Journal Article > ReviewFull Text
Trans R Soc Trop Med Hyg. 2024 May 1; 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. 2024 May 1; 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.
Conference Material > Slide Presentation
Solomos A, Musa AM, Mbui J, Mohammed R, Olobo J, et al.
MSF Scientific Day International 2023. 2023 June 7; DOI:10.57740/81jj-tz57
Journal Article > ReviewFull Text
PLoS Negl Trop Dis. 2021 August 10; Volume 15 (Issue 8); e0009650.; DOI:10.1371/journal.pntd.0009650
Dahal P, Singh-Phulgenda S, Maguire BJ, Harriss E, Ritmeijer KKD, et al.
PLoS Negl Trop Dis. 2021 August 10; Volume 15 (Issue 8); e0009650.; DOI:10.1371/journal.pntd.0009650
BACKGROUND
Reports on the occurrence and outcome of Visceral Leishmaniasis (VL) in pregnant women is rare in published literature. The occurrence of VL in pregnancy is not systematically captured and cases are rarely followed-up to detect consequences of infection and treatment on the mother and foetus.
METHODS
A review of all published literature was undertaken to identify cases of VL infections among pregnant women by searching the following database: Ovid MEDLINE; Ovid Embase; Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials; World Health Organization Global Index Medicus: LILACS (Americas); IMSEAR (South-East Asia); IMEMR (Eastern Mediterranean); WPRIM (Western Pacific); ClinicalTrials.gov; and the WHO International Clinical Trials Registry Platform. Selection criteria included any clinical reports describing the disease in pregnancy or vertical transmission of the disease in humans. Articles meeting pre-specified inclusion criteria and non-primary research articles such as textbook, chapters, letters, retrospective case description, or reports of accidental inclusion in trials were also considered.
RESULTS
The systematic literature search identified 272 unique articles of which 54 records were included in this review; a further 18 records were identified from additional search of the references of the included studies or from personal communication leading to a total of 72 records (71 case reports/case series; 1 retrospective cohort study; 1926-2020) describing 451 cases of VL in pregnant women. The disease was detected during pregnancy in 398 (88.2%), retrospectively confirmed after giving birth in 52 (11.5%), and the time of identification was not clear in 1 (0.2%). Of the 398 mothers whose infection was identified during pregnancy, 346 (86.9%) received a treatment, 3 (0.8%) were untreated, and the treatment status was not clear in the remaining 49 (12.3%). Of 346 mothers, Liposomal amphotericin B (L-AmB) was administered in 202 (58.4%) and pentavalent antimony (PA) in 93 (26.9%). Outcomes were reported in 176 mothers treated with L-AmB with 4 (2.3%) reports of maternal deaths, 5 (2.8%) miscarriages, and 2 (1.1%) foetal death/stillbirth. For PA, outcomes were reported in 88 mothers of whom 4 (4.5%) died, 24 (27.3%) had spontaneous abortion, 2 (2.3%) had miscarriages. A total of 26 cases of confirmed, probable or suspected cases of vertical transmission were identified with a median detection time of 6 months (range: 0-18 months).
CONCLUSIONS
Outcomes of VL treatment during pregnancy are rarely reported and under-researched. The reported articles were mainly case reports and case series and the reported information was often incomplete. From the studies identified, it is difficult to derive a generalisable information on outcomes for mothers and babies, although reported data favours the usage of liposomal amphotericin B for the treatment of VL in pregnant women.
Reports on the occurrence and outcome of Visceral Leishmaniasis (VL) in pregnant women is rare in published literature. The occurrence of VL in pregnancy is not systematically captured and cases are rarely followed-up to detect consequences of infection and treatment on the mother and foetus.
METHODS
A review of all published literature was undertaken to identify cases of VL infections among pregnant women by searching the following database: Ovid MEDLINE; Ovid Embase; Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials; World Health Organization Global Index Medicus: LILACS (Americas); IMSEAR (South-East Asia); IMEMR (Eastern Mediterranean); WPRIM (Western Pacific); ClinicalTrials.gov; and the WHO International Clinical Trials Registry Platform. Selection criteria included any clinical reports describing the disease in pregnancy or vertical transmission of the disease in humans. Articles meeting pre-specified inclusion criteria and non-primary research articles such as textbook, chapters, letters, retrospective case description, or reports of accidental inclusion in trials were also considered.
RESULTS
The systematic literature search identified 272 unique articles of which 54 records were included in this review; a further 18 records were identified from additional search of the references of the included studies or from personal communication leading to a total of 72 records (71 case reports/case series; 1 retrospective cohort study; 1926-2020) describing 451 cases of VL in pregnant women. The disease was detected during pregnancy in 398 (88.2%), retrospectively confirmed after giving birth in 52 (11.5%), and the time of identification was not clear in 1 (0.2%). Of the 398 mothers whose infection was identified during pregnancy, 346 (86.9%) received a treatment, 3 (0.8%) were untreated, and the treatment status was not clear in the remaining 49 (12.3%). Of 346 mothers, Liposomal amphotericin B (L-AmB) was administered in 202 (58.4%) and pentavalent antimony (PA) in 93 (26.9%). Outcomes were reported in 176 mothers treated with L-AmB with 4 (2.3%) reports of maternal deaths, 5 (2.8%) miscarriages, and 2 (1.1%) foetal death/stillbirth. For PA, outcomes were reported in 88 mothers of whom 4 (4.5%) died, 24 (27.3%) had spontaneous abortion, 2 (2.3%) had miscarriages. A total of 26 cases of confirmed, probable or suspected cases of vertical transmission were identified with a median detection time of 6 months (range: 0-18 months).
CONCLUSIONS
Outcomes of VL treatment during pregnancy are rarely reported and under-researched. The reported articles were mainly case reports and case series and the reported information was often incomplete. From the studies identified, it is difficult to derive a generalisable information on outcomes for mothers and babies, although reported data favours the usage of liposomal amphotericin B for the treatment of VL in pregnant women.
Journal Article > ProtocolFull Text
BMJ Open. 2023 December 14; Volume 13 (Issue 12); e074841.; DOI:10.1136/bmjopen-2023-074841
Munir A, Dahal P, Kumar R, Singh-Phulgenda S, Siddiqui NA, et al.
BMJ Open. 2023 December 14; Volume 13 (Issue 12); e074841.; DOI:10.1136/bmjopen-2023-074841
INTRODUCTION
Visceral leishmaniasis (VL) is a parasitic disease with an estimated 30,000 new cases occurring annually. Despite anaemia being a common haematological manifestation of VL, the evolution of different haematological characteristics following treatment remains poorly understood. An individual participant data meta-analysis (IPD-MA) is planned to characterise the haematological dynamics in patients with VL.
METHODS AND ANALYSIS
The Infectious Diseases Data Observatory (IDDO) VL data platform is a global repository of IPD from therapeutic studies identified through a systematic search of published literature (PROSPERO registration: CRD42021284622). The platform currently holds datasets from clinical trials standardised to a common data format. Corresponding authors and principal investigators of the studies indexed in the IDDO VL data platform meeting the eligibility criteria for inclusion were invited to be part of the collaborative IPD-MA. Mixed-effects multivariable regression models will be constructed to identify determinants of haematological parameters by taking clustering within study sites into account.
ETHICS AND DISSEMINATION
This IPD-MA meets the criteria for waiver of ethical review as defined by the Oxford Tropical Research Ethics Committee (OxTREC) granted to IDDO, as the research consists of secondary analysis of existing anonymised data (exempt granted on 29 March 2023, OxTREC REF: IDDO). Ethics approval was granted by the ICMR-Rajendra Memorial Research Institute of Medical Sciences ethics committee (letter no.: RMRI/EC/30/2022) on 4 July 2022. The results of this analysis will be disseminated at conferences, the IDDO website and peer-reviewed publications in open-access journals. The findings of this research will be critically important for control programmes at regional and global levels, policymakers and groups developing new VL treatments.
Visceral leishmaniasis (VL) is a parasitic disease with an estimated 30,000 new cases occurring annually. Despite anaemia being a common haematological manifestation of VL, the evolution of different haematological characteristics following treatment remains poorly understood. An individual participant data meta-analysis (IPD-MA) is planned to characterise the haematological dynamics in patients with VL.
METHODS AND ANALYSIS
The Infectious Diseases Data Observatory (IDDO) VL data platform is a global repository of IPD from therapeutic studies identified through a systematic search of published literature (PROSPERO registration: CRD42021284622). The platform currently holds datasets from clinical trials standardised to a common data format. Corresponding authors and principal investigators of the studies indexed in the IDDO VL data platform meeting the eligibility criteria for inclusion were invited to be part of the collaborative IPD-MA. Mixed-effects multivariable regression models will be constructed to identify determinants of haematological parameters by taking clustering within study sites into account.
ETHICS AND DISSEMINATION
This IPD-MA meets the criteria for waiver of ethical review as defined by the Oxford Tropical Research Ethics Committee (OxTREC) granted to IDDO, as the research consists of secondary analysis of existing anonymised data (exempt granted on 29 March 2023, OxTREC REF: IDDO). Ethics approval was granted by the ICMR-Rajendra Memorial Research Institute of Medical Sciences ethics committee (letter no.: RMRI/EC/30/2022) on 4 July 2022. The results of this analysis will be disseminated at conferences, the IDDO website and peer-reviewed publications in open-access journals. The findings of this research will be critically important for control programmes at regional and global levels, policymakers and groups developing new VL treatments.
Journal Article > ResearchFull Text
Antimicrob Agents Chemother. 2018 December 3; Volume 63 (Issue 2); DOI:10.1128/AAC.01191-18
Parrado R, Ramirez JC, de la Barra A, Alonso-Vega C, Juiz N, et al.
Antimicrob Agents Chemother. 2018 December 3; Volume 63 (Issue 2); DOI:10.1128/AAC.01191-18
This work evaluated a serial blood sampling procedure to enhance the sensitivity of duplex real-time PCR (qPCR) for baseline detection and quantification of parasitic loads and post-treatment identification of failure in the context of clinical trials for treatment of chronic Chagas disease, namely DNDi-CH-E1224-001 (NCT01489228) and MSF-DNDi PCR sampling optimization study (NCT01678599). Patients from Cochabamba (N= 294), Tarija (N= 257), and Aiquile (N= 220) were enrolled. Three serial blood samples were collected at each time-point and qPCR triplicates were tested per sample. The first two samples were collected during the same day and the third one seven days later.A patient was considered PCR positive if at least one qPCR replicate was detectable. Cumulative results of multiple samples and qPCR replicates enhanced the proportion of pre-treatment sample positivity from 54.8 to 76.2%, 59.5 to 77.8%, and 73.5 to 90.2% in Cochabamba, Tarija, and Aiquile cohorts, respectively. This strategy increased the detection of treatment failure from 72.9 to 91.7%, 77.8 to 88.9%, and 42.9 to 69.1% for E1224 low, short, and high dosage regimens, respectively; and from 4.6 to 15.9% and 9.5 to 32.1% for the benznidazole arm in the DNDi-CH-E1224-001 and MSF-DNDi studies, respectively. The addition of the third blood sample and third qPCR replicate in patients with non-detectable PCR results in the first two samples, gave a small, non-statistically significant improvement in qPCR positivity. No change in clinical sensitivity was seen with a blood volume increase from 5 to 10 ml. The monitoring of patients treated with placebo in the DNDi-CH-E1224-001 trial revealed fluctuations in parasitic loads and occasional non-detectable results. In conclusion, serial sampling strategy enhanced PCR sensitivity to detecting treatment failure during follow-up and has the potential for improving recruitment capacity in Chagas disease trials, which require an initial positive qPCR result for patient admission.
Journal Article > ResearchFull Text
J Infect Dev Ctries. 2020 June 30; Volume 14 (Issue 06.1); DOI:10.3855/jidc.11731
Tekalign S, Adera C, den Boer ML, Miecha H, Zewde A, et al.
J Infect Dev Ctries. 2020 June 30; Volume 14 (Issue 06.1); DOI:10.3855/jidc.11731
Introduction: In three health care facilities in the Oromia region, the aim of this study is to report on 1) the number of VL cases registered over time (2013-2018) and 2) the clinical profile, type of treatment used and response to treatment.
Methodology: A retrospective cohort study was conducted among all VL cases admitted with a diagnosis of VL.
Results: A total of 434 VL cases were registered at the three health facilities, but patient files were available for only 188. Most (51.6%) were children and only three presented with VL relapse. 78 (41.5%) of the 188 patients presented within one month of symptom onset. Concurrent severe acute malnutrition (27.1%), tuberculosis (6.4%) and malaria (6.4%) were common. There were only two cases with HIV coinfection. Fourty-three percent were treated with antimonials, 34% with antimonials combined with paromomycin and 23% with AmBisome. Amongst the 188 patients with patient files there were no deaths and one treatment failure. Six months outcome data were however missing for all. Aggregated data from the 434 VL cases reported three deaths, two treatment failures and one relapse.
Conclusions: Children were most commonly affected, suggesting long-term endemicity. While short-term outcomes are encouraging, long-term follow-up data are required.
Methodology: A retrospective cohort study was conducted among all VL cases admitted with a diagnosis of VL.
Results: A total of 434 VL cases were registered at the three health facilities, but patient files were available for only 188. Most (51.6%) were children and only three presented with VL relapse. 78 (41.5%) of the 188 patients presented within one month of symptom onset. Concurrent severe acute malnutrition (27.1%), tuberculosis (6.4%) and malaria (6.4%) were common. There were only two cases with HIV coinfection. Fourty-three percent were treated with antimonials, 34% with antimonials combined with paromomycin and 23% with AmBisome. Amongst the 188 patients with patient files there were no deaths and one treatment failure. Six months outcome data were however missing for all. Aggregated data from the 434 VL cases reported three deaths, two treatment failures and one relapse.
Conclusions: Children were most commonly affected, suggesting long-term endemicity. While short-term outcomes are encouraging, long-term follow-up data are required.
Conference Material > Slide Presentation
Wilson JM, Chowdhury F, Hassan S, Harriss E, Alves F, et al.
MSF Scientific Day International 2024. 2024 May 16; DOI:10.57740/R7W2C8dil
Journal Article > ResearchFull Text
PLoS Negl Trop Dis. 2018 October 22; Volume 12 (Issue 10); e0006830.; DOI:10.1371/journal.pntd.0006830
Goyal V, Mahajan R, Pandey K, Singh SN, Singh RS, et al.
PLoS Negl Trop Dis. 2018 October 22; Volume 12 (Issue 10); e0006830.; DOI:10.1371/journal.pntd.0006830
BACKGROUND
In 2010, WHO recommended the use of new short-course treatment regimens in kala-azar elimination efforts for the Indian subcontinent. Although phase 3 studies have shown excellent results, there remains a lack of evidence on a wider treatment population and the safety and effectiveness of these regimens under field conditions.
METHODS
This was an open label, prospective, non-randomized, non-comparative, multi-centric trial conducted within public health facilities in two highly endemic districts and a specialist referral centre in Bihar, India. Three treatment regimens were tested: single dose AmBisome (SDA), concomitant miltefosine and paromomycin (Milt+PM), and concomitant AmBisome and miltefosine (AmB+Milt). Patients with complicated disease or significant co-morbidities were treated in the SDA arm. Sample sizes were set at a minimum of 300 per arm, taking into account inter-site variation and an estimated failure risk of 5% with 5% precision. Outcomes of drug effectiveness and safety were measured at 6 months. The trial was prospectively registered with the Clinical Trials Registry India: CTRI/2012/08/002891.
RESULTS
Out of 1,761 patients recruited, 50.6% (n = 891) received SDA, 20.3% (n = 358) AmB+Milt and 29.1% (n = 512) Milt+PM. In the ITT analysis, the final cure rates were SDA 91.4% (95% CI 89.3-93.1), AmB+Milt 88.8% (95% CI 85.1-91.9) and Milt+PM 96.9% (95% CI 95.0-98.2). In the complete case analysis, cure rates were SDA 95.5% (95% CI 93.9-96.8), AmB+Milt 95.5% (95% CI 92.7-97.5) and Milt+PM 99.6% (95% CI 98.6-99.9). All three regimens were safe, with 5 severe adverse events in the SDA arm, two of which were considered to be drug related.
CONCLUSION
All regimens showed acceptable outcomes and safety profiles in a range of patients under field conditions. Phase IV field-based studies, although extremely rare for neglected tropical diseases, are good practice and an important step in validating the results of more restrictive hospital-based studies before widespread implementation, and in this case contributed to national level policy change in India.
In 2010, WHO recommended the use of new short-course treatment regimens in kala-azar elimination efforts for the Indian subcontinent. Although phase 3 studies have shown excellent results, there remains a lack of evidence on a wider treatment population and the safety and effectiveness of these regimens under field conditions.
METHODS
This was an open label, prospective, non-randomized, non-comparative, multi-centric trial conducted within public health facilities in two highly endemic districts and a specialist referral centre in Bihar, India. Three treatment regimens were tested: single dose AmBisome (SDA), concomitant miltefosine and paromomycin (Milt+PM), and concomitant AmBisome and miltefosine (AmB+Milt). Patients with complicated disease or significant co-morbidities were treated in the SDA arm. Sample sizes were set at a minimum of 300 per arm, taking into account inter-site variation and an estimated failure risk of 5% with 5% precision. Outcomes of drug effectiveness and safety were measured at 6 months. The trial was prospectively registered with the Clinical Trials Registry India: CTRI/2012/08/002891.
RESULTS
Out of 1,761 patients recruited, 50.6% (n = 891) received SDA, 20.3% (n = 358) AmB+Milt and 29.1% (n = 512) Milt+PM. In the ITT analysis, the final cure rates were SDA 91.4% (95% CI 89.3-93.1), AmB+Milt 88.8% (95% CI 85.1-91.9) and Milt+PM 96.9% (95% CI 95.0-98.2). In the complete case analysis, cure rates were SDA 95.5% (95% CI 93.9-96.8), AmB+Milt 95.5% (95% CI 92.7-97.5) and Milt+PM 99.6% (95% CI 98.6-99.9). All three regimens were safe, with 5 severe adverse events in the SDA arm, two of which were considered to be drug related.
CONCLUSION
All regimens showed acceptable outcomes and safety profiles in a range of patients under field conditions. Phase IV field-based studies, although extremely rare for neglected tropical diseases, are good practice and an important step in validating the results of more restrictive hospital-based studies before widespread implementation, and in this case contributed to national level policy change in India.
Journal Article > ResearchFull Text
PLoS Negl Trop Dis. 2022 August 18; Volume 16 (Issue 8); e0010696.; DOI:10.1371/journal.pntd.0010696
Naylor-Leyland G, Collin SM, Gatluak F, den Boer ML, Alves F, et al.
PLoS Negl Trop Dis. 2022 August 18; Volume 16 (Issue 8); e0010696.; DOI:10.1371/journal.pntd.0010696
BACKGROUND
Visceral Leishmaniasis (VL) is endemic in South Sudan, manifesting periodically in major outbreaks. Provision of treatment during endemic periods and as an emergency response is impeded by instability and conflict. Médecins Sans Frontières (MSF) has provided health care in South Sudan since the late 1980’s, including treatment for 67,000 VL patients. In recent years, MSF monitoring data have indicated increasing numbers of VL relapse cases. A retrospective analysis of these data was performed in order to provide insight into the possible causes of this increase.
METHODOLOGY/PRINCIPAL FINDINGS
Programme monitoring data from the MSF hospital in Lankien, Jonglei State, South Sudan, for the period 2001–2018 were analysed to detect trends in VL relapse as a proportion of all VL cases presenting to MSF treatment centres. Routinely collected patient-level data from relapse and primary VL cases treated at all MSF sites in South Sudan over the same period were analysed to describe patient characteristics and treatments received. VL relapse as a proportion of all VL cases increased by 6.5% per annum (95% CI 0.3% to 13.0%, p = 0.04), from 5.2% during 2001–2003 to 14.4% during 2016–2018. Primary VL and VL relapse patients had similar age, sex and anthropometric characteristics, the latter indicating high indices of undernutrition which were relatively constant over time. Clinical factors (Hb, spleen size, and VL severity score) also did not vary substantially over time. SSG/PM was the main treatment regimen from 2001–2018, used in 68.7% of primary and 70.9% of relapse VL cases; AmBisome was introduced in 2013, received by 22.5% of primary VL and 32.6% of VL relapse cases from 2013–2018.
CONCLUSION
Increasing incidence of VL relapse in South Sudan does not appear to be explained by changes in patient characteristics or other factors. Our data are concerning and may indicate an emergence of treatment-resistant parasite strains, decreasing the effectiveness of treatment regimens. This warrants further investigation as a causal factor. New chemical entities that will enable safe and highly effective short-course oral treatments for VL are urgently needed.
Visceral Leishmaniasis (VL) is endemic in South Sudan, manifesting periodically in major outbreaks. Provision of treatment during endemic periods and as an emergency response is impeded by instability and conflict. Médecins Sans Frontières (MSF) has provided health care in South Sudan since the late 1980’s, including treatment for 67,000 VL patients. In recent years, MSF monitoring data have indicated increasing numbers of VL relapse cases. A retrospective analysis of these data was performed in order to provide insight into the possible causes of this increase.
METHODOLOGY/PRINCIPAL FINDINGS
Programme monitoring data from the MSF hospital in Lankien, Jonglei State, South Sudan, for the period 2001–2018 were analysed to detect trends in VL relapse as a proportion of all VL cases presenting to MSF treatment centres. Routinely collected patient-level data from relapse and primary VL cases treated at all MSF sites in South Sudan over the same period were analysed to describe patient characteristics and treatments received. VL relapse as a proportion of all VL cases increased by 6.5% per annum (95% CI 0.3% to 13.0%, p = 0.04), from 5.2% during 2001–2003 to 14.4% during 2016–2018. Primary VL and VL relapse patients had similar age, sex and anthropometric characteristics, the latter indicating high indices of undernutrition which were relatively constant over time. Clinical factors (Hb, spleen size, and VL severity score) also did not vary substantially over time. SSG/PM was the main treatment regimen from 2001–2018, used in 68.7% of primary and 70.9% of relapse VL cases; AmBisome was introduced in 2013, received by 22.5% of primary VL and 32.6% of VL relapse cases from 2013–2018.
CONCLUSION
Increasing incidence of VL relapse in South Sudan does not appear to be explained by changes in patient characteristics or other factors. Our data are concerning and may indicate an emergence of treatment-resistant parasite strains, decreasing the effectiveness of treatment regimens. This warrants further investigation as a causal factor. New chemical entities that will enable safe and highly effective short-course oral treatments for VL are urgently needed.
Journal Article > ResearchFull Text
PLoS Negl Trop Dis. 2016 September 14; Volume 10 (Issue 9); DOI:10.1371/journal.pntd.0004880
Wassuna M, Njenga SN, Balasegaram M, Alexander N, Omollo R, et al.
PLoS Negl Trop Dis. 2016 September 14; Volume 10 (Issue 9); DOI:10.1371/journal.pntd.0004880
SSG&PM over 17 days is recommended as first line treatment for visceral leishmaniasis in eastern Africa, but is painful and requires hospitalization. Combination regimens including AmBisome and miltefosine are safe and effective in India, but there are no published data from trials of combination therapies including these drugs from Africa.