Viral-induced wheezing

With nearly a third of all children having a wheezing episode before their third birthday and half by age 6 years, wheezing is one of the most 

problems for which preschool children are seen in the pediatrician's office.^1,2 Further, children who wheeze once are likely to wheeze again, making recurrent wheeze a frequent problem.

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The problem for pediatricians is that although there are guidelines for asthma, not all that wheezes is asthma. Further, the medical literature has poorly defined a phenotypic difference the practicing pediatrician commonly sees-the otherwise healthy preschool child with a viral-induced wheezing event versus an asthma exacerbation triggered by a virus. The medical literature commonly cites epidemiologic criteria such as wheezing in the first 3 years of life, transient versus persistent wheeze, or atopic versus nonatopic, but these criteria are retrospective and do not help the practicing pediatrician in the office.¹ Defining wheezing via temporal patterns may be more useful for the busy clinician.

Temporal patterns of wheezing

The European Respiratory Society Task Force recommends differentiating wheezing phenotypes that provide the pediatrician with some evidence that can assist with treatment into episodic viral wheezing and multiple-trigger wheezing.²

Episodic viral wheezing. Episodic viral wheezing is defined as wheezing during discrete time periods in an otherwise healthy child who is without symptoms between these episodes.² Wheezing episodes are generally associated with a clinical diagnosis of viral upper respiratory tract infection (URTI). Rhinovirus, respiratory syncytial virus (RSV), coronavirus, human metapneumovirus, parainfluenza virus, and adenovirus are commonly cited in research studies that attempt to find a diagnosis, but this is not commonly done in clinical practice.² Possible underlying factors include preexisting impaired lung function, tobacco smoke exposure, prematurity, and atopy.^2,3

Repeat episodes commonly occur seasonally, and some children experience severe symptoms from these wheezing episodes. Factors identifying why the episodes recur and why the severity is increased in some preschoolers is poorly understood. In most children episodic viral wheezing declines over time, but it can persist into school age or become multiple-trigger wheezing.³

Multiple-trigger wheezing. Viral illness is not the only trigger for wheezing episodes, which can also include triggers such as smoke and pollen, among others. Patients in this category demonstrate symptoms between episodes. Although some believe multiple-trigger wheezing to be representative of a chronic inflammatory condition, there is limited evidence supporting this.²

Both phenotypes are lacking, however, in that they will not identify children who will go on to develop asthma, children who will outgrow their symptoms, or children who have bronchiolitis for which steroids are not indicated.¹

NEXT: Will wheezing in preschool transition into asthma?

Does preschool wheezing lead to asthma?

Often the first question asked, either by the parent or by the pediatrician, is “Does this wheezing episode represent an asthma diagnosis?” The answer may be different depending on what is really behind the question. From a scientific perspective, the answer is yes if the child has wheezing and shortness of breath, and if the symptoms fluctuate over time. The question of whether the episode results from a process of eosinophilic inflammation is much more difficult to answer in a preschool child. The parent, on the other hand, really wants to know if their child will need medication and treatment beyond the preschool years and is obviously reluctant to subject their child to medication when they appear well most of the time.¹

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Another problem faced by the pediatrician is whether the child was actually wheezing or not. Noisy breathing is common in preschoolers, so pediatricians are often faced with parents stating their child is wheezing, but on examination they cannot find the high-pitched whistling sounds commonly termed “wheezing.” Physician-confirmed wheezing is more likely to be associated with true airway constriction, although noisy breathing responding to bronchodilator therapy is likely to be a true wheeze.³

A number of tools are available to predict future asthma, and these include measuring severity of preschool wheeze, presence of inflammation (elevated eosinophils or immunoglobulin E), or atopic signs and symptoms.^4-7 Based on these studies, it does not appear that children with episodic viral wheezing have an increased risk of atopy or respiratory symptoms after age 14 years. Additionally, there is no evidence that treatment with any particular drug in a preventive manner will prevent future airway remodeling, airflow obstruction, or prevent asthma.¹

Respiratory infections are just one of the risk factors for asthma. Whether or not respiratory infections cause asthma is not currently known.^8,9 Although the risk of asthma following RSV and rhinovirus is known to increase, there are also data that support early infections as protective against development of asthma later in life.^10–12

NEXT: Understanding risk

It's all about risk

One of the problems pediatricians need to be aware of when reading the literature on preschool wheezing is heterogeneity. In many of the studies that look at prevention of recurrent wheezing and symptoms, the patient’s risk for asthma and allergic disease can be very different. Additionally, terms such as "intermittent asthma" and "virus-associated wheeze" are used almost interchangeably and may represent different levels of disease severity or phenotypes in different studies.

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Pediatricians need to be very careful about examining how similar or dissimilar the patients in studies are compared with the patients in their practice before making practice determinations. For example, the Prevention of Early Asthma in Kids (PEAK) trial demonstrated that daily inhaled steroids decreased symptom exacerbations and episodes requiring oral steroids. The children in this trial, however, were at increased risk of asthma.¹³ In another trial examining use of an inhaled corticosteroid (ICS) and a leukotriene receptor antagonist in preschoolers with intermittent wheezing, results were mostly negative when looking at the proportion of episode-free days, but there appeared to be small but statistically significant improvements in symptoms during acute episodes.¹⁴ Most of the benefit appeared among treated children with positive asthma predictive indices, however, compared with children without that risk. This seems to highlight the importance of asthma phenotypes when considering wheezing treatment in these children as well as how to apply results of trials to the pediatrician’s practice.

Treating episodic viral wheeze

Intermittent symptoms are best treated with intermittent therapy, with short-acting bronchodilators usually being first-line therapy.¹ If additional therapy is required, ICSs, leukotriene modifiers, or combination therapy are options.

The PREEMPT trial looked at 220 children aged 2 to 14 years with a history of intermittent asthma and definite symptom-free periods between wheezing episodes.¹⁵ These patients required no medication between wheezing episodes, had at least 3 but no more than 6 wheezing episodes in the previous 12 months, and had either a hospitalization or an emergency department (ED) visit during that time period.

In the trial, parents initiated treatment with montelukast or placebo for 7 days or until symptoms resolved for 48 hours with a maximum of 20 days of treatment with each URTI. The treatment group experienced nearly a 30% reduction in healthcare resource utilization, including reductions in visits to their primary care physician and ED visits. Although there was not a decrease in oral steroid use, asthma symptoms were less with montelukast treatment.

NEXT: More on the impact of ICS

Additionally, montelukast treatment reduced parental work absences and children's missed time from school.¹⁵ As previously mentioned, children with a higher risk of asthma may benefit more from this therapy compared with children with a lower risk of asthma.¹⁴

A Cochrane Review in 2000 concluded that intermittent ICS for the treatment of episodic viral wheezing is partially effective as a strategy for the treatment of mild episodic viral wheeze of childhood. No current evidence favors maintenance low-dose ICS in the prevention and management of episodic mild viral-induced wheeze.¹⁶

A randomized, controlled trial in 129 preschoolers with wheezing given high-dose fluticasone (750 µg twice daily) for 10 days starting at the first sign of a URTI was associated with decreased need for prednisolone, but was also associated with higher rates of adverse effects (decreased gains in height and weight).^3,17

Similarly, other studies have demonstrated high-dose intermittent inhaled steroid for 5 to 10 days results in decreases in oral steroid use and symptoms.^3,16,18-20 Not all studies have demonstrated benefit, however, and it appears that standard, intermittent ICS dosing is not effective.^14,21,22

Current evidence does not support the use of regular dosing of ICS in children who experience intermittent symptoms with distinct symptom-free periods between episodes to prevent either symptoms or further episodes of episodic wheezing.¹

If, however, children experience severe episodes of episodic wheezing requiring hospitalization or particularly bothersome symptoms at home, or it is believed that intermittent symptoms are being missed, it may be reasonable to initiate a trial of ICS. Trials should be short, however, with close monitoring of symptoms and rapid stopping if there is no improvement or decreasing doses as tolerated.¹

Studies have also examined oral prednisolone as an intermittent treatment agent with the onset of URTI symptoms. In 2 studies, more than 900 children were treated and no treatment benefit was noted if a child was able to remain under community-based treatment.^23,24

There is now a small amount of evidence supporting the use of hypertonic saline with a short-acting beta₂-agonist. In a small trial of 41 children presenting to the ED with an acute episode of episodic wheezing, patients were randomized to albuterol treatment either with hypertonic saline or normal saline. Although this was a small study, rates of hospitalization and length of stay were significantly lower in the hypertonic saline group.^1,25

Importantly, there is no evidence to support the use of antibiotics for the treatment of episodic viral wheeze unless the pediatrician believes a bacterial infection is present.^26,27 Given that most preschool wheezing episodes are because of a virus, this is not surprising.

NEXT: How to treat a multi-trigger wheeze

Treating multiple-trigger wheeze

Although there is little evidence, many practitioners believe multiple-trigger wheeze resembles allergic asthma. Treating multiple-trigger wheeze with ICS is more successful than it is in episodic viral wheeze. Given preschool children with a history of wheezing, cough, and other symptoms responsive to bronchodilators who remain symptomatic, a trial of preventive therapy is warranted.

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Treating multiple-trigger wheeze with continuous, standard-dose ICS is associated with increases in the number of symptom-free days, decreased hospitalizations, fewer exacerbations, and improved lung function.^3,28,29

Because airway inflammation cannot be reliably measured in preschool children and many will no longer have symptoms when becoming school aged, it is important to remember that not all children with multiple-trigger wheeze have asthma pathophysiology.¹ Further, the younger the child the less likely true inflammation will be present, and treatment with montelukast may also be a reasonable plan.^1,30

In a recent 2014 review, researchers recommend a 3-step approach that, although not having support from a literature-based approach, prevents patients from being labeled falsely when symptoms would have improved without treatment.¹ They recommend the following for preschoolers with multiple-trigger wheeze:

• Trial of ICS or montelukast for 4 to 8 weeks.

• Stopping treatment because symptoms have not improved or have disappeared. If there is no benefit, further testing is indicated by the pediatrician or referral to an appropriate specialist.

• Restarting treatment if symptoms recur. The goal is to find the minimal medication dose that prevents symptoms.

NEXT: Review of best practices

Conclusion

Wheezing in preschool children is a heterogeneous condition with multiple phenotypes. Although optimal treatment is not currently well defined, this article reviews research supporting a number of options as well as some practices for which research is lacking. Treatments will need to be individualized to patients based on treatment response but may include intermittent treatments with an inhaled steroid or montelukast when therapy beyond a short-acting beta₂-agonist is needed. Because no treatments currently appear to alter disease course and prevent progression from preschool wheezing to asthma, current symptoms will likely guide treatment.

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REFERENCES

1. Bush A, Grigg J, Saglani S. Managing wheeze in preschool children. BMJ. 2014;348:g15.

2. Brand PL, Baraldi E, Bisgaard H, et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J. 2008;32(4):1096-1110.

3. van Aalderen WM, Sprikkelman AB. Inhaled corticosteroids in childhood asthma: the story continues. Eur J Pediatr. 2011;170(6):709-718.

4. Devulapalli CS, Carlsen KC, Håland G, et al. Severity of obstructive airways disease by age 2 years predicts asthma at 10 years of age. Thorax. 2008;63(1):8-13.

5. Guilbert TW, Morgan WJ, Zeiger RS, et al. Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthma. J Allergy Clin Immunol. 2004;114(6):1282-1287.

6. Bacharier LB, Guilbert TW, Zeiger RS, et al; Childhood Asthma Research and Education Network of the National Heart, Lung, and Blood Institute. Patient characteristics associated with improved outcomes with use of an inhaled corticosteroid in preschool children at risk for asthma. J Allergy Clin Immunol. 2009;123(5):1077-1082.

7. Savenije OE, Kerkhof M, Koppelman GH, Postma DS. Predicting who will have asthma at school age among preschool children. J Allergy Clin Immunol. 2012;130(2):325-331.

8. Kuehni CE, Spycher BD, Silverman M. Causal links between RSV infection and asthma: no clear answers to an old question. Am J Respir Crit Care Med. 2009;179(12):1079-1080.

9. Thomsen SF, van der Sluis S, Stensballe LG, et al. Exploring the association between severe respiratory syncytial virus infection and asthma: a registry-based twin study. Am J Respir Crit Care Med. 2009;179(12):1091-1097.

10. Sigurs N, Aljassim F, Kjellman B, et al. Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life. Thorax. 2010;65(12):1045-1052.

11. Jackson DJ, Gangnon RE, Evans MD, et al. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am J Respir Crit Care Med. 2008;178(7):667-672.

12. Illi S, von Mutius E, Lau S, et al; MAS Group. Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study. BMJ. 2001;322(7283):390-395.

13. Bacharier LB. Viral-induced wheezing episodes in preschool children: approaches to therapy. Curr Opin Pulm Med. 2010;16(1):31-35.

14. Bacharier LB, Phillips BR, Zeiger RS, et al; CARE Network. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122(6):1127-1135.

15. Robertson CF, Price D, Henry R, et al. Short-course montelukast for intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med. 2007;175(4):323-329.

16. McKean M, Ducharme F. Inhaled steroids for episodic viral wheeze of childhood. Cochrane Database Syst Rev. 2000;(2):CD001107.

17. Ducharme FM, Lemire C, Noya FJ, et al. Preemptive use of high-dose fluticasone for virus-induced wheezing in young children. N Engl J Med. 2009;360(4):339-353.

18. Svedmyr J, Nyberg E, Thunqvist P, Asbrink-Nilsson E, Hedlin G. Prophylactic intermittent treatment with inhaled corticosteroids of asthma exacerbations due to airway infections in toddlers. Acta Paediatr. 1999;88(1):42-47.

19. Wilson NM, Silverman M. Treatment of acute, episodic asthma in preschool children using intermittent high dose inhaled steroids at home. Arch Dis Child. 1990;65(4):407-410.

20. Connett G, Lenney W. Prevention of viral induced asthma attacks using inhaled budesonide. Arch Dis Child. 1993;68(1):85-87.

21. Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med. 2006;354(19):1998-2005.

22. Papi A, Nicolini G, Baraldi E, et al; BEclomethasone and Salbutamol Treatment (BEST) for Children Study Group. Regular vs prn nebulized treatment in wheeze preschool children. Allergy. 2009;64(10):1463-1471.

23. Panickar J, Lakhanpaul M, Lambert PC, et al. Oral prednisolone for preschool children with acute virus-induced wheezing. N Engl J Med. 2009;360(4):329-338.

24. Oommen A, Lambert PC, Grigg J. Efficacy of a short course of parent-initiated oral prednisolone for viral wheeze in children aged 1-5 years: randomised controlled trial. Lancet. 2003;362(9394):1433-1438.

25. Ater D, Shai H, Bar BE, et al. Hypertonic saline and acute wheezing in preschool children. Pediatrics. 2012;129(6):e1397-e1403.

26. Tahan F, Ozcan A, Koc N. Clarithromycin in the treatment of RSV bronchiolitis: a double-blind, randomised, placebo-controlled trial. Eur Respir J. 2007;29(1):91-97.

27. Farley R, Spurling GK, Eriksson L, Del Mar CB. Antibiotics for bronchiolitis in children under two years of age. Cochrane Database Syst Rev. 2014;10:CD005189.

28. Kaditis AG, Winnie G, Syrogiannopoulos GA. Anti-inflammatory pharmacotherapy for wheezing in preschool children. Pediatr Pulmonol. 2007;42(5):407-420.

29. Castro-Rodriguez JA, Rodrigo GJ. Efficacy of inhaled corticosteroids in infants and preschoolers with recurrent wheezing and asthma: a systematic review with meta-analysis. Pediatrics. 2009;123(3):e519-e525.

30. Saglani S, Malmström K, Pelkonen AS, et al. Airway remodeling and inflammation in symptomatic infants with reversible airflow obstruction. Am J Respir Crit Care Med. 2005;171(7):722-727. 

Dr Bass is chief medical information officer and associate professor of medicine and pediatrics, Louisiana State University Health Science Center–Shreveport. The author has nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.