Michel Boussinesq

The Global Burden of Disease Study 2010: Interpretation and Implications for the Neglected Tropical Diseases

The publication of the Global Burden of Disease Study 2010 (GBD 2010) and the accompanying collection of Lancet articles in December 2012 provided the most comprehensive attempt to quantify the burden of almost 300 diseases, injuries, and risk factors, including neglected tropical diseases (NTDs) [1]–[3]. The disability-adjusted life year (DALY), the metric used in the GBD 2010, is a tool which may be used to assess and compare the relative impact of a number of diseases locally and globally [4]–[6]. Table 1 lists the major NTDs as defined by the World Health Organization (WHO) [7] and their estimated DALYs [1]. With a few exceptions, most of the NTDs currently listed by the WHO [7] or those on the expanded list from PLOS Neglected Tropical Diseases [8] are disablers rather than killers, so the DALY estimates represent one of the few metrics available that could fully embrace the chronic effects of these infections. Table 1 Estimated DALYs (in millions) of the NTDs from the Global Burden of Disease Study 2010. Disease DALYs from GBD 2010 (numbers in parentheses indicate 95% confidence intervals) [1] NTDs 26.06 (20.30–35.12) Intestinal nematode infections 5.19 (2.98–8.81) Hookworm disease 3.23 (1.70–5.73) Ascariasis 1.32 (0.71–2.35) Trichuriasis 0.64 (0.35–1.06) Leishmaniasis 3.32 (2.18–4.90) Schistosomiasis 3.31 (1.70–6.26) Lymphatic filariasis 2.78 (1.8–4.00) Food-borne trematodiases 1.88 (0.70–4.84) Rabies 1.46 ((0.85–2.66) Dengue 0.83 (0.34–1.41) African trypanosomiasis 0.56 (0.08–1.77) Chagas disease 0.55 (0.27–1.05) Cysticercosis 0.50 (0.38–0.66) Onchocerciasis 0.49 (0.36–0.66) Trachoma 0.33 (0.24–0.44) Echinococcosis 0.14 (0.07–0.29) Yellow fever <0.001 Other NTDs * 4.72 (3.53–6.35) Open in a separate window * Relapsing fevers, typhus fever, spotted fever, Q fever, other rickettsioses, other mosquito-borne viral fevers, unspecified arthropod-borne viral fever, arenaviral haemorrhagic fever, toxoplasmosis, unspecified protozoal disease, taeniasis, diphyllobothriasis and sparganosis, other cestode infections, dracunculiasis, trichinellosis, strongyloidiasis, enterobiasis, and other helminthiases. Even DALYs, however, do not tell the complete story of the harmful effects from NTDs. Some of the specific and potential shortcomings of GBD 2010 have been highlighted elsewhere [9]. Furthermore, DALYs measure only direct health loss and, for example, do not consider the economic impact of the NTDs that results from detrimental effects on school attendance and child development, agriculture (especially from zoonotic NTDs), and overall economic productivity [10], [11]. Nor do DALYs account for direct costs of treatment, surveillance, and prevention measures. Yet, economic impact has emerged as an essential feature of the NTDs, which may trap people in a cycle of poverty and disease [10]–[12]. Additional aspects not considered by the DALY metrics are the important elements of social stigma for many of the NTDs and the spillover effects to family and community members [13], [14], loss of tourism [15], and health system overload (e.g., during dengue outbreaks). Ultimately NTD control and elimination efforts could produce social and economic benefits not necessarily reflected in the DALY metrics, especially among the most affected poor communities [11].

Serious reactions after mass treatment of onchocerciasis with ivermectin in an area endemic for Loa loa infection

BACKGROUND In 1995, the World Bank launched an African Programme for Onchocerciasis Control to eliminate Onchocerca volvulus disease from 19 African countries by means of community-based ivermectin treatment (CBIT). Several cases of encephalopathy have been reported after ivermectin in people heavily infected with microfilariae of Loa loa (loiasis). We assessed the incidence of serious events in an area where onchocerciasis and loiasis are both endemic. METHODS Ivermectin (at 150 micrograms/kg) was given to 17877 people living in the Lékié area of Cameroon. 50 microL samples of capillary blood were taken during the daytime before treatment from all adults (aged > or = 15 years), and the numbers of L loa and Mansonella perstans microfilariae in them were counted. Patients were monitored for 7 days after treatment. Adverse reactions were classified as mild, marked, or serious. Serious reactions were defined as those associated with a functional impairment that required at least a week of full-time assistance to undertake normal activities. We calculated the relative risk of developing marked or serious reactions for increasing L loa microfilarial loads. Risk factors for serious reactions were identified and assessed with a logistic regression model. FINDINGS 20 patients (0-11%) developed serious reactions without neurological signs but associated with a functional impairment lasting more than a week. Two other patients were in coma for 2-3 days, associated with L loa microfilariae in cerebrospinal fluid. Occurrence of serious reactions was related to the intensity of pretreatment L loa microfilaraemia. The relative risk of developing marked or serious reactions was significantly higher when the L loa load exceeded 8000 microfilariae/mL; for serious reactions, the risk is very high (odds ratio > 1000) for loads above 50000 microfilariae/mL. INTERPRETATION Epidemiological surveys aimed at assessing the intensity of infection with L loa microfilariae should be done before ivermectin is distributed for onchocerciasis control in areas where loiasis is endemic. In communities at risk, monitoring procedures should be established and adhered to during CBIT so that people developing serious reactions may receive appropriate treatment.

Th2 Cytokines Are Associated with Reduced Worm Burdens in a Human Intestinal Helminth Infection

Although T helper 2 (Th2) cytokines are known to be critical in the generation of protective immunity against intestinal helminths in mouse models, it is unclear whether they are important in natural immunity against gut helminthiases in humans. Therefore, we investigated cytokine production in ex vivo whole-blood cultures in response to Ascaris lumbricoides antigen and mitogen in a cross-section of a community where the parasite is hyperendemic. The intensity of A. lumbricoides infection was significantly reduced after age 11 years. Levels of cytokines associated with Th2 lymphocytes (interleukin [IL]-4, IL-9, IL-10, and IL-13) demonstrated an inverse relationship with intensity of A. lumbricoides infection only in individuals aged >11 years. Furthermore, the IL-9, IL-10, and IL-13 produced in response to parasite antigen were of primary importance in this relationship. These findings promote a role for Th2-mediated responses in the age-dependent reduction of intestinal helminth infections in humans.

Onchocerciasis modulates the immune response to mycobacterial antigens

Chronic helminth infection induces a type‐2 cellular immune response. In contrast to this, mycobacterial infections commonly induce a type‐1 immune response which is considered protective. Type‐2 responses and diminished type‐1 responses to mycobacteria have been previously correlated with active infection states such as pulmonary tuberculosis and lepromatous leprosy. The present study examines the immune responses of children exposed to both the helminth parasite Onchocerca volvulus and the mycobacterial infections, Mycobacterium tuberculosis and M. leprae. Proliferation of peripheral blood mononuclear cells (PBMC) and production of IL‐4 in response to both helminth and mycobacterial antigen (PPD) decreased dramatically with increasing microfilarial (MF) density. Although interferon‐gamma (IFN‐γ) production strongly correlated with cellular proliferation, it was surprisingly not related to MF density for either antigen. IL‐4 production in response to helminth antigen and PPD increased with ascending childrens age. IFN‐γ and cellular proliferation to PPD were not related to age, but in response to helminth antigen were significantly higher in children of age 9–12 years than children of either the younger age group (5–8 years) or the older group (13–16 years). Thus, there was a MF density‐related down‐regulation of cellular responsiveness and age‐related skewing toward type 2 which was paralleled in response to both the helminth antigen and PPD. This parasite‐induced immunomodulation of the response to mycobacteria correlates with a previous report of doubled incidence of lepromatous leprosy in onchocerciasis hyperendemic regions. Moreover, this demonstration that helminth infection in humans can modulate the immune response to a concurrent infection or immunological challenge is of critical importance to future vaccination strategies.

Effect of single-dose ivermectin on Onchocerca volvulus: a systematic review and meta-analysis

The broad-spectrum antiparasitic drug ivermectin was licensed for use against onchocerciasis in 1987, yet the mechanisms by which it exerts a fast decrease and long-lasting suppression of Onchocerca volvulus microfilaridermia, and inhibition of microfilarial release by female worms remain largely unknown. A better understanding of the effects of ivermectin on O volvulus microfilariae and macrofilariae is crucial to improve our ability to predict the long-term effect of treatment. We did a systematic review of individual and population-based ivermectin trials to investigate the temporal dynamics of the drugs microfilaricidal and embryostatic efficacy after administration of a single, standard dose (150 microg/kg). Meta-analyses on data from 26 microfilarial and 15 macrofilarial studies were linked by a mathematical model describing the dynamics of potentially fertile female parasites to skin microfilariae. The model predicts that after treatment, microfilaridermia would be reduced by half after 24 h, by 85% after 72 h, by 94% after 1 week, and by 98-99% after 1-2 months, the latter also corresponding to the time when the fraction of females harbouring live microfilariae is at its lowest (reduced by around 70% from its original value). Our results provide a baseline microfilarial skin repopulation curve against which to compare studies done after long-term treatment.

Effects of standard and high doses of ivermectin on adult worms of Onchocerca volvulus: a randomised controlled trial

BACKGROUND At present, control of onchocerciasis depends almost entirely on yearly treatments with 150 microg/kg ivermectin. We aimed to compare the effect of higher doses, more frequent doses, or both with the standard regimen on adult Onchocerca volvulus. METHODS We randomly allocated 657 patients who had onchocerciasis to 150 microg/kg ivermectin yearly (reference group), 150 microg/kg every 3 months, 400 then 800 microg/kg yearly, or 400 then 800 microg/kg every 3 months. We took skin snip samples from every patient before, and 3 years and 4 years after the first dose, and, at the same time excised one subcutaneous O volvulus nodule, which was examined histologically. The primary outcome was the vital status of the female worms. Analysis was done per protocol. FINDINGS We obtained nodules from 511 patients. After 3 years of treatment, more female worms had died in the groups treated every 3 months than in the reference group (odds ratio=1.84 [95% CI 1.23-2.75], p=0.003 for 150 microg/kg; and 2.17 [1.42-3.31], p<0.001 for high doses). Female worms were also less fertile in these groups than in the reference group (0.24 [0.14-0.43], p<0.0001; and 0.14 [0.06-0.29], p<0.0001, respectively). No difference was recorded between groups treated yearly (p=0.83 for the proportion of dead females). Unexpected side-effects consisted of mild, temporary, subjective visual changes in patients on high-dose regimens. INTERPRETATION Treatment with 3-monthly ivermectin could greatly reduce the number of female worms and acute itching and skin lesions; lower transmission of O volvulus; and change the duration of control programmes.

T Helper Cell Type 2 Responsiveness Predicts Future Susceptibility to Gastrointestinal Nematodes in Humans

Some humans are persistently more susceptible to gastrointestinal nematodes than others. Here, for the first time, susceptibility to reinfection has been linked to host cytokine responses. Ascaris lumbricoides and Trichuris trichiura abundance was assessed immediately before and 8-9 months after deworming in a Cameroonian population (starting n=191). Profiles of whole-blood cytokine responses to parasite antigens (for interleukin [IL]-5, IL-13, IL-10, IL-12p40, tumor necrosis factor- alpha , and interferon- gamma), assayed before treatment, were significantly related both to an overall measure of host susceptibility and to susceptibility to reinfection. Significant effects were primarily due to a negative association between IL-13 and IL-5 responses and infection. Persistently susceptible individuals were, therefore, characterized by a weak T helper cell type 2 response. The apparent plasticity of age-specific cytokine response-worm abundance relationships between different populations is also discussed.

Genetic Selection of Low Fertile Onchocerca volvulus by Ivermectin Treatment

Background Onchocerca volvulus is the causative agent of onchocerciasis, or “river blindness”. Ivermectin has been used for mass treatment of onchocerciasis for up to 18 years, and recently there have been reports of poor parasitological responses to the drug. Should ivermectin resistance be developing, it would have a genetic basis. We monitored genetic changes in parasites obtained from the same patients before use of ivermectin and following different levels of ivermectin exposure. Methods and Findings O. volvulus adult worms were obtained from 73 patients before exposure to ivermectin and in the same patients following three years of annual or three-monthly treatment at 150 µg/kg or 800 µg/kg. Genotype frequencies were determined in β-tubulin, a gene previously found to be linked to ivermectin selection and resistance in parasitic nematodes. Such frequencies were also determined in two other genes, heat shock protein 60 and acidic ribosomal protein, not known to be linked to ivermectin effects. In addition, we investigated the relationship between β-tubulin genotype and female parasite fertility. We found a significant selection for β-tubulin heterozygotes in female worms. There was no significant selection for the two other genes. Quarterly ivermectin treatment over three years reduced the frequency of the β-tubulin “aa” homozygotes from 68.6% to 25.6%, while the “ab” heterozygotes increased from 20.9% to 69.2% in the female parasites. The female worms that were homozygous at the β-tubulin locus were more fertile than the heterozygous female worms before treatment (67% versus 37%; p = 0.003) and twelve months after the last dose of ivermectin in the groups treated annually (60% versus 17%; p<0.001). Differences in fertility between heterozygous and homozygous worms were less apparent three months after the last treatment in the groups treated three-monthly. Conclusions The results indicate that ivermectin is causing genetic selection on O. volvulus. This genetic selection is associated with a lower reproductive rate in the female parasites. We hypothesize that this genetic selection indicates that a population of O. volvulus, which is more tolerant to ivermectin, is being selected. This selection could have implications for the development of ivermectin resistance in O. volvulus and for the ongoing onchocerciasis control programmes.

Clinical picture, epidemiology and outcome of Loa-associated serious adverse events related to mass ivermectin treatment of onchocerciasis in Cameroon

In August 2002, 65 cases of Loa-associated neurological Serious Adverse Events were reported after ivermectin treatment. The first signs, occurring within the 12–24 hours following treatment, included fatigue, generalized arthralgia, and sometimes agitation, mutism, and incontinence. Disorders of consciousness, including coma, generally appeared between 24 and 72 hours, and showed a rapid variation with time. The most frequent objective neurological signs were extrapyramidal. The patients presented with haemorrhages of the conjunctiva and of the retina. Biological examinations showed a massive Loa microfilaruria, the passage of Loa microfilariae into the cerebrospinal fluid, haematuria, and an increase in the C-reactive protein, all of which have been correlated with the high intensity of the initial Loa microfilaraemia. Eosinophil counts decreased dramatically within the first 24 hours, and then rose again rapidly. Electroencephalograms suggested the existence of a diffuse pathological process within the first weeks; the abnormalities disappearing after 3–6 months. Death may occur when patients are not properly managed, i.e. in the absence of good nursing. However, some patients who recovered showed sequelae such as aphasia, episodic amnesia, or extrapyramidal signs. The main risk factor for these encephalopathies is the intensity of the initial Loa microfilaraemia. The disorders of consciousness may occur when there are >50,000 Loa microfilariae per ml. The possible roles of co-factors, such as Loa strains, genetic predisposition of individuals, co-infestations with other parasites, or alcohol consumption, seem to be minor but they should be considered. The mechanisms of the post-ivermectin Loa-related encephalopathies should be investigated to improve the management of patients developing the condition.

Age- and Infection Intensity-Dependent Cytokine and Antibody Production in Human Trichuriasis: The Importance of IgE

The cytokine and antibody response to Trichuris trichiura infection was determined for 96 persons living in an area where the parasite is highly endemic and infection exhibits a convex age intensity profile. In response to stimulation with T. trichiura antigen, a small proportion of the study group produced interleukin (IL)-4 (7%), IL-9 (5%), and IL-13 (17%). A larger proportion produced IL-10 (97%), tumor necrosis factor (TNF)-alpha (93%), and interferon (IFN)-gamma (32%). The levels of TNF-alpha (P =.016) and IFN-gamma (P =.012) significantly increased with age, suggesting a switch to a more chronic infection phenotype. The predominant parasite-specific antibodies produced were IgG1, IgG4, IgA, and IgE. Unlike the IgG subclasses and IgA, parasite-specific IgE correlated negatively with infection intensity, as defined by egg output (P =.008), and positively with host age (P =.010). These findings suggest a mixed cytokine response in trichuriasis and an IgE-associated level of protection.