Estudio de las infecciones virales respiratorias y desarrollo posterior de sibilancias recurrentes en una cohorte de niños de la Comunidad de Madrid

  1. Fernández Rincón, Adelaida
Supervised by:
  1. María Luz García García Director
  2. Cristina Calvo Rey Director

Defence university: Universidad Autónoma de Madrid

Fecha de defensa: 21 September 2017

  1. Francisco Javier Ruza Tarrio Chair
  2. María José Mellado Peña Secretary
  3. Teresa del Rosal Rabes Committee member
  4. Iciar Olabarrieta Arnal Committee member
  5. Teresa Hernández-Sampelayo Matos Committee member

Type: Thesis


Abstract 9 ABSTRACT Background Acute respiratory viral infections, make up the most frequent infectious diseases on humans. They associate an important morbidity, representing a huge health, social and familiar burden during epidemics. During the first years of life, these infections cause a wide range of clinical manifestations being most of them mild or self-limited, although up to 7-13% require hospitalization. Wheezing are common symptom among infants and toddlers, and one out of three will present one episode before three years of age, most of them related to viral infections. Nevertheless the meaning of respiratory viruses identified in asymptomatic children and its role in the development of recurrent wheezing (RW) is under investigation. Although respiratory syncitial virus (RSV) and human rhinovirus (HRV) are the most frequent identified agents, the improvement of the molecular techniquesfor virus detection in the last decades have allowed to identify new viruses and to determine its implication in respiratory infections (human metapneumovirus, bocavirus, etc.) In fact, all respiratory viruses could be associated to bronchiolitis and wheezing, being the most frequent difficulty breathing condition during the first months of life. To suffer a bronchiolitis due to RSV is considered an independent risk factor for the development of RW. Most of studies that have analyzed the relationship between viral infections and the appearance of RW, have been carried out on selected hospitalized patients or in populations with concrete risk factors like familiar background of asthmaatopy. We believe that the different clinical severity of viral infections, might have a relationship with further episodes of RW. Aims To analyze the relationship between the severity of viral respiratory infections of different severity and further development of RW, in a cohort of unselected children for their risk factors, during the first two years of life. Abstract 10 To describe the incidence and the clinical features of asymptomatic, mild, and severe viral respiratory infections. To evaluate any possible relationship between the different etiologic agents, the early onset of respiratory infections, and the environmental or familiar risk factors with the development of RW in the short term. Patients and methods An observational prospective study on viral respiratory infections was carried out, in a cohort of children recruited in the early days of life; in five different Primary Health Care Centres of two cities of the province of Madrid (Spain). The study was approved by The Medical Ethics Committee of Severo Ochoa Hospital and by the Medical management of primary care unit (Leganés. Madrid) All infants borne between september 2012 and august 2013 whose parents or legal tutors accepted to participate, were incluided in the study. Informed consent was given in all cases. Familiar and epidemiologic data were collected. All the episodes of acute respiratory infections that occurred in the first two years of life were analyzed; assessing clinical date and identifying sixteen respiratory viruses by use polymerase chain reaction (PCR) techniques in nasopharyngeal aspirate. During the follow up, samples of nasopharyngeal aspirate were taken for further analysis in asymptomatic children. The presence of RW was defined as three or more episodes of wheezing, excluding acute bronchiolitis. Statistical analysis was carried out whit SPSS, versión 21 (SPSS Inc. Chicago, IL, USA). Results A total of 421 children were included in the study (54.9% males and 45.1% females); 83% were spaniards. Of those 1.9% were premature babies. We found that 44.9% of all the infants had older siblings living with them at their homes. The median of members of the family at home was 3 (interquartile range IQR 2-4 members). Abstract 11 Regarding familiar predisposition to asthma-atopy 19.5% of mothers, 29.7% of fathers and 11.6% of siblings had pathologic backgrounds. 34.6% of children were exposed to tobacco smoke at their homes. 40.4% of children attended to day care and 83.4% of them were breastfed (60% for at least six months and 40 % for less than six months). At least one virus was identified in 91.9% of the children during the study, with a median age of the first positive identification of 2 months (IQR 1-5 months), being the most common pathogen detected HRV in 68.7% of cases. Multiple viral infections occurred in 9.3% of the positive samples. The clinical situation of the first infection was asymptomatic in 64.8% of cases, mild in 29.4% and severe in 5.7%; being the most common diagnosis upper respiratory tract infection (URTI) in 58.5%, follow by bronchiolitis in 34.8%. Mild respiratory infection was suffered by 61.7% of the children (n=260), while 9.5% of the whole population of the study needed hospitalization (n=40). The most frequent diagnosis of mild respiratory infections was URTI in 56.1%. At least one virus was detected in 78.9% of cases and coinfections in 16.4%, being the most prevalent viral agent HRV in 40.5% of cases, followed by RSV in 13.1% and parainfluenza virus in 13% of cases. The number of outpatients infections per child were 3 (IQR 2-4 episodes). Among severe infections, RSV was the most common pathogen (39.1%), followed by HRV (37.5%). Fever was present in 57.4% of severe infections and hypoxia was associated in 67.1% of episodes. The length of stay at the hospital showed a median of 5 days (IQR 3- 6.3). Pathological radiologic signs were observed in 28.2% of cases and were treated whit antibiotics 25% of them. Admission at intensive care unit was required in 12.2% of hospitalized patients. During the follow-up of healthy controls a total of 1597 nasopharyngeal aspirates samples were analyzed. At least one virus was identified in 33.6 % of cases (n=537), and coinfections in 12.1% (n=194). HRV was detected in 70% of samples, followed by adenovirus (AdV) in 10%, parainfluenza 4.6% and RSV in 3%. Of the total number of patients incluided in this study, 13% developed RW, whit a median of 4 episodes (IQR 3.5-6). Abstract 12 Although no significant differences were found in the development of RW regardless the severity of the infection classified as asymptomatic, mild or severe, we observed that whit the clinical signs were bronchiolitis, the risk of RW was sevenfold in comparison to others diagnosis. After the bivariate analysis of the risk factors for the development of RW, we found the the following associations: to have siblings OR 2.8 (95% confidence intervals (CI) 1.4-5.8 p=0.004); to have siblings whit atopic-asthma background OR 2.5 (95% CI 1.2-5.3 p=0.009), to suffer bronchiolitis in contrast to any other clinical diagnosis OR 5.5 (95% CI 2.7-10.9 p ≤ 0.001); symptomatic infection in comparison to asymptomatic OR 2.4 (95% CI 1.3-4.4 p=0.002); first respiratory infection in the first 3 months of life OR 1.9 (95% CI 1.045-3.7 p=0.036) and breastfeeding for at least 6 months OR 0.51 (95% CI 0.26-0.98 p=0.041). We carried out a multiple logistic regression model, observing that to suffer any viral respiratory infection in the first 3 months of life, was an independent risk factor associated with development of RW (adjusted odds ratio) aOR 2.3 (95% CI 1.1-4.5 p=0.019). To undergo a bronchiolitis increased almost seven fold the risk of RW, aOR 6.8 (95%CI 3.3-14.2 p=0.000) and to have siblings whit atopic-asthma background increased 2.6 times the risk of developing RW aOR 2.6 (95% CI 1.1-5.9 p=0.020). Modifiable risk factors like day care attendanceor parent who smoke, didn´t show significant association in our cohort. Breastfeeding, for at least 6 months, showed nearsignificant association with RW, acting possibly as a protection factor against RW. Conclusions In our series, to undergo a viral respiratory infection regardless its severity, included asymptomatic infection, in the first 3 months of life, even considering acute bronchiolitis was an independent risk factor for the development of RW in the two years follow-up period. To have siblings with history of asthma-atopy was also related to RW. On the other hand, we didn´t observe association between attendance to day care or family history of Abstract 13 smoking or even the different viral agent causing simple or multiple infections with RW. Breastfeeding for at least 6 months showed near-significant association, ando could be a modifiable factor of protection against RW, althougt the size of our study has not allowed us to prove it. Key words Birth cohort, respiratory infections, viral infections, asymptomatic infections, recurrent wheezing, toddlers, respiratory sincitial virus, rhinovirus.