Emilie Mosnier

Histoplasmosis or Tuberculosis in HIV-Infected Patients in the Amazon: What Should Be Treated First?

Histoplasmosis and tuberculosis are probably among the most frequent AIDS-defining illnesses in the Amazon region and beyond [1]. Whereas tuberculosis is a well-known disease present in clinical algorithms and in specific public health programs, disseminated histoplasmosis is relatively neglected in South and Central America [2], [3]. Histoplasmosis and tuberculosis are often presented as clinically and paraclinically similar [4]. Recently, we showed that disseminated histoplasmosis, while having some similarities with tuberculosis, had some marked differences with more pulmonary signs and inflammation in tuberculosis whereas histoplasmosis was more likely to be associated with cytopenia, liver enzyme abnormalities, or symptoms from the abdominal sphere [5]. Histoplasmosis and tuberculosis in HIV patients often are disseminated infections with a fatal evolution in the absence of treatment. For both infections, diagnosis is often slow with cultures that may take weeks to isolate the pathogen [6]. Patients with severe disseminated histoplasmosis are at risk of early death within days of their admission, notably if there is treatment delay. For tuberculosis, early mortality in severely immunocompromised patients is also a problem and has led to promote early rather than late initiation of antiretroviral therapy [7]. In practice, once other common opportunistic infections have been excluded, clinicians facing a severely immunocompromised HIV patient will need to conduct investigations and start a presumptive treatment, which often includes antituberculosis drugs but not antifungal drugs. This heuristic of HIV care does not rely on precise epidemiologic data and should be adapted to the local epidemiology. In French Guiana, HIV is a major public health problem [8]. Histoplasmosisand tuberculosis incidences in HIV-infected patients are high [1], [9], [10]. Therefore, clinicians facing a severely immunocompromised patient often need to consider both alternatives and make a decision. Since what treatment to start and when to start it may lead to different survival chances in this very common differential diagnosis situation, we aimed to gather additional evidence to guide clinicians. Longitudinal data from the French Hospital Database on HIV infection (FHDH) in French Guiana between 1996–2008, described in [11], allowed us to collect incidence and mortality rates. The diagnosis of histoplasmosis was performed according to the European Organisation for Research and Treatment of Cancer (EORTC) criteria [12]. The diagnosis of tuberculosis relied on confirmed tuberculosis (culture and identification of Mycobacterium tuberculosis). All HIV patients in French Guiana can receive free antiretroviral treatments (including the most recent drugs) regardless of their origin or socioeconomic level. A total of 2,323 patients were included. This amounted to 40,443 records and 9,608 years at risk. There were 141 first episodes of disseminated histoplasmosis observed and 119 cases of confirmed tuberculosis. Figure 1 shows the incidence rates of first episodes of disseminated histoplasmosis and of tuberculosis for different CD4 strata, and the gradual increase of the incidence rate ratio of histoplasmosis/tuberculosis as immunosuppression increases. Figure 1 Shows the incidence rate for tuberculosis and histoplasmosis for different CD4 strata. Figure 2 shows the respective Kaplan Meier curves for survival for histoplasmosis and tuberculosis in patients with CD4 counts below 200 cells per mm3 within the first 12 months after the opportunistic infection. Histoplasmosis seemed to lead to more deaths than tuberculosis; however, this difference was not statistically significant. For the 141 patients with a first episode of histoplasmosis, there were 13.5% of deaths at one month, 17.5% at three months, and 22.5% at six months after the date of diagnosis of histoplasmosis. Among 119 first episodes of confirmed tuberculosis, 68 were in patients with CD4 counts less than 200 cells per mm3. For patients with CD4 counts below 200 cells per mm3, there was 10% mortality at one month, 19% at three months, and 31% at six months. Figure 2 Shows the incidence of death during the first year afer histoplasmosis or tuberculosis among patients with CD4 counts less than 200. For clinicians, the situation where a severely immunocompromized HIV-infected patient is admitted for a “tuberculosis-like” illness is common and requires prompt identification and treatment of both the opportunistic agent and the underlying immunosuppression. Ideally, treatments should be administered once the opportunistic agent has been identified. However, in the Amazon region, invasive diagnostic procedures are often not performed or available, and laboratory facilities are lacking. Thus, empirical treatment remains an important strategy. Despite the potential adverse events or drug interactions, it is common to simultaneously treat different confirmed or suspected opportunistic infections. However, when possible, it is preferable to target the most likely agent than to give numerous drugs, which makes it difficult to know what leads to improvement or what drug leads to adverse events [13]. In an Amazonian context, among immunosuppressed patients, the incidence of histoplasmosis was higher than that of tuberculosis. Despite comparable overall mortality in terms of proportion of patients with histoplasmosis and tuberculosis dying, the number of histoplasmosis-related deaths was higher. Thus, for HIV patients with CD4 counts below 200 with a tuberculosis-like syndrome (histoplasmosis-like may be a more appropriate heuristic in our epidemiological context), clinicians with poor diagnostic facilities may be better inspired, given the differences in incidence rates, to start with amphotericin B (ideally in its liposomal formulation) than antituberculosis drugs and reevaluate the situation 3–7 days later in view of the treatment response [6], [14]. As shown elsewhere [15], the data also suggests antiretrovirals should be started without delay in order to minimize the duration of the severe immunosuppression that puts the patient at great risk of dying from other opportunistic agents.

Unraveling the genetic diversity and phylogeny of Leishmania RNA virus 1 strains of infected Leishmania isolates circulating in French Guiana

Introduction Leishmania RNA virus type 1 (LRV1) is an endosymbiont of some Leishmania (Vianna) species in South America. Presence of LRV1 in parasites exacerbates disease severity in animal models and humans, related to a disproportioned innate immune response, and is correlated with drug treatment failures in humans. Although the virus was identified decades ago, its genomic diversity has been overlooked until now. Methodology/Principles findings We subjected LRV1 strains from 19 L. (V.) guyanensis and one L. (V.) braziliensis isolates obtained from cutaneous leishmaniasis samples identified throughout French Guiana with next-generation sequencing and de novo sequence assembly. We generated and analyzed 24 unique LRV1 sequences over their full-length coding regions. Multiple alignment of these new sequences revealed variability (0.5%–23.5%) across the entire sequence except for highly conserved motifs within the 5’ untranslated region. Phylogenetic analyses showed that viral genomes of L. (V.) guyanensis grouped into five distinct clusters. They further showed a species-dependent clustering between viral genomes of L. (V.) guyanensis and L. (V.) braziliensis, confirming a long-term co-evolutionary history. Noteworthy, we identified cases of multiple LRV1 infections in three of the 20 Leishmania isolates. Conclusions/Significance Here, we present the first-ever estimate of LRV1 genomic diversity that exists in Leishmania (V.) guyanensis parasites. Genetic characterization and phylogenetic analyses of these viruses has shed light on their evolutionary relationships. To our knowledge, this study is also the first to report cases of multiple LRV1 infections in some parasites. Finally, this work has made it possible to develop molecular tools for adequate identification and genotyping of LRV1 strains for diagnostic purposes. Given the suspected worsening role of LRV1 infection in the pathogenesis of human leishmaniasis, these data have a major impact from a clinical viewpoint and for the management of Leishmania-infected patients.

A Large Outbreak of Thiamine Deficiency Among Illegal Gold Miners in French Guiana.

From September 2013 to July 2014, several gold miners working in the tropical forest consulted the Maripasoula Health Center in French Guiana for edema and findings consistent with right-sided cardiac failure. Of the 42 cases of beriberi that were diagnosed, one patient died. The laboratory and clinical investigation demonstrated vitamin B1 deficiency in most of the patients tested. Furthermore, 30 of 42 patients responded favorably to 500 mg of intravenous or intramuscular thiamine supplementation. In addition, dietary investigation showed insufficient thiamine intake in these patients. We concluded that patients had acquired beriberi because of diet restrictions, hard labor, and infectious diseases, notably malaria. In 2016, cases were still being reported. We recommend screening for compatible symptoms in gold miners, thiamine supplementation, and nutritional intervention.

Incidence and predictive factors of transaminase elevation in patients consulting for dengue fever in Cayenne Hospital, French Guiana

BACKGROUND The objective of the study was to determine the incidence of transaminase elevation during dengue, and its predictive factors. METHODS In 2013, a longitudinal study was performed using data from all cases of dengue seen in Cayenne Hospital. Cox proportional modeling was used. Signs of major transaminase elevation were defined as an increase in aspartate amino transferase (AST) or alanine amino transferase (ALT) concentration over 10 times the normal value (10N). RESULTS There were 1574 patients and 13 249 person-days of follow-up. The incidence rate for signs of transaminase elevation (10N) was 0.55 per 100 person-days. Six patients had major transaminase elevation with AST>1000 units (0.43 per 1000 patient-days), and 73 patients (4.6%) developed transaminase elevation with AST >10N. The variables independently associated with major transaminase elevation were hyponatremia, low platelets, dehydration, hematocrit increase, food intolerance, positive nonstructural protein 1 (NS1), age over 15 years and the notion of paracetamol intake. CONCLUSIONS Although very frequent, the incidence of major transaminase elevation was lower than reported elsewhere perhaps because of good access to care, or of the particular serotype causing this epidemic. The patients with transaminase elevation tended to be older, more severe and taking paracetamol. .

Fatal case of chikungunya and concomitant thrombotic thrombocytopenic purpura in French Guiana during air flight medical evacuation

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy associated to severe ADAMTS13 deficiency. It has been linked to various viral infections. Among arboviruses, only Crimean-Congo haemorrhagic fever and dengue fever have been linked to this severe disease. We report the first documented case of TTP concomitant to Chikungunya virus infection.

[Zika virus outbreak in Latin America: what are the challenges for French Guiana in April 2016?].

Started in 2015 in Brazil, an outbreak linked to a little known arbovirus, Zika virus spread throughout Latin America. This virus, considered until recently as responsible of only mild symptoms, made mention of previously unsuspected complications, with severe neurological manifestations in adults and malformations of the central nervous system, including microcephaly, in newborns of mother infected during the pregnancy. While the continent is more accustomed to the succession of arbovirus epidemics, suspected complications and the many unknowns keys of the latter arriving raise many public health issues. French Guiana, a French territory located in the north-east of the continent, combines both European level of resources and climate and issues specific to the Amazon region and Latin America. We discuss here the issues for 2016 Zika virus epidemic in our region, many of them are generalizable to neighboring countries.

Predictive Factors of Herpes Zoster HIV-Infected Patients: Another Adverse Effect of Crack Cocaine

A retrospective cohort study was conducted on 1541 HIV-infected patients to determine variables associated with the incidence of herpes zoster. A single failure Cox model showed that herpes zoster incidence increased following the first 6 months of antiretroviral treatment adjusted hazard ratio (AHR)=5 (95%CI=2.6-9.2), P<0.001; in the >60 years age group AHR=2 (95%CI=1-4), P=0.04; in patients in the top CD8 quartile AHR=2.1 (95%CI=1.3-3.6), P<0.001; and in patients previously reported to use crack cocaine AHR=5.9, (95%CI=1.4-25), P=0.02. Herpes zoster incidence increased in patients with CD4 counts<500 per mm3 and gradually declined since 1992-1996, with AHR=0.3 (95%CI=0.2-0.5), P<0.001 for the 1997-2002 period and AHR=0.24 (95%CI=0.14-0.4), P<0.001 for the 2002-2008 period. Contrary to what has been described elsewhere, there was no specific effect of protease inhibitors on herpes zoster incidence. The present study is the first to suggest that crack cocaine is associated with an increased incidence of herpes zoster. The neurological or immunological effects of crack are discussed.

La leptospirose en Guyane française et sur le bouclier des Guyanes. État des connaissances en 2016

Leptospirosis is a cosmopolitan zoonosis caused by bacteria of the genus Leptospira. Whether the distribution is worldwide, the hot and humid climate of the tropics is particularly conducive to its expansion. In most French overseas departments and territories, leptospirosis is considered as a public health problem. In French Guiana, a French department located in the northeastern part of the Amazon rainforest, it is supposed to be rare. The objective of this review was to make an inventory of the knowledge on human and animal leptospirosis in French Guiana and neighboring countries. A comprehensive search was conducted through the indexed and informal medical literature in English, French, Spanish and Portuguese. Thus, respectively ten and four publications were identified on human and animal leptospirosis in French Guiana, published between 1940 and 1995 in the form of case reports or case series. The publications concerning this disease in the other countries of the Guiana Shield, eastern Venezuela, Guyana, Suriname, and Brazilian state of Amapá, also scarce or nonexistent. However recent data from the French National Centre of leptospirosis showed a recent and sudden increase in the number of cases in the department, probably partly due to the development of diagnostic tools such as Elisa IgM serology. It is likely that leptospirosis is a neglected disease in the region, due to the lack of diagnostic tools readily available, the lack of knowledge of the local clinicians on this disease and the existence of many other pathogens with similar clinical presentation such as malaria, arboviruses and Q fever and Amazonian toxoplasmosis. The establishment of more large-scale studies on animal and human leptospirosis is necessary and urgent to know the true burden of this disease in our region.

Estimation of the duration between HIV seroconversion and HIV diagnosis in different population groups in French Guiana: Strategic information to reduce the proportion of undiagnosed infections

Background Given the great efforts put into the strategic objective of reducing the proportion of HIV-infected patients that are undiagnosed, the aim of the present study was to review the temporal trends between 1997 and 2016 for median estimates of infection duration and median CD4 count at diagnosis for the main patient origins in French Guiana. Methods CD4 cell count at HIV sero-conversion and square root of CD4 cell decline were obtained using the CD4 decline in a cohort of HIV-infected persons in the UK, fitting random effect (slope and intercept) multilevel linear regression models. Multivariate analysis used robust regression for modeling the delay between estimated HIV seroconversion and diagnosis and quantile regression for CD4 at HIV diagnosis. Results The median interval between the estimated HIV seroconversion and HIV diagnosis was 8 years for patients fromBrazil, 4.5 years for those from Haiti, 6.6 years for those from Suriname, 3.3 years for patients from Guyana, and 3.1 years for French patients. A simple robust regression model with French patients as reference group adjusting for sex and age at the time of diagnosis showed that the interval was significantly longer for Brazilian (β = +3.7 years, P = 0.001), Surinamese (β = +4.2 years, P<0.0001), Haitian origins (β = +1.5 years, P = 0.049) but not for those originating from Guyana (β = -0.03 years, P = 0.9); Men independently had a longer interval than women (β = +3.5 years, P<0.0001). Conclusions Despite great efforts in French Guiana regarding HIV testing both in terms of diversification and intensification we still need to tailor the offer to better reach the communities in need. These results should help authorities scale up and optimize initiatives to reduce the proportion of patients who are unaware of their infection. They also raise the question of the role of stigma and discrimination as a barrier to HIV testing in small communities, and further emphasize the importance of reducing it.

Incidence and Predictive Factors of Central Nervous System Dysfunction in Patients Consulting for Dengue Fever in Cayenne Hospital, French Guiana.

Introduction The frequency, the clinical characteristics, and the prognosis of dengue is highly variable. Dengue fever is associated with a range of neurological manifestations. The objective of the present study was to determine the incidence of neurological signs and their predictive factors using data from cases of dengue seen and followed in Cayenne Hospital during the Dengue 2 epidemic in 2013. Methods In 2013, a longitudinal study using data from all cases of dengue seen in Cayenne hospital was collected. Medical records used a standardized form to collect demographic information, clinical signs and biological results and the date at which they were present. The analysis used Cox proportional modeling to obtain adjusted Hazard ratios. Results A total of 1574 patients were included 221 of whom developed central nervous system signs. These signs were spontaneously resolutive. There were 9298person days of follow-up and the overall incidence rate for central nervous system signs was 2.37 per 100 person-days. The variables independently associated with central nervous system anomalies were headache, Adjusted Hazard ratio (AHR) = 1.9(95%CI = 1.4–2.6), bleeding AHR = 2 ((95%CI = 1.3–3.1), P = 0.001, abdominal pain AHR = 1.9 ((95%CI = 1.4–2.6), P<0.001, aches AHR = 2.1 ((95%CI = 1.5–2.9), P<0.001, and fatigue AHR = 1.5 ((95%CI = 1.3–1.7), P<0.001. Discussion Overall, the present study suggests that neurological signs of dengue are not exceptional even in patients without the most severe features of dengue. These manifestations were spontaneously resolutive. Here it was not possible to distinguish between encephalitis or encephalopathy. Further studies would require more in depth exploration of the patients.