Highlights
- •
Wheezing infants are an important global public health issue in LIMC.
- •
Determining whether wheezing is the correct definition is critical.
- •
A differential diagnosis of the causes of wheezing and other sounds should be made.
- •
Recurrent wheezing [RW] in infants may warrant a therapeutic trial with inhaled steroids.
- •
In LMICS, RW may be prevented by reducing environmental factors such as smoking.
- •
Early exposure to viral infection is a preventable cause of RW.
Abstract
Objective
To review the recent evidence in the literature of various aspects of recurrent/severe wheezing in children under 3 in low-middle income countries [LMICS].
Sources
A non-systematic review including articles in English. We mainly selected publications from the last 5 years. Studies on epidemiology, aetiology, diagnosis, treatment, and prevention were included in the search. We reviewed differential diagnoses of wheezing that focused on LMICS. We also reviewed aspects of prevention.
Summary of the findings
Many epidemiological studies have shown a variable but significant number of wheezy infants [WI] cases in LMICS when compared to other countries.
The differential diagnosis of causes of wheezing in this age group is mandatory, taking into account local facilities.
Few treatment options have been well studied for this age group. In LMICS, a pragmatic approach could be considered, as described in the article.
It is difficult to study primary prevention for WI and secondary prevention (mainly environmental) may have some impact.
A schematic approach for recurrent wheezers is presented, which takes into account settings with limited resources.
Conclusion
Severely or recurrently wheezy children under 3 is a common clinical issue in LMICS. Studies on this age group are needed to reduce the significant morbidity. It may be possible to lower the high burden of wheezing in this age group by selecting the phenotype which may respond to inhaled steroids.
Introduction
Recurrent wheezing (RW) in infants, arbitrarily defined as three or more episodes of wheezing during the first two years of life, is a worldwide public health issue. Epidemiological studies, such as the International Study of Wheezing in Infants (EISL), a general population-based study that surveyed wheezing and related factors, found a high frequency of RW, with high costs for individuals, families, and the healthcare system . In the same study, severity was also greater in low-middle income countries [LMICS].
Wheezing infants, once you exclude those with anatomical, genetic or external causes, may develop asthma as children to varying degrees of severity. However, our current knowledge still does not allow us to be able to differentiate properly at the beginning which infants will become asthmatic and which will not. As a result, doctors hesitate when choosing the best preventive, diagnostic and therapeutic strategies, which are already limited in LMICS.
Poor environmental conditions can interfere with bronchial reactivity by directly affecting the lining of the airways or by modifying the complex immunological pathways affecting them. Exposure to tobacco and indoor solid fuel fumes, being premature and overcrowding, which are all too common in LMICS, are some of the conditions that have been directly related to RW in infants. Groups of people, especially in crowded conditions, facilitate the swift transmission of respiratory viruses via human-to-human close contact. This could explain why, during the COVID-19 pandemic, the global annual surge of acute bronchiolitis in infants almost disappeared during the restrictions, and there was a considerable reduction in pneumonia and asthma hospitalizations . As a consequence, the number of new wheezy infants during the first two years of the pandemics decreased.
The authors will be discussing the topic of wheezy infants, from a LMIC point of view in terms of epidemiology, diagnosis, management, and prevention. There have been some improvements in dealing with wheezy infants in LMICS, and research has also contributed, but there is still a long bumpy road ahead.
Methods
A non-systematic review of wheeze in infants and children under the age of 3 years was undertaken with an emphasis on its epidemiology, diagnosis, management, and prevention. We searched for studies in online databases, including articles in English, mainly in the last 5 years, with appropriate search words that would include subjects from LMICS as much as possible.
Epidemiology
The prevalence of RW varies internationally and within individual countries. The prevalence of RW with asthma-like symptoms varies from 12% in European countries, 15% in Africa to 19% in Latin America (LA) . The frequency is higher in children after bronchiolitis (22.2%) or with a tracheoesophageal fistula (53%), notwithstanding that the pathophysiology may differ . It is more common in boys and the first episode usually occurs between 2 and 4 months of age. More babies are born prematurely in LMICs, and there the prevalence of RW in extremely preterm infants can reach 27% and it is twice as likely in those weighing 500–1000 g compared to those weighing 2 kg or more . Wheezing associated with viral infections is the predominant pattern in Latin America [LA]. In infants with recurrent wheezing, the main association was an upper airway infection in the first 3 months of life and it was related to a higher rate of hospitalisation . Parental asthma, viral infection and disease severity, early environmental exposure, crowding, caesarean section, season of year at birth, air pollution exposure, postnatal maternal psychological distress, are all associated with a greater risk for RW . Passive smoking during and/or after pregnancy is associated with more frequent and severe pneumonia, emergency department visits, wheezing exacerbations, and a higher rate of hospitalization . More than one smoker in the household doubles the risk of wheezing episodes. Low socioeconomic status [SES] is associated with a higher prevalence of hospitalization for wheezing.
Breastfeeding during the first 4 months decreases the risk of wheezing and reduces admissions, although the protective effect diminishes over time. Mothers with better education (>12 years) and children being older when they had their first cold were strong protectors against admissions .
Admissions are high among wheezy infants. Among 2,079 infants with recurrent asthma-like symptoms, the mean prevalence for admissions was 29.8% (95% CI: 27.8–31.7), varying from 11.9% in Curitiba (Brazil) to 47.9% in Buenos Aires (Argentina) (p < 0.001). Almost 60% of infants with recurrent asthma-like symptoms admitted for wheezing were diagnosed with pneumonia . The number of hospitalizations in LMICS is higher than in high-income countries (HIC) and they are inversely associated with SES, and the first episode usually occurs before the age of 3 months . The economic burden was increased by the expense of treatment: about 50% were given systemic or inhaled corticosteroids (<68% in HIC), and 38% bronchodilators. Furthermore, antibiotics are prescribed frequently (22%) in this age group . Recurrent wheezing is a predictor of severe respiratory illness, readmission, ICU admission, death, and the progression of lung disease into adulthood.
Diagnosis/investigation
Establishing the diagnosis in a wheezy infant is challenging and highly controversial since there is no single test able to diagnose it. While almost half of infants have a wheezing episode at least once in their first year of life, usually related to a viral infection, only a smaller proportion will have recurrent episodes .
Since young children are prone to wheezing when they have respiratory viral infections due to inherent anatomical characteristics of their airways and respiratory system, recent research has suggested treating relapses as a “Bronchiolitis Syndrome” that may be recurrent and needs to be better investigated and treated . Given the fact that the wheezy infant diagnosis is clinically defined as the recurrence of wheezing episodes, it becomes critical to ascertain that ‘wheezing’ is the correct auscultatory finding when parents report noisy and troubled breathing .
The fact that it occurs in early childhood also reinforces the need for a differential diagnosis approach to exclude anatomical, genetic and functional causes from the presentation of asthma or asthma-like symptoms (see Table 1 ). Laboratory tests and radiological examinations are not used as standard, unless it is difficult to rule out other conditions, or there is a lack of response to asthma treatments . This is especially relevant for LMICS countries, where access to advanced resources for workups, such as a bronchoscopy, is limited. The most common causes that should be included in a differential diagnosis are described in Table 1 .
| Aetiology | Clinical findings | Investigation |
|---|---|---|
| Early asthma* | -Persistent symptoms, associated with environmental exposure -History of asthma in first-degree relatives -Atopic dermatitis -Significant improvement following asthma treatments | -IgE -Allergen specific IgE -Skin prick test for aeroallergens -Lung clearance index |
| Viral associated wheezing** | -Frequent wheezing, very early onset -Attending nursery at an early age or living in crowded homes | -Patient history -Exclusion of other causes |
| Swallowing Disorders (Aspiration) | -Feeding associated cough/wheezing -Choking | -Speech-Language Assessment -Swallowing study, Chest x-ray or laryngoscopy |
| Post- viral bronchiolitis obliterans | -Severe bronchiolitis/pneumonia | -High-resolution computed tomography (HRCT) |
| Bronchopulmonary malformations | -Continuous wheezing, monophonic -Positional wheezing | -HRCT -Bronchoscopy |
| Bronchopulmonary dysplasia*** | -Preterm delivery -Assisted Breathing as a new-born -Prolonged oxygen therapy | -Patient history -HRCT |
| Wheezy associated to inhalants**** | -Tobacco exposure-Household pollutants (wood burning stove) | -Patient history -Home visit |
| Tuberculosis***** | -Home exposure (e.g. to an adult with tuberculosis) -Prolonged coughing/wheezing, daily feverish episodes -Failing to thrive | -Chest x-ray -HRCT -Mantoux test-Interferon gamma release assay (IGRA) |
| Cardiac diseases | -Cardiac murmur -Persistent tachypnoea -Tachycardia -Failing to thrive | -Chest x-ray -HRCT – Echocardiogram |
| Foreign body aspiration****** | -Acute choking episode | -Chest x-ray -Rigid and flexible bronchoscopy |
| Cystic fibrosis | -Productive cough -Steatorrhea -Failing to thrive | -New-born screening -Sweat testing -CFTR genotyping |
Most of the scientific literature regarding diagnosing wheezy infants focuses on the diagnosis of “early-onset asthma”, in order to try to modify the course of the disease. Data from cohort studies of the origins of asthma has helped us to understand how cases of wheezing in early life connect to established asthma phenotypes later on . Epidemiological data has also helped to develop tools to aid clinical decision-making, such as the score systems, the “asthma predictive index” and the “asthma prediction tool” . However, while these useful tools are practical to use, they are unable to predict a more detailed outcome for infants with RW, such as their response to therapy or the additional risk of overtreating those with a positive score .
Diagnosing a wheezy infant is clinical. Recognizing different patterns of wheezing or the course of wheezing, which have been described in cohort studies on the origins of asthma, can help when making such a diagnosis, and support decisions about therapy. An ERS Task Force proposed an approach in 2008 that classified RW in infancy into two different temporal patterns: ‘An episodic (viral) wheeze’ and ‘a multiple-trigger wheeze’, where the latter was more related to atopy and future asthma . This classification was criticised as not being feasible or practical for clinical use since the studies that used it to select patients found that, during the follow-up, many infants assigned to one category had changed their pattern of wheezing over time and therefore were in a different category .
More recent interventional studies have indicated that while the diagnosis of a wheezy infant is clinical, there are some phenotype markers that can predict the likelihood of successful treatment. The INFANT trial included infants and preschool children between 12 and 59 months old, from 18 sites in the United States, who had been diagnosed with asthma and needed daily controller therapy. They compared three different treatment approaches in a crossover study. The study demonstrated that positive aeroallergen sensitization markers and higher blood eosinophil counts were able to predict a better response to daily inhaled corticosteroids (ICS) compared to daily oral montelukast or as-needed ICS therapy .
Similar studies have not been replicated in LMICS due to the overall cost, since they are very resource-intensive. Still, while these results may seem useful and applicable for clinicians, there is no evidence, yet, that such findings can be reproduced in LMICS where people are exposed to different things, such as helminthic infections, air pollution and heavy smoking.
Managing infants with recurrent wheezing
The management approach to wheezy infants depends on the underlying cause for the wheezing (see Table 1 ). Unfortunately, among these is tuberculosis, which is still relevant in the worst-off LMICS . Delays in a specific diagnosis often occurs when diagnostic resources are limited. The various treatments for the more specific causes of RW include surgery for anatomical anomalies, watchful waiting, swallowing rehabilitation and the use of digestive enzymes or antibiotics.
The other causes of wheezing usually have a more asthma-like, stepwise therapeutic approach. Simple phenotyping, based on clinical information, is used to decide the initial treatment, which is then adjusted accordingly, based on trial-and-error. Alternative causes for the wheezing always need to be kept in mind, and diagnostic procedures should be available to assist the investigation.
Recent recommendations, developed by a panel of experts from different continents, pointed out the importance of more in-depth phenotyping of pre-schoolers with RW, to provide a better guide for diagnosis and more specific therapy . However, no studies have been performed exclusively on children younger than 2 years old to validate this approach. More than this, while the authors ponder, economic constraints in LMICS hinder the chances of this strategy being adopted. In those countries where it is possible to adopt the recommendations, they have, however, been slowly appearing as part of the diagnostic process for older children.
According to two recent studies, it was possible to identify and classify clusters (phenotypes) in wheezing pre-schoolers, through the presence of sensitization, eosinophilia, structural abnormalities, and broncho-alveolar microbiology. They found at least four to five clusters with different aetiologies and pathologies and which, most likely, would respond differently to different treatments . However, apart from measuring peripheral eosinophilia and some allergic sensitization profiles, we still do not have readily available, simple and low-cost biomarkers that would allow us to quickly assign a case to a complex phenotype, especially in LMICS. Nonetheless, phenotyping, using the predictive indexes, such as the traditional asthma predictive index (API), could make low resource studies feasible . A recent study from Chile demonstrated that such an approach could help to ascertain a basic phenotyping of children for more appropriate treatment .
There is data that supports the use of ICS in wheezy infants. A systematic review showed that in infants/pre-schoolers with RW and asthma, daily ICS significantly reduced severe wheezing exacerbations that required systemic corticosteroids compared to a placebo, even when adjusting for the type of ICS used, for the use of an MDI or a nebulizer, or for age (infant or pre-schooler) .
Montelukast has been included in the guidelines as an alternative to ICS in small children (including infants) with asthma or asthma-like symptoms and who respond to short-acting beta-agonists. However, in 2015, a systematic review reported that daily montelukast, compared to a placebo, had no effect in reducing severe exacerbations. Likewise, intermittent montelukast had no effect in children with viral-induced wheezing compared to a placebo. A recent meta-analysis supported these findings, adding that daily ICS was better than daily montelukast in preventing severe wheezing exacerbations in children with recurrent wheezing, and intermittent ICS was superior to a placebo . The intermittent use of ICS, starting as respiratory symptoms appear, seems as effective as daily ICS, with the added benefit that it is more likely to be adhered to .
Azithromycin has also been proposed as an adjunct therapy for RW in small children. The COPSAC 2000 study found that a short course of azithromycin, when compared to a placebo, significantly reduced the duration of recurrent asthma-like symptoms in children of one to three years old. There is a plausible explanation for this result, bacterial colonisation of the oropharynx, although the role of bacteria in wheezing is not clearly understood. In another RCT, children (aged 12 to 71 months) with a history of recurrent, severe lower respiratory tract infections (LTRI) were randomly given either azithromycin (12 mg/k/d for 5 days) or a placebo at the first sign of a respiratory tract illness before the symptoms of LTRI developed over a period of 12 to 18 months . Azithromycin significantly reduced the risk of the illness progressing to a severe LTRI by 37%. In relation to the development of antimicrobial resistance, at the end of the study, 16.7% of the children that took azithromycin vs 10.8% that took the placebo acquired azithromycin-resistant organisms. Nevertheless, the use of azithromycin should be used in individual cases.
Therefore, we propose a simple guide to the treatment of wheezing infants/pre-schoolers in LMICs ( Fig. 1 ). Those with recurrent wheezing (>3 times in the last year) should start with daily ICS (budesonide 200 ug bid or fluticasone 125 ug bid), if the child responds, continue the treatment for 6–12 months and try to wean them off it. If the child does not respond, measure the peripheral eosinophils. If it is > 300 uL use intermittent ICS (budesonide 1 mg bid for 7 days or equivalent) at the onset of URTI, because those parents may not adhere to daily ICS. However, if the peripheral eosinophils < 300 uL, then they could use intermittent azithromycin 12 mg/K/d for 5 days starting at the first sign of respiratory infection. If there is no response to either intermittent ICS or azithromycin, you should check for other respiratory diseases ( Table 1 ).
