Impacts de l'environnement sur les diarrhées infantiles à Madagascar (Analyse du risque Campylobacter)

Les maladies diarrhéiques demeurent une cause majeure de mortalité infantile dans les pays en développement (PED). Du fait de l'insuffisance des plateaux techniques, les diagnostics étiologiques sont rarement réalisés et les traitements sont alors probabilistes. A Madagascar les données sur les diarrhées sont souvent parcellaires et anciennes. Le Réseau de surveillance sentinelle développé par l'Institut Pasteur de Madagascar à partir de 2007 nous a permis d'étudier la distribution spatio-temporelle des consultations pour diarrhée. Mais cette surveillance syndromique n'est pas couplée systématiquement à une surveillance biologique. Pour étudier les agents étiologiques des diarrhées, nous avons réalisé une enquête cas-témoins menée en 2008-2009 en milieu communautaire, chez les enfants de moins de 5 ans dans 14 districts. Nous avons pu identifier au moins un pathogène chez plus de la moitié des enfants (55%), avec une prédominance des étiologies parasitaires (37,2% des diarrhées), suivies par les bactéries (15%) puis les virus (6,7% de rotavirus). Les parasites ont été les seules étiologies pour lesquelles une pathogénicité a pu être mise en évidence. Parmi les étiologies bactériennes, l'infection à Campylobacter a été la plus fréquente (9,5%). Pour analyser le rôle de Campylobacter et les effets des facteurs environnementaux dans la survenue des diarrhées infantiles, nous avons initié et coordonné depuis 2010 une étude de cohorte dynamique d'enfants inclus avant l'âge de 24 mois et suivis jusqu'à l'âge de 36 mois à Moramanga, site où la prévalence de Campylobacter a été la plus élevée au cours de l'étude de 2008 (20,6%). Une surveillance des diarrhées a été menée 2 fois par semaine et les portages asymptomatiques évalués à l'inclusion et tous les 2 mois. Une étude de portage familial a été mise en œuvre ainsi qu'un suivi coprologique bi-annuel de la population avicole, des points d'eaux collectifs et de l'eau de boisson des familles. La recherche de Campylobacter chez les volailles portait sur les écouvillonnages rectaux. De janvier 2010 à mai 2012, 508 enfants correspondant à 256 346 enfant-jour ont participé à l'étude. La prévalence globale d'isolement de Campylobacter a été de 9,3%. Plus de 2/5 des enfants (43,3%) ont eu au moins un épisode d'infection à Campylobacter au cours de leur suivi. Les taux d'incidence annuelle des diarrhées ainsi que des infections symptomatiques ont été faibles, respectivement de 0,7 épisode /enfant et de 5,8 épisodes/100 enfant pouvant s'expliquer par le faible niveau d'exposition environnementale des enfants. Nous avons pu étudier l'importance des facteurs liés à l'hôte comme l'âge. Le pic d'infection à Campylobacter se situe entre 18 à 29 mois, celui des diarrhées entre 6 à 11 mois puis diminue ensuite. La 1ère infection à Campylobacter a été toujours pathogène chez les plus jeunes. Elle se situe vers le 8ème mois de la vie pour 10% d'entre eux. Les réinfections se font à des distances différentes de l'événement initial en fonction de l'âge. Ce profil d'infection pourrait traduire une compétence immunitaire différente selon l'âge et/ou une immunité acquise au cours du temps suite aux expositions répétées des enfants. L'environnement pourrait avoir un effet indirect dans l'entretien d'une immunité protectrice s'exprimant par un taux élevé d'infection asymptomatique. Il apparaît nécessaire de poursuivre des études de cohorte dans des zones à plus fort risque de transmission avec des données immunologiques car la compréhension actuelle des interactions entre l'hôte, le Campylobacter et l'environnement ne permet pas d'expliquer la variabilité de l'expression clinique de l'infection.Diarrheal diseases remain a major cause of infant mortality in developing countries (DCs). Due to the lack of technical platforms, the etiologic diagnoses are rarely made and treatments are then probabilistic. In Madagascar data on diarrhea are often fragmented and old. The sentinel surveillance network developed by the Institut Pasteur of Madagascar from 2007 allowed us to study the spatial and temporal distribution of consultations for diarrhea. But this syndromic surveillance cannot be coupled to biological monitoring for many diseases. In this context, we have no information on the causative agents of diarrhea. To achieve the coupling of syndromic and etiologic data, we performed a case-control study conducted in 2008-2009 in children less than 5 years in 14 districts. We have identified at least one pathogen in more than half of the children (55%), with a predominance of parasitic etiologies (37.2% diarrhea), followed by bacteria (15%) and viruses (6.7% rotavirus). Parasites were the only etiologies for which pathogenicity has been demonstrated. Among the bacterial etiologies, Campylobacter infection was the most common (9.5%). To better understand the role of Campylobacter in the occurrence of diarrhea in children and analyze the effect of environmental factors, we initiated and coordinated a dynamical cohort study including of children before the age of 24 months and followed up till the age of 36 months in Moramanga site, where the prevalence of Campylobacter was highest during the 2008 study (20.6%). Diarrhea surveillance was conducted two times per week and asymptomatic carriers assessed at baseline and every 2 months. A family study has been implemented and bi-annual stool follow-up in poultry population, water points and community drinking water for families. Campylobacter monitoring in poultry focused on rectal swabs. From January 2010 to May 2012, 508 children - corresponding to 256,346 child days -participated in the study. The overall prevalence of Campylobacter isolation was 9.3%. More than two fifths of children (43.3%) had at least one episode of Campylobacter during follow-up. The annual incidence of diarrhea and symptomatic infections were low, respectively 0.7 episodes / child and 5.8 episodes /100 children, can be explained by the low level of environmental exposure of children. We have studied the role of host factors such as age. The peak of Campylobacter infection is between 18 to 29 months, the diarrhea between 6 to 11 months then decreases. The first Campylobacter infection was always pathogen in the youngest children. It happens to the eighth month of life for 10% of them. Reinfections are at different distances from the initial event according to the age. This pattern of infection may reflect a variation of the immune competence according the age and / or acquired immunity over time after repeated exposure of the children. The local environment may have an indirect impact on maintaining protective immunity expressed by a high rate of asymptomatic infection. However, it is necessary to continue cohort study with immunologic data in a high risk transmission area as the current understanding of the interactions between the host, the environment and Campylobacter does not explain the variability of the clinical expression of infection.SAVOIE-SCD - Bib.électronique (730659901) / SudocGRENOBLE1/INP-Bib.électronique (384210012) / SudocGRENOBLE2/3-Bib.électronique (384219901) / SudocSudocFranceF

Remote sensing and urban malaria: radar Envisat contribution for the determination of potential Anopheles breeding site in Antananarivo (Madagascar)

International audienceMost studies of anopheline mosquito larval ecology have been done in rural settings. However, latest data based on two cross-sectional surveys in Antananarivo, the capitol of Madagascar, shown low rate of malaria cases among febrile episodes but autochthonous malaria cases exist. Anopheles funestus constitutes the main vector of malaria in the highlands of Madagascar. This paper described the determination of their potential breeding site using remotely sensed data. A supervised classification by the classical method of maximum likelihood was used for enhanced thematic mapper image of Landsat 7. Overall accuracy of the classification was 86% and kappa index was 0.835. Determination of landscape change by subtraction of images acquired on January and July was carried out for the Advanced Synthetic Aperture Image Precision images of Envisat. Increased backscatter coefficient between the two periods made possible to raise ambiguity between rice fields and other vegetation. That may improve the determination of potential anopheles breeding sites

Cutting sequences on Bouw-Moeller surfaces : an S-adic characterization.

Résumé. On considère un codage symbolique des géodésiques sur une famille de surfaces de Veech (surfaces de translation riches en symétries affines) récemment découverte par Bouw et Möller. Ces surfaces, comme l’a remarqué Hooper, peuvent être réalisées en coupant et collant une collection de polygones semi-réguliers. Dans cet article, on caractérise l’ensemble des suites symboliques (“suites de coupage”) qui correspondent au codage de trajectoires linéaires, à l’aide de la suite des côtés des polygones croisés. On donne une caractérisation complète de l’adhérence de l’ensemble des suites de coupage, dans l’esprit de la caractérisation classique des suites sturmiennes et de la récente caractérisation par Smillie-Ulcigrai des suites de coupage des trajectoires linéaires dans les polygones réguliers. La caractérisation est donnée en termes d’un système fini de substitutions (connu aussi sous le nom de présentation S-adique), réglé par une transformation unidimensionnelle qui ressemble à l’algorithme de fraction continue. Comme dans le cas sturmien et dans celui des polygones réguliers, la caractérisation est basée sur la renormalisation et sur la définition d’un opérateur combinatoire de dérivation approprié. Une des nouveautés est que la dérivation se fait en deux étapes, sans utiliser directement les éléments du groupe de Veech, mais en utilisant un difféomorphisme affine qui envoie une surface de Bouw-Möller vers sa surface “duale”, qui est dans le même disque de Teichmüller. Un outil technique utilisé est la présentation des surfaces de Bouw-Möller par les diagrammes de Hooper. ABSTRACT. We consider a symbolic coding for geodesics on the family of Veech surfaces (translation surfaces rich with affine symmetries) recently discovered by Bouw and Möller. These surfaces, as noticed by Hooper, can be realized by cutting and pasting a collection of semi-regular polygons. We characterize the set of symbolic sequences (cutting sequences) that arise by coding linear trajectories by the sequence of polygon sides crossed. We provide a full characterization for the closure of the set of cutting sequences, in the spirit of the classical characterization of Sturmian sequences and the recent characterization of Smillie-Ulcigrai of cutting sequences of linear trajectories on regular polygons. The characterization is in terms of a system of finitely many substitutions (also known as an S-adic presentation), governed by a one-dimensional continued fraction-like map. As in the Sturmian and regular polygon case, the characterization is based on renormalization and the definition of a suitable combinatorial derivation operator. One of the novelties is that derivation is done in two steps, without directly using Veech group elements, but by exploiting an affine diffeomorphism that maps a Bouw- Möller surface to the dual Bouw-Möller surface in the same Teichmüller disk. As a technical tool, we crucially exploit the presentation of Bouw-Möller surfaces via Hooper diagrams

The impact of COVID-19 on clinical research for Neglected Tropical Diseases (NTDs): A case study of bubonic plague.

BACKGROUND: Among the many collaterals of the COVID-19 pandemic is the disruption of health services and vital clinical research. COVID-19 has magnified the challenges faced in research and threatens to slow research for urgently needed therapeutics for Neglected Tropical Diseases (NTDs) and diseases affecting the most vulnerable populations. Here we explore the impact of the pandemic on a clinical trial for plague therapeutics and strategies that have been considered to ensure research efforts continue. METHODS: To understand the impact of the COVID-19 pandemic on the trial accrual rate, we documented changes in patterns of all-cause consultations that took place before and during the pandemic at health centres in two districts of the Amoron'I Mania region of Madagascar where the trial is underway. We also considered trends in plague reporting and other external factors that may have contributed to slow recruitment. RESULTS: During the pandemic, we found a 27% decrease in consultations at the referral hospital, compared to an 11% increase at peripheral health centres, as well as an overall drop during the months of lockdown. We also found a nation-wide trend towards reduced number of reported plague cases. DISCUSSION: COVID-19 outbreaks are unlikely to dissipate in the near future. Declining NTD case numbers recorded during the pandemic period should not be viewed in isolation or taken as a marker of things to come. It is vitally important that researchers are prepared for a rebound in cases and, most importantly, that research continues to avoid NTDs becoming even more neglected

An open-label, randomized, non-inferiority trial of the efficacy and safety of ciprofloxacin versus streptomycin + ciprofloxacin in the treatment of bubonic plague (IMASOY): study protocol for a randomized control trial.

BACKGROUND: Bubonic plague is the primary manifestation of infection with Yersinia pestis, accounting for 90% of all plague cases and with 75% of global cases reported in Madagascar. All drugs in use for treating plague are registered based on experimental data and anecdotal evidence, and no regimen currently recommended is supported by a randomized clinical trial. The IMASOY trial intends to fill this knowledge gap by comparing two 10-day regimens included in the national guidelines in Madagascar. The primary objective of the trial is to test the hypothesis that ciprofloxacin monotherapy is non-inferior to streptomycin followed by ciprofloxacin for the treatment of bubonic plague, thus avoiding the need for injectable, potentially toxic, aminoglycosides. METHODS: A two-arm parallel-group randomized control trial will be conducted across peripheral health centres in Madagascar in five districts. Males and non-pregnant females of all ages with suspected bubonic or pneumonic plague will be recruited over the course of three plague 'seasons'. The primary endpoint of the trial is to assess the proportion of patients with bubonic plague who have a therapeutic response to treatment (defined as alive, resolution of fever, 25% reduction in the size of measurable buboes, has not received an alternative treatment and no clinical decision to continue antibiotics) as assessed on day 11. DISCUSSION: If successful, the trial has the potential to inform the standard of care guidelines not just in Madagascar but in other countries afflicted by plague. The trial is currently ongoing and expected to complete recruitment in 2022. TRIAL REGISTRATION: ClinicalTrials.gov NCT04110340 . Registered on 1 October 2019

Viral Etiology of Influenza-Like Illnesses in Antananarivo, Madagascar, July 2008 to June 2009

In Madagascar, despite an influenza surveillance established since 1978, little is known about the etiology and prevalence of viruses other than influenza causing influenza-like illnesses (ILIs).From July 2008 to June 2009, we collected respiratory specimens from patients who presented ILIs symptoms in public and private clinics in Antananarivo (the capital city of Madagascar). ILIs were defined as body temperature ≥38°C and cough and at least two of the following symptoms: sore throat, rhinorrhea, headache and muscular pain, for a maximum duration of 3 days. We screened these specimens using five multiplex real time Reverse Transcription and/or Polymerase Chain Reaction assays for detection of 14 respiratory viruses. We detected respiratory viruses in 235/313 (75.1%) samples. Overall influenza virus A (27.3%) was the most common virus followed by rhinovirus (24.8%), RSV (21.2%), adenovirus (6.1%), coronavirus OC43 (6.1%), influenza virus B (3.9%), parainfluenza virus-3 (2.9%), and parainfluenza virus-1 (2.3%). Co-infections occurred in 29.4% (69/235) of infected patients and rhinovirus was the most detected virus (27.5%). Children under 5 years were more likely to have one or more detectable virus associated with their ILI. In this age group, compared to those ≥5 years, the risk of detecting more than one virus was higher (OR = 1.9), as was the risk of detecting of RSV (OR = 10.1) and adenovirus (OR = 4.7). While rhinovirus and adenovirus infections occurred year round, RSV, influenza virus A and coronavirus OC43 had defined period of circulation.In our study, we found that respiratory viruses play an important role in ILIs in the Malagasy community, particularly in children under 5 years old. These data provide a better understanding of the viral etiology of outpatients with ILI and describe for the first time importance of these viruses in different age group and their period of circulation

Seroprevalence of malaria in inhabitants of the urban zone of Antananarivo, Madagascar

BACKGROUND: Antananarivo, the capital of Madagascar, is located at an altitude of over 1,200 m. The environment at this altitude is not particularly favourable to malaria transmission, but malaria nonetheless remains a major public health problem. The aim of this study was to evaluate exposure to malaria in the urban population of Antananarivo, by measuring the specific seroprevalence of Plasmodium falciparum. METHODS: Serological studies specific for P. falciparum were carried out with an indirect fluorescent antibody test (IFAT). In a representative population of Antananarivo, 1,059 healthy volunteers were interviewed and serum samples were taken. RESULTS: The seroprevalence of IgG+IgA+IgM was 56.1% and that of IgM was 5.9%. The major risk factor associated with a positive IgG+IgA+IgM IFAT was travel outside Antananarivo, whether in the central highlands or on the coast. The abundance of rice fields in certain urban districts was not associated with a higher seroprevalence. CONCLUSION: Malaria transmission levels are low in Antananarivo, but seroprevalence is high. Humans come into contact with the parasite primarily when travelling outside the city. Further studies are required to identify indigenous risk factors and intra-city variations more clearly

Novel point-of-care cytokine biomarker lateral flow test for the screening for sexually transmitted infections and bacterial vaginosis: study protocol of a multicentre multidisciplinary prospective observational clinical study to evaluate the performance and feasibility of the Genital InFlammation Test (GIFT).

INTRODUCTION: A prototype lateral flow device detecting cytokine biomarkers interleukin (IL)-1α and IL-1β has been developed as a point-of-care test-called the Genital InFlammation Test (GIFT)-for detecting genital inflammation associated with sexually transmitted infections (STIs) and/or bacterial vaginosis (BV) in women. In this paper, we describe the rationale and design for studies that will be conducted in South Africa, Zimbabwe and Madagascar to evaluate the performance of GIFT and how it could be integrated into routine care. METHODS AND ANALYSIS: We will conduct a prospective, multidisciplinary, multicentre, cross-sectional and observational clinical study comprising two distinct components: a biomedical ('diagnostic study') and a qualitative, modelling and economic ('an integration into care study') part. The diagnostic study aims to evaluate GIFT's performance in identifying asymptomatic women with discharge-causing STIs (Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Trichomonas vaginalis (TV) and Mycoplasma genitalium (MG)) and BV. Study participants will be recruited from women attending research sites and family planning services. Several vaginal swabs will be collected for the evaluation of cytokine concentrations (ELISA), STIs (nucleic acid amplification tests), BV (Nugent score) and vaginal microbiome characteristics (16S rRNA gene sequencing). The first collected vaginal swab will be used for the GIFT assay which will be performed in parallel by a healthcare worker in the clinic near the participant, and by a technician in the laboratory. The integration into care study aims to explore how GIFT could be integrated into routine care. Four activities will be conducted: user experiences and/or perceptions of the GIFT device involving qualitative focus group discussions and in-depth interviews with key stakeholders; discrete choice experiments; development of a decision tree classification algorithm; and economic evaluation of defined management algorithms. ETHICS AND DISSEMINATION: Findings will be reported to participants, collaborators and local government for the three sites, presented at national and international conferences, and disseminated in peer-reviewed publications.The protocol and all study documents such as informed consent forms were reviewed and approved by the University of Cape Town Human Research Ethics Committee (HREC reference 366/2022), Medical Research Council of Zimbabwe (MRCZ/A/2966), Comité d'Ethique pour la Recherche Biomédicale de Madagascar (N° 143 MNSAP/SG/AMM/CERBM) and the London School of Hygiene and Tropical Medicine ethics committee (LSHTM reference 28046).Before the start, this study was submitted to the Clinicaltrials.gov public registry (NCT05723484). TRIAL REGISTRATION NUMBER: NCT05723484

Impact of the environment in childhood diarrhoea in Madagascar : Campylobacter risk analysis

Les maladies diarrhéiques demeurent une cause majeure de mortalité infantile dans les pays en développement (PED). Du fait de l'insuffisance des plateaux techniques, les diagnostics étiologiques sont rarement réalisés et les traitements sont alors probabilistes. A Madagascar les données sur les diarrhées sont souvent parcellaires et anciennes. Le Réseau de surveillance sentinelle développé par l'Institut Pasteur de Madagascar à partir de 2007 nous a permis d'étudier la distribution spatio-temporelle des consultations pour diarrhée. Mais cette surveillance syndromique n'est pas couplée systématiquement à une surveillance biologique. Pour étudier les agents étiologiques des diarrhées, nous avons réalisé une enquête cas-témoins menée en 2008-2009 en milieu communautaire, chez les enfants de moins de 5 ans dans 14 districts. Nous avons pu identifier au moins un pathogène chez plus de la moitié des enfants (55%), avec une prédominance des étiologies parasitaires (37,2% des diarrhées), suivies par les bactéries (15%) puis les virus (6,7% de rotavirus). Les parasites ont été les seules étiologies pour lesquelles une pathogénicité a pu être mise en évidence. Parmi les étiologies bactériennes, l'infection à Campylobacter a été la plus fréquente (9,5%). Pour analyser le rôle de Campylobacter et les effets des facteurs environnementaux dans la survenue des diarrhées infantiles, nous avons initié et coordonné depuis 2010 une étude de cohorte dynamique d'enfants inclus avant l'âge de 24 mois et suivis jusqu'à l'âge de 36 mois à Moramanga, site où la prévalence de Campylobacter a été la plus élevée au cours de l'étude de 2008 (20,6%). Une surveillance des diarrhées a été menée 2 fois par semaine et les portages asymptomatiques évalués à l'inclusion et tous les 2 mois. Une étude de portage familial a été mise en œuvre ainsi qu'un suivi coprologique bi-annuel de la population avicole, des points d'eaux collectifs et de l'eau de boisson des familles. La recherche de Campylobacter chez les volailles portait sur les écouvillonnages rectaux. De janvier 2010 à mai 2012, 508 enfants correspondant à 256 346 enfant-jour ont participé à l'étude. La prévalence globale d'isolement de Campylobacter a été de 9,3%. Plus de 2/5 des enfants (43,3%) ont eu au moins un épisode d'infection à Campylobacter au cours de leur suivi. Les taux d'incidence annuelle des diarrhées ainsi que des infections symptomatiques ont été faibles, respectivement de 0,7 épisode /enfant et de 5,8 épisodes/100 enfant pouvant s'expliquer par le faible niveau d'exposition environnementale des enfants. Nous avons pu étudier l'importance des facteurs liés à l'hôte comme l'âge. Le pic d'infection à Campylobacter se situe entre 18 à 29 mois, celui des diarrhées entre 6 à 11 mois puis diminue ensuite. La 1ère infection à Campylobacter a été toujours pathogène chez les plus jeunes. Elle se situe vers le 8ème mois de la vie pour 10% d'entre eux. Les réinfections se font à des distances différentes de l'événement initial en fonction de l'âge. Ce profil d'infection pourrait traduire une compétence immunitaire différente selon l'âge et/ou une immunité acquise au cours du temps suite aux expositions répétées des enfants. L'environnement pourrait avoir un effet indirect dans l'entretien d'une immunité protectrice s'exprimant par un taux élevé d'infection asymptomatique. Il apparaît nécessaire de poursuivre des études de cohorte dans des zones à plus fort risque de transmission avec des données immunologiques car la compréhension actuelle des interactions entre l'hôte, le Campylobacter et l'environnement ne permet pas d'expliquer la variabilité de l'expression clinique de l'infection.Diarrheal diseases remain a major cause of infant mortality in developing countries (DCs). Due to the lack of technical platforms, the etiologic diagnoses are rarely made and treatments are then probabilistic. In Madagascar data on diarrhea are often fragmented and old. The sentinel surveillance network developed by the Institut Pasteur of Madagascar from 2007 allowed us to study the spatial and temporal distribution of consultations for diarrhea. But this syndromic surveillance cannot be coupled to biological monitoring for many diseases. In this context, we have no information on the causative agents of diarrhea. To achieve the coupling of syndromic and etiologic data, we performed a case-control study conducted in 2008-2009 in children less than 5 years in 14 districts. We have identified at least one pathogen in more than half of the children (55%), with a predominance of parasitic etiologies (37.2% diarrhea), followed by bacteria (15%) and viruses (6.7% rotavirus). Parasites were the only etiologies for which pathogenicity has been demonstrated. Among the bacterial etiologies, Campylobacter infection was the most common (9.5%). To better understand the role of Campylobacter in the occurrence of diarrhea in children and analyze the effect of environmental factors, we initiated and coordinated a dynamical cohort study including of children before the age of 24 months and followed up till the age of 36 months in Moramanga site, where the prevalence of Campylobacter was highest during the 2008 study (20.6%). Diarrhea surveillance was conducted two times per week and asymptomatic carriers assessed at baseline and every 2 months. A family study has been implemented and bi-annual stool follow-up in poultry population, water points and community drinking water for families. Campylobacter monitoring in poultry focused on rectal swabs. From January 2010 to May 2012, 508 children - corresponding to 256,346 child days -participated in the study. The overall prevalence of Campylobacter isolation was 9.3%. More than two fifths of children (43.3%) had at least one episode of Campylobacter during follow-up. The annual incidence of diarrhea and symptomatic infections were low, respectively 0.7 episodes / child and 5.8 episodes /100 children, can be explained by the low level of environmental exposure of children. We have studied the role of host factors such as age. The peak of Campylobacter infection is between 18 to 29 months, the diarrhea between 6 to 11 months then decreases. The first Campylobacter infection was always pathogen in the youngest children. It happens to the eighth month of life for 10% of them. Reinfections are at different distances from the initial event according to the age. This pattern of infection may reflect a variation of the immune competence according the age and / or acquired immunity over time after repeated exposure of the children. The local environment may have an indirect impact on maintaining protective immunity expressed by a high rate of asymptomatic infection. However, it is necessary to continue cohort study with immunologic data in a high risk transmission area as the current understanding of the interactions between the host, the environment and Campylobacter does not explain the variability of the clinical expression of infection