Emilie Alirol

Urbanisation and infectious diseases in a globalised world

Summary The world is becoming urban. The UN predicts that the worlds urban population will almost double from 3·3 billion in 2007 to 6·3 billion in 2050. Most of this increase will be in developing countries. Exponential urban growth is having a profound effect on global health. Because of international travel and migration, cities are becoming important hubs for the transmission of infectious diseases, as shown by recent pandemics. Physicians in urban environments in developing and developed countries need to be aware of the changes in infectious diseases associated with urbanisation. Furthermore, health should be a major consideration in town planning to ensure urbanisation works to reduce the burden of infectious diseases in the future.

Mitochondria and cancer: is there a morphological connection?

Mitochondria are key players in several cellular functions including growth, division, energy metabolism, and apoptosis. The mitochondrial network undergoes constant remodelling and these morphological changes are of direct relevance for the role of this organelle in cell physiology. Mitochondrial dysfunction contributes to a number of human disorders and may aid cancer progression. Here, we summarize the recent contributions made in the field of mitochondrial dynamics and discuss their impact on our understanding of cell function and tumorigenesis.

Tolerance and safety of nifurtimox in patients with chronic chagas disease.

BACKGROUND Nifurtimox has been used to treat Chagas disease for 40 years, but tolerance and safety data in adults are scarce. We aimed to evaluate nifurtimox tolerance and safety in a cohort of Trypanosoma cruzi-infected adult patients in a country of nonendemicity. METHODS This observational study included all consecutive adults patients who were given a diagnosis of T. cruzi infection from June through December 2008. Eligible patients received nifurtimox at 10 mg/kg/day for 60 days, with regular medical and biological follow-up. Adverse events (AEs) were recorded according to Common Terminology Criteria for Adverse Events, version 3.0. RESULTS Eighty-one patients received nifurtimox. Eight were lost to follow-up during treatment, and 41 (56.2%) completed the 60-day course. All premature treatment terminations were caused by AEs; 97.5% of patients suffered from AEs, mostly expected (90.5%) and not severe. Gastrointestinal symptoms predominated. Six (7.4%) patients presented with a suspected unexpected serious adverse reaction: drug reaction with eosinophilia and systemic symptoms (n = 3), Quincke edema (n = 1), acute myocarditis (n = 1), and anaphylaxis (n = 1). Patients with 3 or more AEs had an increased risk of premature treatment termination (hazard ratio, 8.42; 95% confidence interval, 1.6-45.5). CONCLUSION Nifurtimox is poorly tolerated among adults with chronic Chagas disease, resulting in a low treatment completion rate. Considering the significant risk of serious AEs, close monitoring is required, which may be difficult to implement in poor rural areas of countries of endemicity. The safety and efficacy of nifurtimox and benznidazole should be compared to improve current therapeutic recommendations, and pharmacovigilance systems should be enhanced.

Rapid diagnostic tests for non-malarial febrile illness in the tropics

The recent roll-out of rapid diagnostic tests (RDTs) for malaria has highlighted the decreasing proportion of malaria-attributable illness in endemic areas. Unfortunately, once malaria is excluded, there are few accessible diagnostic tools to guide the management of severe febrile illnesses in low resource settings. This review summarizes the current state of RDT development for several key infections, including dengue fever, enteric fever, leptospirosis, brucellosis, visceral leishmaniasis and human African trypanosomiasis, and highlights many remaining gaps. Most RDTs for non-malarial tropical infections currently rely on the detection of host antibodies against a single infectious agent. The sensitivity and specificity of host-antibody detection tests are both inherently limited. Moreover, prolonged antibody responses to many infections preclude the use of most serological RDTs for monitoring response to treatment and/or for diagnosing relapse. Considering these limitations, there is a pressing need for sensitive pathogen-detection-based RDTs, as have been successfully developed for malaria and dengue. Ultimately, integration of RDTs into a validated syndromic approach to tropical fevers is urgently needed. Related research priorities are to define the evolving epidemiology of fever in the tropics, and to determine how combinations of RDTs could be best used to improve the management of severe and treatable infections requiring specific therapy.

Nifurtimox-Eflornithine Combination Therapy for Second-Stage Gambiense Human African Trypanosomiasis: Médecins Sans Frontières Experience in the Democratic Republic of the Congo

BACKGROUND Existing diagnostic and treatment tools for human African trypanosomiasis (HAT) are limited. The recent development of nifurtimox-eflornithine combination therapy (NECT) has brought new hopes for patients in the second stage. While NECT has been rolled out in most endemic countries, safety data are scarce and derive only from clinical trials. The World Health Organization (WHO) coordinates a pharmacovigilance program to collect additional data on NECT safety and efficacy. We report here the results of 18 months of experience of NECT use in treatment centers run by Médecins Sans Frontières in the Democratic Republic of the Congo (DRC). METHODS This cohort study included 684 second-stage HAT patients (including 120 children) treated with NECT in Doruma and Dingila hospitals, northeastern DRC, between January 2010 and June 2011. All treatment-emergent adverse events (AEs) were recorded and graded according to the Common Terminology Criteria for Adverse Events version 3.0. Safety and efficacy data were retrieved from the WHO pharmacovigilance forms and from Epitryps, a program monitoring database. RESULTS Eighty-six percent of the patients experienced at least 1 AE during treatment. On average, children experienced fewer AEs than adults. Most AEs were mild (37.9%) or moderate (54.7%). Severe AEs included vomiting (n = 32), dizziness (n = 16), headache (n = 11), and convulsions (n = 11). The in-hospital case fatality rate was low (0.15%) and relapses were rare (n = 14). CONCLUSIONS In comparison with previous treatments, NECT was effective, safe, and well tolerated in nontrial settings in DRC, further supporting the roll-out of NECT as first-line treatment in second-stage Trypanosoma brucei gambiense HAT. Tolerance was particularly good in children.

Rapid diagnostic tests for neurological infections in central Africa

Infections are a leading cause of life-threatening neuropathology worldwide. In central African countries affected by endemic diseases such as human African trypanosomiasis, tuberculosis, HIV/AIDS, and schistosomiasis, delayed diagnosis and treatment often lead to avoidable death or severe sequelae. Confirmatory microbiological and parasitological tests are essential because clinical features of most neurological infections are not specific, brain imaging is seldom feasible, and treatment regimens are often prolonged or toxic. Recognition of this diagnostic bottleneck has yielded major investment in application of advances in biotechnology to clinical microbiology in the past decade. We review the neurological pathogens for which rapid diagnostic tests are most urgently needed in central Africa, detail the state of development of putative rapid diagnostic tests for each, and describe key technical and operational challenges to their development and implementation. Promising field-suitable rapid diagnostic tests exist for the diagnosis of human African trypanosomiasis and cryptococcal meningoencephalitis. For other infections-eg, syphilis and schistosomiasis-highly accurate field-validated rapid diagnostic tests are available, but their role in diagnosis of disease with neurological involvement is still unclear. For others-eg, tuberculosis-advances in research have not yet yielded validated tests for diagnosis of neurological disease.

High Mortality among Older Patients Treated with Pentavalent Antimonials for Visceral Leishmaniasis in East Africa and Rationale for Switch to Liposomal Amphotericin B

Visceral leishmaniasis (kala azar), a fatal disease if left untreated, is one of the most neglected tropical diseases. Poor and remote areas of South Asia and East Africa are the most affected. Pentavalent antimonial (SbV) drugs have been the mainstay of visceral leishmaniasis (VL) therapy in East Africa for the past 70 years. These drugs are administered parenterally for 30 days. Their potential for toxicity is high among VL patients, and drug-induced renal failure, acute pancreatitis, or cardiotoxicity can result in death. A growing body of clinical evidence shows that patients ≥45 years of age with leishmaniasis are at higher risk of death or severe adverse reactions during SbV treatment (1-6). Two separate studies conducted by Medecins Sans Frontieres (MSF) in South Sudan showed that VL patients ≥45 years old treated with the SbV drug sodium stibogluconate (SSG) had 4.6 (odds ratio [OR]; 95% confidence interval [CI], 2.7 to 7.7) (1) and 6.8 (relative risk [RR]; 95% CI, 4.4 to 10.4) (6) times higher risks of dying than younger patients (Table ​(Table11). TABLE 1. Summary of Medecins Sans Frontieres studies examining an age of ≥45 years as a possible risk factor for death among VL patients treated with SbV in East Africa More recent data analysis of MSFs VL programs in Uganda and Ethiopia showed similar findings. In Uganda, where patients were primarily treated with either SSG or another SbV drug, meglumine antimoniate, an age of ≥45 years was the strongest independent risk factor for mortality, with an adjusted OR of 38.2 (95% CI, 11.8 to 123.2) (4). In Ethiopia, patients ≥45 years old treated with SSG had a 6.6 (OR; 95% CI, 3.2 to 13.9) times higher risk of death than patients 5 to 29 years old (2). These risk ratios translated into case fatality rates (CFRs) of 12% (2) to 30%, with three of the four studies demonstrating CFRs of 26 to 30% (Table ​(Table1)1) (1, 4, 6). This brief meta-analysis of MSF VL data shows that SbV treatment of patients ≥45 years old results in unacceptably high mortality in East Africa. This may be caused by SbV toxicity, increased disease severity, or a combination of both. It is therefore urgent to evaluate potentially safer and more rapidly active treatments in this age group, such as liposomal amphotericin B (LAmB), miltefosine, or combination therapies (e.g., SbV with paromomycin for 17 days), and adapt national guidelines accordingly. LAmB (total dose, 30 mg/kg of body weight) is now used by MSF in East Africa as compassionate treatment for patients ≥45 years old and for other groups of patients at increased risk of complications or death due to SbV (e.g., HIV-tuberculosis coinfected, severely sick, or pregnant patients). Of 87 patients ≥45 years old treated with LAmB by MSF in Sudan, Kenya, and Ethiopia since 2002, 7 patients have died, giving a CFR of 8% (unpublished data). Despite recent drug price decreases, the cost of LAmB remains higher than the cost of SbV drugs, hindering its wider use. However, the incremental cost for increasing LAmB use would be expected to be relatively modest, since patients ≥45 years old represent a relatively small fraction (1.7 to 6.4%) of VL patients (Table ​(Table1).1). With a relatively small investment in LAmB, mortality among VL patients ≥45 years old in East Africa could be reduced with little delay.

Antivenoms for Snakebite Envenoming: What Is in the Research Pipeline?

Of the 24 neglected tropical diseases (NTDs) and conditions listed by WHO, snakebite is among the top killers [1]. Tens of thousands of people die each year as a result of snakebite envenoming, with close to 50,000 deaths in India alone [2] and up to 32,000 in sub-Saharan Africa [3]. Yet there are few sources of effective, safe, and affordable antivenoms. The regions that bear the highest snakebite burden are especially underserved [4]. The Fav-Afrique antivenom, produced by Sanofi Pasteur (France), is considered safe and effective and is one of the few antivenoms to be approved by a Stringent Regulatory Authority (French National Regulatory Authority), although limited formal evidence has been published [5,6]. It is polyvalent, targeting most of the medically important snake species in sub-Saharan Africa. In particular, it is highly effective in treating envenoming by Echis ocellatus, the West African saw-scaled viper [5–7] that causes great morbidity and mortality throughout the West and Central African savannah. The venom of E. ocellatus may induce systemic haemorrhage, coagulopathy, and shock, as well as extensive local tissue damage. In the absence of treatment, the case fatality rate is 10%–20% [8]. Medecins Sans Frontieres (MSF) uses Fav-Afrique in its projects in sub-Saharan Africa, notably in Paoua in Central African Republic (CAR), where E. ocellatus envenoming is frequent [9]. Worryingly, MSF has been informed that the production of Fav-Afrique by Sanofi Aventis will be permanently discontinued. The last batch was released in January 2014, with an expiry date of June 2016. All the vials produced have already been sold by Sanofi Pasteur. Although several alternative antivenom products target a similar list of species as Fav-Afrique, there is currently no evidence of their safety and effectiveness. We aimed to review the evidence for the efficacy and safety of existing and in-development snake antivenoms, and to list the alternatives to Fav-Afrique in sub-Saharan Africa.

Liposomal amphotericin B for complicated visceral leishmaniasis (kala-azar) in eastern Sudan: how effective is treatment for this neglected disease?

The aim of this study was to report the patient profile and treatment outcomes, including relapses, of patients with visceral leishmaniasis (VL) treated with liposomal amphotericin B (AmBisome) in Gedaref, Sudan.

Use of Molecular Diagnostic Tools for the Identification of Species Responsible for Snakebite in Nepal: A Pilot Study.

Snakebite is an important medical emergency in rural Nepal. Correct identification of the biting species is crucial for clinicians to choose appropriate treatment and anticipate complications. This is particularly important for neurotoxic envenoming which, depending on the snake species involved, may not respond to available antivenoms. Adequate species identification tools are lacking. This study used a combination of morphological and molecular approaches (PCR-aided DNA sequencing from swabs of bite sites) to determine the contribution of venomous and non-venomous species to the snakebite burden in southern Nepal. Out of 749 patients admitted with a history of snakebite to one of three study centres, the biting species could be identified in 194 (25.9%). Out of these, 87 had been bitten by a venomous snake, most commonly the Indian spectacled cobra (Naja naja; n = 42) and the common krait (Bungarus caeruleus; n = 22). When both morphological identification and PCR/sequencing results were available, a 100% agreement was noted. The probability of a positive PCR result was significantly lower among patients who had used inadequate “first aid” measures (e.g. tourniquets or local application of remedies). This study is the first to report the use of forensic genetics methods for snake species identification in a prospective clinical study. If high diagnostic accuracy is confirmed in larger cohorts, this method will be a very useful reference diagnostic tool for epidemiological investigations and clinical studies.