ABSTRACT

Objective: To determine the prevalence of recurrent wheezing (RW) in preterm infants who received prophylaxis against severe infection with respiratory syncytial virus (RSV) and to identify genetic susceptibility (atopy or asthma) and risk factors for RW. Methods: This was a cross-sectional study involving preterm infants who received prophylaxis with palivizumab at a referral center in Brazil during the first two years of age. A structured questionnaire was administered in a face-to-face interview with parents or legal guardians. Results: The study included 410 preterm infants (median age = 9 months [0-24 months]). In the sample as a whole, 111 children (27.1%; [95% CI, 22.9-31.5]) had RW. The univariate analysis between the groups with and without RW showed no differences regarding the following variables: sex, ethnicity, maternal level of education, gestational age, birth weight, breastfeeding, number of children in the household, day care center attendance, pets in the household, and smoking caregiver. The prevalence of RW was twice as high among children with bronchopulmonary dysplasia (adjusted OR = 2.08; 95% CI, 1.11-3.89; p = 0.022) and almost five times as high among those with a personal/family history of atopy (adjusted OR = 4.96; 95% CI, 2.62-9.39; p < 0.001) as among those without these conditions. Conclusions: Preterm infants who received prophylaxis with palivizumab but have a personal/family history of atopy or bronchopulmonary dysplasia are more likely to have RW than do those without these conditions.

Keywords: Infant, premature; Respiratory sounds; Asthma; Palivizumab; respiratory syncytial viruses; Respiratory hypersensitivity.

RESUMO

Objetivo: Determinar a prevalência de sibilância recorrente (SR) em crianças pré-termo que receberam profilaxia contra infecção grave pelo vírus sincicial respiratório (VSR) e identificar susceptibilidade genética (atopia ou asma) e fatores de risco para SR. Métodos: Estudo transversal envolvendo crianças pré-termo que receberam profilaxia com palivizumabe em um centro de referência no Brasil durante os primeiros dois anos de vida. Um questionário estruturado foi aplicado em entrevista presencial com os pais ou responsáveis. Resultados: O estudo incluiu 410 crianças pré-termo (mediana de idade = 9 meses [0-24 meses]). Na amostra total, 111 crianças (27,1%; IC95%: 22,9-31,5) apresentavam SR. A análise univariada entre os grupos com e sem SR não mostrou diferenças em relação às seguintes variáveis: sexo, etnia, escolaridade materna, idade gestacional, peso ao nascer, aleitamento materno, número de crianças no domicílio, frequência em creche, presença de animais de estimação no domicílio e cuidador tabagista. A prevalência de SR foi duas vezes maior entre crianças com displasia broncopulmonar (OR ajustada = 2,08; IC95%: 1,11-3,89; p = 0,022) e quase cinco vezes maior entre aquelas com história pessoal/familiar de atopia (OR ajustada = 4,96; IC95%: 2,62-9,39; p < 0,001) do que entre aquelas sem essas condições. Conclusões: Crianças pré-termo que receberam profilaxia com palivizumabe, mas apresentam história pessoal/familiar de atopia ou displasia broncopulmonar, têm maior probabilidade de apresentar SR do que aquelas sem essas condições.

Palavras-chave: Recém-nascido prematuro; Sons respiratórios; Asma; Palivizumab; Vírus sinciciais respiratórios; Hipersensibilidade Respiratória.

INTRODUCTION
 
Children up to three years of age are subject to several diseases that are manifested by wheezing.(1) Approximately 45% of infants have one episode of wheezing in their first year of life, and about 20% have recurrent wheezing (RW).(1) This condition can decrease their quality of life and increase the demand for health care services and consequent hospitalizations due to the high prevalence of severe wheezing episodes.(2)
 
Preterm newborns, especially extremely premature infants, are more likely to have chronic lung diseases.(3-5) The structural damage to the lungs of infants caused by pregnancy-related events, such as intrauterine growth restriction, chorioamnionitis, and neonatal diseases, leads to impaired lung function.(6) A systematic review published in 2014 showed that prematurity is related to an increased risk of RW, especially in the group of infants born at fewer than 32 weeks of gestational age. (7) A cross-sectional study with 445 children evaluated the risk factors associated with RW in preterm infants.(8) Birth weight < 1,000 g, < 28 weeks of gestational age, personal or family history of atopy, and two or more children living in the same household were considered risk factors for RW.(8)
 
Up to two years of age, due to the immaturity of the immune system and modulation of innate and adaptive responses, children are more prone to the action of infectious agents.(9) Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection (LRTI) in breastfed young children(10-13) and is responsible for approximately 60 million respiratory infections per year worldwide.(14-16) Exposure to RSV occurs in 60-70% of infants during their first year of life.(11) It is estimated that almost all children have already been infected with RSV by the age of two,(17) and approximately 40% will present with LRTI symptoms due to the initial infection. (18) The risk of severe respiratory disease caused by this pathogen is related both to the immunological characteristics of the host and to the viral ability to cause damage.(17,18)
 
Severe RSV infection in the first two years of life has been associated with long-term respiratory morbidity, decreased pulmonary function, RW, and asthma.(19) Blanken et al.(20) showed that hospitalization caused by viral infection of the lower respiratory tract is a determining factor for RW in healthy preterm children.
 
Carbonell-Estrany et al.(21) evaluated the impact of hospitalization due to RSV infection on the health of six-year-old children who had been preterm infants (32-35 weeks of gestational age) and confirmed an increased risk of asthma after severe RSV infection in childhood. However, other authors have shown that there is no well-established association between RSV infection and asthma in healthy preterm infants.(22,23) In a study involving preterm children who received prophylaxis with palivizumab and were monitored until they reached six years of age, the authors concluded that immunoprophylaxis had no impact on asthma prevention, but there was a reduction in the RW rate.(24) However, Simões et al.(25) found that the use of passive immunization decreased the risk of RW only in children without a family history of atopy, which suggests that RSV predisposes to RW regardless of atopy.(26) Simões et al.(8) evaluated risk factors associated with RW in preterm children with a high probability of severe RSV infection. In that study, the authors concluded that low gestational age and presence of atopy were the major risk factors associated with RW.(8)
 
In 2020, a review by experts convened by the World Health Organization showed that a causal association of RSV-related LRTI with RW and asthma was inconclusive. (27) It is not yet clear whether severe RSV infection during the first year of life alters the immune response and triggers the onset of RW or whether it is simply a marker of genetic predisposition to RW.(28) Therefore, the present study is justified, because risk factors associated with RW can be evaluated despite the possible bias of RSV infection in the population of preterm infants who received immunoprophylaxis against RSV.
 
The aims of the present study were to determine the prevalence of RW in preterm infants who received prophylaxis with palivizumab against severe RSV infection and to identify genetic susceptibility (atopy/asthma) and risk factors for RW.
 
METHODS
 
This was a cross-sectional study based on interviews with parents or legal guardians of preterm infants who received passive immunization (palivizumab) against RSV at the Centro de Referência para Imunobiológicos Especiais (Referral Center for Special Immunobiologics) at the State University at Campinas, Brazil. Patient selection and interviews took place in two different years (2012 and 2016) in order to increase the convenience cohort size. The same individuals interviewed the participants using the same questionnaire in both years in order to avoid measurement bias. All preterm infants with gestational age < 36 weeks were included. Full-term newborns and infants diagnosed with heart disease, pulmonary malformation, or pulmonary hypertension were excluded.
 
RW was defined as three or more wheezing attacks during a one-year-period, either in the first year of life or in the year prior to the interview. Asthma is a disease with several phenotypes and can present with respiratory signs and symptoms, including wheezing. Many children have RW, but this is not always indicative of asthma.(27) In our study, children with RW were considered atopic if they had a history of atopic dermatitis, a medical diagnosis of asthma, or a father or mother with a history of asthma.
 
A structured questionnaire was used, based on a reduced version of the International Study of Wheezing in Infants questionnaire,(29) which was developed to standardize the investigation of RW. That questionnaire is a tool that provides information on the frequency of RW in childhood, as well as on the treatment and risk factors associated with the condition. The questionnaire was administered to the parents or legal guardians at the referral center.
 
All statistical analyses were performed with the Statistical Package for the Social Sciences, version 16.0 (SPSS Inc., Chicago, IL, USA). We determined the prevalence of RW (95% CI). In order to evaluate the association of RW with selected variables (sex, ethnicity, maternal level of education, gestational age, birth weight, breastfeeding duration, day care center attendance, maternal smoking during pregnancy, smoking caregiver, pets in the household, number of children in the household, presence of bronchopulmonary dysplasia, and presence of atopy), we used ORs, initially determined by univariate logistic regression and, subsequently, in an adjusted manner, by unconditional multivariate logistic regression using the Wald method (forward stepwise technique). The probability of inclusion in the model was 0.05, and the probability of exclusion from the model was 0.10. All predictor variables with p ≤ 0.05 in the univariate analysis and those considered as potential confounding factors (i.e., 0.05 < p < 0.20) were selected for inclusion in the multivariate model.
 
The present research project was approved by the Research Ethics Committee of the State University at Campinas (#142,928/2012 and #1,030,707/2015). All parents or legal guardians signed the written informed consent form.
 
RESULTS
 
We interviewed parents or legal guardians of 745 patients who received palivizumab. Preterm patients with gestational age < 36 weeks were selected for the study. Of the 745 individuals interviewed, 57 declined to participate. In addition, 265 and 13 of the infants had heart disease and pulmonary malformation or pulmonary hypertension, respectively, and were excluded. Therefore, 410 preterm children who received palivizumab were included in the study (Figure 1).

 
The children were classified as having RW (three or more episodes of wheezing in 1 year) or as not having RW. Data on the presence of atopy and the gestational age were collected. Table 1 shows the demographic and clinical characteristics of the sample.

 
The overall prevalence of RW was 27.1% (95% CI, 22.9-31.5). Table 2 shows the prevalence of RW in relation to independent variables. The univariate logistic regression analysis showed no differences regarding the following variables: sex, ethnicity, maternal level of education, gestational age, birth weight, breastfeeding duration, number of children in the household, day care center attendance, pets in the household, and smoking caregiver.

 
The chance of developing RW was higher among children whose mothers reported having smoked during pregnancy than among those whose mothers did not (OR = 2.54; 95% CI, 1.06-6.09; p = 0.037; Table 2). Children with a personal history of allergy or whose parents (one or both) had a history of atopy were almost six times more likely to have RW (OR = 5.79; 95% CI, 3.59-9.35; p < 0.001), whereas those diagnosed with bronchopulmonary dysplasia were twice more likely to have RW (OR = 2.10; 95% CI, 1.34-3.29; p = 0.001; Table 2).
 
For the unconditional multivariate logistic regression analysis, we selected the following variables: atopy, maternal smoking during pregnancy, and bronchopulmonary dysplasia. Sex, number of children in the household, and day care center attendance were considered confounding variables (i.e., 0.05 < p < 0.20). After the analysis, only atopy (p < 0.001) and bronchopulmonary dysplasia (p = 0.022) remained in the model (Table 3). The prevalence of RW was twice as high among children with bronchopulmonary dysplasia (adjusted OR = 2.08; 95% CI, 1.11-3.89; p = 0.022) and almost five times as high among those with a personal/family history of atopy (adjusted OR = 4.96; 95% CI, 2.62-9.39; p < 0.001) as among those without these conditions (Table 3).

 
DISCUSSION
 
There are several risk factors reported in the literature associated with RW in the pediatric age group. The prevalence of RW was 27.1% in preterm infants who received palivizumab in the present study. In our sample, the chance of RW was five times higher in the presence of family or personal history of atopy. Although it is well established that there is an association between RSV-related LRTI and RW, it is still unclear whether this association is causal.(30) Several risk factors are related to RW, one of those being atopy.(23)
 
Simões et al.(25) reported that preventing RSV infection with the use of palivizumab in premature infants without a history of atopy appears to decrease by 80% the relative risk of RW in children from 2 to 5 years of age, an effect that is not seen in those with a history of atopy. In a Brazilian study,(8) atopy and low gestational age were risk factors for RW, and the authors concluded that prophylaxis with palivizumab against RSV significantly reduced the relative risk of subsequent RW in nonatopic premature infants. A systematic review showed that a family history of asthma or atopy is important in the association between severe RSV infection and RW.(23) The authors also suggested that the data in the literature do not support the hypothesis of a causal link between RSV-related LRTI and subsequent wheezing.(23) Another finding of that review was that there was no evidence that immunoprophylaxis protects against subsequent wheezing illness.(23)
 
Bronchopulmonary dysplasia is a risk factor for severe RSV infection, but its association with RW in infants is unclear.(31,32) Preterm patients who received immunoprophylaxis and were diagnosed with bronchopulmonary dysplasia were twice more likely to have RW when compared with those who were not. The literature shows that children with severe bronchopulmonary dysplasia at 6 months of age will more commonly present with respiratory symptoms than will those with mild or moderate bronchopulmonary dysplasia.(31,32) However, other risk factors should be investigated as markers of future onset of respiratory symptoms.(31)
 
We concluded that maternal smoking during pregnancy is a risk factor for RW. However, this factor was eliminated in the unconditional multivariate logistic regression analysis. Our conclusion was corroborated by a meta-analysis that evaluated seven articles, involving a total of 8,579 infant cases of RW, regarding the association between maternal smoking during pregnancy and the risk of RW in childhood.(33) The authors concluded that maternal smoking during pregnancy could increase the risk of RW in childhood.(33) However, that association was found only in the cross-sectional studies evaluated, but not in the cohort studies.(33) In addition, the authors considered that the maintenance of maternal smoking during the postnatal period was a confounding factor and emphasized the need for further studies with a cohort design in order to elucidate this issue better.(33)
 
On the basis of our study group results, family atopy and bronchopulmonary dysplasia were risk factors for RW. Simões et al.(8) demonstrated an increased chance of RW in preterm infants with a personal history of food allergy or atopic dermatitis. A review article that evaluated the relationship between severe RSV infection and subsequent asthma concluded that there is a high probability that environmental factors, such as RSV infection, act as triggering events.(34) Therefore, we highlight the importance of immunoprophylaxis to prevent preterm infants from having severe RSV infection.
 
Memory bias can be considered a limitation of the present study, given the importance of the exact number of wheezing episodes for classifying the patient as a recurrent wheezer, and the fact that this information was obtained from parents or legal guardians rather than from medical reports. Another limitation is that there was no control group, because it would be unethical to deprive preterm children of the immunoprophylaxis program in accordance with the criteria defined by health care authorities.(35) Data collected in two nonconsecutive years might have introduced a patient selection bias. However, there were no changes in the palivizumab prophylaxis protocol (gestational age, association with pulmonary disease, and heart disease), and the population treated at our center was the same in terms of socioeconomic characteristics.
 
In conclusion, RW has different phenotypes, and the risk factors involved are yet to be fully understood. In the present study, the use of immunoprophylaxis against RSV infection did not prevent 27,1% of infants from having RW. Thus, genetic factors related to atopy might play an important role as a predictive factor of RW. Other cohort studies are needed to improve the elucidation of the cause-effect relationship between RSV infection and RW.
 
AUTHOR CONTRIBUTIONS
 
MBM and AADCT: conception and design of the study; data acquisition and interpretation; drafting the article; critical review of the relevant intellectual content; and approval of the final version. NYM, LG, MSO, MRVC, GLMTR, EOM, MAGOR, and JDR: data acquisition; critical review of relevant intellectual content; and approval of the final version. AMM: Data acquisition, analysis, and interpretation; critical review of relevant intellectual content; and approval of the final version.
 
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Brasil. Ministério da Saúde. Secretaria de Atenção à Saúde, Secretaria de Ciência, Tecnologia e Insumos Estratégicos [homepage on the Internet]. Brasília: Ministério da Saúde; c2021 [updated 2021 Feb 11; cited 2021 Apr 01]. Portaria Conjunta 23, de 3 de outubro de 2018. Available from: https://www.gov.br/saude/pt-br/assuntos/protocolos-clinicos-e-diretrizes-terapeuticas-pcdt/arquivos/2018/protocolouso_palivizumabe.pdf/view