Breastfeeding and family history of atopy as predictors of clinical course for acute uncomplicated bronchiolitis in infants: a prospective, longitudinal, cohort study.

doi:10.21203/rs.3.rs-4000667/v1

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Breastfeeding and family history of atopy as predictors of clinical course for acute uncomplicated bronchiolitis in infants: a prospective, longitudinal, cohort study.

https://doi.org/10.21203/rs.3.rs-4000667/v1

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Background: Acute bronchiolitis (AB) is the most common lower airway disease in infants. The high incidence of this pathology and the risk of severe complications make it necessary to identify prognostic factors. The aim of this study was to determine whether there is an association between a family history of atopy and breastfeeding for more than six months and clinical outcomes in patients with AB.

Methods: This was a prospective, longitudinal cohort study. Patients who visited the emergency department of the General Hospital of Cuautitlán from October 1, 2020, to January 31, 2021 were included. Data collection was performed by means of a questionnaire with open-ended questions. Oxygen saturation data were collected at admission at 6, 12, 24, 24, 48, 72 and 120 hours.

Results: A sample of 108 participants was analyzed. We found a decrease of -3.69% (p=0.005, 95% CI: -6.24, -1.14) in oxygen saturation at admission in participants with a history of paternal atopy and an increased risk for hospitalization. Breastfeeding increased SaO2 by 2.41% (p=0.001, 95% CI: 1.02, 3.81) but was also a protective factor against hospitalization (OR=0.13, p=0.001 95% CI: 0.041 - 0.44).

Conclusions: A history of paternal atopy is a poor prognostic factor for the clinical course of AB. Breastfeeding proved to be a protective factor.

bronchiolitis

atopy

family history

breastfeeding

Acute bronchiolitis (AB) is the most common lower airway disease in infants and one of the leading causes of pediatric consultation worldwide, and the most common cause of hospital admission for infants in high-income countries. [1–5] AB is a seasonal infection that occurs most frequently during the months of January and February in the USA. [4] For the purpose of this study AB was defined as the first episode of acute onset wheezing with previous signs of upper airway infection in children under 24 months of age. [2, 6, 7]

During the first year of life, the incidence has been reported to be approximately 11–15% and there are at least 5 hospitalizations for every 1000 children younger than 2 years of age [9]; AB is responsible for 199,000 deaths per year and approximately one million hospitalizations worldwide.^[1,4] The main agents responsible for AB worldwide are respiratory syncytial virus (RSV) (50%-80%), rhinovirus (5%-25%) and parainfluenza virus (5%-25%). [6, 10] In 2022 in Mexico, RSV accounted for 8% of all cases of acute respiratory infections during the winter season.[8]

It is estimated that by the age of two years, 95% of the pediatric population will experience RSV infection.[1] The clinical features of AB include low-grade fever, upper respiratory symptoms (nasal congestion and rhinorrhea), lower respiratory symptoms (cough, tachypnea, and respiratory distress), and the presence of fine inspiratory rales and/or expiratory wheezing on auscultation. [2, 4] The treatment of AB remains under constant review. The latest research has shown no improvement with previously used practices, such as: the administration of systemic or inhaled steroids, salbutamol (albuterol) or adrenaline and nebulization with hypertonic solutions. Currently, the only recommendation is to administer supplemental oxygen in patients whose oxygen saturation on pulse oximetry is less than 90%. [11–13] During the usual course of AB only 2–3% of patients will require hospitalization.[3]

The prognostic factors for adverse outcomes included age under 4 weeks, prematurity, cystic fibrosis, bronchopulmonary dysplasia, heart disease, immunodeficiency, and malnutrition. [6, 7] Some studies have shown an association between genetic factors and the severity of disease and the risk of requiring neonatal intensive care unit management. [7, 14]

Breastfeeding has been shown to confer immunological benefits to infants, reducing the incidence of infections and long-term conditions such as chronic wheezing and asthma. These advantages are believed to be due to the transfer of various immunological factors in human milk, including immunoglobulins, lactoferrin, and oligosaccharides, which provide passive protection to the infants. [15]

Recently, atopy has been associated with an increase in the risk of acute bronchiolitis in infants. When individuals with atopy are exposed to common environmental allergens, their immune system produces an exaggerated response, leading to inflammation and the release of histamine and other proinflammatory mediators that cause bronchoconstriction. This exaggerated response can make infants who have not yet developed a robust immune system, particularly susceptible to developing acute bronchiolitis. Therefore, understanding the role of atopy (which is associated with a predisposition to develop allergies) in the pathogenesis of acute bronchiolitis is crucial for identifying infants at increased risk and for developing targeted interventions to reduce the risk of early asthma development. [16]

The aim of this study was to determine whether breastfeeding and a family history of atopy could be predictors of clinical outcome in uncomplicated AB in an infant population.

A prospective, longitudinal, cohort study was performed in a tertiary-care hospital located in the State of Mexico, Mexico. The sample size was calculated for an expected multiple linear regression R² coefficient of 0.3% and a statistical power of 80%, and a minimum sample size of 103 participants was obtained. [17]

Definitions

AB is defined as the initial occurrence of sudden wheezing in children under 24 months of age, accompanied by symptoms preceding of upper airway infection [2, 6, 7]. The investigation also considered a family history of atopy, signifying the presence of atopic dermatitis, allergic rhinitis, or asthma in either parent of the participating infants [18]. Clinical improvement was assessed based on oxygen saturation levels equal to or above 95% or upon hospital discharge as recommended by a pediatrician. Breastfeeding is characterized by the exclusive consumption of breast milk on demand for the first 6 months of life, with the exclusion of other foods, liquids, bottles, teats, or pacifiers [19]. Length of stay is determined by spending more than 24 hours under observation due to a lack of improvement in oxygen saturation levels or clinical well-being, at the discretion of the treating pediatrician. Hospital admission is defined as the process whereby an infant stays at least 8 hours for clinical data indicative of acute bronchiolitis.

Inclusion criteria

We included infants of both sexes between 2 and 24 months of age who attended the emergency department of the Hospital General de Cuautitlán, Instituto de Salud del Estado de México, with a diagnosis of AB, from October 1, 2020, to January 31, 2021.

Exclusion criteria

We excluded infants with congenital conditions, infants who had a premature birth, infants with a diagnosis of any genetic disease, infants with any complication of AB, infants with a baseline diagnosis of any pathology associated with poor prognosis and infants whose parents requested voluntary discharge or transfer to another institution.

Data collection

A questionnaire with closed questions was used to collect the following data: age, socioeconomic level, family history of maternal and paternal atopy, parents' level of schooling and history of exclusive breastfeeding. In addition, the following clinical data were extracted from the hospital records during the hospital stay: degree of respiratory distress, oxygen saturation levels (SaO2%) measured by pulse oximetry, antibiotic use and type of inhalation treatment received.

Measurement of the oxygen saturation SaO2%.

Oxygen saturation measurements by pulse oximetry were performed at admission, after rescue nebulization and in those who required hospitalization due to lack of clinical improvement at 6, 12, 24, 48, 72, 96 and 120 hours.

Statistical analysis.

Descriptive statistics for qualitative variables are expressed as percentages. For quantitative variables, the means and medians were used as measures of central tendency, and the standard deviation and interquartile range P25-P75 were used as measures of dispersion according to the normality of the sample distribution. An analysis was performed between the main dependent and independent variables, and Kruskal-Wallis tests were performed for differences in pulse oximetry levels (O2%) and the variables of interest. To explore the longitudinal relationship between SaO2% and the effect of inhalation therapy, family history of maternal and/or paternal atopy and exclusive breastfeeding and adjusted and unadjusted linear mixed models were generated. To observe the effect of treatment of the aforementioned variables on the length of hospital stay, Poisson generalized linear and logistic regression models were used. To explore the variables to be included, bivariate analyses were performed in relation to our dependent variables. Stata Intercooled See. 15 (Stata Corporation, College Station, TX) was used for the statistical analysis.

Ethical aspects.

The study was approved by the Ethics and Research Committee of the Instituto de Salud del Estado de México - Hospital General de Cuautitlán, IRB number: 15CEI3120140110, registered by the Comisión Nacional de Bioética México - Secretaría de Salud. All parents of the infants who participated in the study agreed to participate in the study through an informed consent process, based on the Regulations of the General Health Law on Health Research (Mexico), the International Declaration of Human Rights and the Declaration of Helsinki.

A sample of 108 participants was obtained. Of the study population 54.63% (59) were male, 45.37% (49) were female, and the mean age was 7.89 months, with a standard deviation of 3.49 months. At admission they presented an average oximetry level of 86.84%, which when compared with the oximetry at discharge of 94.85%, reflects an adequate clinical outcome. Of the patients, 50.93% (55) received 3% hypertonic solution plus salbutamol (albuterol), and 49.07% (53) received physiological solution plus salbutamol. A history of atopy in both parents was measured and a maternal history was found in 37.04% (40) of the patients, while a paternal history was reported in only 4.63% (5). Regarding exclusive breastfeeding, 82.41% (89) of the infants received more than 6 months of exclusive breastfeeding. With respect to the need for hospitalization, 67.59% (73) of patients received outpatient management, and 32.41% (35) required in-hospital management for one or more days. More than 50% of the respondents fell into the lowest socioeconomic categories. (Table 1).

Table 1

Characteristics of the 108 infants with bronchiolitis
Variable	Total
Age (months)	7.89 (3.49)*
Admission oximetry levels SaO₂ (%)	86.84(1.61)*
Discharge oximetry levels SaO₂ (%)	94.85(1.70)*
Breastfeeding length (months)	5.8(3.97)*
Gender
Men	54.63(59)**
Women	45.37(49)**
Family history of maternal atopy
Yes	37.04(40)**
No	62.96(68)**
Family history of paternal atopy
Yes	4.63(5)**
No	95.37(103)**
Antibiotic use
No	91.67(99)**
Yes	8.33(9)**
Exclusive breastfeeding (≥ 6 months)
Yes	74.07(80)**
No	28.93(28)**
Type of treatment (used solution)
Hypertonic solution (3%) + Salbutamol	50.93(55)**
Normal saline solution + Salbutamol	49.07(53)**
Patient Status
Outpatient infant	67.59(73)**
Inpatient infant	32.41(35)**
Socioeconomic status
A/B (highest lifestyle status	0.93(1)**
C+ (Limitations to future investment and savings)	1.85(2)**
C (practical living and certain conveniences)	13.89(15)**
C- (sanitation and space requirements are met)	13.89(15)**
D+ (minimum health infrastructure)	14.81(16)**
D (lacking in services and satisfiers, has property ownership)	45.37(49)**
E (lacking in services and satisfiers, does not have property ownership)	9.26(10)**
Days of hospital stay
0 days	67.59(73)**
2 days	5.56(6)**
3 days	15.54(17)**
4 days	2.78(3)**
5 days	8.33(9)**
Mean (standard deviation) *Percentage (number of patients)

In the analysis of the mean oxygen saturation levels (SaO2%) of each of the patients with respect to the variables of interest, no statistically significant changes were observed in the variables of maternal history of atopy and the use of nebulization with a hypertonic solution + salbutamol vs saline solution + salbutamol. However, it was observed that participants with a paternal history of atopy had lower oxygen saturation than did to those without this risk factor; the final adjusted model showed that this history decreased SaO2% levels by -3.69% (p = 0.005, CI 95%: -6.24 - -1.14) with respect to patients who did not have it. In the analysis of the variable of exclusive breastfeeding for more than six months, an increase of 2.41% in SaO2% was observed with respect to those who did not have this antecedent (Table 2).

Table 2

Mixed models of oximetry-related factors in 108 infants with acute uncomplicated bronchitis
	Unadjusted model			Adjusted model
	B	p value	CI (95%)	B	p value	CI (95%)
Treatment *	-0.037	0.945	(-1.15, 1.07)	0.087	0.870	(-1.01, 1.20)
FH of maternal atopy	0.00022	1	(-1.15, 1.15)	-0.31	0.957	(-1.15, 1.08)
FH of paternal atopy	-3.21	0.011	(-5.65, -0.76)	-3.69	0.005	(-6.24, -1.14)
Breastfeeding for more than 6 months	2.26	0.001	(-1.46, -0.73)	2.41	0.001	(1.02, 3.81)
* hypertonic solution + salbutamol (albuterol) vs Normal saline solution (0.9%) + salbutamol (albuterol)
*Adjusted for treatment, mother's family history (FH) of atopy, father's family history (FH) of atopy, breastfeeding, mother's schooling, father's schooling, infant's socioeconomic status, sex and age

An adjusted Poisson regression model was used to assess the relationships between days of hospital stay and the variables of interest. No statistically significant association was found between treatment and maternal atopy. Regarding family history of atopy, paternal atopy and breastfeeding for more than six months were significantly associated with the length of hospital stay (Table 3).

Table 3

Association between days of hospital stay and clinical factors in 108 infants (Poisson Generalized Linear Models)
	Unadjusted model			Adjusted model
	B	p value	CI (95%)	B	p value	CI (95%)
Treatment *	-0.09	0.59	(-0.45, 0.26)	-0.01	0.95	(-0.41, 0.38)
FH of maternal atopy	0.09	0.62	(-0.28, 0.45)	0.006	0.97	(-0.37, 0.38)
FH of paternal atopy	1.07	p < 0.000	(0.49, 1.58)	1.19	0.0002	(0.53, 1.79)
Breastfeeding for more than 6 months	-1.10	p < 0.000	(-1.46, -0.73)	-1.08	p < 0.000	(-1.47, -0.68)
* hypertonic solution + salbutamol (albuterol) vs Normal saline solution (0.9%) + salbutamol (albuterol)
*Adjusted for treatment, mother's family history (FH) of atopy, father's family history (FH) of atopy, breastfeeding, mother's schooling, father's schooling, infant's socioeconomic status, sex and age

Compared with not receiving breastfeeding, exclusive breastfeeding for more than six months had a protective effect, decreasing the possibility of being hospitalized (OR = 0.13, p = 0.001 95% CI: 0.041–0.44); on the other hand, a paternal history of atopy increased the likelihood of hospitalization (OR = 14.31 p = 0.04 95% CI: 1.13–18.88). With respect to maternal atopy and the type of treatment implemented, no associations were found (Table 4).

Table 4

Predisposing factors for hospitalization in 108 infants with acute uncomplicated bronchiolitis (ambulatory vs. hospitalized)
	OR	p value	CI (95%)
Breastfeeding for more than 6 months	0.13	0.001	(0.041–0.044)
FH of paternal atopy	14.31	0.04	(1.13–18.88)
FH of maternal atopy	0.86	0.761	(0.33–2.23)
Treatment*	1.12	0.816	(0.42–2.95)
* hypertonic solution + salbutamol (albuterol) vs Normal saline solution (0.9%) + salbutamol (albuterol)
*Adjusted for treatment, mother's family history (FH) of atopy, father's family history (FH) of atopy, breastfeeding, mother's schooling, father's schooling, infant's socioeconomic status, sex and age

Acute bronchiolitis is the main respiratory cause of hospitalization in children under 12 months of age, and although the natural evolution of the disease is characterized by a tendency toward self-limitation in most cases, approximately 3% of patients may require hospitalization or even admission to intensive care units and management with invasive ventilation.[3] The importance of studies that evaluate the predictive factors for a poor clinical course lies in the timely detection of infants who require closer monitoring to prevent hospitalization or a longer stay.

Multiple studies have demonstrated the association of a poor clinical course with underlying pathologies such as bronchopulmonary dysplasia, heart disease, Down syndrome, etc. Likewise, perinatal factors have been studied and it has been found that low birth weight, multiparity, prematurity and birth close to the season of greatest virus circulation are associated with a worse outcome during the disease. [7, 10] The most studied predictors are the clinical characteristics of children at the time of arrival at the emergency department, such as: age less than 3 months, saturation less than 94%, use of accessory muscles, tachypnea and management with bronchodilators or epinephrine. [20, 21] However, few studies have considered patient-independent factors as predictors of clinical outcome.

Our results showed that exclusive breastfeeding for more than six months was a prognostic factor for adequate clinical outcomes, reducing the requirement and length of hospital stay and improving the SaO2% during treatment in our patients. Epidemiological evidence has shown that breastfeeding human milk is a protective factor against the development of multiple diseases, including AB, due to the high transmission of immunological factors present in breast milk. [23–26] A recent systematic review showed that exclusive and partial breastfeeding reduces the severity of the disease, length of hospital stay and supplemental oxygen requirement. This review demonstrated that hospitalized infants were significantly more likely to be breastfed for less than 6 months. [26]

Exclusive breastfeeding during the first 6 months of life confers a significant immune advantage to infants, as evidenced by a lower incidence of infections during infancy. This advantage is likely due to an adequate infant nutritional state and the presence of immunoglobulins, lactoferrin, and oligosaccharides in breast milk, which provide passive protection. The factors responsible for modulating infant immune system development may also play a critical role in reducing susceptibility to infectious diseases. The development of an infant's immune system is influenced by primary exposure to antigens, which can promote either humoral immune responses dominated by antibodies (Th2-mediated), or cytokine-cell mediated responses (Th1-mediated). The balance between Th2 and Th1 responses can be influenced by several factors, including diet composition and primary exposure to Th1 or Th2-promoting antigens. [22, 27]

In our study, we found a statistically significant association between a history of paternal atopy and the need for hospitalization and a longer hospital stay; however, no recent studies in which this antecedent was considered a predictor of clinical evolution were found. This finding could be explained by the pathophysiology of asthma and other allergic pathologies which are characterized by genetic and environmental factors. Toll-like receptor 4 (TLR4) and cluster of differentiation 14 (CD14) gene polymorphisms, which are pattern recognition receptors associated with immunoglobulin E concentrations, have been studied as risk factors for the development of asthma and other allergic diseases. [28] These polymorphisms were studied in a pediatric population with bronchiolitis, and it was found that the c.159C > T and c.550C > T polymorphisms of the gene encoding for the CD14 protein were associated with an increased risk of disease development and severity.[29]

Some limitations of our study are that we do not have information on exposure to environmental risks such as indoor air pollutants or a history of complementary feeding. Information-recall bias may underestimate the antecedent of paternal atopy, since the questionnaires were mainly completed by mothers. The confidence intervals for the associations were wide, reducing the statistical significance of our findings; it is necessary to expand the sample size to achieve a stronger statistical association. The results of this study can only be applied to infants living in metropolitan areas adjacent to Mexico City and belonging to a low socioeconomic stratum.

Acute bronchiolitis

RSV

Respiratory Syncytial Virus

SaO2%

Oxygen saturation levels

Family History

CD14

Cluster of Differentiation 14

Ethics approval and consent to participate.

The study was approved by the Ethics and Research Committee of the Instituto de Salud del Estado de México - Hospital General de Cuautitlán, IRB number: 15CEI3120140110, registered by the Comisión Nacional de Bioética México - Secretaría de Salud. All parents of the infants who participated in the study agreed to participate in the study through an informed consent process, based on the Regulations of the General Health Law on Health Research (Mexico), the International Declaration of Human Rights and the Declaration of Helsinki.

Consent for publication.

Not applicable

Availability of data and materials
The datasets generated and/or analyzed during the current study are not publicly available to protect study participant privacy, but are available from the corresponding author on reasonable request.

Competing interests

No, I declare that the authors have no competing interests as defined by BMC, or other interests that might be perceived to influence the results and/or discussion reported in this paper.

Author contributions
P.F.O.S

Contribution: Development of the epidemiological study design and clinical follow-up, development of the measurement instruments, cleaning and processing of the database, development of the statistical analysis plan, drafting of the manuscript, theoretical discussion of results and conclusions, critical review of the scientific article for approval.

A.V.A

Contribution: Development of the database, measurement instruments used to collect data, clinical follow-up of patients, theoretical discussion of results and conclusions, critical review of the scientific article for approval.

S.G.L

Contribution: Drafting of the scientific article, development of the conceptual theoretical framework and theoretical discussion of results and conclusions, critical review of the scientific article for approval.

D.A.V.T

Contribution: Processing of the database, development of the statistical analysis, presentation and discussion of results, critical review of the scientific article for approval.

E.B.DC

Contribution: Development and validation of measurement instruments, participation in clinical follow-up of patients, drafting of the scientific article and theoretical discussion of results and conclusions, critical review of the scientific article for approval.

R.V.P

F.V.O

Contribution: Design of the epidemiological study, development of the clinical follow-up strategy, development of statistical analysis, theoretical discussion of results and conclusions, critical review of the scientific article for approval.

Funding

No funding was received for the elaboration of this research.

Acknowledgments

Dr. José Luis Texcalac - Sangrador for his help describing multiple statistical analysis regression models used in this research.

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No competing interests reported.

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Breastfeeding and family history of atopy as predictors of clinical course for acute uncomplicated bronchiolitis in infants: a prospective, longitudinal, cohort study.

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