Published online July 1, 2008
PEDIATRICS Vol. 122 No. 1 July 2008, pp. 177-179 (doi:10.1542/10.1542/peds.2007-3323)
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COMMENTARY

Bronchiolitis: Lingering Questions About Its Definition and the Potential Role of Vitamin D

Jonathan M. Mansbach, MDa and Carlos A. Camargo, Jr, MD, DrPHb

a Department of Medicine, Children's Hospital Boston
b Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

Abbreviations: RSV, respiratory syncytial virus

BRONCHIOLITIS IS THE leading cause of hospitalization for infants younger than 1 year,1 and the associated hospitalization costs are more than $500 million per year in the United States.2 In this issue of Pediatrics, Carroll et al3 describe the increasing disease burden of bronchiolitis from 1996 to 2003 in healthy, term infants enrolled in the Tennessee Medicaid program. Over these 7 years, children with the International Classification of Diseases, Ninth Revision (ICD-9) codes 466.1 (bronchiolitis and bronchitis) or 480.1 (pneumonia caused by respiratory syncytial virus [RSV]) had an increasing number of visits at all levels of care: outpatient office visits, emergency department visits, and hospitalizations, including 23-hour observations. These data raise important questions not only about the definition of bronchiolitis but also about the reason for the increasing number of medical visits for bronchiolitis.

The clinical picture of bronchiolitis was provided by the American Academy of Pediatrics in its 2006 position statement, which states that children with bronchiolitis typically have "rhinitis, tachypnea, wheezing, cough, crackles, use of accessory muscles, and/or nasal flaring."4 This recognizable constellation of signs and symptoms makes bronchiolitis seem like a straightforward clinical diagnosis that then leads to assignment of the International Classification of Diseases, Ninth Revision codes used by Carroll et al.3 However, astute clinicians continue to debate when young children with an acute lower respiratory tract infection and wheezing should be diagnosed as having bronchiolitis, reactive airways disease, or even asthma.

In addition to this basic diagnostic challenge, there is a microbiologic issue. Bronchiolitis is caused by many infectious pathogens, most notably RSV, which accounts for approximately two thirds of clinically significant cases.5 Other viral causes of bronchiolitis include adenovirus, parainfluenza, influenza A/B, human metapneumovirus, rhinovirus, and coronaviruses.6,7 Two other viruses were also discovered recently: HKU18 and human bocavirus.9 Bacterial causes of bronchiolitis include Mycoplasma pneumoniae10 and Bordetella pertussis, which may be an unrecognized copathogen in bronchiolitis.11

Despite the multiple infectious etiologies, most of these infectious agents are not readily identified in most laboratories, and only RSV and influenza have actual point-of-care tests available. However, do all of the aforementioned pathogens truly produce the same clinical manifestations? And, are these clinical manifestations different when bronchiolitis is caused by a single pathogen versus multiple pathogens (as is found in 20%–27% of hospitalized patients with lower respiratory tract infection?6,7) These unanswered questions raise the possibility that clinicians eventually might stop describing bronchiolitis solely as a clinical entity and, instead, describe it by the specific infecting pathogen(s).

When considering these diagnostic issues, it is helpful to look beyond the acute clinical manifestations to both the short-term and long-term outcomes. Except for treating influenza with oseltamivir in children >12 months old and for inpatient cohorting, the current consensus is that knowledge of the viral etiology (among those viruses with established testing) does not affect treatment of the individual patient.4 However, recent data about rhinovirus bronchiolitis are intriguing. In the Childhood Origins of Asthma (COAST) birth-cohort study, the most significant predictor of wheezing at 3 years of age was a moderate-to-severe rhinovirus illness with wheezing during infancy.12 In addition, 1 trial of prednisolone for 3 days (versus placebo) for children hospitalized with their first or second episode of wheezing caused by rhinovirus demonstrated reduced relapses during a 2-month period after the hospitalization13 and reduced recurrent wheezing at 1 year for those with the first episode of wheezing.14 These and other data15 suggest that children with bronchiolitis may have only subtle clinical differences at presentation but more dramatic differences in their short-term or long-term prognosis. Therefore, as rapid tests and more data become available, identifying the infectious etiology of a child's lower respiratory tract infection may become easier and change treatment decisions and follow-up plans.

Carroll et al3 question why the rates of bronchiolitis are increasing in Tennessee. Although national data do not support such an increase over similar years,16,17 an earlier study by Shay et al1 did show a clear increase in bronchiolitis hospitalizations from 1980 to 1996. Some of the possible reasons for the observed increase include overall trends in child care practice, changes in hospitalization practices, and the possibility of increased pathogen virulence. There may also be an increase in visits resulting from increased awareness of asthma and children's respiratory health in general or an unmeasured host factor that is causing more children to become symptomatic.

This final possibility led us to propose that the already large and potentially increasing frequency of more severe bronchiolitis, may be caused by population increases in vitamin D deficiency. We note that almost all clinical cases of bronchiolitis in temperate climates occur between November and March, months that also are associated with vitamin D deficiency. The major source of vitamin D for most humans is exposure of skin to the B fraction of ultraviolet light (UV-B). However, in northern latitudes between November and March, there are insufficient UV-B rays to produce vitamin D and people have to rely on their dietary intake of vitamin D.18 Although breast milk, the diet for many infants, has numerous health benefits, it is a poor source of vitamin D.18

Low levels of vitamin D actually are quite common among US newborns19,20 and have been associated with an increased incidence of pneumonia21 and lower respiratory tract disease requiring hospitalization,22,23 as well as an increased risk of cold/influenza symptoms in adults24 and, possibly, tuberculosis.25 The pathophysiology of these observations may relate to the role of vitamin D in the activity of the innate immune system.26,27 The innate immune system, specifically the activities of cathelicidin and defensin, helps prevent infections with bacteria and viruses.28,29 Janssen et al30 recently showed significant genetic associations of a number of single-nucleotide polymorphisms of innate immunity genes (including the vitamin D receptor) with the severity of RSV bronchiolitis.

Camargo et al31 recently found in a Massachusetts population that lower maternal intake of vitamin D during pregnancy had a statistically significant, independent association with increased risk of recurrent childhood wheeze. These findings were replicated in 5-year old Scottish children.32 In addition, Camargo et al confirmed these findings in a separate birth cohort from New Zealand (41°S) in which low vitamin D levels in cord blood were associated with increased risk of respiratory infections at 3 months of age and of wheezing in early childhood.33 Additional research is needed to elucidate the connection between vitamin D and bronchiolitis, and this topic is an active area of research for our group.

In summary, recent publications about bronchiolitis by the American Academy of Pediatrics4 and a number of investigators14,34–37 have been welcome news for pediatricians. The epidemiologic work of Carroll et al3 highlights the importance of continuing to pursue answers to the many questions that still exist about this common condition. In a cooperative agreement with the National Institutes of Health, our group is trying to answer several of the questions we have raised. A recently initiated prospective, multicenter study will examine the clinical utility of testing for the cause(s) of bronchiolitis in 2250 hospitalized children and create prediction rules to assist clinicians in the management of severe bronchiolitis (eg, children requiring respiratory support). A substudy will examine the role of vitamin D deficiency in the severity of bronchiolitis. The already large and potentially rising incidence of bronchiolitis is a call to action for pediatric researchers to close the gaps in our understanding about the etiology, pathogenesis, management, and, ultimately, prevention of this important condition.


   FOOTNOTES
 
Accepted Nov 19, 2007.

Address correspondence to Jonathan M. Mansbach, MD, Children's Hospital Boston, Main Clinical Building 9 South, 9157, Boston, MA 02115. E-mail: jonathan.mansbach{at}childrens.harvard.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

Opinions expressed in these commentaries are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees.


   REFERENCES
TOP
 REFERENCES
 

  1. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-associated hospitalizations among US children, 1980–1996. JAMA.1999; 282 (15):1440 –1446[Abstract/Free Full Text]
  2. Pelletier AJ, Mansbach JM, Camargo CA Jr. Direct medical costs of bronchiolitis hospitalizations in the United States. Pediatrics.2006; 118 (6):2418 –2423[Abstract/Free Full Text]
  3. Carroll K, Gebretsadik T, Griffin MR, et al. The increasing burden and risk factors for bronchiolitis-related medical visits in infants enrolled in a state health care insurance plan. Pediatrics.2008; 122 (1):58 –64[Abstract/Free Full Text]
  4. American Academy of Pediatrics, Subcommittee on Diagnosis and Management of Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics.2006; 118 (4):1774 –1793[Abstract/Free Full Text]
  5. Glezen WP, Loda FA, Clyde WA Jr, et al. Epidemiologic patterns of acute lower respiratory disease of children in a pediatric group practice. J Pediatr.1971; 78 (3):397 –406[CrossRef][Web of Science][Medline]
  6. Jennings LC, Anderson TP, Werno AM, Beynon KA, Murdoch DR. Viral etiology of acute respiratory tract infections in children presenting to hospital: role of polymerase chain reaction and demonstration of multiple infections. Pediatr Infect Dis J.2004; 23 (11):1003 –1007[Medline]
  7. Legg JP, Warner JA, Johnston SL, Warner JO. Frequency of detection of picornaviruses and seven other respiratory pathogens in infants. Pediatr Infect Dis J.2005; 24 (7):611 –616[CrossRef][Web of Science][Medline]
  8. Lau SK, Woo PC, Yip CC, et al. Coronavirus HKU1 and other coronavirus infections in Hong Kong. J Clin Microbiol.2006; 44 (6):2063 –2071[Abstract/Free Full Text]
  9. Ma X, Endo R, Ishiguro N, et al. Detection of human bocavirus in Japanese children with lower respiratory tract infections. J Clin Microbiol.2006; 44 (3):1132 –1134[Abstract/Free Full Text]
  10. Henderson FW, Clyde WA Jr, Collier AM, et al. The etiologic and epidemiologic spectrum of bronchiolitis in pediatric practice. J Pediatr.1979; 95 (2):183 –190[CrossRef][Web of Science][Medline]
  11. Korppi M, Hiltunen J. Pertussis is common in nonvaccinated infants hospitalized for respiratory syncytial virus infection. Pediatr Infect Dis J.2007; 26 (4):316 –318[CrossRef][Web of Science][Medline]
  12. Lemanske RF Jr, Jackson DJ, Gangnon RE, et al. Rhinovirus illnesses during infancy predict subsequent childhood wheezing. J Allergy Clin Immunol.2005; 116 (3):571 –577[CrossRef][Web of Science][Medline]
  13. Jartti T, Lehtinen P, Vanto T, et al. Evaluation of the efficacy of prednisolone in early wheezing induced by rhinovirus or respiratory syncytial virus. Pediatr Infect Dis J.2006; 25 (6):482 –488[CrossRef][Web of Science][Medline]
  14. Lehtinen P, Ruohola A, Vanto T, Vuorinen T, Ruuskanen O, Jartti T. Prednisolone reduces recurrent wheezing after a first wheezing episode associated with rhinovirus infection or eczema. J Allergy Clin Immunol.2007; 119 (3):570 –575[CrossRef][Web of Science][Medline]
  15. Mansbach J, McAdam A, Clark S, et al. Prospective multicenter study of the viral etiology of bronchiolitis in the emergency department. Acad Emerg Med.2008; 15 (2):111 –118[CrossRef][Web of Science][Medline]
  16. Mansbach JM, Emond JA, Camargo CA Jr. Bronchiolitis in US emergency departments 1992 to 2000: epidemiology and practice variation. Pediatr Emerg Care.2005; 21 (4):242 –247[CrossRef][Medline]
  17. Mansbach JM, Pelletier AJ, Camargo CA Jr. US outpatient office visits for bronchiolitis, 1993–2004. Ambul Pediatr.2007; 7 (4):304 –307[CrossRef][Web of Science][Medline]
  18. Holick MF. Vitamin D deficiency. N Engl J Med.2007; 357 (3):266 –281[Free Full Text]
  19. Lee JM, Smith JR, Philipp BL, Chen TC, Mathieu J, Holick MF. Vitamin D deficiency in a healthy group of mothers and newborn infants. Clin Pediatr (Phila).2007; 46 (1):42 –44[Abstract/Free Full Text]
  20. Ziegler EE, Hollis BW, Nelson SE, Jeter JM. Vitamin D deficiency in breastfed infants in Iowa. Pediatrics.2006; 118 (2):603 –610[Abstract/Free Full Text]
  21. Muhe L, Lulseged S, Mason KE, Simoes EA. Case-control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children. Lancet.1997; 349 (9068):1801 –1804[CrossRef][Web of Science][Medline]
  22. Najada AS, Habashneh MS, Khader M. The frequency of nutritional rickets among hospitalized infants and its relation to respiratory diseases. J Trop Pediatr.2004; 50 (6):364 –368[Abstract/Free Full Text]
  23. Wayse V, Yousafzai A, Mogale K, Filteau S. Association of subclinical vitamin D deficiency with severe acute lower respiratory infection in Indian children under 5 y. Eur J Clin Nutr.2004; 58 (4):563 –567[CrossRef][Web of Science][Medline]
  24. Aloia JF, Talwar SA, Pollack S, Yeh J. A randomized controlled trial of vitamin D3 supplementation in African American women. Arch Intern Med.2005; 165 (14):1618 –1623[Abstract/Free Full Text]
  25. Martineau AR, Wilkinson RJ, Wilkinson KA, et al. A single dose of vitamin D enhances immunity to mycobacteria. Am J Respir Crit Care Med.2007; 176 (2):208 –213[Abstract/Free Full Text]
  26. Wang TT, Nestel FP, Bourdeau V, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol.2004; 173 (5):2909 –2912[Abstract/Free Full Text]
  27. Schauber J, Dorschner RA, Coda AB, et al. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest.2007; 117 (3):803 –811[CrossRef][Web of Science][Medline]
  28. Ganz T. Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol.2003; 3 (9):710 –720[CrossRef][Web of Science][Medline]
  29. Leikina E, Delanoe-Ayari H, Melikov K, et al. Carbohydrate-binding molecules inhibit viral fusion and entry by crosslinking membrane glycoproteins. Nat Immunol.2005; 6 (10):995 –1001[CrossRef][Web of Science][Medline]
  30. Janssen R, Bont L, Siezen CL, et al. Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. J Infect Dis.2007; 196 (6):826 –834[CrossRef][Web of Science][Medline]
  31. Camargo CA Jr, Rifas-Shiman SL, Litonjua AA, et al. Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age. Am J Clin Nutr.2007; 85 (3):788 –795[Abstract/Free Full Text]
  32. Devereux G, Litonjua AA, Turner SW, et al. Maternal vitamin D intake during pregnancy and early childhood wheezing. Am J Clin Nutr.2007; 85 (3):853 –859[Abstract/Free Full Text]
  33. Camargo CA Jr, Ingham T, Wickens K, et al. Cord blood 25-hydroxyvitamin D levels and risk of childhood wheeze in New Zealand [abstract]. Am J Respir Crit Care Med.2008; 177 (7 suppl): In press
  34. Wainwright C, Altamirano L, Cheney M, et al. A multicenter, randomized, double-blind, controlled trial of nebulized epinephrine in infants with acute bronchiolitis. N Engl J Med.2003; 349 (1):27 –35[Abstract/Free Full Text]
  35. Corneli HM, Zorc JJ, Majahan P, et al. A multicenter, randomized, controlled trial of dexamethasone for bronchiolitis. N Engl J Med.2007; 357 (4):331 –339[Abstract/Free Full Text]
  36. Welliver TP, Garofalo RP, Hosakote Y, et al. Severe human lower respiratory tract illness caused by respiratory syncytial virus and influenza virus is characterized by the absence of pulmonary cytotoxic lymphocyte responses. J Infect Dis.2007; 195 (8):1126 –1136[CrossRef][Web of Science][Medline]
  37. Bennett BL, Garofalo RP, Cron SG, et al. Immunopathogenesis of respiratory syncytial virus bronchiolitis. J Infect Dis.2007; 195 (10):1532 –1540[CrossRef][Web of Science][Medline]
PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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