Acute respiratory infections (ARI) caused by influenza and other respiratory viruses affect millions of people annually. Although usually self-limiting a more complicated or severe course may occur in previously healthy people but are more likely in individuals with underlying illnesses. The most common viral agent is rhinovirus whereas influenza is less frequent but is well known to cause winter epidemics. In primary care, rapid diagnosis of influenza virus infections is essential in order to provide treatment. Clinical presentations vary among the different pathogens but may overlap and may also depend on host factors. Predictive models have been developed for influenza but study results may be biased because only individuals presenting with fever were included. Most of these models have not been adequately validated and their predictive power, therefore, is likely overestimated. The main objective of this thesis was to compare different mathematical models for the derivation of clinical prediction rules in individuals presenting with symptoms of ARI to better distinguish between influenza, influenza A subtypes and entero-/rhinovirus-related illness in children and adults and to evaluate model performance by using data-splitting for internal validation. Data from a completed prospective cluster-randomized trial for the indirect effect of influenza vaccination in children of Hutterite communities served as a basis of my thesis. There were a total of 3288 first episodes per season of ARI in 2202 individuals and 321 (9.8%) influenza positive events over three influenza seasons (2008-2011). The data set was divided into children under 18 years and adults. Both data sets were randomly split by subjects into a derivation (2/3 of the dataset) and a validation population (1/3 of the dataset). All predictive models were developed in the derivation sets. Demographic factors and the classical symptoms of ARI were evaluated with logistic regression and Cox proportional hazard models using forward stepwise selection applying robust estimators to account for non-independent data and by means of recursive partitioning. The beta coefficients of the independent predictors were used to develop different point scores. These scores were then tested in the validation groups and performance between validation and derivation set was compared using receiver operating characteristics (ROC) curves. We determined sensitivities and specificities, positive and negative predictive values, and likelihood ratios at different cut-points which could reflect test and treatment thresholds. Fever, chills, and cough were the most important predictors in children whereas chills and cough but not fever were most predictive of influenza virus infection in adults. Performance of the individual models was moderate with areas under the receiver operating characteristic curves between 0.75 and 0.80 for the main outcome influenza A or B virus infection. There was no statistically significant difference in performance between the derivation and validation sets for the main outcome. The results have shown, that various mathematical models have similar discriminative ability to distinguish influenza from other respiratory viruses. The scores could assist clinicians in their decision-making. However, performance of the models was slightly overestimated due to potential clustering of data and the results would first needed to be validated in a different population before application in clinical practice. / Thesis / Master of Science (MSc) / Every year, millions of people are attacked by "the flu" or the common cold. Certain signs and symptoms apparently are more discriminative between the common cold and the flu. However, the decision between starting a simple symptom orientated treatment, treating empirically for influenza or ordering a rapid diagnostic test that has only moderate sensitivity and specificity can be challenging. This thesis, therefore, aims to help physicians in their decision-making process by developing simple scores and decision trees for the diagnosis of influenza versus non-influenza respiratory infections. Data from a completed trial for the indirect effect of influenza vaccination in children of Hutterite communities served as a basis of my thesis. There were a total of 3288 first seasonal episodes of ARI in 2202 individuals and 321 (9.8%) influenza positive events over three influenza seasons (2008-2011). The data set was divided into children under 18 years and adults. Both data sets were split into a derivation and a validation set (=holdout group). Different mathematical models were applied to the derivation set and demographic factors as well as the classical symptoms of ARI were evaluated. The scores generated from the most important factors that remained in the model were then tested in the validation group and performance between validation and derivation set was compared. Accuracy was determined at different cut-points which could reflect test and treatment thresholds. Fever, chills, and cough were the most important predictors in children whereas chills and cough but not fever were most predictive of influenza virus infection in adults. Performance of the individual models was moderate for the main outcome influenza A or B virus infection. There was no statistically significant difference in performance between the derivation and validation sets for the main outcome. The results have shown, that various mathematical models have similar discriminative ability to distinguish influenza from other respiratory viruses. The scores could assist clinicians in their decision-making. However, the results would first needed to be validated in a different population before application in clinical practice.

Contexte : Les infections respiratoires aiguës (ARI) sont reconnues comme une cause importante de morbidité, de mortalité et d'hospitalisation chez les enfants dans les pays en développement. Le virus respiratoire syncytial humain (HRSV) est l’agent étiologique principal de maladie sévère des voies respiratoires basses chez les nourrissons, les jeunes enfants et les personnes âgées. Identifié en 2001, le Metapneumovirus humain (HMPV) est un nouveau paramyxovirus. Les études ont montré la cocirculation des sous groupes de ces deux virus avec la domination de l’un des sous groupes selon les zones géographiques et selon les années. Les données restent cependant limitées dans les pays de l’Afrique subsaharienne, sur la prévalence, la saisonnalité et la caractérisation génétique de ces deux virus respiratoires. Au Cameroun, ces deux virus ont été décrits seulement une seule fois (5,7 et 5% pour HRSV et HMPV respectivement) chez des patients présentant des syndromes grippaux en 2012. Objectif : Cette étude rapporte la prévalence, la saisonnalité et la variabilité génétique des souches HRSV et HMPV chez des enfants camerounais pendant 3 saisons épidémiques consécutives (de Septembre 2011 à Octobre 2014). Par ailleurs, la diversité génétique d’autres virus respiratoires détectés au cours de ce travail est présentée comme objectif secondaire.Méthodes : Une surveillance prospective a été menée pour identifier les enfants hospitalisés et ambulatoires âgés de moins de 15 ans présentant des symptômes respiratoires ≤ 5 jours. Les échantillons nasopharyngés ont été testés pour 17 virus respiratoires en utilisant une réaction multiplex de polymérisation en chaîne. La distribution virale et les données démographiques ont été analysées statistiquement. Les échantillons positifs du HRSV et HMPV ont été amplifiés par polymérisation en chaine semi nichée puis séquencés partiellement au niveau du gène G. Des analyses phylogénétiques ont été effectuées sur les séquences nucléotidiques et protéiques partielles du gène G.Résultats : De septembre 2011 à octobre 2014, 822 enfants âgés de moins de 15 ans ont été inscrits dans l’étude. Au moins un virus a été identifié chez chacun des 72,6% (597/822) d'enfants, dont 31,7% (189/597) étaient des codétections; 28,5% (226/822) étaient positifs pour l'adénovirus humain, 21,4% (176/822) pour le virus Influenza, 15,5% (127.822) pour le rhinovirus/entérovirus, 9,4% (77/822) pour le bocavirus, 9% (74/822) pour le HRSV, 8,2% (67/822) pour les coronavirus humain, 6,2% (50/822) pour le parainfluenzavirus humain et 3,9% (32/822) pour le HMPV. L’infection HRSV était plus fréquente chez les enfants de moins de 2 ans (70,3% ; 52/74) et chez les participants hospitalisés (70,3% ; 52/74). Alors que le HRSV a montré un profil saisonnier avec une circulation de septembre à décembre, des cas sporadiques de HMPV ont été détectés tout au long de l'année. HRSV-A (19,1%, 9/47) et HRSV-B (17% ; 8/47) ont été observés relativement à la même fréquence avec (63,8% ; 30/47) de cas en codétection HRSV-A/HRSV-B alors que HMPV-A (71,4% ; 10/14) était majoritaire comparé à HMPV-B (28,6 ; 4/14). L'analyse phylogénétique a révélé que les souches HRSV de l’étude sont groupées au sein du sous groupe NA-1 (pour HRSV-A) et BA-9 (pour HRSV-B). Les souches HMPV camerounaises sont groupés parmi les membres du génotype A2b (pour HMPV-A), B1 et B2 (pour HMPV-B).Conclusion : Cette étude suggère qu’environ 70% des ARI enregistrés chez des enfants au Cameroun sont causés par des virus. La présente étude est également le premier rapport sur la variabilité génétique du gène G des souches de HRSV et HMPV dans la région. Bien que ce travail comble partiellement certaines lacunes d’informations, des études supplémentaires sont requises pour une clarification de l’épidémiologie moléculaire et du mode d’évolution des virus respiratoires présents en Afrique subsaharienne en général et plus singulièrement au Cameroun. / Background: Acute respiratory infections (ARI) are recognized as an important cause of morbidity, mortality and hospitalization among children in developing countries. Human respiratory syncytial virus (HRSV) is the main cause of severe lower respiratory tract disease in infants, young children and the elderly. Identified in 2001, Human Metapneumovirus (HMPV) is a new paramyxovirus. Studies have shown the co-circulation of the subgroups of these two viruses with domination of one of the sub-groups according to the geographical zones and according of years. These two viruses encode two major surface glycoproteins, the highly conserved fusion F protein and the highly variable attachment G protein. Data are still limited in sub-Saharan African countries on prevalence, seasonality and genetic characterization of these two respiratory viruses. In Cameroon, these two viruses have been described only once (5.7 and 5% for HRSV and HMPV respectively) in patients with influenza-like illness in 2012.Objective: This study reports the prevalence, seasonality and the genetic variability of HRSV and HMPV strains in Cameroonian children for 3 consecutive epidemic seasons (September 2011-October 2014). Moreover, the genetic diversity of other respiratory viruses detected during this work is presented as a secondary objective.Methods: A prospective surveillance was conducted to identify inpatient and outpatient children less than 15 years with respiratory symptoms ≤ 5 days. The nasopharyngeal samples were tested for 17 respiratory viruses using a multiplex polymerase chain reaction. Viral distribution and demographic data were analyzed statistically. Positive samples for HRSV and HMPV were amplified by semi-nested polymerize chain reaction and then partially sequenced at the G gene. Phylogenetic analyzes were performed on the partial nucleotide and protein sequences of the G gene.Results: From September 2011 to October 2014, 822 children under 15 years were enrolled in the study. At least one virus was identified in each of 72.6% (577/822) of children, 31.7% (189/597) of whom were co-detections; 28.5% (226/822) were positive for human adenovirus, 21.4% (176/822) for influenza virus, 15.5% (127.822) for rhinovirus/enterovirus, 9.4% (77/822) for bocavirus, 9% (74/822) for HRSV, 8.2% (67/822) for human coronavirus, 6.2% (50/822) for human parainfluenzavirus, and 3.9% (32/822) for HMPV. HRSV infection was more frequent in children under 2 years (70.3%, 52/74) and hospitalized participants (70.3%, 52/74). While HRSV showed a seasonal pattern with circulation from September to December, sporadic cases of HMPV were detected throughout the year. HRSV-A (19.1%, 9/47) and HRSV-B (17%; 8/47) were observed relatively at the same frequency with (63.8%, 30/47) codetections of HRSV-A/HRSV-B. HMPV-A (71.4%; 10/14) was predominant compared to HMPV-B (28.6; 4/14). Phylogenetic analysis revealed that the HRSV strains of the study are grouped within subgroup NA-1 (for HRSV-A) and BA-9 (for HRSV-B). Cameroonian HMPV strains are grouped among the members of genotype A2b (for HMPV-A), B1 and B2 (for HMPV-B).Conclusion: This study suggests that about 70% of ARI recorded in children in Cameroon are caused by viruses. The present study is also the first report on the genetic variability of the G gene of HRSV and HMPV strains in the region. Although this work partially fills gaps for some information, additional studies are required to clarify the molecular epidemiology and evolutionary pattern of respiratory viruses in sub-Saharan Africa in general and more particularly in Cameroon.

Objetivo: Describir la distribución de patógenos responsables de IRA durante el período 2009-2010 en Cajamarca, Perú: en el contexto de la pandemia del virus de la Influenza AH1N1 2009. Resultados: Se encontraron 17 patógenos respiratorios (14 virus y 3 bacterias) en 124 niños, de los cuales el 50% eran hombres y el 50% mujeres, con un 55,6% (69/124) de 1 a 5 años y un 15,3% (19/124) de 6 a 11 años. Los patógenos más comunes fueron: Influenza A (20,2%, 25/124), Mycoplasma pneumoniae (14,5%, 18/124), RSV-A (12,1%, 15/124), Chlamydia pneumoniae (9,7%, 12/124). No se pudo identificar un patógeno específico en el 33,8% de los pacientes (42/124). Los signos y síntomas más comunes fueron fiebre 90,3%, tos 85,5%, rinorrea 74,2% y malestar 66,9%. El distrés respiratorio y la hospitalización fueron las complicaciones más comunes con 37,1% y 28,2% de los casos. Se informó una sola muerte de un niño diagnosticado con el virus de la influenza A. Además, se identificaron 12 casos de coinfecciones: 9 con 2 patógenos, 2 con tres patógenos y 1 con 4. Conclusión: Los patógenos respiratorios más comunes encontrados durante la pandemia de la Influenza AH1N1 2009-2010 fueron Influenza A, Mycoplasma pneumoniae, RSV-A y Chlamydia pneumoniae. La mayoría de patógenos presentan un perfil clínico similar Se detectaron varios casos de coinfecciones, con hasta 4 patógenos en un solo paciente. / Objective: To describe the distribution of pathogens responsible for ARI during the 2009-2010 period in Cajamarca, Peru: in the context of the 2009 AH1N1 influenza virus pandemic. Results: 17 respiratory pathogens (14 viruses and 3 bacteria) were found in 124 children, of which 50% were men and 50% women, with 55.6% (69/124) aged 1 to 5 years and a 15.3% (19/124) from 6 to 11 years old. The most common pathogens were Influenza A (20.2%, 25/124), Mycoplasma pneumoniae (14.5%, 18/124), RSV-A (12.1%, 15/124), Chlamydia pneumoniae (9,7%, 12/124). A specific pathogen could not be identified in 33.8% of patients (42/124). The most common signs and symptoms were fever 90.3%, cough 85.5%, rhinorrhea 74.2% and discomfort 66.9%. Respiratory distress and hospitalization were the most common complications with 37.1% and 28.2% of the cases. A single death was reported in a child diagnosed with influenza A virus. In addition, 12 cases of coinfections were identified: 9 with 2 pathogens, 2 with 3 pathogens, and 1 with 4. Conclusion: The most common respiratory pathogens encountered during the 2009-2010 AH1N1 influenza pandemic were influenza A, Mycoplasma pneumoniae, RSV-A, and Chlamydia pneumoniae. Most pathogens have a similar clinical profile. Several cases of coinfections were detected, with up to 4 pathogens in a single patient. / Tesis

Objetivo: describir y analizar la percepción sobre factores predisponentes a Infecciones Respiratorias Agudas en madres de preescolares de una comunidad de Pomalca. Método: Investigación cualitativa, descriptiva, en una muestra de 12 madres de preescolares de la comunidad el Combo, determinada por saturación y redundancia de datos, el muestreo fue no probabilístico por conveniencia. Los datos se recolectaron a través de la entrevista semiestructurada, la cual fue validada por juicio de expertos y por una prueba piloto en 2 madres que cumplían con los criterios de inclusión. Los datos fueron procesados por el método de análisis de contenido temático. Resultados: Se obtuvieron 4 categorías: identificación de factores individuales, reconocimiento de factores en la vivienda, asimismo, identificación de los factores familiares y reconocimiento de factores ambientales como factor predisponente. Conclusión: En su mayoría, las madres de familia tienen una percepción adecuada y reconocen los diversos factores que predisponen a presentar una IRA en los menores de 5 años. Reconocen de manera correcta dentro de los factores familiares, la presencia de algún familiar fumador debido a las sustancias tóxicas que pueden inhalar los preescolares; pero existe una percepción incorrecta sobre la asociación del fumador pasivo (inhala el humo del cigarrillo) con presentar TBC. / Objective: to describe and analyze the perception of predisposing factors to Acute Respiratory Infections in mothers of preschoolers in a community of Pomalca. Method: Qualitative, descriptive research, in a sample of 12 mothers of preschoolers from the Combo community, determined by data saturation and redundancy, sampling was non-probabilistic for convenience. The data were collected through a semi-structured interview, which was validated by expert judgment and by a pilot test on 2 mothers who met the inclusion criteria. The data were processed by the thematic content analysis method. Results: 4 categories were obtained: identification of individual factors, recognition of factors in the home, also, identification of family factors and recognition of environmental factors as a predisposing factor. Conclusion: For the most part, mothers have an adequate perception and recognize the various factors that predispose children under 5 years of age to having an ARI. They correctly recognize within family factors, the presence of a family member who smokes due to the toxic substances that preschoolers can inhale; But there is an incorrect perception about the association of passive smoking (inhaling cigarette smoke) with developing TB.

<p><strong>Background</strong>: Human rhinovirus/enterovirus (HRV/ENT) infections are commonly identified in children with acute respiratory infections (ARIs), but data on their clinical severity remains limited. We compared the clinical severity of HRV/ENT to respiratory syncytial virus (RSV), influenza A/B (FLU) and other common respiratory virus in children.</p> <p><strong>Methods</strong>: Retrospective study of children with ARIs and confirmed single positive viral infections on mid-turbinate swabs by molecular assays. Outcome measures included hospital admission and, for inpatients, a composite end-point consisting of intensive care admission, hospitalization greater than 5 days, oxygen requirements or death.</p> <p><strong>Results</strong>: A total of 116 HRV/ENT, 102 RSV, 99 FLU and 64 other common respiratory viruses were identified. Children with single HRV/ENT infections presented with significantly higher rates of underlying immunosuppressive conditions compared to those with RSV (37.9% vs 13.6%; p</p> <p><strong>Conclusions</strong>: Children with HRV/ENT had a more severe clinical course than those with RSV and FLUA/B infections and often had significant comorbidities. These findings emphasize the importance of considering HRV/ENT infection in children presenting with severe acute respiratory tract infections.</p> / Master of Science (MSc)