Indian Pediatrics 2001; 38: 821-826  

Wheezing and the Management Algorithms for Pneumonia in Developing Countries

Pneumonia is a leading cause of mortality in children worldwide. Estimates of the mortality burden are problematic but the World Health Organization (WHO) proposes 2.6 million childhood deaths annually attributable to acute lower respiratory tract illness (ALRI)(1). Although the delivery of current and new vaccines is obviously a key issue in the control of ALRI, case manage-ment has been the mainstay of international attempts to reduce this burden of disease. During the last 20 years many countries have implemented the case management algorithms developed by the WHO. There is good evidence that such programs have reduced mortality from this condition in developing countries(2). In the last few years these and other disease specific algorithms have been incorporated into the integrated management of childhood illness (IMCI) approach that has been developed by WHO. The ALRI algorithms depend primarily on two key clinical signs: elevated respiratory rate and chest indrawing. The current IMCI algorithm proscribes that children with wheeze and fast breathing presenting to first level health facilities are given antibiotics if they continue to have fast breathing after two doses of bronchodilator. The primary purpose of the algorithm is to prevent mortality due to bacterial pneumonia. However, an unknown proportion of children managed in this fashion will have a viral related wheezing illness or asthma rather than pneumonia. Although it is unlikely that wheezing syndromes are a significant cause of mortality for children in developing countries, these algorithms are likely to result in unnecessary administration of antibiotics as well as inadequate treatment of recurrent wheezing illness. If these issues are to be tackled then we need to carefully review the existing evidence about wheezing illness in early life.

What is Known About Prevalence and Natural History?

There are only a small number of population based studies of natural history that assess symptoms and lung function in the first six years of life. All these studies are from developed countries. The most import-ant of these is the Tucson Children’s Respira-tory Study commenced in the early 1980s in Arizona, USA(3). This group prospectively enrolled 1246 newborn children between 1980 and 1984. Follow up data was available at both 3 and 6 years of age for 826 children. This study demonstrated that:

· Almost 60% of children with wheeze in the first few years of life have ceased wheezing by age 6.

· Most children with wheeze in the first three years of life have a transient syndrome that may be related to pre-existing reduced airways function (possibly on the basis of decreased airway size) at birth and this condition is not associated with features of atopy or future development of asthma.

· Only half the children with persistent wheeze at age 6 years had commenced wheezing before age 3.

Non-asthmatic wheeze in early childhood is associated with intercurrent viral infections. The risk factors for this syndrome appear to be:

· Reduced lung function that may reflect impaired lung growth in the intrauterine period.

· Exposure to tobacco smoke either during the prenatal or early childhood period (3,4).

During the 1990s the first major international study of asthma prevalence in childhood was conducted(5). This study examined children from 155 centers in 56 countries. Six to 7 year old children were the youngest age category studied and data was reported on 257,800 participants in this group. The prevalence of wheezing illness in this group varied widely from 4.1% to 32.1%. The low prevalence countries included Indonesia, Iran and Malaysia while high prevalence countries were Australia, Brazil, Costa Rica, New Zealand and Panama.

There are two major sources of potential bias in the estimation of asthma prevalence in this study. Firstly while many developing countries were included in the study, their centers were predominantly in urban regions and the true prevalence of wheezing illness or asthma in rural areas has not been established. Secondly the questionnaire instrument was developed in English and it may be that inadequate translation of the term wheeze was a potential source of bias in some countries.

In both developed and developing countries respiratory syncytial virus is the predominant etiological agent responsible for bronchiolitis and wheezing illness in the first two years of life(6,7). Moreover data from several studies demonstrates that RSV infection and the bronchiolitis syndrome are a major component of the total ALRI in children living in developing countries(6). The relevant literature on therapy includes studies in which children were labelled as bronchiolitis and others in which children were classified as wheezing illness.

Acute Management of Young Children Presenting with Wheezing Illness

Unfortunately, we do not have clear evidence about whether antibiotics can be withheld in some categories of children with wheeze. It is clear that wheeze can occur in bacterial infection and in addition co-infection with virus and bacteria has been well demonstrated in several studies of pneumonia etiology in children. Although some studies have found that children with more severe disease or who are blood culture positive are more likely to be febrile at presentation, this sign is not sufficiently sensitive or specific to determine whether antibiotics should be administered(8,9).

Treatment of Bronchiolitis in Infants

Systemic steroids for bronchiolitis have been assessed in a meta-analysis. This report suggests a small benefit that is probably restricted to those children who are hospital-ized with severe disease(10). Nebulized corticosteroids in the acute management of wheezing illness in children aged less than 18 months have been assessed in a parallel group randomized control trial(11). Amongst 79 children aged less than 12 months, those who received nebulized or systemic corticosteroids had fewer treatment failures than those treated with nebulized terbutaline or placebo. The effect of nebulized corticosteroids alone was not studied. Cade reported a randomized placebo controlled trial of nebulized cortico-steroids in children aged less than 12 months of age presenting with acute RSV bronchio-litis(12). The main outcome measures were: duration of hospital admission; time taken to become symptom free; readmission rates; general practitioner consultation rates and use of anti-wheeze medication during follow up. There were no significant differences in any outcome measure.

A systematic review of bronchodilator therapy in treatment of bronchiolitis in children under 24 months of age has been reported(13). A small benefit in one outcome measure was demonstrated but this was predominantly due to the results of two studies in which recurrent wheezers were included. The report did not demonstrate a clinically significant benefit from broncho-dilators in this population of children. The evidence presented here does not support the use of bronchodilators, systemic or inhaled steroids for children aged 12 months or less presenting to first level health facilities with a first episode of acute wheezing illness, likely to be bronchiolitis. Such children should be managed according to the existing WHO algorithms that prescribe the administration of antibiotics if there is fast breathing. It may be appropriate for the first referral level hospital to administer bronchodilator medications alone to referred children with a history of recurrent wheeze.

Treatment of Acute Wheezing Illness in Infants and Young Children

There has been extensive debate about whether infants and young children in the first year of life respond to bronchodilator therapy. Proposed reasons for a lack of response have included: immaturity of bronchiolar smooth muscle, increased dynamic airway closure and relatively larger degrees of mucosal edema. A literature search between 1980 and 2000 reveals five randomized placebo controlled trials of beta agonist administered to acutely wheezing infants in which clinical outcomes were determined(14-18). Overall these studies support the hypothesis that children aged less than 12 to 18 months are less responsive to bronchodilator therapy than older children. However, they also demons-trate that use of inhaled short acting bronchodilators for the acute treatment of wheeze offers some benefits for clinical outcomes even in this young age group. The benefits of beta agonists may be restricted to children with recurrent wheezing and at most provide a very small clinical benefit. The data from these studies provide some options for treatment guidelines:

1. Since first time wheezers may not benefit or benefit only slightly from beta agonists; most first time wheezers will occur in the first year of life and infants respond to beta agonists less than do older children, it may be reasonable not to treat first time wheeze with beta agonist. This would simplify the algorithm for children under 12 months of age.

2. Since meta-analysis of bronchiolitis therapy with beta-agonists suggests that side effects are minimal, some countries may choose to simplify the algorithm by treating all wheezers with beta agonists since the first time wheezers may get a small benefit and are unlikely to be harmed.

Delivery of Inhaled Bronchodilators

Wet nebulizers are currently widely used for the delivery of bronchodilator therapy to young children in emergency and outpatient settings. However, the use of metered dose inhalers (MDIs) with holding chambers for this purpose has a number of strategic advantages, especially in the primary care setting. The nebulizer is a costly piece of equipment and requires a power source as well as maintenance to perform as it was designed. A holding chamber and MDI is a less sophisticated piece of equipment that is cheaper to purchase and requires no power source.

A recent systematic review has compared the effectiveness of holding chamber devices and wet nebulizers in the acute management of asthma(19). A total of 16 trials were identified including 7 that were conducted in children, mainly aged over 3 or 4 years. Trials that reported data from children demons-trated that, compared with wet nebulizers, administration of beta agonist aerosols by MDI with holding chamber resulted in less time spent in the emergency room, better oxygenation and a lower pulse rate. The two delivery methods did not differ in their effects on the rate of improvement in lung function or the need for admission to hospital. The authors of this meta-analysis concluded that for treatment of severe bronchoconstriction in children, four actuations of the MDI into the holding chamber given each 10-15 minutes until recovery, was a safe and effective dosage regimen.

Bronchodilator administered by a holding chamber with an attached mask has recently been shown to be equivalent to bronchodilator administered by wet nebulizers in terms of its effect on clinical asthma score, respiratory rate, pulse and oxygen saturation in 42 young children (aged 10 months to 4 years) with severe wheezing(20).

The efficiency of plastic holding chambers for delivery of aerosol is seriously impaired by the electrostatic charge that exists within these devices(21-22). Aerosol deposi-tion is improved by priming the devices with active drug or placebo or by soaking the device in an ionic detergent prior to use. The holding chambers that have been studied in most clinical trials are all proprietary devices. However some investigators have assessed the value of more readily available, non-proprietary devices. In 88 South African children presenting with acute asthma, a sealed 500 ml plastic bottle was as effective for delivery of fenoterol hydrobromide as a commercial spacer(23). Equivalence was demonstrated for clinical score and lung function improvement. Unsealed plastic bottle and a polystyrene cup were less effective than the sealed bottle or the commercial spacer. In summary, holding chambers are at least as effective as wet nebulizers for the adminis-tration of bronchodilators to children of all ages. For young children, a mask is necessary to connect the chamber to the child’s face.

In areas where MDIs or bronchodilator solutions are not available, subcutaneous adrenaline has been used to treat acute asthma. Predictably there are few data to support this strategy in young children. Lowell(24) performed a randomized control-led trial comparing adrenaline and placebo, administered subcutaneously in children aged less than 24 months presenting to an emer-gency department with acute wheezing illness. More children improved with adrena-line (9 of 16) than with placebo (1 of 16) (p = 0.0067).

Application of these data will allow improvement in the current algorithms for the management of ALRI with wheeze. The benefits of such improvements will primarily be in better acute management of children with wheeze. The question of which children with wheeze can safely have antibiotics with-held remains a major question for further research.

Competing interests: None stated.

Paul J. Torzillo,
Clinical Associate Professor,
University of Sydney and Department of Respiratory Medicine,
Royal Prince Alfred Hospital, Sydney, Australia.
Correspondence:

Dr. Paul J. Torzillo,
420/RPAH Medical Center,
100 Carillon Avenue,
Newtown NSW 2042,
Australia
E-mail: [email protected]

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