Conference Material > Slide Presentation
Wilson JM, Chowdhury F, Hassan S, Harriss E, Alves F, et al.
MSF Scientific Day International 2024. 16 May 2024; DOI:10.57740/R7W2C8dil
Conference Material > Abstract
Wilson JM, Chowdhury F, Hassan S, Harriss E, Alves F, et al.
MSF Scientific Day International 2024. 16 May 2024; DOI:10.57740/9SthRqK
INTRODUCTION
Visceral leishmaniasis (VL) is a neglected tropical disease prevalent in populations affected by poverty, war, and famine. Without effective treatment, death is the norm. Prognostic models, as used by Médecins Sans Frontières (MSF) in East Africa, are used to identify high-risk patients for intensive management, including hospital admission, treatment with liposomal amphotericin B, broad-spectrum antibiotics, and blood transfusions. We provide a comprehensive and objective resource for policymakers, healthcare providers, and investigators, by identifying, summarising, and appraising the available prognostic models predicting clinical outcomes in patients with VL.
METHODS
We performed a systematic review of published studies that developed, validated, or updated models predicting future clinical outcomes in patients diagnosed with VL. We searched five bibliographic databases (Ovid Embase, Ovid MEDLINE, Web of Science Core Collection, SciELO, and LILACS) on March 1, 2023, for papers published from database inception, with no language restriction. Screening, data extraction, and risk of bias assessment were performed in duplicate. This study is registered with PROSPERO (ID: CRD42023417226).
RESULTS
Eight prognostic model studies, published between 2003 and 2021, were identified describing 12 prognostic model developments and 19 external validations. Nine models were developed in Brazil and three in East Africa by MSF investigators (two developed in South Sudan and one in Ethiopia). In-hospital mortality was the outcome for all but two Brazilian models, which predicted registry-reported mortality. Three models were developed exclusively in adolescents or children. Risk of bias was assessed as high for all model evaluations. Model overfitting due to small sample sizes, leading to optimistic model performance measures and exaggerated risk estimates, was identified for all but one model development. Only half of the presented risk scores were reproducible by following the authors’ methodology.
CONCLUSION
A poorly developed model can result in inaccurate risk estimation, potentially leading to harmful and inequitable decision making. With half of all risk scores incorrectly calculated, and a high risk of bias identified across all model evaluations, caution must be exercised when using these models to guide patient management. In the first systematic review of VL prognostic models, we show that no models predicted treatment failure and relapse, and despite South Asia representing the highest VL burden before 2010, no models were developed in this population. These represent important evidence gaps, which should be prioritised when developing new models. Using the Infectious Diseases Data Observatory repository of VL individual patient data from clinical trials, we are currently building a prognostic model for VL relapse in South Asia, which we hope to serve the ongoing elimination campaign.
Visceral leishmaniasis (VL) is a neglected tropical disease prevalent in populations affected by poverty, war, and famine. Without effective treatment, death is the norm. Prognostic models, as used by Médecins Sans Frontières (MSF) in East Africa, are used to identify high-risk patients for intensive management, including hospital admission, treatment with liposomal amphotericin B, broad-spectrum antibiotics, and blood transfusions. We provide a comprehensive and objective resource for policymakers, healthcare providers, and investigators, by identifying, summarising, and appraising the available prognostic models predicting clinical outcomes in patients with VL.
METHODS
We performed a systematic review of published studies that developed, validated, or updated models predicting future clinical outcomes in patients diagnosed with VL. We searched five bibliographic databases (Ovid Embase, Ovid MEDLINE, Web of Science Core Collection, SciELO, and LILACS) on March 1, 2023, for papers published from database inception, with no language restriction. Screening, data extraction, and risk of bias assessment were performed in duplicate. This study is registered with PROSPERO (ID: CRD42023417226).
RESULTS
Eight prognostic model studies, published between 2003 and 2021, were identified describing 12 prognostic model developments and 19 external validations. Nine models were developed in Brazil and three in East Africa by MSF investigators (two developed in South Sudan and one in Ethiopia). In-hospital mortality was the outcome for all but two Brazilian models, which predicted registry-reported mortality. Three models were developed exclusively in adolescents or children. Risk of bias was assessed as high for all model evaluations. Model overfitting due to small sample sizes, leading to optimistic model performance measures and exaggerated risk estimates, was identified for all but one model development. Only half of the presented risk scores were reproducible by following the authors’ methodology.
CONCLUSION
A poorly developed model can result in inaccurate risk estimation, potentially leading to harmful and inequitable decision making. With half of all risk scores incorrectly calculated, and a high risk of bias identified across all model evaluations, caution must be exercised when using these models to guide patient management. In the first systematic review of VL prognostic models, we show that no models predicted treatment failure and relapse, and despite South Asia representing the highest VL burden before 2010, no models were developed in this population. These represent important evidence gaps, which should be prioritised when developing new models. Using the Infectious Diseases Data Observatory repository of VL individual patient data from clinical trials, we are currently building a prognostic model for VL relapse in South Asia, which we hope to serve the ongoing elimination campaign.
Journal Article > ReviewFull Text
Trans R Soc Trop Med Hyg. 1 May 2024; Online ahead of print; DOI:10.1093/trstmh/trae018
Dahal P, Singh-Phulgenda S, Wilson JM, Cota G, Ritmeijer K, et al.
Trans R Soc Trop Med Hyg. 1 May 2024; Online ahead of print; DOI:10.1093/trstmh/trae018
Blood transfusion remains an important aspect of patient management in visceral leishmaniasis (VL). However, transfusion triggers considered are poorly understood. This review summarises the transfusion practices adopted in VL efficacy studies using the Infectious Diseases Data Observatory VL clinical trials library. Of the 160 studies (1980–2021) indexed in the IDDO VL library, description of blood transfusion was presented in 16 (10.0%) (n=3459 patients) studies. Transfusion was initiated solely based on haemoglobin (Hb) measurement in nine studies, combining Hb measurement with an additional condition (epistaxis/poor health/clinical instability) in three studies and the criteria was not mentioned in four studies. The Hb threshold range for triggering transfusion was 3–8 g/dL. The number of patients receiving transfusion was explicitly reported in 10 studies (2421 patients enrolled, 217 underwent transfusion). The median proportion of patients who received transfusion in a study was 8.0% (Interquartile range: 4.7% to 47.2%; range: 0–100%; n=10 studies). Of the 217 patients requiring transfusion, 58 occurred before VL treatment initiation, 46 during the treatment/follow-up phase and the time was not mentioned in 113. This review describes the variation in clinical practice and is an important initial step in policy/guideline development, where both the patient's Hb concentration and clinical status must be considered.
Journal Article > ResearchFull Text
PLOS One. 31 May 2011; Volume 6 (Issue 5); DOI:10.1371/journal.pone.0020175
Bonnet MMB, Gagnidze L, Guerin PJ, Bonte L, Ramsay AR, et al.
PLOS One. 31 May 2011; Volume 6 (Issue 5); DOI:10.1371/journal.pone.0020175
Sputum microscopy is the only diagnostic for tuberculosis (TB) available at peripheral levels of health service in resource-poor countries. Its sensitivity is reduced in high HIV-prevalence settings. Sodium hypochlorite (NaOCl) specimen sedimentation prior microscopy and light-emitting diode (LED)-fluorescence microscopy (FM) can individually improve performance of microscopy. This study aimed to evaluate the performance of combined LED-FM and NaOCl sputum sedimentation for TB detection at peripheral level of health services.
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 1 September 2007
Bonnet MMB, Ramsay AR, Gagnidze L, Githui W, Guerin PJ, et al.
Int J Tuberc Lung Dis. 1 September 2007
SETTING: Urban health clinic, Nairobi. OBJECTIVE: To evaluate the impact on tuberculosis (TB) case detection and laboratory workload of reducing the number of sputum smears examined and thresholds for diagnosing positive smears and positive cases. DESIGN: In this prospective study, three Ziehl-Neelsen stained sputum smears from consecutive pulmonary TB suspects were examined blind. The standard approach (A), > or = 2 positive smears out of 3, using a cut-off of 10 acid-fast bacilli (AFB)/100 high-power fields (HPF), was compared with approaches B, > or = 2 positive smears (> or = 4 AFB/100 HPF) out of 3, one of which is > or = 10 AFB/100 HPF; C, > or = 2 positive smears (> or = 4 AFB/100 HPF) out of 3; D, > or = 1 positive smear (> or = 10 AFB/100 HPF) out of 2; and E, > or = 1 positive smear (> or = 4 AFB/100 HPF) out of 2. The microscopy gold standard was detection of at least one positive smear (> or = 4 AFB/100 HPF) out of 3. RESULTS: Among 644 TB suspects, the alternative approaches detected from 114 (17.7%) (approach B) to 123 cases (19.1%) (approach E) compared to 105 cases (16.3%) for approach A (P < 0.005). Sensitivity ranged between 82.0% (105/128) for A and 96.1% (123/128) for E. The single positive smear approaches reduced the number of smears by 36% compared to approach A. CONCLUSION: Reducing the number of specimens and the positivity threshold to define a positive case increased the sensitivity of microscopy and reduced laboratory workload.
Journal Article > ResearchFull Text
Lancet Infect Dis. 1 December 2005; Volume 5 (Issue 12); DOI:10.1016/S1473-3099(05)70296-6
Olliaro PL, Guerin PJ, Gerstl S, Haaskjold AA, Rottingen JA, et al.
Lancet Infect Dis. 1 December 2005; Volume 5 (Issue 12); DOI:10.1016/S1473-3099(05)70296-6
The state of Bihar in India carries the largest share of the world's burden of antimony-resistant visceral leishmaniasis. We analysed clinical studies done in Bihar with different treatments between 1980 and 2004. Overall, 53 studies were included (all but one published), of which 15 were comparative (randomised, quasi-randomised, or non-randomised), 23 dose-finding, and 15 non-comparative. Data from comparative studies were pooled when appropriate for meta-analysis. Overall, these studies enrolled 7263 patients in 123 treatment arms. Adequacy of methods used to do the studies and report on them varied. Unresponsiveness to antimony has developed steadily in the past to such an extent that antimony must now be replaced, despite attempts to stop its progression by increasing dose and duration of therapy. The classic second-line treatments are unsuited: pentamidine is toxic and its efficacy has also declined, and amphotericin B deoxycholate is effective but requires hospitalisation for long periods and toxicity is common. Liposomal amphotericin B is very effective and safe but currently unaffordable because of its high price. Miltefosine-the first oral drug for visceral leishmaniasis-is now registered and marketed in India and is effective, but should be used under supervision to prevent misuse. Paromomycin (or aminosidine) is effective and safe, and although not yet available, a regulatory submission is due soon. To preserve the limited armamentarium of drugs to treat visceral leishmaniasis, drugs should not be deployed unprotected; combinations can make drugs last longer, improve treatment, and reduce costs to households and health systems. India, Bangladesh, and Nepal agreed recently to undertake measures towards the elimination of visceral leishmaniasis. The lessons learnt in Bihar could help inform policy decisions both regionally and elsewhere.
Journal Article > ResearchFull Text
CPT Pharmacometrics Syst Pharmacol. 13 November 2013; Volume 2 (Issue 11); e83.; DOI:10.1038/psp.2013.59
Kloprogge F, Piola P, Dhorda M, Muwanga S, Turyakira E, et al.
CPT Pharmacometrics Syst Pharmacol. 13 November 2013; Volume 2 (Issue 11); e83.; DOI:10.1038/psp.2013.59
Pregnancy alters the pharmacokinetic properties of many antimalarial compounds. The objective of this study was to evaluate the pharmacokinetic properties of lumefantrine in pregnant and nonpregnant women with uncomplicated Plasmodium falciparum malaria in Uganda after a standard fixed oral artemether-lumefantrine treatment. Dense venous (n = 26) and sparse capillary (n = 90) lumefantrine samples were drawn from pregnant patients. A total of 17 nonpregnant women contributed with dense venous lumefantrine samples. Lumefantrine pharmacokinetics was best described by a flexible absorption model with multiphasic disposition. Pregnancy and body temperature had a significant impact on the pharmacokinetic properties of lumefantrine. Simulations from the final model indicated 27% lower day 7 concentrations in pregnant women compared with nonpregnant women and a decreased median time of 0.92 and 0.42 days above previously defined critical concentration cutoff values (280 and 175 ng/ml, respectively). The standard artemether-lumefantrine dose regimen in P. falciparum malaria may need reevaluation in nonimmune pregnant women.
Journal Article > ResearchFull Text
Vaccine. 29 May 2006; Volume 24 (Issue 22); 4890-4895.; DOI:10.1016/j.vaccine.2005.10.006
Cavailler P, Perroud V, Mcchesney M, Ampuero S, Guerin PJ, et al.
Vaccine. 29 May 2006; Volume 24 (Issue 22); 4890-4895.; DOI:10.1016/j.vaccine.2005.10.006
We conducted a study to assess the feasibility and the potential vaccine coverage of a mass vaccination campaign using a two-dose oral cholera vaccine in an urban endemic neighbourhood of Beira, Mozambique. The campaign was conducted from December 2003 to January 2004. Overall 98,152 doses were administered, and vaccine coverage of the target population was 58.6% and 53.6% for the first and second rounds, respectively. The direct cost of the campaign, which excludes the price of the vaccine, amounted to slightly over 90,000 dollars, resulting in the cost per fully vaccinated person of 2.09 dollars, which is relatively high. However, in endemic settings where outbreaks are likely to occur, integrating cholera vaccination into the routine activities of the public health system could reduce such costs.
Journal Article > ResearchFull Text
PLOS One. 11 June 2010; Volume 5 (Issue 6); DOI:10.1371/journal.pone.0011086
Rose AMC, Mueller JE, Gerstl S, Njanpop-Lafourcade BM, Page AL, et al.
PLOS One. 11 June 2010; Volume 5 (Issue 6); DOI:10.1371/journal.pone.0011086
Meningococcal meningitis outbreaks occur every year during the dry season in the "meningitis belt" of sub-Saharan Africa. Identification of the causative strain is crucial before launching mass vaccination campaigns, to assure use of the correct vaccine. Rapid agglutination (latex) tests are most commonly available in district-level laboratories at the beginning of the epidemic season; limitations include a short shelf-life and the need for refrigeration and good technical skills. Recently, a new dipstick rapid diagnostic test (RDT) was developed to identify and differentiate disease caused by meningococcal serogroups A, W135, C and Y. We evaluated the diagnostic performance of this dipstick RDT during an urban outbreak of meningitis caused by N. meningitidis serogroup A in Ouagadougou, Burkina Faso; first against an in-country reference standard of culture and/or multiplex PCR; and second against culture and/or a highly sensitive nested PCR technique performed in Oslo, Norway. We included 267 patients with suspected acute bacterial meningitis. Using the in-country reference standard, 50 samples (19%) were positive. Dipstick RDT sensitivity (N = 265) was 70% (95%CI 55-82) and specificity 97% (95%CI 93-99). Using culture and/or nested PCR, 126/259 (49%) samples were positive; dipstick RDT sensitivity (N = 257) was 32% (95%CI 24-41), and specificity was 99% (95%CI 95-100). We found dipstick RDT sensitivity lower than values reported from (i) assessments under ideal laboratory conditions (>90%), and (ii) a prior field evaluation in Niger [89% (95%CI 80-95)]. Specificity, however, was similar to (i), and higher than (ii) [62% (95%CI 48-75)]. At this stage in development, therefore, other tests (e.g., latex) might be preferred for use in peripheral health centres. We highlight the value of field evaluations for new diagnostic tests, and note relatively low sensitivity of a reference standard using multiplex vs. nested PCR. Although the former is the current standard for bacterial meningitis surveillance in the meningitis belt, nested PCR performed in a certified laboratory should be used as an absolute reference when evaluating new diagnostic tests.
Journal Article > ResearchFull Text
Clin Pharmacol Ther
Clinical Pharmacology and Therapeutics. 1 June 2019
Chotsiri P, Denoeud-Ndam L, Baudin E, Guindo O, Diawara H, et al.
Clin Pharmacol Ther
Clinical Pharmacology and Therapeutics. 1 June 2019
Severe acute malnutrition (SAM) has been reported to be associated with increased malaria morbidity in Sub‐Saharan African children and may affect the pharmacology of antimalarial drugs. This population pharmacokinetic‐pharmacodynamic study included 131 SAM and 266 non‐SAM children administered artemether‐lumefantrine twice daily for 3 days. Lumefantrine capillary plasma concentrations were adequately described by two transit‐absorption compartments followed by two distribution compartments. Allometrically scaled body weight and an enzymatic maturation effect were included in the pharmacokinetic model. Mid‐upper arm circumference (MUAC) was associated with decreased absorption of lumefantrine (25.4% decrease per 1 cm reduction). Risk of recurrent malaria episodes (i.e. reinfection) were characterised by an interval‐censored time‐to‐event model with a sigmoid EMAX‐model describing the effect of lumefantrine. SAM children were at risk of under‐exposure to lumefantrine and an increased risk of malaria reinfection compared to well‐nourished children. Research on optimised regimens should be considered for malaria treatment in malnourished children.