Pediatric Bronchiectasis Is Preventable and Hardly an Orphan Disease, Review Suggests

Pediatric Bronchiectasis Is Preventable and Hardly an Orphan Disease, Review Suggests

Bronchiectasis, while still considered an orphan disease, is increasingly seen to cause substantial morbidity and mortality in both children and adults. An Australian review discussed the current status of knowledge about the disease in children, showing that in certain population groups, pediatric bronchiectasis might be preventable to a large degree.

The review by Queensland Children’s Medical Research Institute researcher Vikas Goyal and colleagues, Pediatric Bronchiectasis: No Longer an Orphan Disease, was published in the journal Pediatric Pulmonology.

Studies have shown that bronchiectasis in children might have different etiologies than in adults — involving different pathogens and natural history — even though many adults have symptoms lingering from childhood. Estimating how common bronchiectasis is among children is difficult, since diagnosis is often delayed and depends on the studied population. Physician awareness of the disease is variable, as is the availability of high-resolution computed tomography (cHRCT) scans used to diagnose the condition.

As a result, the rates of newly diagnosed children varies between countries like Finland, reporting 0.5 cases per 100,000 child years, to 1,500 per 100,000 child years in Aboriginal children from Central Australia and the South-West Alaskan Native community. Studies in other native populations also show high rates.

Mortality rates in children with the disease tend to follow similar patterns and even though reliable data from many developing countries is not available, data generalization suggests high rates in areas characterized by overcrowding, poor hygiene, and limited healthcare access. Consequently, bronchiectasis is a problem deserving more attention, particularly in socially disadvantaged indigenous groups.

Bronchiectasis is known to have multiple underlying causes, but researchers believe that a complex interplay between the host, and respiratory pathogens and environmental factors lead to the disease. A study involving 989 children found that 63 percent had an underlying cause, with pneumonia and immunodeficiency being the most frequently reported. The authors highlighted the importance of investigating the underlying causes of bronchiectasis, since differing disease origins might lead to different disease management strategies.

In certain genetic conditions and ethnic groups, bronchiectasis appear to be more common, suggesting that there might be genetic factors predisposing some individuals to disease. There are, however, no large-scale genetic studies investigating this assumption.

The pathological lung changes in bronchiectasis consist of dilated and inflamed bronchi. Early in the disease the wall of the bronchi thickens because of edema and lymph follicle formation, which destroys elastin. The loss of this elastic protein results in bronchial dilatation. As the disease progresses, airway smooth muscle cartilage also becomes damaged, further worsening symptoms. In time, the bronchial changes lead to altered blood vessel properties, including enlarged bronchial arteries and new vessel formation. 

Increased shunting of blood may contribute to pulmonary hypertension, but this condition usually does not develop until adulthood. Inflammatory changes contribute to this process, and higher levels of immune neutrophils and macrophage cells have been found in the airway mucosa of bronchiectasis children.

Researchers have proposed that inflammatory processes initiated during infection weaken the ability to clear mucus from the airways. This can lead to a downward spiral of repeat infection and inflammation, resulting in bronchial dilation, but it is currently not known what triggers this process. Paradoxically, inadequate immune responses can also lead to bronchiectasis.

Altered immune responses to nontypeable Haemophilus influenzae (NTHi) have been found in children with post-infectious bronchiectasis, and include a lower secretion of the pro-inflammatory factor IFN-γ. Yet the decreased IFN-γ signaling has been associated with increased inflammatory responses. Numerous other studies also show upregulation of other immune factors, painting a rather complex picture of underlying mechanisms.

Pro-inflammatory factors MMP-8,  MMP-9, neutrophil elastase, TNF-α, and IL-8, which are known to destroy airway architecture, have all been found in higher levels in the bronchoalveolar lavage fluid of bronchiectasis children. In addition to neutrophils, also eosinophils — another immune cell type — are believed to be involved in driving bronchiectasis pathology, in part by recruiting neutrophils.

Although all cases of bronchiectasis seem to be caused by pathogens, symptoms become worse when bacterial infections are present. Studies showed that children and adults with bronchiectasis tend to have different microbiological profiles in their lungs. NTHi is the most common pathogen in both adults and children, and while often present in adults with bronchiectasis, Pseudomonas aeruginosa, Aspergillus, and non-tuberculous mycobacterial infections are not usually found in children. But infections with S. pneumoniae and Moraxella catarrhalis are common. Some studies showed that particular bacterial profiles are associated with exacerbations, although studies tend to diverge on this point.

Viruses, such as human adenovirus, have frequently been detected in children with bronchiectasis, and research suggests that these children may have impaired antiviral responses. Again, the reason why common viral infections lead to bronchiectasis is not known, and the previously mentioned altered immune response is likely a contributing factor. In most cases, viral infections are, however, not causing bronchiectasis, but are known to trigger exacerbation of symptoms, with rhinovirus being identified in 50 percent of exacerbations in one study.

The most common symptom in children with bronchiectasis is a chronic wet cough. In general, children tend to be diagnosed earlier today with milder forms of the disease, although some studies found that symptoms can often be present for months or years before the diagnosis is considered. Studies in adults having symptoms since childhood showed that lung function is worse compared to adults with a shorter duration of symptoms.

cHRCT is the main method for diagnosing bronchiectasis, measuring the ratio between the diameter of the bronchi and the lung artery, with a ratio larger than 0.8 being indicative of bronchiectasis in children. cHRCT scans can, however, give rise to both false positive and negative results, and clinicians argue that a diagnosis needs to be supported by relevant clinical history and findings in addition to radiographic examination. Australia and New Zealand recently published guidelines including a comprehensive list of investigations that can be chosen according to the individual patient history. The guidelines aim to help physicians establish etiology, severity, and extent of disease.

Spirometry, although often normal in children with bronchiectasis, may be useful in determining disease severity in older children, according to some studies. Bronchoscopy can also be used to identify underlying structural irregularities, excluding foreign bodies, identifying the macroscopic appearance of chronic bronchitis, and obtaining lower airway secretions from children unable to cough up mucus.

There is currently no standardized method to classify severity in children, except for measures of lung function or radiological findings. When bronchiectasis is still mild, spirometry and radiological findings are not necessarily in agreement. The most common classification is based on cHRCT findings divided into the subtypes cylindrical, varicose, and cystic, but other systems based on CT findings also exist.

Exacerbations in children with bronchiectasis are common and known to be associated with a decrease in lung function. The importance of treating exacerbations cannot be underscored enough, since the increased inflammatory activity during the worsened state drives further destruction of the lung. There is, however, no solid definition of what constitutes an exacerbation in a child. One study proposed a system with two major and a number of minor criteria, where the presence of both major, or one major and two minor, criteria would define an exacerbation. The major criteria were significantly increased cough frequency and wet cough for 72 hours, and the minor consisted of both clinical and laboratory findings including dyspnea, chest pain, wheeze, and increased inflammatory markers IL-6, CRP, and SAA. More studies are needed to validate this definition.

As previously mentioned, proper disease management and treatment of exacerbations can reduce lung damage. Studies showed that exacerbation frequency is reduced in children receiving specialist, multi-disciplinary care at an early disease stage. Management of bronchiectasis in children aims to improve life quality, reduce exacerbation frequency and severity, prevent complications, and preserve lung function. In practice, this comes down to attempts to limit the recurrent  infection and inflammation.

Acute exacerbations are treated with antibiotics, at times long term, and long-term use in unstable patients is common to prevent exacerbations, as they can improve quality of life and halt lung function decline. Long-term antibiotic treatment always poses a risk for the emergence of resistance, and there are currently no studies showing which patients could benefit from such treatment. Also, while antibiotics are recommended for the treatment of exacerbations, some studies suggest that they do little good in exacerbations caused by viral infections.

Clinical studies investigating the efficacy of antibiotic treatment during worsened disease states are not available. Macrolide antibiotics, having both antibacterial and anti-inflammatory properties, might be particularly suitable for bronchiectasis treatment, and a clinical trial in children showed a 50 percent reduction in exacerbation frequency following once-weekly administration of azithromycin for up to two years. From studies in adults, it is known that adherence to long-term treatment might be as low as 16 percent. Parental education is therefore important to maintain adherence, and prevent disease exacerbations.

Studies exploring the efficiency of inhaled antibiotics have generally been disappointing, showing unsatisfactory results and poor treatment tolerance. There are exceptions, with a study of inhaled gentamicin and two studies of inhaled ciprofloxacin showing decreased exacerbation frequency. No studies of inhaled antibiotics in children with bronchiectasis, however, exist.

There are currently no clinical studies investigating the efficiency of antiviral drugs for respiratory infections in bronchiectasis. One class of antivirals, neuraminidase inhibitors (NAI) used for influenza virus infections, might speed up recovery, reduce the risk of hospitalization, and improve survival for already hospitalized patients. The authors argued that while waiting for clinical trials to confirm the efficiency of NAI, this antiviral class should be used in children with bronchiectasis hospitalized with a confirmed influenza infection.

Bronchodilators and corticosteroids might be used if  the disease co-exists with asthma, but are otherwise not recommended. Instead, techniques for airway clearance are regarded as important parts of both stable and exacerbation states. Training in these techniques should be overseen by an experienced pediatric respiratory physiotherapist and adapted to the individual patient.

Children’s vaccine schedules also need to be kept up-to-date covering annual influenza vaccinations, as well as measles, pertussis, H. influenzae type b, and pneumococcal vaccines.

Surgery is uncommon in children, but severe and localized disease might require surgical resection of a bronchiectatic lobe.

Some studies suggested that bacterial bronchitis might lead to bronchiectasis if left untreated. Considering the unfavorable statistics from socially disadvantaged populations, it is obvious that bronchiectasis can be prevented to a certain degree. Public health measures targeting adequate housing, sanitation and nutrition, as well as access to healthcare and vaccine programs — along with intensive management of children with chronic and recurrent wet cough — may prevent progression to bronchiectasis in high-risk children. Some studies even show that bronchiectasis can be reversed in children.

The authors concluded that with the increasing knowledge and earlier diagnosis of children, bronchiectasis no longer seems to be an “orphan disease.” Training of health professionals in diagnosing and treating bronchiectasis, as well as patients support and education, will not only improve short- and long-term outcomes in children, but also help to prevent severe bronchiectasis in adults.

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