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Figure 1.
Distribution of Serum Albumin Levels Among Infants With or Without Apnea During Hospitalization
Distribution of Serum Albumin Levels Among Infants With or Without Apnea During Hospitalization

The dotted blue line represents the serum albumin level categorized as normal (≥3.8 g/dL). To convert albumin level to grams per liter, multiply by 10.

Figure 2.
Locally Weighted Scatterplot Smoothing of Serum Albumin Level and the Estimated Probability of Apnea
Locally Weighted Scatterplot Smoothing of Serum Albumin Level and the Estimated Probability of Apnea

The dotted blue line represents the serum albumin level categorized as normal (≥3.8 g/dL). The predicted probability of inpatient apnea was obtained from a logistic regression model of serum albumin (<3.8 g/dL vs ≥3.8 g/dL) and weight-for-age z score. To convert albumin level to grams per liter, multiply by 10.

Table 1.  
Associations of Clinical Variables With Inpatient Apnea Among Infants Admitted for Bronchiolitis
Associations of Clinical Variables With Inpatient Apnea Among Infants Admitted for Bronchiolitis
Table 2.  
Associations of Clinical Variables With Apnea Before or During Hospitalization Among Infants Admitted for Bronchiolitis
Associations of Clinical Variables With Apnea Before or During Hospitalization Among Infants Admitted for Bronchiolitis
1.
Hasegawa  K, Tsugawa  Y, Brown  DF, Mansbach  JM, Camargo  CA  Jr.  Trends in bronchiolitis hospitalizations in the United States, 2000-2009.  Pediatrics. 2013;132(1):28-36. doi:10.1542/peds.2012-3877PubMedGoogle ScholarCrossref
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Byington  CL, Wilkes  J, Korgenski  K, Sheng  X.  Respiratory syncytial virus-associated mortality in hospitalized infants and young children.  Pediatrics. 2015;135(1):e24-e31. doi:10.1542/peds.2014-2151PubMedGoogle ScholarCrossref
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Sloan  CD, Gebretsadik  T, Rosas-Salazar  C,  et al.  Seasonal timing of infant bronchiolitis, apnea and sudden unexplained infant death.  PLoS One. 2016;11(7):e0158521. doi:10.1371/journal.pone.0158521PubMedGoogle ScholarCrossref
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Schroeder  AR, Mansbach  JM, Stevenson  M,  et al.  Apnea in children hospitalized with bronchiolitis.  Pediatrics. 2013;132(5):e1194-e1201. doi:10.1542/peds.2013-1501PubMedGoogle ScholarCrossref
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Ralston  S, Hill  V.  Incidence of apnea in infants hospitalized with respiratory syncytial virus bronchiolitis: a systematic review.  J Pediatr. 2009;155(5):728-733. doi:10.1016/j.jpeds.2009.04.063PubMedGoogle ScholarCrossref
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Levitt  DG, Levitt  MD.  Human serum albumin homeostasis: a new look at the roles of synthesis, catabolism, renal and gastrointestinal excretion, and the clinical value of serum albumin measurements.  Int J Gen Med. 2016;9:229-255. doi:10.2147/IJGM.S102819PubMedGoogle ScholarCrossref
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Herrmann  FR, Safran  C, Levkoff  SE, Minaker  KL.  Serum albumin level on admission as a predictor of death, length of stay, and readmission.  Arch Intern Med. 1992;152(1):125-130. doi:10.1001/archinte.1992.00400130135017PubMedGoogle ScholarCrossref
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Horowitz  IN, Tai  K.  Hypoalbuminemia in critically ill children.  Arch Pediatr Adolesc Med. 2007;161(11):1048-1052. doi:10.1001/archpedi.161.11.1048PubMedGoogle ScholarCrossref
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Leite  HP, Rodrigues da Silva  AV, de Oliveira Iglesias  SB, Koch Nogueira  PC.  Serum albumin is an independent predictor of clinical outcomes in critically ill children.  Pediatr Crit Care Med. 2016;17(2):e50-e57. doi:10.1097/PCC.0000000000000596PubMedGoogle ScholarCrossref
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Shindo  Y, Ito  R, Kobayashi  D,  et al; Central Japan Lung Study Group.  Risk factors for 30-day mortality in patients with pneumonia who receive appropriate initial antibiotics: an observational cohort study.  Lancet Infect Dis. 2015;15(9):1055-1065. doi:10.1016/S1473-3099(15)00151-6PubMedGoogle ScholarCrossref
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Hasegawa  K, Mansbach  JM, Ajami  NJ,  et al; MARC-35 Investigators.  Association of nasopharyngeal microbiota profiles with bronchiolitis severity in infants hospitalised for bronchiolitis.  Eur Respir J. 2016;48(5):1329-1339. doi:10.1183/13993003.00152-2016PubMedGoogle ScholarCrossref
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Ralston  SL, Lieberthal  AS, Meissner  HC,  et al; American Academy of Pediatrics.  Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis.  Pediatrics. 2014;134(5):e1474-e1502. doi:10.1542/peds.2014-2742PubMedGoogle ScholarCrossref
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Luna  PN, Hasegawa  K, Ajami  NJ,  et al.  The association between anterior nares and nasopharyngeal microbiota in infants hospitalized for bronchiolitis.  Microbiome. 2018;6(1):2. doi:10.1186/s40168-017-0385-0PubMedGoogle ScholarCrossref
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Mansbach  JM, Piedra  PA, Teach  SJ,  et al; MARC-30 Investigators.  Prospective multicenter study of viral etiology and hospital length of stay in children with severe bronchiolitis.  Arch Pediatr Adolesc Med. 2012;166(8):700-706. doi:10.1001/archpediatrics.2011.1669PubMedGoogle ScholarCrossref
15.
Leroy  J.  Zscore06: Stata Command for the Calculation of Anthropometric z-Scores Using the 2006 WHO Child Growth Standards [computer program]. Boston, MA: Boston College Department of Economics; 2011. http://www.ifpri.org/staffprofile/jef-leroy. Accessed March 19, 2019.
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Merlot  AM, Kalinowski  DS, Richardson  DR.  Unraveling the mysteries of serum albumin-more than just a serum protein.  Front Physiol. 2014;5:299. doi:10.3389/fphys.2014.00299PubMedGoogle ScholarCrossref
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Lee  JL, Oh  ES, Lee  RW, Finucane  TE.  Serum albumin and prealbumin in calorically restricted, nondiseased individuals: a systematic review.  Am J Med. 2015;128(9):1023.e1-1023.e22. doi:10.1016/j.amjmed.2015.03.032PubMedGoogle ScholarCrossref
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Bharadwaj  S, Ginoya  S, Tandon  P,  et al.  Malnutrition: laboratory markers vs nutritional assessment.  Gastroenterol Rep (Oxf). 2016;4(4):272-280.PubMedGoogle Scholar
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Piedimonte  G, Rodriguez  MM, King  KA, McLean  S, Jiang  X.  Respiratory syncytial virus upregulates expression of the substance P receptor in rat lungs.  Am J Physiol. 1999;277(4):L831-L840.PubMedGoogle Scholar
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King  KA, Hu  C, Rodriguez  MM, Romaguera  R, Jiang  X, Piedimonte  G.  Exaggerated neurogenic inflammation and substance P receptor upregulation in RSV-infected weanling rats.  Am J Respir Cell Mol Biol. 2001;24(2):101-107. doi:10.1165/ajrcmb.24.2.4264PubMedGoogle ScholarCrossref
21.
Rossi  GA, Colin  AA.  Respiratory syncytial virus-Host interaction in the pathogenesis of bronchiolitis and its impact on respiratory morbidity in later life.  Pediatr Allergy Immunol. 2017;28(4):320-331. doi:10.1111/pai.12716PubMedGoogle ScholarCrossref
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Piedimonte  G.  Neural mechanisms of respiratory syncytial virus-induced inflammation and prevention of respiratory syncytial virus sequelae.  Am J Respir Crit Care Med. 2001;163(3 Pt 2):S18-S21. doi:10.1164/ajrccm.163.supplement_1.2011113PubMedGoogle ScholarCrossref
23.
Mansbach  JM, Hasegawa  K, Piedra  PA,  et al.  Haemophilus-dominant nasopharyngeal microbiota is associated with delayed clearance of respiratory syncytial virus in infants hospitalized for bronchiolitis.  J Infect Dis. 2019;219(11):1804-1808. doi:10.1093/infdis/jiy741PubMedGoogle ScholarCrossref
24.
Mansbach  JM, Hasegawa  K, Ajami  NJ,  et al.  Serum LL-37 levels associated with severity of bronchiolitis and viral etiology.  Clin Infect Dis. 2017;65(6):967-975. doi:10.1093/cid/cix483PubMedGoogle ScholarCrossref
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Mansbach  JM, Hasegawa  K, Henke  DM,  et al.  Respiratory syncytial virus and rhinovirus severe bronchiolitis are associated with distinct nasopharyngeal microbiota.  J Allergy Clin Immunol. 2016;137(6):1909-1913.e4. doi:10.1016/j.jaci.2016.01.036PubMedGoogle ScholarCrossref
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Greenland  S, Mansournia  MA, Altman  DG.  Sparse data bias: a problem hiding in plain sight.  BMJ. 2016;352:i1981. doi:10.1136/bmj.i1981PubMedGoogle ScholarCrossref
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    3 Comments for this article
    EXPAND ALL
    Making headway with bronchiolitis
    Frederick Rivara, MD, MPH | University of Washington
    Bronchiolitis is one of the most frustrating diseases that puts infants into the hospital. It is frustrating because we have only symptomatic care like oxygen and fluids, and nothing to abate the symptoms or hasten recovery. Some infants with it can get quite sick, for example, develop apnea. This is an interesting and I think important study showing that infants with low serum albumin have a more than 4-fold risk of developing apnea than infants with normal levels. The reasons are unknown but perhaps this can eventually be used prognostically.
    CONFLICT OF INTEREST: Editor in Chief, JAMA Network Open.
    Albumin as Biomarker to Predict Apnea in Bronchiolitis
    Sunil Kumar Rao, MD | Associate Professor Pediatrics, Institute of Medical Science, Banaras Hindu University
    Albumin is a globular protein with molecular weight of 66.5 kilodaltans and is abundant as a circulating protein in plasma. The physiological functions of serum albumin are regulation of plasma oncotic pressure, capillary membrane permeability, ligand binding and transport. Serum albumin production is inhibited during inflammation. In critical illness, serum albumin level has high sensitivity and negative predictive value for elevated pulmonary vascular permeability and acute respiratory distress syndrome. Therefore, hypoalbuminemia in acute illness is reflection of acute phase response; however, in normal children albumin has good utility as nutritional biomarker.

    Apnea may manifest in early
    course of illness in bronchiolitis or after established clinical features of bronchiolitis. This study by Mansbach et al found 13 children with apnea during hospitalization, 12 children had apnea before and after hospitalization, and 44 children with a history of apnea before hospitalization. It has previously been reported in the literature that history of apnea and nutritional status are independent risk factors of apnea(1). In secondary analysis, the authors observed that association between low albumin and apnea before and during hospitalization (OR, 2.50:95%CI, 1.53-4.08). This decrease in albumin levels may be a consequence of an acute phase response, or of the nutritional status of children. The authors correlate degree of under-nutrition with apnea; it could be correlated with degree of wasting (weight for height) , albumin levels and severity of illness. There might be different observations if analyzing the effect of severity of bronchiolitis in children with a prior history of apnea and who developed apnea during hospitalization. The others did not mention the effect of apnea on the outcome of disease; to date there is no evidence-based guideline for management of apnea in bronchiolitis by any pediatric association of the world except early respiratory support and the questionable utility of caffeine citrate. It is to early too recommending routine use of serum albumin to predict apnea in bronchiolitis as sensitivity is low and unacceptable levels of false positivity.

    1.Schroeder AR, Mansbach JM, Stevenson M, et al. Apnea in children hospitalized with bronchiolitis. Pediatrics.2013;132(5):e1194-e1201. doi:10.1542/peds.2013-1501
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Modulating Effect of Breastfeeding on Serum Albumin May Protect Against Bronchiolitis.
    Sergi Verd, M.D. | Department of Primary Care, Balearic Health Authority, Majorca, Spain
    Both clinical trials and animal studies have suggested that breastfeeding may affect the biochemical profiles of children and program cholesterol metabolism of later life. Several pathways for these effects have been proposed. Irrespective of its nature, a tracking of lipid profiles from infancy to young adulthood has revealed sequential variations in blood lipid levels following breastfeeding.

    Similarly, a tracking of serum albumin levels during infancy shows sequential variations that might be associated with some kind of breastfeeding programming. There are no differences between formula-fed and breastfed neonates younger than five days or infants older than six months with
    respect to serum albumin levels (El-Hawary & Akeson). Conversely, breastfed infants at three weeks and even more at eight weeks of age show significantly higher levels of serum albumin than formula-fed infants (Gross & Wu).

    Mansbach et al. remind us that managing bronchiolitis remains a challenge to the treating pediatrician. One of the most serious complications of bronchiolitis is apnea, but unfortunately it remains unclear which infants with bronchiolitis will develop this rare outcome. Fortunately, Mansbach’s new approach may predict which patients will not develop apnea with very low false negative rates (0.5%). They have unveiled for the first time the association between low serum albumin levels and apnea. This association remained significant after adjustment for age, preterm birth, and weight-for-age (OR, 4.42; 95% CI, 1.21-16.18). Formula-feeding is another reputed predisposing factor for disease progression5, but Mansbach et al. have not adjusted for this.

    They stress that although the mechanism of low albumin levels in bronchiolitis is uncertain, poor nutrition is commonly considered the main origin of hypoalbuminemia. Notwithstanding the attempts to disentangle the mechanism of low serum albumin levels in bronchiolitis, they do not find an explanation for infants younger than one month with low albumin levels; taking into account that the half-life of albumin is approximately three weeks, these infants would be malnourished from birth. However, their results show that the association between albumin and apnea is independent of low birth weight. Had they included feeding type in the deliberation, it would have been possible to add to previous research on the mechanisms by which breastfeeding protects against bronchiolitis.

    To summarize, it is reasonable to speculate that human milk may confer additional benefits to the development of prediction tools for bronchiolitis severity, yet breastfeeding is an invaluable predictor of outcomes in a wide
    spectrum of clinical conditions in infancy, from bronchodysplasia to retinopathy of prematurity.

    Sergio Verd, M.D.,
    Sara Beiro, M.D.
    La Vileta Surgery. Department of Primary Care. Baleares Health Authority. 07013 Palma de Mallorca, Spain.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Original Investigation
    Pediatrics
    July 17, 2019

    Association of Serum Albumin With Apnea in Infants With Bronchiolitis: A Secondary Analysis of Data From the MARC-35 Study

    Author Affiliations
    • 1Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts
    • 2Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston
    • 3Department of Pediatrics, Emergency Medicine, Norton Children’s Hospital, University of Louisville School of Medicine, Louisville, Kentucky
    JAMA Netw Open. 2019;2(7):e197100. doi:10.1001/jamanetworkopen.2019.7100
    Key Points español 中文 (chinese)

    Question  Is serum albumin level associated with the risk of apnea in infants with bronchiolitis?

    Findings  In this secondary analysis of a cohort of 1016 infants hospitalized for bronchiolitis, low serum albumin was statistically significantly associated with a higher risk of apnea during the hospitalization. This association was independent of known apnea risk factors (younger age, premature birth, and weight-for-age z score).

    Meaning  Albumin levels may have a role in identifying apnea in bronchiolitis.

    Abstract

    Importance  Apnea is a rare, life-threatening complication of bronchiolitis, the leading cause of infant hospitalization in the United States. Currently, no objective method exists for identifying which infants will become apneic.

    Objective  To investigate whether serum albumin levels are associated with apnea in infants with severe bronchiolitis.

    Design, Setting, and Participants  A secondary data analysis of the 35th Multicenter Airway Research Collaboration, an ongoing multicenter cohort study of infants hospitalized for bronchiolitis, was conducted from December 11, 2018, to May 30, 2019. Seventeen hospitals across the United States enrolled infants (n = 1016) during 3 consecutive bronchiolitis seasons (November 1 to April 30) between 2011 and 2014. Infants with heart-lung disease or a gestational age less than 32 weeks were excluded.

    Exposures  Serum albumin level was categorized as low (<3.8 g/dL) or normal (≥3.8 g/dL).

    Main Outcomes and Measures  Apnea during the hospitalization.

    Results  Of the 1016 infants hospitalized for bronchiolitis, the median (interquartile range [IQR]) age was 3 (2-6) months, 610 (60.0%) were male, and 186 (18.3%) were born preterm (32-37 weeks’ gestation). Among the 25 infants (2.5%) with apnea while hospitalized, the median (IQR) serum albumin level was 3.5 (3.1-3.6) g/dL, and 22 (88.0%) had low serum albumin levels. The prevalence of apnea was 5.7% among all infants with low albumin levels, compared with 0.5% prevalence in infants with normal serum albumin levels. In unadjusted analyses, apnea was associated with younger age, preterm birth, weight-for-age z score, and low albumin (odds ratio [OR], 12.69; 95% CI, 3.23-49.82). After adjustment for age, preterm birth, and weight-for-age z score, low serum albumin levels remained statistically significantly associated with apnea (OR, 4.42; 95% CI, 1.21-16.18).

    Conclusions and Relevance  Low serum albumin levels appeared to be associated with increased risk of apnea after adjustment for known apnea risk factors. This finding provides a path to potentially identifying apnea, a life-threatening complication of bronchiolitis.

    Introduction

    Infants with bronchiolitis usually have mild symptoms, but every year in the United States approximately 130 000 hospitalizations, 50 known deaths, and an unclear number of sudden unexplained deaths among infants occur are associated with bronchiolitis.1-3 One of the potentially life-threatening complications of bronchiolitis is apnea.4 The incidence of apnea among infants with bronchiolitis varies by the population under study. Retrospective and prospective studies over the past 20 years have found the incidence of apnea to range from 1% in healthy term infants to 17% in preterm infants.5 Although risk factors have been identified for apnea (eg, young age, preterm birth), it remains unclear which infants with bronchiolitis will develop this rare outcome. As a result, clinicians try to balance the safety of infants who have bronchiolitis and are at risk for apnea with potentially unnecessary hospitalizations for observation.4

    Albumin is a critical multifunctional serum protein that drives colloidal osmotic pressure, binds biologically important compounds (eg, medications, bilirubin, and vitamin D), and has antioxidant activity.6 Although the mechanism remains unclear, low serum albumin is associated with higher mortality risk in children and adults with several medical conditions, including respiratory illness.7-10

    We conducted a secondary data analysis of the 35th Multicenter Airway Research Collaboration (MARC-35), a prospective, multicenter study of infants with severe bronchiolitis (ie, requiring hospitalization).11 Our goal for the present study was to examine the association between serum albumin levels and apnea in this population.

    Methods

    The MARC-35 study, as described elsewhere,11 is an ongoing 17-center prospective cohort study of hospitalized infants (aged <1 year). The overall objective of MARC-35 is to examine the association between the characteristics of severe bronchiolitis and the risk of recurrent wheezing and asthma. All participants in MARC-35 have an attending physician’s diagnosis of bronchiolitis as defined by the American Academy of Pediatrics.12 This secondary analysis, conducted from December 11, 2018, to May 30, 2019, focused on infants who were enrolled across the United States during 3 consecutive bronchiolitis seasons (November 1 to April 30) from 2011 to 2014. Infants with heart-lung disease or a gestational age less than 32 weeks were excluded. The institutional review boards at the 17 enrolling hospitals approved the present study, and all participating families provided written informed consent.

    Site teams extracted data from outpatient clinic, emergency department, and inpatient records. To complement these data, the teams also conducted structured interviews with parents or legal guardians while the infants were hospitalized.

    Site teams used standardized equipment (Medline Industries) and followed a protocol13 to collect nasopharyngeal aspirates from all infants within 24 hours of hospitalization. Quantitative real-time reverse transcriptase–polymerase chain reaction was conducted at Baylor College of Medicine for respiratory syncytial virus (RSV) types A and B and 15 other viruses, as previously described.14 For the current analysis, the viral origin was categorized as RSV infection (ie, includes viral co-infections) or non-RSV infection.

    In addition, site teams collected blood from all infants within 24 hours of hospitalization. The serum was tested for albumin using the albumin BCP assay (Abbott Laboratories). The primary exposure, serum albumin level, was dichotomized at the lower bound of the pediatric reference range and categorized as low (<3.8 g/dL) or normal (≥3.8 g/dL) (to convert albumin level to grams per liter, multiply by 10).

    The primary outcome was the occurrence of apnea during the hospitalization. A secondary outcome was apnea occurring either before (emergency department or clinic) or during hospitalization. Both outcomes were obtained from medical record reviews (ie, by history or observation in the hospital). Undocumented presence of apnea was categorized as no apnea.

    Statistical Analysis

    Bivariate analyses included the Kruskal-Wallis test, χ2 tests, and logistic regression. We assessed the distributions of albumin levels by presence of apnea using histograms. Multivariable logistic regression models were adjusted for age at hospitalization; preterm birth, defined as 32 to 37 weeks’ gestation; and weight-for-age z score at hospitalization. Weight-for-age z scores were calculated according to the 2006 World Health Organization child growth standards, using the Stata package zscore06.15 We reverse-coded age to estimate the risk of apnea associated with younger age and weight-for-age z score to estimate the risk of apnea associated with lower weight for age.

    Sensitivity analyses adjusted (1) for corrected age4 (chronological age corrected for gestational age at birth) and weight-for-age z score and (2) for age, preterm birth, and birth weight less than 5 lbs (to convert to kilograms, multiply by 0.45). Given the possibility of variable collinearity, the variance inflation factor was calculated for all multivariable models. We also fit a locally weighted scatterplot smoothing (LOWESS) plot to show the association between serum albumin levels and the estimated probability of apnea from the multivariable model. All models accounted for potential patient clustering by site.

    Final data analyses were conducted from February 25, 2019, to May 13, 2019, and used Stata, version 14.2 (StataCorp LLC). The comparison of RSV with non-RSV infection used a χ2 test. A 2-sided α = .05 was used to indicate statistical significance.

    Results

    Of the 1016 infants hospitalized for bronchiolitis, the median (interquartile range [IQR]) age was 3 (2-6) months, 610 (60.0%) were male, and 186 (18.3%) were born preterm (32-37 weeks’ gestation). The median (IQR) serum albumin level was 3.9 (3.6-4.1) g/dL, and 385 (37.9%) had low serum albumin levels. The prevalence of apnea among infants with a normal albumin level was 0.5% compared with a prevalence of 5.7% among all infants with a low albumin level and 14.6% among infants younger than 1 month with low albumin levels. Twenty-five infants (2.5%) had apnea while hospitalized, composing the cases for the primary analysis; among these 25 infants, the median (IQR) serum albumin level was 3.5 (3.1-3.6) g/dL, and 22 (88.0%) had low serum albumin levels. Figure 1 shows the distribution of albumin levels among infants with (n = 25) or without (n = 991) apnea during hospitalization. In addition to the 25 infants with apnea during their hospitalization (12 both before and during and 13 only during), 44 infants (4.3%) were apneic before but not during the hospitalization. These 44 infants were included in the secondary analysis of all apnea cases in the cohort (n = 69).

    In unadjusted analyses (Table 1), low albumin level was associated with apnea (odds ratio [OR], 12.69; 95% CI, 3.23-49.82). As expected, younger age, preterm birth, and lower weight-for-age z score were all associated with apnea. However, when comparing infants with or without RSV infection, we found no difference in the prevalence of apnea (2.4% vs 2.6% P = .92). After adjustment for age, preterm birth, and weight-for-age z score, low serum albumin levels remained associated with a statistically significantly higher risk of apnea (OR, 4.42; 95% CI, 1.21-16.18; Table 1). The inverse association between serum albumin levels and estimated probability of apnea is shown in the LOWESS plot (Figure 2). Models adjusting for corrected age or birth weight (<5 lbs) yielded similar results. Calculation of variance inflation factor for all models did not suggest multicollinearity (all variance inflation factors <1.6). In the secondary analysis of all 69 infants with apnea, we observed an attenuated, but still significant, association between low serum albumin levels and apnea before and during hospitalization (OR, 2.50; 95% CI, 1.53-4.08; Table 2).

    Discussion

    In a large, prospective, multicenter cohort of infants hospitalized for bronchiolitis, low serum albumin levels were associated with increased risk of apnea after adjustment for known apnea risk factors (young age, preterm birth, and weight for age at hospitalization). Although needing replication and lacking a clear mechanism, these results suggest, for the first time to our knowledge, that albumin levels are a promising line of inquiry to help identify apnea in children hospitalized for bronchiolitis.

    These results confirmed 2 important findings from a previous bronchiolitis cohort.4 First, in the previous severe bronchiolitis cohort, the viral origin of bronchiolitis was not associated with the risk of apnea.4 In the present cohort, compared with non-RSV infection, RSV bronchiolitis was not associated with higher risk of apnea. Second, in the previous severe bronchiolitis cohort, most children with a history of apnea did not have apnea while hospitalized. Specifically, 60% of children with a history of apnea did not have apnea in the hospital.4 In the present cohort, 44 (78.6%) of the 56 infants with a history of apnea did not have apnea in the hospital. This finding may be reassuring to families who have infants with a history of apnea, but a corollary of this result is that 13 (18.8%) of 69 infants with apnea in the present cohort only had apnea while in the hospital. Given that apnea does not always occur early in the clinical course of bronchiolitis4 and that many children who ultimately become apneic have no history of apnea, identifying an objective marker of apnea risk has the potential to change clinical practice and improve the quality of care for infants with bronchiolitis.

    Although using albumin as a variable of apnea or as a component of an apnea prediction tool is promising, the distribution of albumin levels among infants with or without inpatient apnea shows many false-positives (94% of infants with low albumin levels did not have inpatient apnea) and a few false-negatives (0.5% of infants with normal albumin level had inpatient apnea). Until further research is completed, we do not recommend clinicians check albumin levels in infants with bronchiolitis unless otherwise clinically indicated. Replication of this finding in a larger cohort of infants is warranted.

    Nonetheless, serum albumin levels may eventually play a role in identifying apnea in infants with severe bronchiolitis. Low serum levels of albumin, a multifunctional protein,16 have been associated with mortality in children and adults with multiple medical conditions, including respiratory illnesses.7-10 The present results extend this association with mortality to apnea, a life-threatening complication of bronchiolitis. The mechanism of low albumin levels in bronchiolitis is uncertain. One possibility is decreased synthesis of albumin. Although poor nutrition is commonly considered the main origin of hypoalbuminemia, not all malnourished individuals have low albumin levels.17 The present results show that the association between albumin and apnea is independent of weight-for-age z score. Furthermore, because the half-life of albumin is approximately 3 weeks,18 infants younger than 1 month with low albumin levels would be malnourished from birth. The multivariable models, however, suggest that the association between albumin and apnea is independent of low birth weight. Thus, although decreased synthesis of albumin from poor nutrition may be part of the mechanism of low serum albumin levels in bronchiolitis, it is not the only factor. Another possible mechanism of low serum albumin would be increased losses in the urine or stool, or increased breakdown of albumin. In the present cohort, we did not measure urine or stool albumin levels and have not conducted serum amino acid analysis to suggest increased albumin breakdown.

    Another potential mechanism for the low serum albumin levels observed in this cohort is the inflammatory process associated with viral infections, specifically neurogenic inflammation. Piedimonte and colleagues19 have demonstrated in animal models that RSV via nerve growth factor increases nociceptive fibers; substance P; and 1 of its receptor subtypes, neurokinin 1.20 Of particular relevance to the association between albumin and apnea is that, with the use of labeled albumin in RSV-inoculated F-344 rats, substance P mediated the extravasation of albumin into the airways.19,21,22 What remains unclear is why neurogenic inflammation and albumin extravasation exist in the rare cases of apnea compared with other infants with severe bronchiolitis. Different virus-host interactions, virus microbiome, or even differing viral gene sequences all potentially exist and require further research.11,23-25

    Limitations

    This study has several limitations. First, the apnea cases were identified by medical record review. Although it was possible that these infants were not truly apneic, the prevalence of inpatient apnea (2.5%) was within the range of previous prevalence estimates. Moreover, diagnosis in the hospital setting (rather than at home) made it more likely that these infants were truly apneic. Second, the mechanism for low albumin levels in bronchiolitis with apnea remains uncertain, despite the intriguing animal data about neurogenic inflammation. Third, given the small number of apnea outcomes in the hospitals, sparse data bias was likely.26 However, when we extended the apnea cases to those that occurred both before and during the hospitalization, the association between low serum albumin levels and apnea remained significant. Fourth, the association between albumin and apnea may not be generalizable beyond the study population of infants hospitalized for bronchiolitis. These results, however, would apply to the approximately 130 000 infants hospitalized with bronchiolitis annually.1

    Conclusions

    In a large, prospective, multicenter cohort of infants hospitalized for bronchiolitis, low serum albumin level appeared to be associated with increased risk of apnea after adjustment for known apnea risk factors (young age, preterm birth, and weight-for-age z score). Although in need of replication, this finding may help inform and encourage future efforts to anticipate apnea, a life-threatening complication of bronchiolitis.

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    Article Information

    Accepted for Publication: May 24, 2019.

    Published: July 17, 2019. doi:10.1001/jamanetworkopen.2019.7100

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Mansbach JM et al. JAMA Network Open.

    Corresponding Author: Jonathan M. Mansbach, MD, MPH, Department of Pediatrics, Boston Children's Hospital, 300 Longwood Ave, Main Clinical Bldg, Ste 9157, Boston, MA 02115 (jonathan.mansbach@childrens.harvard.edu).

    Author Contributions: Dr Mansbach had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Mansbach, Camargo.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Mansbach, Geller.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Mansbach, Geller, Hasegawa, Espinola.

    Obtained funding: Mansbach, Hasegawa, Camargo.

    Administrative, technical, or material support: Hasegawa, Sullivan, Camargo.

    Supervision: Mansbach, Espinola, Camargo.

    Conflict of Interest Disclosures: Drs Mansbach, Stevenson, and Camargo reported grants from the National Institutes of Health (NIH) during the conduct of the study. No other disclosures were reported.

    Funding/Support: This study was supported by grants U01 AI-087881, R01 AI-114552, R01 AI-108588, R01 AI-137091, and R01 AI-134940 from the National Institute of Allergy and Infectious Diseases (NIAID) and by grant UG3/UH3 OD-023253 from the Office of the Director at the NIH.

    Role of the Funder/Sponsor: The NIAID and NIH funded this study through a cooperative agreement grant. A NIAID project scientist participated in the design and monitoring of study progress but not in the conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: The views expressed herein are those of the authors and do not reflect the official policy or position of the NIH.

    Additional Contributions: Pedro (Tony) A. Piedra, MD, Baylor College of Medicine, provided support and virology expertise. We thank the research personnel of the 17 study hospitals for their ongoing dedication to bronchiolitis research. None of these contributors received compensation for their contributions. The principal investigators in MARC-35 are Amy D. Thompson, MD, Alfred I. duPont Hospital for Children, Wilmington, Delaware; Federico R. Laham, MD, MS, Arnold Palmer Hospital for Children, Orlando, Florida; Jonathan M. Mansbach, MD, MPH, Boston Children's Hospital, Boston, Massachusetts; Vincent J. Wang, MD, MHA, Children's Hospital of Los Angeles, Los Angeles, California; Michelle B. Dunn, MD, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Juan C. Celedon, MD, DrPH, at Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; Michael Gomez, MD, MS-HCA, and Nancy Inhofe, MD, The Children's Hospital at St Francis, Tulsa, Oklahoma; Brian M. Pate, MD, and Henry T. Puls, MD, The Children's Mercy Hospital & Clinics, Kansas City, Missouri; Stephen J. Teach, MD, MPH, Children's National Medical Center, Washington, DC; Richard T. Strait, MD, Cincinnati Children's Hospital and Medical Center, Cincinnati, Ohio; Ilana Waynik, MD, Connecticut Children's Medical Center, Hartford; Sujit Iyer, MD, Dell Children's Medical Center of Central Texas, Austin; Michelle D. Stevenson, MD, MS, Kosair Children's Hospital, Louisville, Kentucky; Wayne G. Shreffler, MD, PhD, and Ari R. Cohen, MD, Massachusetts General Hospital, Boston; Anne K. Beasley, MD, Phoenix Children's Hospital, Phoenix, Arizona; Thida Ong, MD, Seattle Children's Hospital, Seattle, Washington; and Charles G. Macias, MD, MPH, Texas Children's Hospital, Houston.

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