Post-infectious Bronchiolitis Obliterans
Alejandro Teper, MD and Alejandro Colom, MD
Respiratory Center of the Ricardo Gutiérrez Children’s Hospital of Buenos Aires, Argentina.
Bronchiolitis obliterans (BO) is an uncommon and severe form of chronic obstructive lung
disease in children that results from an insult to the lower respiratory tract. Published reports have
stated that bronchiolitis obliterans has been known to occur after Stevens-Johnson syndrome, as a
complication of graft versus host disease in bone marrow transplant recipients, and as a
manifestation of chronic graft rejection in lung transplant recipients. In many parts of the world,
however, bronchiolitis obliterans is most commonly seen in children after severe viral lower
respiratory tract infections. A number of respiratory viruses, especially adenovirus (AV), have been
associated with severe lung injury that can lead to bronchiolitis obliterans.
Bronchiolitis obliterans is characterized by partial or complete occlusion of the lumens of
terminal and respiratory bronchioles by inflammatory and fibrous tissue. It is interesting to see the
similarity of pathological findings in patients of different etiologies, suggesting that bronchiolitis
obliterans would be the final common pathway of response to different injuries to the lower
respiratory tract. Bronchiolitis obliterans could be divided pathologically into two major categories.
The first is proliferative BO (also called pure-type BO), characterized by obstruction of the airway
lumen by polyps of granulation tissue. When this granulation tissue extends into the alveoli, the
lesion is called bronchiolitis obliterans with organizing pneumonia (BOOP). The second category is
constrictive BO, which is characterized by peribronchiolar fibrosis with different degrees of lumen
narrowing. Post-infectious BO is characterized histologically mainly by a constrictive pattern, with
variable degrees of inflammation and airway obliteration. Other signs of airway disease, such as
bronchiolar inflammation, mucostasis, macrophage accumulation and bronchiolar distortion and
dilatation, were frequently reported in these patients. The histological analysis of lung biopsies in
BO is limited by the multifocal pattern of the disease.
Post-infectious bronchiolitis obliterans has commonly been observed after viral infections.
A number of respiratory viruses, including respiratory syncytial virus (RSV), parainfluenza,
influenza and especially adenovirus (AV), have been associated with severe lung injury leading to
BO. Other etiologies include mycoplasma, measles, legionella, pertussis and human
immunodeficiency virus-1. Cytomegalovirus infection in lung allograft transplantation has also been
suggested as being associated with the subsequent appearance of BO.
We performed a case-control study that included 109 cases (with bronchiolitis followed by
bronchiolitis obliterans) and 99 controls (patients with bronchiolitis who did not develop
bronchiolitis obliterans). The two main factors associated with the development of bronchiolitis
obliterans were adenovirus bronchiolitis (odds ratio (OR) 49) and mechanical ventilation (OR 11).
Although mechanical ventilation was a significant risk factor for post-infectious BO, the results do
not indicate whether it causes injury to the lung that increases the risk for developing postinfectious BO or whether it merely serves as an indicator of severity of illness. The central role of
AV in the development of postinfectious BO has been well documented and in our cohort is present
in 70–80% of post-infectious BO patients. Since 1984 a new genotype of adenovirus, AV7h, has
stood out as the most virulent serotype, but other AVs such as 3, 5 and 21 also were reported to
cause BO. Patients with severe AV infection have been shown to have immune complexes
containing AV antigen in the lung, as well as increased serum levels of interleukin-6, interleukin-8,
and tumor necrosis factor (TNF-α).
The susceptibility to develop bronchiolitis obliterans seems to be associated with the
geographical origin of the human groups studied. Child populations from New Zealand, central
Canada, Alaska and South America exhibit a higher incidence of post-infectious bronchiolitis
obliterans than populations from Europe and other American regions. Recent studies developed in
Argentine Amerindians with post-adenoviral BO show that the HLA haplotype DR8-DQB1*0302
and the Native American ethnic ancestry, determined by mtDNA markers, were increased in the
affected patients. Although the data are limited, these previous studies suggest that the host
immunological response may play an important role in the severity of adenoviral respiratory
infections as well as the subsequent development of BO in selected populations.
In our cohort of post-infectious BO patients, illness occurred in very young infants, younger
than six months, but our findings did not show that age was a risk factor for developing postinfectious BO. Initially, these patients present with symptoms that do not differ from a typical RSV
bronchiolitis. During the admission examination, most patients are found to have severe airway
obstruction with hypoxemia and in many cases require mechanical ventilation. Physical findings are
usually nonspecific. Expiratory wheezing and occasional crackles may be heard on chest
auscultation. When an AV infection is detected and the patients do not get better after three weeks,
BO should be suspected. After patients’ conditions have become stable they still show persistently
high respiratory rates, rigid thorax, wheeze and productive cough. Oxygen saturation is often lower
than normal. Other patients who initially contracted intranosocomial AV pneumonia with severe
respiratory compromise (accessory muscle use and crackles) show similar development and require
intensive care and lengthy hospitalization.
Chest X-rays in BO patients are nonspecific but show air trapping, atelectasis, peri-bronchial
thickening and honeycombing (Figure 1). Some patients show unilateral lung/lobe involvement,
with hyperlucent and small lung, known as Swyer-James or MacLeod syndrome, due to loss of the
pulmonary vascular structure and air trapping. Lung perfusion scans show perfusion defects, with
lobar, segmental, or subsegmental pattern. Comparing lung perfusion scans with chest radiographs,
the defects on lung scans correspond to areas with more prominent abnormalities, such as bronchial
wall thickening and bronchiectasis. Lung perfusion scans cannot describe the nature of
bronchopulmonary abnormalities; however, this examination provides an objective evaluation
regarding the extent, distribution and severity of bronchopulmonary lesions.
The most characteristic signs of BO with High-resolution CT (HRCT) are areas of mosaic
attenuation pattern due to shunting of blood away from the under-ventilated to the normally
ventilated lung, where perfusion is reduced in areas of decreased parenchyma attenuation due to
hypoxic pulmonary vasoconstriction (Figure 2). Other signs include air trapping, especially on
expiratory CT, and bronchial abnormalities. Air trapping, as detected on expiratory HRCT, has been
described as the most sensitive and accurate radiological indicator of BO in the lung transplant
population.
Infant pulmonary function in post-viral BO shows severe and fixed bronchial obstruction decreased
pulmonary distensibility and increased airway resistance. These patients have more severely
affected V’maxFRC than in other diseases such as bronchopulmonary dysplasia or asthma which,
even in their most severe forms, usually respond to bronchodilators. These findings might represent
the functional expression of the histopathological damage of bronchiolitis obliterans. Another factor
associated with BO is gastroesophageal reflux (GER), which itself is relatively common and may
adversely affect lung function. Extensive studies in children have not been carried out to confirm
this complication, although our experience suggests that GER needs to be investigated in postinfectious BO patients.
When other causes of chronic lung disease have been eliminated, the patient’s clinical history, chest
radiographies and HRCT images are sufficient in most cases to confirm the diagnosis and to
differentiate post-infectious BO from other pulmonary disorders. These clinical evaluations should
be considered in tandem with the functional pattern in post-infectious BO. Usually it is not
accessible to perform an Infant PFT. To develop and to validate a clinical prediction rule to
diagnose children under 2 years old with post viral bronchiolitis obliterans, we have designed a
retrospective cohort study of children with chronic lung disease using multiple objectively
measured parameters readily available in most medical centers. We compared a group of confirmed
BO patients under 2 years old (clinical history, lung function tests and CT scan compatible) with
infants and young children with other confirmed chronic lung diseases such as primary ciliary
diskinesia (PCD), cystic fibrosis (CF) and bronchiectasis of different etiologies than BO, PCD and
CF. BO diagnosis was considered the dependent variable. Predictive variables were: a) “clinical
history”, defined as a previous healthy child, who suffered a severe viral infection and remained
with chronic respiratory symptoms and hypoxemia (SaO2 <92%) for more than 60 days; b)
antecedent of “adenoviral infection”; c) “mechanical ventilation” requirement; and three HRCT
patterns: d) “mosaic pattern”; e) “atelectasis” and f) “bronchiectasis”. The BO-Score (area under
ROC curve= 0.96; 95% CI, 0.9–1.0%) was developed by assigning points to the following
variables: typical clinical history (four points), adenovirus infection (three points), and highresolution computed tomography with mosaic perfusion (four points). A Score equal or higher than
7, predicted the diagnosis of BO with a specificity of 100% (95% CI, 79–100%) and a sensitivity of
67% (95% CI, 47–80%). If doubt persists about the diagnosis, a lung biopsy may be needed.
Most patients with post-infectious BO require oxygen supplementation for nearly a year
after discharge from the initial hospital admission. Readmission to hospital will probably be
required for subsequent infections of the lower respiratory tract. In older children, only few patients
require oxygen supplementation. Spirometry test results show evidence of airflow limitation, and
pletismography demonstrates gas trapping with normal or high total lung volumes. Therefore,
pulmonary function remains severely impaired, showing a moderate-severe obstructive pattern.
Children with postinfectious BO have moderate compromise of mechanics as measured by forced
oscillation, with high resistance and low compliance. In most patients, perfusion defects shown by
the initial lung scans persisted and occasionally increased. Clinical improvement during the disease
process may be due to the growth of the lungs in these children, and probably does not indicate
regression of the pathology in the small airways. The overall prognosis of pulmonary function was
poor in the majority of the cohort studies published. Mortality and morbidity rates associated with
post-infectious BO remain uncertain. Prognosis in an individual patient may relate to several
factors, including length of oxygen requirement, mechanical ventilation requirements, severity of
re-infections of the lower respiratory tract and probably others. Large case-control studies will be
necessary in order to address this knowledge gap.
The majority of evidence suggests that BO is immune mediated, so therapeutic
interventions have focused on the suppression of the inflammatory response. Anti-inflammatory
therapy such as corticosteroids, chloroquine and hydroxylchloroquine has been tried in small
clinical trials and case reports with minimal success. Because bronchiolitis obliterans is so rare,
controlled and randomized therapeutic clinical trials have been impossible to perform. Although
multiple cytokines and chemokines have been identified in the pathogenesis of BO, tumour necrosis
factor (TNF-α) seems to play a central role in the inflammatory reaction and enhances fibroblast
proliferation. A case report describes successful treatment of BO in a bone marrow transplant
patient with TNF-α blockade (Infliximab). Other studies suggest a potential role for maintenance of
macrolide therapy in the treatment of bronchiolitis obliterans where the anti-inflammatory
properties and ability to reduce inflammatory mediators of interleukin IL-8, TNF-α, and IL-1ß may
play a role. When the disease is well established, however, the principal treatment is supportive and
includes bronchodilators, chest physical therapy, antibiotics for acute respiratory infections, and in
some patients, diuretics. Gastroesophageal reflux has been increasingly recognized as a factor that
may significantly contribute to BO, so when it is recognized, treatment is warranted.
Post-infectious BO has been reported in limited areas, where its impact is profound.
Although research has identified the risk factors that can lead to post-infectious BO, knowledge
about factors inherent to the population, such as a genetic predisposition to develop the disease is
still scarce. Clinical trials of potential therapeutic agents should be multicentre studies in order to
include a significant number of patients. Important factors to consider include the ideal timing,
dosage and best choice of immunosuppressive agent to avoid the development of the disease.
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Figures
Figure 1: Chest radiograph of patient with post-infectious BO, with air trapping, atelectasis and bronchiectasis.
Figure 2: CT scan of patient with post infectious BO, with mosaic attenuation pattern, atelectasis and bronchiectasis.