecular tests suitable for a point-of-care setting (minimal equipment, sample preparation, and biosafety requirements, with results within two hours of sample collection). We included all reference standards that define the presence or absence of SARS-CoV-2 (including reverse transcription polymerase chain reaction (RT-PCR) tests and established diagnostic criteria). DATA COLLECTION AND ANALYSIS Studies were screened independently in duplicate with disagreements resolved by discussion with a third author. Study characteristics were extracted by one author and checked by a second; extraction of study results and assessments of risk of bias and applicability (made using the QUADAS-2 tool) were undertaken independently in duplicate. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test and pooled data using the bivariate model separately for antigen and molecular-based tests. We tabulated results by test manufacturer and compliance with manufacturer instructions for use and according to symptom status. MAIN RESULTS Seventy-eight study cohorts were included (described in 64 study reports, including 20 pre-prints), reporting results for 24,087 samples (7,415 with confirmed SARS-CoV-2). Studies were mainly from Europe (n = 39) or North America (n = 20), and evaluated 16 antigen and five molecular assays. We considered risk of bias to be high in 29 (50%) studies because of participant selection; in 66 (85%) because of weaknesses in the reference standard for absence of infection; and in 29 (45%) for participant flow and timing. Studies of antigen tests were of a higher methodological quality compared to studies of molecular tests, particularly regarding the risk of bias for participant selection and the index test. Characteristics of participants in 35 (45%) studies differed from those in whom the test was intended to be used and the delivery of the index test in 39 (50%) studies differed from the way in which the test was intended to be used. Nearly all studies (97%) defined the presence or absence of SARS-CoV-2 based on a single RT-PCR result, and none included participants meeting case definitions for probable COVID-19. Antigen tests Forty-eight studies reported 58 evaluations of antigen tests. Estimates of sensitivity varied considerably between studies. There were differences between symptomatic (72.0%, 95% CI 63.7% to 79.0%; 37 evaluations; 15530 samples, 4410 cases) and asymptomatic participants (58.1%, 95% CI 40.2% to 74.1%; 12 evaluations; 1581 samples, 295 cases). Average sensitivity was higher in the first week after symptom onset (78.3%, 95% CI 71.1% to 84.1%; 26 evaluations; 5769 samples, 2320 cases) than in the second week of symptoms (51.0%, 95% CI 40.8% to 61.0%; 22 evaluations; 935 samples, 692 cases). Sensitivity was high in those with cycle threshold (Ct) values on PCR ≤25 (94.5%, 95% CI 91.0% to 96.7%; 36 evaluations; 2613 cases) compared to those with Ct values >25 (40.7%, 95% CI 31.8% to 50.3%; 36 evaluations; 2632 cases). Sensitivity varied between brands. Using data from instructions for use (IFU) compliant evaluations in symptomatic participants, summary sensitivities ranged from 34.1% (95% CI 29.7% to 38.8%; Coris Bioconcept) to 88.1% (95% CI 84.2% to 91.1%; SD Biosensor STANDARD Q). Average specificities were high in symptomatic and asymptomatic participants, and for most brands (overall summary specificity 99.6%, 95% CI 99.0% to 99.8%). At 5% prevalence using data for the most sensitive assays in symptomatic people (SD Biosensor STANDARD Q and Abbott Panbio), positive predictive values (PPVs) of 84% to 90% mean that between 1 in 10 and 1 in 6 positive results will be a false positive, and between 1 in 4 and 1 in 8 cases will be missed. At 0.5% prevalence applying the same tests in asymptomatic people would result in PPVs of 11% to 28% meaning that between 7 in 10 and 9 in 10 positive results will be false positives, and between 1 in 2 and 1 in 3 cases will be missed. No studies assessed the accuracy of repeated lateral flow testing or self-testing. Rapid molecular assays Thirty studies reported 33 evaluations of five different rapid molecular tests. Sensitivities varied according to test brand. Most of the data relate to the ID NOW and Xpert Xpress assays. Using data from evaluations following the manufacturer's instructions for use, the average sensitivity of ID NOW was 73.0% (95% CI 66.8% to 78.4%) and average specificity 99.7% (95% CI 98.7% to 99.9%; 4 evaluations; 812 samples, 222 cases). For Xpert Xpress, the average sensitivity was 100% (95% CI 88.1% to 100%) and average specificity 97.2% (95% CI 89.4% to 99.3%; 2 evaluations; 100 samples, 29 cases). Insufficient data were available to investigate the effect of symptom status or time after symptom onset. AUTHORS' CONCLUSIONS Antigen tests vary in sensitivity. In people with signs and symptoms of COVID-19, sensitivities are highest in the first week of illness when viral loads are higher. The assays shown to meet appropriate criteria, such as WHO's priority target product profiles for COVID-19 diagnostics ('acceptable' sensitivity ≥ 80% and specificity ≥ 97%), can be considered as a replacement for laboratory-based RT-PCR when immediate decisions about patient care must be made, or where RT-PCR cannot be delivered in a timely manner. Positive predictive values suggest that confirmatory testing of those with positive results may be considered in low prevalence settings. Due to the variable sensitivity of antigen tests, people who test negative may still be infected. Evidence for testing in asymptomatic cohorts was limited. Test accuracy studies cannot adequately assess the ability of antigen tests to differentiate those who are infectious and require isolation from those who pose no risk, as there is no reference standard for infectiousness. A small number of molecular tests showed high accuracy and may be suitable alternatives to RT-PCR. However, further evaluations of the tests in settings as they are intended to be used are required to fully establish performance in practice. Several important studies in asymptomatic individuals have been reported since the close of our search and will be incorporated at the next update of this review. Comparative studies of antigen tests in their intended use settings and according to test operator (including self-testing) are required.

Journal article

A. Rao
S. Popper
S. Gupta
V. Davong
K. Vaidya
A. Chanthongthip
Sabine Dittrich
et al.

A robust host-response-based signature distinguishes bacterial and viral infections across diverse global populations.

In: Cell Reports. Medicine vol. 3 pg. 100842

(2022)

DOI: 10.1016/j.xcrm.2022.100842

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Limited sensitivity and specificity of current diagnostics lead to the erroneous prescription of antibiotics. Host-response-based diagnostics could address these challenges. However, using 4,200 samples across 69 blood transcriptome datasets from 20 countries from patients with bacterial or viral infections representing a broad spectrum of biological, clinical, and technical heterogeneity, we show current host-response-based gene signatures have lower accuracy to distinguish intracellular bacterial infections from viral infections than extracellular bacterial infections. Using these 69 datasets, we identify an 8-gene signature to distinguish intracellular or extracellular bacterial infections from viral infections with an area under the receiver operating characteristic curve (AUROC) > 0.91 (85.9% specificity and 90.2% sensitivity). In prospective cohorts from Nepal and Laos, the 8-gene classifier distinguished bacterial infections from viral infections with an AUROC of 0.94 (87.9% specificity and 91% sensitivity). The 8-gene signature meets the target product profile proposed by the World Health Organization and others for distinguishing bacterial and viral infections.

Journal article

T. Shimelis
S. Vaz Nery
B. Tadesse
A. Bartlett
F. Belay
G. Schierhout
Sabine Dittrich
J. Crump
J. Kaldor

Clinical management and outcomes of acute febrile illness in children attending a tertiary hospital in southern Ethiopia.

In: BMC Infectious Diseases vol. 22 pg. 434

04.05.2022 (2022)

DOI: 10.1186/s12879-022-07424-0

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BACKGROUND The management of febrile illnesses is challenging in settings where diagnostic laboratory facilities are limited, and there are few published longitudinal data on children presenting with fever in such settings. We have previously conducted the first comprehensive study of infectious aetiologies of febrile children presenting to a tertiary care facility in Ethiopia. We now report on clinicians' prescribing adherence with guidelines and outcomes of management in this cohort. METHODS We consecutively enrolled febrile children aged 2 months and under 13 years, who were then managed by clinicians based on presentation and available laboratory and radiologic findings on day of enrolment. We prospectively collected outcome data on days 7 and 14, and retrospectively evaluated prescribing adherence with national clinical management guidelines. RESULTS Of 433 children enrolled, the most common presenting syndromes were pneumonia and acute diarrhoea, diagnosed in 177 (40.9%) and 82 (18.9%), respectively. Antibacterial agents were prescribed to 360 (84.7%) of 425 children, including 36 (34.0%) of 106 children without an initial indication for antibacterials according to guidelines. Antimalarial drugs were prescribed to 47 (11.1%) of 425 children, including 30 (7.3%) of 411 children with negative malaria microscopy. Fever had resolved in 357 (89.7%) of 398 children assessed at day 7, and in-hospital death within 7 days occurred in 9 (5.9%) of 153 admitted patients. Among children with pneumonia, independent predictors of persisting fever or death by 7 days were young age and underweight for age. Antibacterial prescribing in the absence of a guideline-specified indication (overprescribing) was more likely among infants and those without tachypnea, while overprescribing antimalarials was associated with older age, anaemia, absence of cough, and higher fevers. CONCLUSION Our study underscores the need for improving diagnostic support to properly guide management decisions and enhance adherence by clinicians to treatment guidelines.

Journal article

L. Koeppel
Sabine Dittrich
S. Brenner Miguel
S. Carmona
S. Ongarello
B. Vetter
J. Cohn
T. Baernighausen
P. Geldsetzer
C. Denkinger

Addressing the diagnostic gap in hypertension through possible interventions and scale-up: A microsimulation study.

In: PLoS Medicine vol. 19 pg. e1004111

06.12.2022 (2022)

DOI: 10.1371/journal.pmed.1004111

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BACKGROUND Cardiovascular diseases (CVDs) are the leading cause of mortality globally with almost a third of all annual deaths worldwide. Low- and middle-income countries (LMICs) are disproportionately highly affected covering 80% of these deaths. For CVD, hypertension (HTN) is the leading modifiable risk factor. The comparative impact of diagnostic interventions that improve either the accuracy, the reach, or the completion of HTN screening in comparison to the current standard of care has not been estimated. METHODS AND FINDINGS This microsimulation study estimated the impact on HTN-induced morbidity and mortality in LMICs for four different scenarios: (S1) lower HTN diagnostic accuracy; (S2) improved HTN diagnostic accuracy; (S3) better implementation strategies to reach more persons with existing tools; and, lastly, (S4) the wider use of easy-to-use tools, such as validated, automated digital blood pressure measurement devices to enhance screening completion, in comparison to the current standard of care (S0). Our hypothetical population was parametrized using nationally representative, individual-level HPACC data and the global burden of disease data. The prevalence of HTN in the population was 31% out of which 60% remained undiagnosed. We investigated how the alteration of a yearly blood pressure screening event impacts morbidity and mortality in the population over a period of 10 years. The study showed that while improving test accuracy avoids 0.6% of HTN-induced deaths over 10 years (13,856,507 [9,382,742; 17,395,833]), almost 40 million (39,650,363 [31,34,233, 49,298,921], i.e., 12.7% [9.9, 15.8]) of the HTN-induced deaths could be prevented by increasing coverage and completion of a screening event in the same time frame. Doubling the coverage only would still prevent 3,304,212 million ([2,274,664; 4,164,180], 12.1% [8.3, 15.2]) CVD events 10 years after the rollout of the program. Our study is limited by the scarce data available on HTN and CVD from LMICs. We had to pool some parameters across stratification groups, and additional information, such as dietary habits, lifestyle choice, or the blood pressure evolution, could not be considered. Nevertheless, the microsimulation enabled us to include substantial heterogeneity and stochasticity toward the different income groups and personal CVD risk scores in the model. CONCLUSIONS While it is important to consider investing in newer diagnostics for blood pressure testing to continuously improve ease of use and accuracy, more emphasis should be placed on screening completion.

Journal article

T. Fox
J. Geppert
J. Dinnes
K. Scandrett
J. Bigio
G. Sulis
D. Hettiarachchi
Y. Mathangasinghe
P. Weeratunga
D. Wickramasinghe
H. Berman
B. Buckley
K. Probyn
Y. Sguassero
C. Davenport
J. Cunningham
Sabine Dittrich
et al.

Antibody tests for identification of current and past infection with SARS-CoV-2.

In: The Cochrane Database of Systematic Reviews vol. 11 pg. CD013652

17.11.2022 (2022)

DOI: 10.1002/14651858.CD013652.pub2

show abstract

BACKGROUND The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and resulting COVID-19 pandemic present important diagnostic challenges. Several diagnostic strategies are available to identify current infection, rule out infection, identify people in need of care escalation, or to test for past infection and immune response. Serology tests to detect the presence of antibodies to SARS-CoV-2 aim to identify previous SARS-CoV-2 infection, and may help to confirm the presence of current infection. OBJECTIVES To assess the diagnostic accuracy of antibody tests to determine if a person presenting in the community or in primary or secondary care has SARS-CoV-2 infection, or has previously had SARS-CoV-2 infection, and the accuracy of antibody tests for use in seroprevalence surveys. SEARCH METHODS We undertook electronic searches in the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID-19 publications. We did not apply any language restrictions. We conducted searches for this review iteration up to 27 April 2020. SELECTION CRITERIA We included test accuracy studies of any design that evaluated antibody tests (including enzyme-linked immunosorbent assays, chemiluminescence immunoassays, and lateral flow assays) in people suspected of current or previous SARS-CoV-2 infection, or where tests were used to screen for infection. We also included studies of people either known to have, or not to have SARS-CoV-2 infection. We included all reference standards to define the presence or absence of SARS-CoV-2 (including reverse transcription polymerase chain reaction tests (RT-PCR) and clinical diagnostic criteria). DATA COLLECTION AND ANALYSIS We assessed possible bias and applicability of the studies using the QUADAS-2 tool. We extracted 2x2 contingency table data and present sensitivity and specificity for each antibody (or combination of antibodies) using paired forest plots. We pooled data using random-effects logistic regression where appropriate, stratifying by time since post-symptom onset. We tabulated available data by test manufacturer. We have presented uncertainty in estimates of sensitivity and specificity using 95% confidence intervals (CIs). MAIN RESULTS We included 57 publications reporting on a total of 54 study cohorts with 15,976 samples, of which 8526 were from cases of SARS-CoV-2 infection. Studies were conducted in Asia (n = 38), Europe (n = 15), and the USA and China (n = 1). We identified data from 25 commercial tests and numerous in-house assays, a small fraction of the 279 antibody assays listed by the Foundation for Innovative Diagnostics. More than half (n = 28) of the studies included were only available as preprints. We had concerns about risk of bias and applicability. Common issues were use of multi-group designs (n = 29), inclusion of only COVID-19 cases (n = 19), lack of blinding of the index test (n = 49) and reference standard (n = 29), differential verification (n = 22), and the lack of clarity about participant numbers, characteristics and study exclusions (n = 47). Most studies (n = 44) only included people hospitalised due to suspected or confirmed COVID-19 infection. There were no studies exclusively in asymptomatic participants. Two-thirds of the studies (n = 33) defined COVID-19 cases based on RT-PCR results alone, ignoring the potential for false-negative RT-PCR results. We observed evidence of selective publication of study findings through omission of the identity of tests (n = 5). We observed substantial heterogeneity in sensitivities of IgA, IgM and IgG antibodies, or combinations thereof, for results aggregated across different time periods post-symptom onset (range 0% to 100% for all target antibodies). We thus based the main results of the review on the 38 studies that stratified results by time since symptom onset. The numbers of individuals contributing data within each study each week are small and are usually not based on tracking the same groups of patients over time. Pooled results for IgG, IgM, IgA, total antibodies and IgG/IgM all showed low sensitivity during the first week since onset of symptoms (all less than 30.1%), rising in the second week and reaching their highest values in the third week. The combination of IgG/IgM had a sensitivity of 30.1% (95% CI 21.4 to 40.7) for 1 to 7 days, 72.2% (95% CI 63.5 to 79.5) for 8 to 14 days, 91.4% (95% CI 87.0 to 94.4) for 15 to 21 days. Estimates of accuracy beyond three weeks are based on smaller sample sizes and fewer studies. For 21 to 35 days, pooled sensitivities for IgG/IgM were 96.0% (95% CI 90.6 to 98.3). There are insufficient studies to estimate sensitivity of tests beyond 35 days post-symptom onset. Summary specificities (provided in 35 studies) exceeded 98% for all target antibodies with confidence intervals no more than 2 percentage points wide. False-positive results were more common where COVID-19 had been suspected and ruled out, but numbers were small and the difference was within the range expected by chance. Assuming a prevalence of 50%, a value considered possible in healthcare workers who have suffered respiratory symptoms, we would anticipate that 43 (28 to 65) would be missed and 7 (3 to 14) would be falsely positive in 1000 people undergoing IgG/IgM testing at days 15 to 21 post-symptom onset. At a prevalence of 20%, a likely value in surveys in high-risk settings, 17 (11 to 26) would be missed per 1000 people tested and 10 (5 to 22) would be falsely positive. At a lower prevalence of 5%, a likely value in national surveys, 4 (3 to 7) would be missed per 1000 tested, and 12 (6 to 27) would be falsely positive. Analyses showed small differences in sensitivity between assay type, but methodological concerns and sparse data prevent comparisons between test brands. AUTHORS' CONCLUSIONS The sensitivity of antibody tests is too low in the first week since symptom onset to have a primary role for the diagnosis of COVID-19, but they may still have a role complementing other testing in individuals presenting later, when RT-PCR tests are negative, or are not done. Antibody tests are likely to have a useful role for detecting previous SARS-CoV-2 infection if used 15 or more days after the onset of symptoms. However, the duration of antibody rises is currently unknown, and we found very little data beyond 35 days post-symptom onset. We are therefore uncertain about the utility of these tests for seroprevalence surveys for public health management purposes. Concerns about high risk of bias and applicability make it likely that the accuracy of tests when used in clinical care will be lower than reported in the included studies. Sensitivity has mainly been evaluated in hospitalised patients, so it is unclear whether the tests are able to detect lower antibody levels likely seen with milder and asymptomatic COVID-19 disease. The design, execution and reporting of studies of the accuracy of COVID-19 tests requires considerable improvement. Studies must report data on sensitivity disaggregated by time since onset of symptoms. COVID-19-positive cases who are RT-PCR-negative should be included as well as those confirmed RT-PCR, in accordance with the World Health Organization (WHO) and China National Health Commission of the People's Republic of China (CDC) case definitions. We were only able to obtain data from a small proportion of available tests, and action is needed to ensure that all results of test evaluations are available in the public domain to prevent selective reporting. This is a fast-moving field and we plan ongoing updates of this living systematic review.

Journal article

A. Chandna
R. Mahajan
P. Gautam
L. Mwandigha
K. Gunasekaran
D. Bhusan
A. Cheung
N. Day
Sabine Dittrich
A. Dondorp
T. Geevar
S. Ghattamaneni
S. Hussain
C. Jimenez
R. Karthikeyan
S. Kumar
V. Kumar
D. Kundu
A. Lakshmanan
A. Manesh
C. Menggred
M. Moorthy
J. Osborn
M. Richard-Greenblatt
S. Sharma
V. Singh
J. Suri
S. Suzuki
J. Tubprasert
P. Turner
A. Villanueva
N. Waithira
P. Kumar
G. Varghese
C. Koshiaris
Y. Lubell
S. Burza

Facilitating safe discharge through predicting disease progression in moderate COVID-19: a prospective cohort study to develop and validate a clinical prediction model in resource-limited settings.

In: Clinical Infectious Diseases (an official publication of the Infectious Diseases Society of America)

21.03.2022 (2022)

DOI: 10.1093/cid/ciac224

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BACKGROUND In locations where few people have received COVID-19 vaccines, health systems remain vulnerable to surges in SARS-CoV-2 infections. Tools to identify patients suitable for community-based management are urgently needed. METHODS We prospectively recruited adults presenting to two hospitals in India with moderate symptoms of laboratory-confirmed COVID-19 in order to develop and validate a clinical prediction model to rule-out progression to supplemental oxygen requirement. The primary outcome was defined as any of the following: SpO2 < 94%; respiratory rate > 30 bpm; SpO2/FiO2 < 400; or death. We specified a priori that each model would contain three clinical parameters (age, sex and SpO2) and one of seven shortlisted biochemical biomarkers measurable using commercially-available rapid tests (CRP, D-dimer, IL-6, NLR, PCT, sTREM-1 or suPAR), to ensure the models would be suitable for resource-limited settings. We evaluated discrimination, calibration and clinical utility of the models in a held-out temporal external validation cohort. RESULTS 426 participants were recruited, of whom 89 (21.0%) met the primary outcome. 257 participants comprised the development cohort and 166 comprised the validation cohort. The three models containing NLR, suPAR or IL-6 demonstrated promising discrimination (c-statistics: 0.72 to 0.74) and calibration (calibration slopes: 1.01 to 1.05) in the validation cohort, and provided greater utility than a model containing the clinical parameters alone. CONCLUSIONS We present three clinical prediction models that could help clinicians identify patients with moderate COVID-19 suitable for community-based management. The models are readily implementable and of particular relevance for locations with limited resources.

Journal article

P. Nawtaisong
M. Robinson
K. Khammavong
P. Milavong
A. Rachlin
Sabine Dittrich
A. Dubot-Pérès
M. Vongsouvath
P. Horwood
P. Dussart
W. Theppangna
B. Douangngeum
A. Fine
M. Pruvot
P. Newton

Zoonotic Pathogens in Wildlife Traded in Markets for Human Consumption, Laos.

In: Emerging Infectious Diseases vol. 28 pg. 860-864

(2022)

DOI: 10.3201/eid2804.210249

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We tested animals from wildlife trade sites in Laos for the presence of zoonotic pathogens. Leptospira spp. were the most frequently detected infectious agents, found in 20.1% of animals. Rickettsia typhi and R. felis were also detected. These findings suggest a substantial risk for exposure through handling and consumption of wild animal meat.

Journal article

T. Shimelis
G. Schierhout
B. Tadesse
Sabine Dittrich
J. Crump
J. Kaldor
S. Vaz Nery

Timely health care seeking and first source of care for acute febrile illness in children in Hawassa, southern Ethiopia.

In: PLoS One vol. 17 pg. e0269725

09.06.2022 (2022)

DOI: 10.1371/journal.pone.0269725

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BACKGROUND Timely health care seeking with access to quality health care are crucial to improve child survival. We conducted a study which aimed to identify factors influencing timely health care seeking and choice of first source of health care in Ethiopia. METHODS A total of 535 caregivers who sought health care for febrile children aged under 5 years at a tertiary hospital, and one urban and two rural health centres in Hawassa, southern Ethiopia were recruited to participate in the study from August to November 2019. Caregivers were interviewed using pretested structured questionnaires on socio-demographic and clinical factors to identify associations with health care seeking practice and first source of care, and reasons for particular practices. Delayed care seeking was defined as seeking care from a health facility after 24 hours of onset of fever. RESULTS Of 535 caregivers who participated, 271 (50.7%) had sought timely health care; 400 (74.8%) utilized a primary health care (PHC) facility as first source; and 282 (52.7%) bypassed the nearest PHC facility. Rural residents (adjusted odds ratio (AOR) 1.85; 95% CI 1.11-3.09), and those who reported cough (AOR 1.87; 95% CI 1.20-2.93) as a reason for consultation were more likely to delay seeking health care. While caregivers were less likely delayed for children aged 24-35 months (AOR 0.50; 95% CI 0.28-0.87) compared to infants. Utilizing higher-level hospitals as the first source of care was less frequent among rural residents (AOR 0.15; 95% CI 0.06-0.39) and in those with no formal education (AOR 0.03; 95% CI 0.01-0.27). Those having a longer travel time to the provider (AOR 2.11; 95% CI 1.09-4.08) more likely utilized higher hospitals. CONCLUSION We identified a need to improve timely health seeking among rural residents, infants, and those presenting with respiratory symptoms. Improvements may be achieved by educating communities on the need of early care seeking, and ensuring the communities members' expectations of services at each level consistent with the services capacity.

Journal article

B. Holloway
H. Chandrasekar
M. Purohit
A. Sharma
A. Mathur
A. Kc
L. Fernandez-Carballo
Sabine Dittrich
H. Hildenwall
A. Bergström

Antibiotic Use before, during, and after Seeking Care for Acute Febrile Illness at a Hospital Outpatient Department: A Cross-Sectional Study from Rural India.

In: Antibiotics vol. 11

25.04.2022 (2022)

DOI: 10.3390/antibiotics11050574

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Antibiotic resistance is a naturally occurring phenomenon, but the misuse and overuse of antibiotics is accelerating the process. This study aimed to quantify and compare antibiotic use before, during, and after seeking outpatient care for acute febrile illness in Ujjain, India. Data were collected through interviews with patients/patient attendants. The prevalence and choice of antibiotics is described by the WHO AWaRe categories and Anatomical Therapeutic Chemical classes, comparing between age groups. Units of measurement include courses, encounters, and Defined Daily Doses (DDDs). The antibiotic prescription during the outpatient visit was also described in relation to the patients' presumptive diagnosis. Of 1000 included patients, 31.1% (n = 311) received one antibiotic course, 8.1% (n = 81) two, 1.3% (n = 13) three, 0.4% (n = 4) four, 0.1% (n = 1) five, and the remaining 59.0% (n = 590) received no antibiotics. The leading contributors to the total antibiotic volume in the DDDs were macrolides (30.3%), combinations of penicillins, including β-lactamase inhibitors (18.8%), tetracyclines (14.8%), fluoroquinolones (14.6%), and third-generation cephalosporins (13.7%). 'Watch' antibiotics accounted for 72.3%, 52.7%, and 64.0% of encounters before, during, and after the outpatient visit, respectively. Acute viral illness accounted for almost half of the total DDDs at the outpatient visit (642.1/1425.3, 45.1%), for which the macrolide antibiotic azithromycin was the most frequently prescribed antibiotic (261.3/642.1, 40.7%).

Journal article

H. Yu
F. Mohammed
M. Abdel Hamid
F. Yang
Y. Kassim
A. Mohamed
R. Maude
X. Ding
E. Owusu
S. Yerlikaya
Sabine Dittrich
S. Jaeger

Patient-level performance evaluation of a smartphone-based malaria diagnostic application.

In: Malaria Journal vol. 22 pg. 33

27.01.2023 (2023)

DOI: 10.1186/s12936-023-04446-0

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BACKGROUND Microscopic examination is commonly used for malaria diagnosis in the field. However, the lack of well-trained microscopists in malaria-endemic areas impacted the most by the disease is a severe problem. Besides, the examination process is time-consuming and prone to human error. Automated diagnostic systems based on machine learning offer great potential to overcome these problems. This study aims to evaluate Malaria Screener, a smartphone-based application for malaria diagnosis. METHODS A total of 190 patients were recruited at two sites in rural areas near Khartoum, Sudan. The Malaria Screener mobile application was deployed to screen Giemsa-stained blood smears. Both expert microscopy and nested PCR were performed to use as reference standards. First, Malaria Screener was evaluated using the two reference standards. Then, during post-study experiments, the evaluation was repeated for a newly developed algorithm, PlasmodiumVF-Net. RESULTS Malaria Screener reached 74.1% (95% CI 63.5-83.0) accuracy in detecting Plasmodium falciparum malaria using expert microscopy as the reference after a threshold calibration. It reached 71.8% (95% CI 61.0-81.0) accuracy when compared with PCR. The achieved accuracies meet the WHO Level 3 requirement for parasite detection. The processing time for each smear varies from 5 to 15 min, depending on the concentration of white blood cells (WBCs). In the post-study experiment, Malaria Screener reached 91.8% (95% CI 83.8-96.6) accuracy when patient-level results were calculated with a different method. This accuracy meets the WHO Level 1 requirement for parasite detection. In addition, PlasmodiumVF-Net, a newly developed algorithm, reached 83.1% (95% CI 77.0-88.1) accuracy when compared with expert microscopy and 81.0% (95% CI 74.6-86.3) accuracy when compared with PCR, reaching the WHO Level 2 requirement for detecting both Plasmodium falciparum and Plasmodium vivax malaria, without using the testing sites data for training or calibration. Results reported for both Malaria Screener and PlasmodiumVF-Net used thick smears for diagnosis. In this paper, both systems were not assessed in species identification and parasite counting, which are still under development. CONCLUSION Malaria Screener showed the potential to be deployed in resource-limited areas to facilitate routine malaria screening. It is the first smartphone-based system for malaria diagnosis evaluated on the patient-level in a natural field environment. Thus, the results in the field reported here can serve as a reference for future studies.

Journal article

X. Ding
S. Incardona
E. Serra-Casas
S. Charnaud
H. Slater
G. Domingo
E. Adams
F. Kuile
A. Samuels
S. Kariuki
Sabine Dittrich

Malaria in pregnancy (MiP) studies assessing the clinical performance of highly sensitive rapid diagnostic tests (HS-RDT) for Plasmodium falciparum detection.

In: Malaria Journal vol. 22 pg. 60

20.02.2023 (2023)

DOI: 10.1186/s12936-023-04445-1

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BACKGROUND Rapid diagnostic tests (RDTs) are effective tools to diagnose and inform the treatment of malaria in adults and children. The recent development of a highly sensitive rapid diagnostic test (HS-RDT) for Plasmodium falciparum has prompted questions over whether it could improve the diagnosis of malaria in pregnancy and pregnancy outcomes in malaria endemic areas. METHODS This landscape review collates studies addressing the clinical performance of the HS-RDT. Thirteen studies were identified comparing the HS-RDT and conventional RDT (co-RDT) to molecular methods to detect malaria in pregnancy. Using data from five completed studies, the association of epidemiological and pregnancy-related factors on the sensitivity of HS-RDT, and comparisons with co-RDT were investigated. The studies were conducted in 4 countries over a range of transmission intensities in largely asymptomatic women. RESULTS Sensitivity of both RDTs varied widely (HS-RDT range 19.6 to 85.7%, co-RDT range 22.8 to 82.8% compared to molecular testing) yet HS-RDT detected individuals with similar parasite densities across all the studies including different geographies and transmission areas [geometric mean parasitaemia around 100 parasites per µL (p/µL)]. HS-RDTs were capable of detecting low-density parasitaemias and in one study detected around 30% of infections with parasite densities of 0-2 p/µL compared to the co-RDT in the same study which detected around 15%. CONCLUSION The HS-RDT has a slightly higher analytical sensitivity to detect malaria infections in pregnancy than co-RDT but this mostly translates to only fractional and not statistically significant improvement in clinical performance by gravidity, trimester, geography or transmission intensity. The analysis presented here highlights the need for larger and more studies to evaluate incremental improvements in RDTs. The HS-RDT could be used in any situation where co-RDT are currently used for P. falciparum diagnosis, if storage conditions can be adhered to.

Journal article

P. Olliaro
J. Nkeramahame
P. Horgan
H. Tinto
F. Kiemde
R. Baiden
A. Adjei
J. Kapisi
H. Hopkins
O. Salami
C. Moore
Sabine Dittrich
et al.

Synthesis and Meta-analysis of 3 Randomized Trials Conducted in Burkina Faso, Ghana, and Uganda Comparing the Effects of Point-of-Care Tests and Diagnostic Algorithms Versus Routine Care on Antibiotic Prescriptions and Clinical Outcomes in Ambulatory Patients <18 Years of Age With Acute Febrile Illness.

In: Clinical Infectious Diseases (an official publication of the Infectious Diseases Society of America) vol. 77 pg. S199-S205

(2023)

DOI: 10.1093/cid/ciad324

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This meta-analysis included 3 randomized trials conducted in sub-Saharan Africa comparing the effects of point-of-care tests and diagnostic algorithms versus routine care on antibiotic prescriptions and clinical outcomes in ambulatory patients presenting at outpatient facilities with acute uncomplicated febrile illness.

Journal article

A. Adjei
V. Kukula
C. Narh
S. Odopey
E. Arthur
G. Odonkor
M. Mensah
P. Olliaro
P. Horgan
Sabine Dittrich
et al.

Impact of Point-of-Care Rapid Diagnostic Tests on Antibiotic Prescription Among Patients Aged <18 Years in Primary Healthcare Settings in 2 Peri-Urban Districts in Ghana: Randomized Controlled Trial Results.

In: Clinical Infectious Diseases (an official publication of the Infectious Diseases Society of America) vol. 77 pg. S145-S155

(2023)

DOI: 10.1093/cid/ciad328

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BACKGROUND Inappropriate antibiotic prescriptions are a known driver of antimicrobial resistance in settings with limited diagnostic capacity. This study aimed to assess the impact of diagnostic algorithms incorporating rapid diagnostic tests on clinical outcomes and antibiotic prescriptions compared with standard-of-care practices, of acute febrile illness cases at outpatient clinics in Shai-Osudoku and Prampram districts in Ghana. METHODS This was an open-label, centrally randomized controlled trial in 4 health facilities. Participants aged 6 months to <18 years of both sexes with acute febrile illness were randomized to receive a package of interventions to guide antibiotic prescriptions or standard care. Clinical outcomes were assessed on day 7. RESULTS In total, 1512 patients were randomized to either the intervention (n = 761) or control (n = 751) group. Majority were children aged <5 years (1154 of 1512, 76.3%) and male (809 of 1512, 53.5%). There was 11% relative risk reduction of antibiotic prescription in intervention group (RR, 0.89; 95% CI, .79 to 1.01); 14% in children aged <5 years (RR, 0.86; 95% CI, .75 to .98), 15% in nonmalaria patients (RR, 0.85; 95% CI, .75 to .96), and 16% in patients with respiratory symptoms (RR, 0.84; 95% CI, .73 to .96). Almost all participants had favorable outcomes (759 of 761, 99.7% vs 747 of 751, 99.4%). CONCLUSIONS In low- and middle-income countries, the combination of point-of-care diagnostics, diagnostic algorithms, and communication training can be used at the primary healthcare level to reduce antibiotic prescriptions among children with acute febrile illness, patients with nonmalarial fevers, and respiratory symptoms. CLINICAL TRIALS REGISTRATION NCT04081051.

Journal article

S. Shakoor
Sabine Dittrich

Better diagnostic tools needed to distinguish typhoid from other causes of acute febrile illness. Editorial.

In: Bulletin of the World Health Organization vol. 101 pg. 683-683A

(2023)

DOI: 10.2471/blt.23.290678

Journal article

F. Kiemde
D. Valia
B. Kabore
T. Rouamba
A. Kone
S. Sawadogo
A. Compaore
O. Salami
P. Horgan
C. Moore
Sabine Dittrich
et al.

A Randomized Trial to Assess the Impact of a Package of Diagnostic Tools and Diagnostic Algorithm on Antibiotic Prescriptions for the Management of Febrile Illnesses Among Children and Adolescents in Primary Health Facilities in Burkina Faso.

In: Clinical Infectious Diseases (an official publication of the Infectious Diseases Society of America) vol. 77 pg. S134-S144

(2023)

DOI: 10.1093/cid/ciad331

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BACKGROUND Low- and middle-income countries face significant challenges in differentiating bacterial from viral causes of febrile illnesses, leading to inappropriate use of antibiotics. This trial aimed to evaluate the impact of an intervention package comprising diagnostic tests, a diagnostic algorithm, and a training-and-communication package on antibiotic prescriptions and clinical outcomes. METHODS Patients aged 6 months to 18 years with fever or history of fever within the past 7 days with no focus, or a suspected respiratory tract infection, arriving at 2 health facilities were randomized to either the intervention package or standard practice. The primary outcomes were the proportions of patients who recovered at day 7 (D7) and patients prescribed antibiotics at day 0. RESULTS Of 1718 patients randomized, 1681 (97.8%; intervention: 844; control: 837) completed follow-up: 99.5% recovered at D7 in the intervention arm versus 100% in standard practice (P = .135). Antibiotics were prescribed to 40.6% of patients in the intervention group versus 57.5% in the control arm (risk ratio: 29.3%; 95% CI: 21.8-36.0%; risk difference [RD]: -16.8%; 95% CI: -21.7% to -12.0%; P < .001), which translates to 1 additional antibiotic prescription saved every 6 (95% CI: 5-8) consultations. This reduction was significant regardless of test results for malaria, but was greater in patients without malaria (RD: -46.0%; -54.7% to -37.4%; P < .001), those with a respiratory diagnosis (RD: -38.2%; -43.8% to -32.6%; P < .001), and in children 6-59 months old (RD: -20.4%; -26.0% to -14.9%; P < .001). Except for the period July-September, the reduction was consistent across the other quarters (P < .001). CONCLUSIONS The implementation of the package can reduce inappropriate antibiotic prescription without compromising clinical outcomes. CLINICAL TRIALS REGISTRATION clinicaltrials.gov; NCT04081051.

Journal article

G. Gwaza
M. Leqheka
T. Motsoane
Sabine Dittrich
K. Kao

Missed opportunities for integrated testing of HIV and tuberculosis on the GeneXpert platform in Lesotho.

In: African Journal of Laboratory Medicine vol. 12 pg. 2132

28.08.2023 (2023)

DOI: 10.4102/ajlm.v12i1.2132

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BACKGROUND Integrated testing, treatment and care are key strategies for addressing the dual burdens of tuberculosis and HIV. The GeneXpert instrument allows simultaneous HIV and tuberculosis testing, but its utilisation for integrated testing remains suboptimal. OBJECTIVE The study determined the extent to which tuberculosis testing and HIV early infant detection (EID) were integrated on the GeneXpert platform, or the potential for integration at selected health facilities. METHODS A mixed methods evaluation was conducted using retrospective secondary data analysis of laboratory records from 2017 to 2019, and semi-structured interviews. Data were collected between January 2020 and March 2020 in Lesotho. RESULTS Forty-four health staff were interviewed across 13 health facilities: one regional, nine district, and three clinic level. Six were government facilities, six were mission hospitals, and one was a non-profit clinic. All facilities selected had at least one GeneXpert instrument used for tuberculosis or HIV testing; none included simultaneous testing for tuberculosis and HIV. In 2017, the average utilisation rate for the GeneXpert instrument for tuberculosis and EID testing was 63% and 24%, while in 2019, the average utilisation rate was 61% for tuberculosis testing and 27% for EID. CONCLUSION Except for three sites where the testing rates were high, utilisation rates were sufficiently low that all the HIV EID and tuberculosis tests undertaken in 2017 and 2019 could have been performed using only the instruments currently dedicated to tuberculosis testing. There is a missed opportunity for the integration of testing for tuberculosis and HIV on the GeneXpert instrument. WHAT THIS STUDY ADDS This study adds to the body of evidence on the need for integration of testing and highlights some practical and technical considerations for successful implementation of integrated tuberculosis and HIV testing.

Journal article

N. Nguyen
N. Do
D. Vu
R. Greer
Sabine Dittrich
et al.

Outpatient antibiotic prescribing for acute respiratory infections in Vietnamese primary care settings by the WHO AWaRe (Access, Watch and Reserve) classification: An analysis using routinely collected electronic prescription data.

In: The Lancet Regional Health. Western Pacific vol. 30 pg. 100611

11.10.2022 (2023)

DOI: 10.1016/j.lanwpc.2022.100611

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BACKGROUND This study aims to investigate patterns of antibiotic prescribing and to determine patient-specific factors associated with the choice of antibiotics by the World Health Organization's Access-Watch-Reserve (WHO AWaRe) class for acute respiratory infections (ARIs) in rural primary care settings in northern Vietnam. METHODS We retrospectively reviewed health records for outpatients who were registered with the Vietnamese Health Insurance Scheme, visited one of 112 commune health centres in 6 rural districts of Nam Dinh province, Vietnam during 2019, and were diagnosed with ARIs. Patient-level prescription data were collected from the electronic patient databases. We used descriptive statistics to investigate patterns of antibiotic prescribing, with the primary outcomes including total antibiotic prescriptions and prescriptions by WHO AWaRe group. We identified patient-specific factors associated with watch-group antibiotic prescribing through multivariable logistic regression analysis. FINDINGS Among 193,010 outpatient visits for ARIs observed in this study, 187,144 (97.0%) resulted in an antibiotic prescription, of which 172,976 (92.5%) were access-antibiotics, 10,765 (5.6%) were watch-antibiotics, 3366 (1.8%) were not-recommended antibiotics. No patients were treated with reserve-antibiotics. The proportion of watch-antibiotic prescription was highest amongst children under 5-years old (18.1%, compared to 9.5% for 5-17-years, 4.9% for 18-49-years, 4.3% for 50-64-years, and 3.7% for 65-and-above-years). In multivariable logistic regression, children, district, ARI-type, comobid chronic respiratory illness, and follow-up visit were associated with higher likelihood of prescribing watch-group antibiotics. INTERPRETATION The alarmingly high proportion of antibiotic prescriptions for ARIs in primary care, and the frequent use of watch-antibiotics for children, heighten concerns around antibiotic overuse at the community level. Antimicrobial stewardship interventions and policy attention are needed in primary care settings to tackle the growing threat of antibiotic resistance. FUNDING This work was supported through Australian government and UK aid from the UK government funding to FIND (Foundation for Innovative New Diagnostics) grant number FO17-0015, in addition to a Wellcome Trust grant (213920/Z/18/Z), and an Oxford University Clinical Research Unit internal grant from the Wellcome Trust Africa Asia Programme core grant in Vietnam (106680/Z/14/Z).

Journal article

A. Compaoré
D. Ekusai-Sebatta
D. Kaawa-Mafigiri
V. Kukula
S. Odopey
J. Kapisi
H. Hopkins
F. Kiemde
H. Tinto
R. Baiden
P. Olliaro
J. Nkeramahame
Sabine Dittrich
P. Horgan

Viewpoint: Antimicrobial Resistance Diagnostics Use Accelerator: Qualitative Research on Adherence to Prescriptions.

In: Clinical Infectious Diseases (an official publication of the Infectious Diseases Society of America) vol. 77 pg. S206-S210

(2023)

DOI: 10.1093/cid/ciad323

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In this Viewpoint, the authors explore the determinants of patients' prescription adherence behaviors as part of FIND's Advancing Access to Diagnostic Innovation essential for Universal Health Coverage and AMR Prevention (ADIP) trials (ClinicalTrials.gov identifier: NCT04081051). Research findings from Burkina Faso, Ghana, and Uganda show that basic knowledge and understanding of prescription instructions are essential for adherence and can be improved through better communication. However, there are a range of other factors that influence adherence, some of which can be influenced through tailored communication messages from healthcare workers. These messages may contribute to changes in adherence behavior but may require other reinforcing interventions to be effective. Finally, there are some drivers of nonadherence centered around costs and time pressure that require other forms of intervention.

Journal article

A. Chandna
R. Mahajan
P. Gautam
L. Mwandigha
Sabine Dittrich
et al.

Point-of-care prognostication in moderate Covid-19: Analytical validation and prognostic accuracy of a soluble urokinase plasminogen activator receptor (suPAR) rapid test.

In: PLOS Global Public Health vol. 3 pg. e0001538

21.08.2023 (2023)

DOI: 10.1371/journal.pgph.0001538

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The soluble urokinase plasminogen activator receptor (suPAR) has been proposed as a biomarker for risk stratification of patients presenting with acute infections. However, most studies evaluating suPAR have used platform-based assays, the accuracy of which may differ from point-of-care tests capable of informing timely triage in settings without established laboratory capacity. Using samples and data collected during a prospective cohort study of 425 patients presenting with moderate Covid-19 to two hospitals in India, we evaluated the analytical performance and prognostic accuracy of a commercially-available rapid diagnostic test (RDT) for suPAR, using an enzyme-linked immunosorbent assay (ELISA) as the reference standard. Our hypothesis was that the suPAR RDT might be useful for triage of patients presenting with moderate Covid-19 irrespective of its analytical performance when compared with the reference test. Although agreement between the two tests was limited (bias = -2.46 ng/mL [95% CI = -2.65 to -2.27 ng/mL]), prognostic accuracy to predict supplemental oxygen requirement was comparable, whether suPAR was used alone (area under the receiver operating characteristic curve [AUC] of RDT = 0.73 [95% CI = 0.68 to 0.79] vs. AUC of ELISA = 0.70 [95% CI = 0.63 to 0.76]; p = 0.12) or as part of a published multivariable prediction model (AUC of RDT-based model = 0.74 [95% CI = 0.66 to 0.83] vs. AUC of ELISA-based model = 0.72 [95% CI = 0.64 to 0.81]; p = 0.78). Lack of agreement between the RDT and ELISA in our cohort warrants further investigation and highlights the importance of assessing candidate point-of-care tests to ensure management algorithms reflect the assay that will ultimately be used to inform patient care. Availability of a quantitative point-of-care test for suPAR opens the door to suPAR-guided risk stratification of patients with Covid-19 and other acute infections in settings with limited laboratory capacity.

Journal article

S. Pokharel
L. White
J. Sacks
C. Escadafal
A. Toporowski
S. Mohammed
S. Abera
K. Kao
M. Freitas
Sabine Dittrich

Correction: Two-test algorithms for infectious disease diagnosis: Implications for COVID-19. Published Erratum.

In: PLOS Global Public Health vol. 3 pg. e0002511

11.10.2023 (2023)

DOI: 10.1371/journal.pgph.0002511

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[This corrects the article DOI: 10.1371/journal.pgph.0000293.].

Journal article

N. Do
T. v. d. Vu
R. Greer
Sabine Dittrich
et al.

Implementation of point-of-care testing of C-reactive protein concentrations to improve antibiotic targeting in respiratory illness in Vietnamese primary care: a pragmatic cluster-randomised controlled trial.

In: The Lancet. Infectious diseases vol. 23 pg. 1085-1094

22.05.2023 (2023)

DOI: 10.1016/s1473-3099(23)00125-1

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BACKGROUND In previous trials, point-of-care testing of C-reactive protein (CRP) concentrations safely reduced antibiotic use in non-severe acute respiratory infections in primary care. However, these trials were done in a research-oriented context with close support from research staff, which could have influenced prescribing practices. To better inform the potential for scaling up point-of-care testing of CRP in respiratory infections, we aimed to do a pragmatic trial of the intervention in a routine care setting. METHODS We did a pragmatic, cluster-randomised controlled trial at 48 commune health centres in Viet Nam between June 1, 2020, and May 12, 2021. Eligible centres served populations of more than 3000 people, handled 10-40 respiratory infections per week, had licensed prescribers on site, and maintained electronic patient databases. Centres were randomly allocated (1:1) to provide point-of-care CRP testing plus routine care or routine care only. Randomisation was stratified by district and by baseline prescription level (ie, the proportion of patients with suspected acute respiratory infections to whom antibiotics were prescribed in 2019). Eligible patients were aged 1-65 years and visiting the commune health centre for a suspected acute respiratory infection with at least one focal sign or symptom and symptoms lasting less than 7 days. The primary endpoint was the proportion of patients prescribed an antibiotic at first attendance in the intention-to-treat population. The per-protocol analysis included only people who underwent CRP testing. Secondary safety outcomes included time to resolution of symptoms and frequency of hospitalisation. This trial is registered with ClinicalTrials.gov, NCT03855215. FINDINGS 48 commune health centres were enrolled and randomly assigned, 24 to the intervention group (n=18 621 patients) and 24 to the control group (n=21 235). 17 345 (93·1%) patients in the intervention group were prescribed antibiotics, compared with 20 860 (98·2%) in the control group (adjusted relative risk 0·83 [95% CI 0·66-0·93]). Only 2606 (14%) of 18 621 patients in the intervention group underwent CRP testing and were included in the per-protocol analysis. When analyses were restricted to this population, larger reductions in prescribing were noted in the intervention group compared with the control group (adjusted relative risk 0·64 [95% CI 0·60-0·70]). Time to resolution of symptoms (hazard ratio 0·70 [95% CI 0·39-1·27]) and frequency of hospitalisation (nine in the intervention group vs 17 in the control group; adjusted relative risk 0·52 [95% CI 0·23-1·17]) did not differ between groups. INTERPRETATION Use of point-of-care CRP testing efficaciously reduced prescription of antibiotics in patients with non-severe acute respiratory infections in primary health care in Viet Nam without compromising patient recovery. The low uptake of CRP testing suggests that barriers to implementation and compliance need to be addressed before scale-up of the intervention. FUNDING Australian Government, UK Government, and the Foundation for Innovative New Diagnostics.

Journal article

S. Calarco
B. Fernandez-Carballo
T. Keller
S. Weber
M. Jakobi
P. Marsall
N. Schneiderhan-Marra
Sabine Dittrich

Analytical performance of 17 commercially available point-of-care tests for CRP to support patient management at lower levels of the health system.

In: PLoS One vol. 18 pg. e0267516

20.01.2023 (2023)

DOI: 10.1371/journal.pone.0267516

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Accurate and precise point-of-care (POC) testing for C-reactive protein (CRP) can help support healthcare providers in the clinical management of patients. Here, we compared the analytical performance of 17 commercially available POC CRP tests to enable more decentralized use of the tool. The following CRP tests were evaluated. Eight quantitative tests: QuikRead go (Aidian), INCLIX (Sugentech), Spinit (Biosurfit), LS4000 (Lansionbio), GS 1200 (Gensure Biotech), Standard F200 (SD Biosensor), Epithod 616 (DxGen), IFP-3000 (Xincheng Biological); and nine semi-quantitative tests: Actim CRP (ACTIM), NADAL Dipstick (nal von minden), NADAL cassette (nal von minden), ALLTEST Dipstick (Hangzhou Alltest Biotech), ALLTEST Cassette cut-off 10-40-80 (Hangzhou Alltest Biotech), ALLTEST Cassette cut-off 10-30 (Hangzhou Alltest Biotech), Biotest (Hangzhou Biotest Biotech), BTNX Quad Line (BTNX), BTNX Tri Line (BTNX). Stored samples (n = 660) had previously been tested for CRP using Cobas 8000 Modular analyzer (Roche Diagnostics International AG, Rotkreuz, Switzerland (reference standards). CRP values represented the clinically relevant range (10-100 mg/L) and were grouped into four categories (<10 mg/L, 10-40 mg/L or 10-30 mg/L, 40-80 mg/L or 30-80 mg/L, and > 80mg/L) for majority of the semi-quantitative tests. Among the eight quantitative POC tests evaluated, QuikRead go and Spinit exhibited better agreement with the reference method, showing slopes of 0.963 and 0.921, respectively. Semi-quantitative tests with the four categories showed a poor percentage agreement for the intermediate categories and higher percentage agreement for the lower and upper limit categories. Analytical performance varied considerably for the semi-quantitative tests, especially among the different categories of CRP values. Our findings suggest that quantitative tests might represent the best choice for a variety of use cases, as they can be used across a broad range of CRP categories.

Journal article

T. Shimelis
A. Mulu
M. Mengesha
A. Alemu
A. Mihret
B. Tadesse
A. Bartlett
F. Belay
G. Schierhout
Sabine Dittrich
et al.

Detection of dengue virus infection in children presenting with fever in Hawassa, southern Ethiopia.

In: Scientific Reports (Nature Publishing Group) vol. 13 pg. 7997

17.05.2023 (2023)

DOI: 10.1038/s41598-023-35143-2

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Dengue fever is a mosquito-borne viral infection, with rising incidence globally. Eastern Ethiopia has had dengue fever outbreaks in recent years. However, the extent to which the infection contributes to hospital presentation among children with fever in southern Ethiopia is unknown. We examined 407 stored plasma samples collected to investigate the aetiology of fever in children aged at least 2 months and under 13 years presenting to the outpatient of the largest tertiary hospital in southern Ethiopia. We analyzed samples for dengue virus non-structural 1 antigen using enzyme-linked immunosorbent assay. The median (interquartile range) age of the 407 children examined was 20 (10-48) months, and 166 (40.8%) of the children were females. Of 407 samples analyzed, 9 (2.2%) were positive for dengue virus non-structural 1 antigen, of whom 2 were initially treated with antimalarial drugs despite having negative malaria microscopy, and 1 of the 8 patients had a persistent fever at the seventh day of follow-up time. The presence of active dengue virus infection in the study area highlights the need for studies at the community level as well as the integration of dengue diagnostics into fever-management strategies. Further research to characterize circulating strains is warranted.

Journal article

J. Sapkota
T. Roberts
B. Basnyat
S. Baker
L. Hampton
Sabine Dittrich

Diagnostics for Typhoid Fever: Current Perspectives and Future Outlooks for Product Development and Access.

In: Open Forum Infectious Diseases vol. 10 pg. S17-S20

02.06.2023 (2023)

DOI: 10.1093/ofid/ofad120

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Typhoid is an enteric disease caused by Salmonella Typhi. Like many febrile illnesses, typhoid presents with nonspecific symptoms. In routine healthcare settings in low- and middle-income countries, typhoid fever is suspected and treated empirically. Though many diagnostic tests are available for typhoid diagnosis, there are currently no diagnostic tests that meet ideal requirements for sensitivity, specificity, speed, and cost-effectiveness. With introduction of typhoid conjugate vaccine, it is essential to explore the current and future typhoid approach in the context of use case and access to ensure their utilization for disease control.

Journal article

J. Nkeramahame
P. Olliaro
P. Horgan
Sabine Dittrich

Perspective on the Integration of Diagnostic Algorithms for Fever Management.

In: Clinical Infectious Diseases (an official publication of the Infectious Diseases Society of America) vol. 77 pg. S211-S213

(2023)

DOI: 10.1093/cid/ciad325

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The AMR Diagnostics Use Accelerator Program was established to address antimicrobial resistance. Here, we bring into broad perspective the findings and missed opportunities of the first phase of the program and look toward the second phase.

Journal article

P. Olliaro
J. Nkeramahame
O. Salami
C. Moore
P. Horgan
R. Baiden
V. Kukula
A. Adjei
J. Kapisi
H. Hopkins
D. Kaawa-Mafigiri
D. Ekusai-Sebatta
E. Rutebemberwa
F. Kitutu
H. Tinto
F. Kiemde
A. Compaoré
D. Valia
Sabine Dittrich

Advancing Access to Diagnostic Tools Essential for Universal Health Coverage and Antimicrobial Resistance Prevention: An Overview of Trials in Sub-Saharan Africa.

In: Clinical Infectious Diseases (an official publication of the Infectious Diseases Society of America) vol. 77 pg. S125-S133

(2023)

DOI: 10.1093/cid/ciad326

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We introduce the Antimicrobial Resistance Diagnostic Use Accelerator program, and the articles in this Supplement, which cover the program in 3 sub-Saharan Africa countries.

Journal article

J. Kapisi
A. Sserwanga
F. Kitutu
E. Rutebemberwa
P. Awor
S. Weber
T. Keller
D. Kaawa-Mafigiri
D. Ekusai-Sebatta
P. Horgan
Sabine Dittrich
et al.

Impact of the Introduction of a Package of Diagnostic Tools, Diagnostic Algorithm, and Training and Communication on Outpatient Acute Fever Case Management at 3 Diverse Sites in Uganda: Results of a Randomized Controlled Trial.

In: Clinical Infectious Diseases (an official publication of the Infectious Diseases Society of America) vol. 77 pg. S156-S170

(2023)

DOI: 10.1093/cid/ciad341

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BACKGROUND Increasing trends of antimicrobial resistance are observed around the world, driven in part by excessive use of antimicrobials. Limited access to diagnostics, particularly in low- and middle-income countries, contributes to diagnostic uncertainty, which may promote unnecessary antibiotic use. We investigated whether introducing a package of diagnostic tools, clinical algorithm, and training-and-communication messages could safely reduce antibiotic prescribing compared with current standard-of-care for febrile patients presenting to outpatient clinics in Uganda. METHODS This was an open-label, multicenter, 2-arm randomized controlled trial conducted at 3 public health facilities (Aduku, Nagongera, and Kihihi health center IVs) comparing the proportions of antibiotic prescriptions and clinical outcomes for febrile outpatients aged ≥1 year. The intervention arm included a package of point-of-care tests, a diagnostic and treatment algorithm, and training-and-communication messages. Standard-of-care was provided to patients in the control arm. RESULTS A total of 2400 patients were enrolled, with 49.5% in the intervention arm. Overall, there was no significant difference in antibiotic prescriptions between the study arms (relative risk [RR]: 1.03; 95% CI: .96-1.11). In the intervention arm, patients with positive malaria test results (313/500 [62.6%] vs 170/473 [35.9%]) had a higher RR of being prescribed antibiotics (1.74; 1.52-2.00), while those with negative malaria results (348/688 [50.6%] vs 376/508 [74.0%]) had a lower RR (.68; .63-.75). There was no significant difference in clinical outcomes. CONCLUSIONS This study found that a diagnostic intervention for management of febrile outpatients did not achieve the desired impact on antibiotic prescribing at 3 diverse and representative health facility sites in Uganda.

Journal article

A. Alabi
F. Musangomunei
F. Lotola-Mougeni
J. Bie-Ondo
K. Murphy
P. Essone
A. Kabwende
S. Mahmoudou
A. Macé
V. Harris
M. Ramharter
M. Grobusch
M. Yazdanbakhsh
B. Fernandez-Carballo
C. Escadafal
P. Kremsner
Sabine Dittrich
S. Agnandji

Performance evaluation of a combination Plasmodium dual-antigen CRP rapid diagnostic test in Lambaréné, Gabon.

In: Infection

23.08.2024 (2024)

DOI: 10.1007/s15010-024-02366-y

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PURPOSE The consequent use of malaria rapid diagnostic tests (RDTs) preceding a treatment decision has improved the global management of malaria. A combination RDT, including an inflammation marker to potentially guide antibiotic prescription, could improve the management of acute febrile illness (AFI). METHODS We performed a prospective, cross-sectional study in Gabon evaluating the STANDARD Malaria/CRP DUO (S-DUO) RDT. Participants aged 2 to 17 years with fever at presentation and/or a history of fever < 7 days were enrolled. Expert microscopy, SD Bioline Malaria Ag P.f/Pan test for malaria detection, and NycoCard CRP device for CRP were used as comparators. AFI cases were classified on a spectrum encompassing bacterial vs. non-bacterial infection. RESULTS 415 participants with AFI were enrolled. S-DUO RDT sensitivity and specificity for malaria detection vs. microscopy were 99·1% (95·2-100%) and 72·7% (64·3-80·1%); and for CRP detection (20 mg/L and above) 86·9% (80-92%) and 87% (79·2-92·7%), respectively. The difference in CRP levels between bacterial infection (mean = 41·2 mg/L) and other causes of fever, measured from our study population using the Nycocard device, was statistically significant (p < 0·01); CRP precision-recall AUC to distinguish bacterial infection class vs. non-bacterial classifications was 0·79. CONCLUSION S-DUO RDT is suitable for malaria detection in moderate-to-high malaria transmission settings such as in Lambaréné; however, a CRP band detection limit > 40 mg/L is more adequate for indication of antibiotic prescription for AFI cases in Gabon.

Journal article

P. van Dorst
S. van der Pol
P. Olliaro
Sabine Dittrich
J. Nkeramahame
M. Postma
C. Boersma
A. van Asselt

Cost-Effectiveness of Test-and-Treat Strategies to Reduce the Antibiotic Prescription Rate for Acute Febrile Illness in Primary Healthcare Clinics in Africa.

In: Applied Health Economics and Health Policy vol. 22 pg. 701-715

25.05.2024 (2024)

DOI: 10.1007/s40258-024-00889-x

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BACKGROUND Inappropriate antibiotic use increases selective pressure, contributing to antimicrobial resistance. Point-of-care rapid diagnostic tests (RDTs) would be instrumental to better target antibiotic prescriptions, but widespread implementation of diagnostics for improved management of febrile illnesses is limited. OBJECTIVE Our study aims to contribute to evidence-based guidance to inform policymakers on investment decisions regarding interventions that foster more appropriate antibiotic prescriptions, as well as to address the evidence gap on the potential clinical and economic impact of RDTs on antibiotic prescription. METHODS A country-based cost-effectiveness model was developed for Burkina Faso, Ghana and Uganda. The decision tree model simulated seven test strategies for patients with febrile illness to assess the effect of different RDT combinations on antibiotic prescription rate (APR), costs and clinical outcomes. The incremental cost-effectiveness ratio (ICER) was expressed as the incremental cost per percentage point (ppt) reduction in APR. RESULTS For Burkina Faso and Uganda, testing all patients with a malaria RDT was dominant compared to standard-of-care (SoC) (which included malaria testing). Expanding the test panel with a C-reactive protein (CRP) test resulted in an ICER of $ 0.03 and $ 0.08 per ppt reduction in APR for Burkina Faso and Uganda, respectively. For Ghana, the pairwise comparison with SoC-including malaria and complete blood count testing-indicates that both testing with malaria RDT only and malaria RDT + CRP are dominant. CONCLUSION The use of RDTs for patients with febrile illness could effectively reduce APR at minimal additional costs, provided diagnostic algorithms are adhered to. Complementing SoC with CRP testing may increase clinicians' confidence in prescribing decisions and is a favourable strategy.

Journal article

R. Hasan
Z. Azizullah
H. Shams
Sabine Dittrich
J. Andrews
R. Charles
J. Esfandiari
D. Gunasekera
K. Tetteh
J. Sapkota

Evaluation of a point-of-care multiplex immunochromatographic assay for the diagnosis of typhoid: results from a retrospective diagnostic accuracy study.

In: Journal of Clinical Microbiology vol. 62 pg. e0042824

20.09.2024 (2024)

DOI: 10.1128/jcm.00428-24

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UNLABELLED There is a clear medical need for an accurate diagnostic test for typhoid that can be performed at point of care. Two antigens (lipopolysaccharide [LPS] and hemolysin E [HlyE]) have recently been identified that can distinguish typhoid from other bacterial infections. Here, we present the results of a diagnostic accuracy study of the Dual Path Platform (DPP) Typhoid assay (Chembio) that detects IgA to both LPS and HlyE using blood culture as the reference standard. This was a retrospective, observational, laboratory study conducted at the Aga Khan University research laboratory, Pakistan, to evaluate the sensitivity and specificity of the DPP Typhoid assay, using archived frozen serum samples collected during a previous typhoid diagnostic accuracy study (NCT04801602). The sensitivity, specificity, and accuracy (area under the receptor operating characteristics curve [AUC]) were then assessed using the manufacturer's and Youden's optimal thresholds. In total, 385 samples were included in the analysis. Using the manufacturer's thresholds, the sensitivity, specificity, and AUC were 97.8% (95% confidence interval [CI] 94.6-99.2), 65.3% (95% CI 58.5-71.6), and 81.5% (95% CI 75.5-85.3), respectively. At Youden's optimal threshold, the overall sensitivity of the DPP Typhoid assay was 89.7% and the specificity was 82.2%. In latent class modeling compared with other nine rapid diagnostic tests evaluated from the same cohort sample, the DPP Typhoid assay demonstrated the highest balanced accuracy (89.2%). The DPP Typhoid assay demonstrated a high diagnostic accuracy for typhoid fever. However, further adjustment to new thresholds is recommended to enhance its performance capabilities. IMPORTANCE Currently available diagnostic tests for typhoid have several limitations, including low sensitivity and specificity. Dual Path Platform Typhoid assay is a multiplex rapid test that detects IgA antibodies to lipopolysaccharide and hemolysin E antigen. It is considered to have high sensitivity and specificity, and its results were found to be highly correlated with ELISA results. However, very few studies have been conducted to evaluate this test and limited information about the accuracy of this test is present. Hence, this study evaluated the new typhoid test.

Journal article

S. Dhawan
Sabine Dittrich
S. Arafah
S. Ongarello
A. Mace
S. Panapruksachat
et al.

Diagnostic accuracy of DPP Fever Panel II Asia tests for tropical fever diagnosis.

In: PLoS Neglected Tropical Diseases vol. 18 pg. e0012077

10.04.2024 (2024)

DOI: 10.1371/journal.pntd.0012077

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BACKGROUND Fever is the most frequent symptom in patients seeking care in South and Southeast Asia. The introduction of rapid diagnostic tests (RDTs) for malaria continues to drive patient management and care. Malaria-negative cases are commonly treated with antibiotics without confirmation of bacteraemia. Conventional laboratory tests for differential diagnosis require skilled staff and appropriate access to healthcare facilities. In addition, introducing single-disease RDTs instead of conventional laboratory tests remains costly. To overcome some of the delivery challenges of multiple separate tests, a multiplexed RDT with the capacity to diagnose a diverse range of tropical fevers would be a cost-effective solution. In this study, a multiplex lateral flow immunoassay (DPP Fever Panel II Assay) that can detect serum immunoglobulin M (IgM) and specific microbial antigens of common fever agents in Asia (Orientia tsutsugamushi, Rickettsia typhi, Leptospira spp., Burkholderia pseudomallei, Dengue virus, Chikungunya virus, and Zika virus), was evaluated. METHODOLOGY/PRINCIPAL FINDINGS Whole blood (WB) and serum samples from 300 patients with undefined febrile illness (UFI) recruited in Vientiane, Laos PDR were tested using the DPP Fever Panel II, which consists of an Antibody panel and Antigen panel. To compare reader performance, results were recorded using two DPP readers, DPP Micro Reader (Micro Reader 1) and DPP Micro Reader Next Generation (Micro Reader 2). WB and serum samples were run on the same fever panel and read on both micro readers in order to compare results. ROC analysis and equal variance analysis were performed to inform the diagnostic validity of the test compared against the respective reference standards of each fever agent (S1 Table). Overall better AUC values were observed in whole blood results. No significant difference in AUC performance was observed when comparing whole blood and serum sample testing, except for when testing for R. typhi IgM (p = 0.04), Leptospira IgM (p = 0.02), and Dengue IgG (p = 0.03). Linear regression depicted R2 values had ~70% agreement across WB and serum samples, except when testing for leptospirosis and Zika, where the R2 values were 0.37 and 0.47, respectively. No significant difference was observed between the performance of Micro Reader 1 and Micro Reader 2, except when testing for the following pathogens: Zika IgM, Zika IgG, and B pseudomallei CPS Ag. CONCLUSIONS/SIGNIFICANCE These results demonstrate that the diagnostic accuracy of the DPP Fever Panel II is comparable to that of commonly used RDTs. The optimal cut-off would depend on the use of the test and the desired sensitivity and specificity. Further studies are required to authenticate the use of these cut-offs in other endemic regions. This multiplex RDT offers diagnostic benefits in areas with limited access to healthcare and has the potential to improve field testing capacities. This could improve tropical fever management and reduce the public health burden in endemic low-resource areas.

Journal article

F. Kiemde
J. Nkeramahame
A. Ibarz
Sabine Dittrich
P. Olliaro
D. Valia
et al.

Impact of a package of point-of-care diagnostic tests, a clinical diagnostic algorithm and adherence training on antibiotic prescriptions for the management of non-severe acute febrile illness in primary health facilities during the COVID-19 pandemic in Burkina Faso.

In: BMC Infectious Diseases vol. 24 pg. 870

27.08.2024 (2024)

DOI: 10.1186/s12879-024-09787-y

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OBJECTIVE To assess the impact of an intervention package on the prescription of antibiotic and subsequently the rate of clinical recovery for non-severe acute febrile illnesses at primary health centers. METHODS Patients over 6 months of age presenting to primary health care centres with fever or history of fever within the past 7 days were randomized to receive either the intervention package constituted of point-of-care tests including COVID-19 antigen tests, a diagnostic algorithm and training and communication packages, or the standard practice. The primary outcomes were antibiotic prescriptions at Day 0 (D0) and the clinical recovery at Day 7 (D7). Secondary outcomes were non-adherence of participants and parents/caregivers to prescriptions, health workers' non-adherence to the algorithm, and the safety of the intervention. RESULTS A total of 1098 patients were enrolled. 551 (50.2%) were randomized to receive the intervention versus 547 (49.8%) received standard care. 1054 (96.0%) completed follow-up and all of them recovered at D7 in both arms. The proportion of patients with antibiotic prescriptions at D0 were 33.2% (183/551) in the intervention arm versus 58.1% (318/547) under standard care, risk difference (RD) -24.9 (95% CI -30.6 to -19.2, p < 0.001), corresponding to one more antibiotic saved every four (95% CI: 3 to 5) consultations. This reduction was also statistically significant in children from 6 to 59 months (RD -34.5; 95% CI -41.7 to -27.3; p < 0.001), patients over 18 years (RD -35.9; 95%CI -58.5 to -13.4; p = 0.002), patients with negative malaria test (RD -46.9; 95% CI -53.9 to -39.8; p < 0.001), those with a respiratory diagnosis (RD -48.9; 95% CI -56.9 to -41.0, p < 0.001) and those not vaccinated against COVID-19 (-24.8% 95%CI -30.7 to -18.9, p-value: <0.001). A significant reduction in non-adherence to prescription by patients was reported (RD -7.1; 95% CI -10.9 to -3.3; p < 0.001). CONCLUSION The intervention was associated with significant reductions of antibiotic prescriptions and non-adherence, chiefly among patients with non-malaria fever, those with respiratory symptoms and children below 5 years of age. The addition of COVID-19 testing did not have a major impact on antibiotic use at primary health centers. TRIAL REGISTRATION Clinitrial.gov; NCT04081051 registered on 06/09/2019.

UnpublishedWork

G. Gwaza
A. Plüddemann
M. McCall
Sabine Dittrich
C. Heneghan

Criteria for designing integrated diagnosis interventions in low resource settings at the primary care level: A Delphi consensus study. [Preprint; under review].

2024 (2024)

DOI: 10.21203/rs.3.rs-4450006/v1

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Background: Integrated diagnosis is crucial for addressing health challenges, particularly in managing comorbidities and chronic conditions. Technological advancements allow for rapid, simultaneous testing and diagnosis of multiple diseases. Integrated diagnosis interventions vary in purpose, models, diseases targeted, populations served, scale, and outcomes, which complicates identifying effective strategies. An effective integrated diagnosis approach can lead to early detection of critical and chronic conditions, improve patient experiences, and ultimately improve disease surveillance. This study aimed to establish core criteria for designing same-day integrated diagnosis interventions in primary care settings to enhance patient experiences and health outcomes in low- and middle-income countries (LMICs). Methods A two-round Delphi process engaged an international panel of fifty-five experts from diverse professions to establish consensus on core criteria for effective integrated diagnosis interventions. Predetermined consensus thresholds were set at 70% for critical to include. Results A total of 55 experts participated in the first round. Participants represented various geographical regions, including Africa (n = 33), Europe (n = 17), Asia (n = 2), and the Americas (n = 2), and could be categorized into implementers (n = 36), policymakers (n = 7), and academics (n = 12). At the end of Round 1, fourteen of the thirty-three criteria reached a consensus as being critical to include, and nine criteria were removed. In Round 2, a total of 48 out of 55 experts participated and twelve criteria were considered. Four criteria reached a consensus as being critical to include. Through the two rounds of surveys, experts reached a consensus on 18 criteria. Conclusion The study provides key criteria for prioritizing and developing integrated diagnosis interventions in primary care, in low-resource settings, particularly in Africa. The guidance is invaluable for policymakers, funders, implementers, and manufacturers. The primary goal of integrated diagnosis is to enhance patient experiences and health outcomes. It is essential to consider all critical success factors during intervention design. The study emphasizes taking a holistic approach that addresses the full spectrum of patient needs and integrates with other aspects of the healthcare system. These criteria may evolve as our understanding of integrated diagnosis advances.

Journal article

M. Hamid
A. Mohamed
F. Mohammed
A. Elaagip
S. Mustafa
T. Elfaki
W. Jebreel
M. Albsheer
Sabine Dittrich
E. Owusu
S. Yerlikaya

Diagnostic accuracy of an automated microscope solution (miLab™) in detecting malaria parasites in symptomatic patients at point-of-care in Sudan: a case-control study.

In: Malaria Journal vol. 23 pg. 200

28.06.2024 (2024)

DOI: 10.1186/s12936-024-05029-3

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BACKGROUND Microscopic detection of malaria parasites is labour-intensive, time-consuming, and expertise-demanding. Moreover, the slide interpretation is highly dependent on the staining technique and the technician's expertise. Therefore, there is a growing interest in next-generation, fully- or semi-integrated microscopes that can improve slide preparation and examination. This study aimed to evaluate the clinical performance of miLab™ (Noul Inc., Republic of Korea), a fully-integrated automated microscopy device for the detection of malaria parasites in symptomatic patients at point-of-care in Sudan. METHODS This was a prospective, case-control diagnostic accuracy study conducted in primary health care facilities in rural Khartoum, Sudan in 2020. According to the outcomes of routine on-site microscopy testing, 100 malaria-positive and 90 malaria-negative patients who presented at the health facility and were 5 years of age or older were enrolled consecutively. All consenting patients underwent miLab™ testing and received a negative or suspected result. For the primary analysis, the suspected results were regarded as positive (automated mode). For the secondary analysis, the operator reviewed the suspected results and categorized them as either negative or positive (corrected mode). Nested polymerase chain reaction (PCR) was used as the reference standard, and expert light microscopy as the comparator. RESULTS Out of the 190 patients, malaria diagnosis was confirmed by PCR in 112 and excluded in 78. The sensitivity of miLab™ was 91.1% (95% confidence interval [CI] 84.2-95.6%) and the specificity was 66.7% (95% Cl 55.1-67.7%) in the automated mode. The specificity increased to 96.2% (95% Cl 89.6-99.2%), with operator intervention in the corrected mode. Concordance of miLab with expert microscopy was substantial (kappa 0.65 [95% CI 0.54-0.76]) in the automated mode, but almost perfect (kappa 0.97 [95% CI 0.95-0.99]) in the corrected mode. A mean difference of 0.359 was found in the Bland-Altman analysis of the agreement between expert microscopy and miLab™ for quantifying parasite counts. CONCLUSION When used in a clinical context, miLab™ demonstrated high sensitivity but low specificity. Expert intervention was shown to be required to improve the device's specificity in its current version. miLab™ in the corrected mode performed similar to expert microscopy. Before clinical application, more refinement is needed to ensure full workflow automation and eliminate human intervention. Trial registration ClinicalTrials.gov: NCT04558515.

Journal article

M. Burtnick
D. Dance
M. Vongsouvath
P. Newton
Sabine Dittrich
et al.

Identification of Burkholderia cepacia strains that express a Burkholderia pseudomallei-like capsular polysaccharide.

In: Microbiology Spectrum vol. 12 pg. e0332123

01.02.2024 (2024)

DOI: 10.1128/spectrum.03321-23

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Burkholderia pseudomallei and Burkholderia cepacia are Gram-negative, soil-dwelling bacteria that are found in a wide variety of environmental niches. While B. pseudomallei is the causative agent of melioidosis in humans and animals, members of the B. cepacia complex typically only cause disease in immunocompromised hosts. In this study, we report the identification of B. cepacia strains isolated from either patients or soil in Laos and Thailand that express a B. pseudomallei-like 6-deoxyheptan capsular polysaccharide (CPS). These B. cepacia strains were initially identified based on their positive reactivity in a latex agglutination assay that uses the CPS-specific monoclonal antibody (mAb) 4B11. Mass spectrometry and recA sequencing confirmed the identity of these isolates as B. cepacia (formerly genomovar I). Total carbohydrates extracted from B. cepacia cell pellets reacted with B. pseudomallei CPS-specific mAbs MCA147, 3C5, and 4C4, but did not react with the B. pseudomallei lipopolysaccharide-specific mAb Pp-PS-W. Whole genome sequencing of the B. cepacia isolates revealed the presence of genes demonstrating significant homology to those comprising the B. pseudomallei CPS biosynthetic gene cluster. Collectively, our results provide compelling evidence that B. cepacia strains expressing the same CPS as B. pseudomallei co-exist in the environment alongside B. pseudomallei. Since CPS is a target that is often used for presumptive identification of B. pseudomallei, it is possible that the occurrence of these unique B. cepacia strains may complicate the diagnosis of melioidosis.IMPORTANCEBurkholderia pseudomallei, the etiologic agent of melioidosis, is an important cause of morbidity and mortality in tropical and subtropical regions worldwide. The 6-deoxyheptan capsular polysaccharide (CPS) expressed by this bacterial pathogen is a promising target antigen that is useful for rapidly diagnosing melioidosis. Using assays incorporating CPS-specific monoclonal antibodies, we identified both clinical and environmental isolates of Burkholderia cepacia that express the same CPS antigen as B. pseudomallei. Because of this, it is important that staff working in melioidosis-endemic areas are aware that these strains co-exist in the same niches as B. pseudomallei and do not solely rely on CPS-based assays such as latex-agglutination, AMD Plus Rapid Tests, or immunofluorescence tests for the definitive identification of B. pseudomallei isolates.

Journal article

L. Shrestha
B. Adhikari
M. Bajracharya
N. Aryal
A. Rajbhandari
S. Shrestha
R. Pariyar
R. Maharjan
M. Otieno
M. Watson
J. Sapkota
Sabine Dittrich
K. Tetteh
D. Das

Triage processes in primary, secondary, and tertiary health care facilities in the Kathmandu Valley, Nepal: a mixed-methods study.

In: BMC Emergency Medicine vol. 24 pg. 222

25.11.2024 (2024)

DOI: 10.1186/s12873-024-01139-y

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BACKGROUND In healthcare facilities, an efficient triage system is critical to optimize patient care. The main objective of this study was to explore the triage processes and practices in three different tiers of healthcare facilities in the Kathmandu Valley, Nepal. METHODS A mixed-methods approach in this study comprised observations and interviews in ten healthcare settings across primary care centers (PHC; n = 6), secondary care centers (SHC; n = 3), and tertiary care hospital (n = 1). Data were collected from June to November 2023. Semi-structured interviews were conducted among patients (n = 30) including survey questionnaires among 144 healthcare workers (HCWs) focused on triage. The qualitative data were analyzed using Interpretative Phenomenological Analysis and quantitative data were analyzed to explore the median score on the consistent practice of triage based on the Likert scale. RESULTS PHCs had designated space for triage with less equipped emergency services and outpatient departments (OPDs) and received severely ill patients rarely. Although prioritizing critical patients and prompt care was part of the services, there was a lack of triage protocols with more than half of the HCWs (56.3%; 36/64) from the tertiary hospital reporting the availability of triage guidelines compared to SHCs (28.1%; 9/32) and PHCs (6.3%; 3/48). The majority of HCWs from the tertiary level recognized triage's effectiveness in reducing time lag, and prioritizing patients. Tertiary level had the consistent use of triage (94%; 60/64) compared to only around two-thirds in SHCs (66%; 19/29) and PHCs (62%; 28/45). Patients often attended PHC services for routine check-ups and were motivated by health insurance, affordability, free medicines, referral cards, and proximity. In the SHC, there was a well-equipped emergency department (ED) with specific guidelines, but its use was infrequent. Patients were unaware of the triage process and its utility. In all settings, while most HCWs had a basic knowledge of triage, some were not confident due to limited exposure to the triage process and training. Many HCWs reported the need for triage-related training and its' consistent implementation. CONCLUSIONS Consistent utilization of triage protocols, coupled with improved infrastructure, resource allocation, and training for healthcare workers is critical for the optimization of triage processes in healthcare settings in the Kathmandu Valley, Nepal.

Journal article

S. Bajaj
S. Chen
R. Creswell
R. Naidoo
J. Tsui
O. Kolade
et int.
EY-Oxford Health Analytics Consortium
R. Aguas
M. Amswych
B. Andersen-Waine
Sabine Dittrich
et al.

COVID-19 testing and reporting behaviours in England across different sociodemographic groups: a population-based study using testing data and data from community prevalence surveillance surveys.

In: The Lancet. Digital Health vol. 6 pg. e778-e790

(2024)

DOI: 10.1016/S2589-7500(24)00169-9

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BACKGROUND Understanding underlying mechanisms of heterogeneity in test-seeking and reporting behaviour during an infectious disease outbreak can help to protect vulnerable populations and guide equity-driven interventions. The COVID-19 pandemic probably exerted different stresses on individuals in different sociodemographic groups and ensuring fair access to and usage of COVID-19 tests was a crucial element of England's testing programme. We aimed to investigate the relationship between sociodemographic factors and COVID-19 testing behaviours in England during the COVID-19 pandemic. METHODS We did a population-based study of COVID-19 testing behaviours with mass COVID-19 testing data for England and data from community prevalence surveillance surveys (REACT-1 and ONS-CIS) from Oct 1, 2020, to March 30, 2022. We used mass testing data for lateral flow device (LFD; data for approximately 290 million tests performed and reported) and PCR (data for approximately 107 million tests performed and returned from the laboratory) tests made available for the general public and provided by date and self-reported age and ethnicity at the lower tier local authority (LTLA) level. We also used publicly available data on mean population size estimates for individual LTLAs, and data on ethnic groups, age groups, and deprivation indices for LTLAs. We did not have access to REACT-1 or ONS-CIS prevalence data disaggregated by sex or gender. Using a mechanistic causal model to debias the PCR testing data, we obtained estimates of weekly SARS-CoV-2 prevalence by both self-reported ethnic groups and age groups for LTLAs in England. This approach to debiasing the PCR (or LFD) testing data also estimated a testing bias parameter defined as the odds of testing in infected versus not infected individuals, which would be close to zero if the likelihood of test seeking (or seeking and reporting) was the same regardless of infection status. With confirmatory PCR data, we estimated false positivity rates, sensitivity, specificity, and the rate of decline in detection probability subsequent to reporting a positive LFD for PCR tests by sociodemographic groups. We also estimated the daily incidence, allowing us to calculate the fraction of cases captured by the testing programme. FINDINGS From March, 2021 onwards, individuals in the most deprived regions reported approximately half as many LFD tests per capita as individuals in the least deprived areas (median ratio 0·50 [IQR 0·44-0·54]). During the period October, 2020, to June, 2021, PCR testing patterns showed the opposite trend, with individuals in the most deprived areas performing almost double the number of PCR tests per capita than those in the least deprived areas (1·8 [1·7-1·9]). Infection prevalences in Asian or Asian British individuals were considerably higher than those of other ethnic groups during the alpha (B.1.1.7) and omicron (B.1.1.529) BA.1 waves. Our estimates indicate that the England Pillar 2 COVID-19 testing programme detected 26-40% of all cases (including asymptomatic cases) over the study period with no consistent differences by deprivation levels or ethnic groups. Testing biases for PCR were generally higher than those for LFDs, in line with the general policy of symptomatic and asymptomatic use of these tests. Deprivation and age were associated with testing biases on average; however, the uncertainty intervals overlapped across deprivation levels, although the age-specific patterns were more distinct. We also found that ethnic minorities and older individuals were less likely to use confirmatory PCR tests through most of the pandemic and that delays in reporting a positive LFD test were possibly longer in populations self-reporting as "Black; African; Black British or Caribbean". INTERPRETATION Differences in testing behaviours across sociodemographic groups might be reflective of the higher costs of self-isolation to vulnerable populations, differences in test accessibility, differences in digital literacy, and differing perceptions about the utility of tests and risks posed by infection. This study shows how mass testing data can be used in conjunction with surveillance surveys to identify gaps in the uptake of public health interventions both at fine-scale levels and across sociodemographic groups. It provides a framework for monitoring local interventions and yields valuable lessons for policy makers in ensuring an equitable response to future pandemics. FUNDING UK Health Security Agency.

Journal article

T. Weitzel
Sabine Dittrich
F. Mockenhaupt
A. Lindner

Serological diagnosis of strongyloidiasis: An evaluation of three commercial assays.

In: PLoS Neglected Tropical Diseases vol. 18 pg. e0012319

05.07.2024 (2024)

DOI: 10.1371/journal.pntd.0012319

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BACKGROUND Strongyloidiasis is caused by a neglected nematode, manifesting as chronic intestinal infection with potentially severe manifestations. The disease is an emerging problem in non-endemic countries affecting travelers and migrants. Diagnosis of strongyloidiasis is hampered by the lack of standardization and absence of a gold standard. Since adequate direct methods to detect the motile larvae in stool samples are not widely available, other techniques such as serology have been developed. METHODS We evaluated three commercial ELISA kits (DRG Instruments, IVD Research, and Bordier Affinity Products) to detect IgG antibodies against Strongyloides stercoralis assays utilizing serum samples from travelers with microscopically confirmed strongyloidiasis (n = 50) and other imported helminthic infections (n = 159) as well as healthy controls (n = 50). RESULTS The DRG, IVD, and Bordier assays showed sensitivities of 58.0%, 64.0%, and 56.0%, respectively. Specificity values were 96.0%, 96.0%, and 92.0% in healthy controls, and 67.3%, 62.9%, and 76.7% in cases with other helminth infections, respectively. Cross-reactions were mostly observed in cases with other nematodes (37.5%, 42.5%, and 20.0%, respectively), but also in trematode (33.3%, 38.1%, and 19.0%, respectively) and in cestode infections (25.0%, 30.0%, and 32.5%, respectively). CONCLUSION The study demonstrates the diagnostic limitations of serological assays to detect or exclude cases of strongyloidiasis in returning travelers, who frequently present with recent or acute infections.

projects

Use of diagnostic to support patient management and public health decision making (multiple projects)

core competencies

Pubic Health Microbiology
Tropical fever diagnostic (malaria, zoonoitic bacterial pathogens, typhoid, vector borne diseases)
Epidemiolgy of bacterial zoonotic pathogens
Technology development for global public health (from TPP development to access)
Global Health Diagnostic

Forschungs- und Lehrgebiete

Prof Dr Sabine Dittrich is a public health microbiologist passionate about diagnostic and how we can best utilize different tools and interventions to support patient management and public health decision making. Her research and teaching predominantly focuses on the development and deployment of technical solutions (from digital guidelines to improved diagnostic tools) in the global public health context to improve patient based and public health decision making. In addition, her passion are zoonotic and vector-borne diseases that cause febrile illnesses (malaria, scrub typhus, typhoid) and her work has focused on the epidemiology and diagnostic development pipeline of those. Since joining DIT in Pfarrkirchen she continues to support international organizations like the World Health Organization as part of expert groups (typhoid and meningitis diagnostic) and applied research that helps inform policy decision making. Her research group is made up of PhD and MSc students based in the UK, Switzerland and Germany all exploring optimized ways and tools to improve the utilization of diagnostic as a key tool to improve management and decision making. The goals of all her research projects are to optimize the care that care providers can deliver with a view towards reducing the threat from AMR and future pandemics.

Since joining the faculty of the DIT her goal is to continue to establish the MSc in Global Public Health to enable current and prospective students to get a balanced education as well as a network of contacts that will make them the future leaders in global public health.

Vita

Prof Dr Dittrich holds an engineering degree in Biotechnolgy (Dipl. Ing) from the University of Applied Science Weihenstephan (Germany), a PhD in Biomolecular Science from the University of Manchester (UK) and subsequently completed a fellowship with the European CDC on public health microbiology (EPIET/EUPHEM) and outbreak response, based at the Dutch National Institute of Public Health with Prof Marion Koopmans. She has been supporting the development of appropriate diagnostic tools from the local level at the Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit oft the University of Oxford in the Lao PDR, to the global level in Geneva at FIND, the global alliance for diagnostic. She still holds a honorary affiliation research fellowship (https://www.tropicalmedicine.ox.ac.uk/team/sabine-dittrich) with the University of Oxford (Nuffield Deperatment of Medicine) and supports research and teaching at the University of Oxford (UK).