Pediatric interstitial lung disease masquerading as difficult asthma : Management dilemmas for rare lung disease in children

Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, Ontario Correspondence: Dr Sharon Dell, Division of Respiratory Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8. Telephone 416-813-6248, fax 416-813-6246, e-mail sharon.dell@sickkids.ca EY Chan, SD Dell. Pediatric interstitial lung disease masquerading as difficult asthma: Management dilemmas for rare lung disease in children. Can Respir J 2005;12(6):317-320.

Pediatric interstitial lung disease masquerading as difficult asthma: Management dilemmas for rare lung disease in children Idiopathic nontransplant-related childhood bronchiolitis obliterans is an uncommon disease.Most patients present with chronic recurrent dyspnea, cough and wheezing, which are also features of asthma, by far a much more common condition.The present case study reports on a six-year-old girl who presented to a tertiary care centre with recurrent episodes of respiratory distress on a background of baseline tachypnea, chronic hypoxemia and exertional dyspnea.Her past medical history revealed significant lung disease in infancy, including respiratory syncytial virus bronchiolitis and repaired gastroesophageal reflux.She was treated for 'asthma exacerbations' throughout her early childhood years.Bronchiolitis obliterans was subsequently diagnosed with an open lung biopsy.She did not have sustained improvement with systemic corticosteroids, hydroxychloroquine or clarithromycin.Cardiac catheterization confirmed the presence of secondary pulmonary hypertension.Treatment options remain a dilemma for this patient because there is no known effective treatment for this condition, and the natural history is not well understood.The present case demonstrates the need for careful workup in 'atypical asthma', and the urgent need for further research into the rare lung diseases of childhood.
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CROSS CANADA ROUNDS
The cases in this section have been presented by pediatric respiratory residents at monthly video conferences where they were discussed by the trainees and respirologists across Canada.They are published as a result of these proceedings and literature reviews undertaken by the residents A lthough asthma remains the most common cause of recur- rent wheezing and respiratory distress in children, the present case highlights the importance of exploring alternative diagnoses in cases of 'difficult asthma' that do not respond to conventional treatment.
Although there are vast differential diagnoses, pediatric interstitial lung disease (pILD) is one of the main considerations in the face of long-standing tachypnea and hypoxemia.The term 'pILD' encompasses a heterogeneous group of rare lung disorders in children (1).Invasive procedures, including lung biopsy, are usually required for diagnosis, albeit with suboptimal yield (2). Therapeutic options have generally not been systematically studied and have limited success.Furthermore, the natural history of these disorders is not well understood because of a lack of longitudinal data for these conditions.

CASE PRESENTATION
A six-year-old African Canadian girl with a past history of asthma presented to her local community hospital with a one-week history of shortness of breath, cough and coryzal symptoms.She had little improvement after one week of outpatient treatment with prednisone, regular salbutamol and fluticasone.A diagnosis of pneumonia on the background of asthma was made.Inpatient treatment at her local hospital included oxygen, cefuroxime, clarithromycin, hydrocortisone, salbutamol and ipratropium bromide.Due to a lack of significant improvement and marked ongoing hypoxemia, she was transferred the following week to the authors' tertiary care centre for further investigation.
Physical examination revealed marked finger clubbing, increased work of breathing (tracheal tug, nasal flaring and a respiratory rate of 38 breaths/min) and hypoxia (oxygen saturation rapidly dropped to less than 80% in room air) in a small, afebrile child with a weight in the 10th percentile and a height in the 50th percentile for her age.On auscultation of the lung fields, there was reduced air entry to both bases, bilateral basal crackles and wheezing.Heart sounds were normal.The liver was palpable 3 cm below the costal margin.There was no evidence of rash or joint swelling.
The patient had a long history of tachypnea and shortness of breath on exertion.Her past medical history included multiple hospitalizations with respiratory distress since infancy, with the first hospital admission at two months of age for respiratory syncytial virus (RSV) bronchiolitis.She was diagnosed with gastroesophageal reflux at 10 months of age, resulting in fundoplication and three months of gastrostomy tube feeding.Following this, her subsequent hospital admissions (at ages three and four years) with respiratory distress were treated as asthma exacerbations.Her maintenance therapy included inhaled salbutamol and fluticasone.Her family history and birth history were unremarkable.
Baseline bloodwork including complete blood count, clotting indexes, erythrocyte sedimentation rate, electrolyte and liver function tests was normal except for an elevated hemoglobin level (155 g/L) reflecting chronic hypoxemia.Her capillary blood gas revealed a pH of 7.45 and partial pressure of carbon dioxide of 50 mmHg.Diagnostic imaging including chest radiograph (Figure 1) and high-resolution computed tomography (HRCT) (Figure 2 An open lung biopsy was performed.Histology revealed bronchioles with varying degrees of narrowing associated with smooth muscle hypertrophy and peribronchiolar fibrosis.Alveolar septae were thickened by extensive fibrous tissue.The features were in keeping with bronchiolitis obliterans (BO) (Figure 3).The histology specimen was negative by immunofluorescence for RSV, cytomegalovirus (CMV), varicellazoster virus and adenovirus, but positive for EBV by polymerase chain reaction.
The patient was treated with prednisone and a six-week course of gancyclovir on the basis of the positive EBV nuclear antigen and viral capsid antigen IgG.She was discharged home on prednisone, salbutamol, fluticasone and nasal prong oxygen at 3 L/min.
In her subsequent follow-up one month later, lung function tests revealed some improvement in flows with a forced expiratory volume in 1 s of 49% predicted.She had normal resting lung volumes (total lung capacity was 103% predicted) with significant gas trapping (residual volume/total lung capacity Figure 1) Chest radiograph on admission showing hyperinflation and bilateral linear opacities throughout the lungs, particularly in the bases was 47% and forced vital capacity was 67% predicted) and an obstructive pattern.She was commenced on oral hydroxychloroquine at a dose of 10 mg/kg with a view to wean her steroid dose because she was cushingoid by this time.However, her clinical course waxed and waned, requiring the adjustment of steroid dosing down and up in response.She remained very hypoxic and dependent on continuous high-flow oxygen.A six-week trial of high-dose clarithromycin was unhelpful.She underwent cardiac catheterization to exclude extracardiac shunting.This revealed a mean pulmonary artery pressure of 30 mmHg, with maximal improvement on 100% oxygen when pulmonary artery pressure dropped to 24 mmHg.
Overall, oral maintenance steroids and hydroxychloroquine have not produced a substantial clinical improvement in the patient.She remains hypoxic with secondary pulmonary hypertension.

DISCUSSION
BO is a rare condition in childhood.It is histologically defined by inflammation and fibrosis occurring predominantly in the walls and contiguous tissues of membranous and respiratory bronchioles, thus resulting in narrowing of the lumens (3).BO has diverse etiologies (4) (Table 1), of which the most common are post-transplantation-related and postinfectious.Certain Aboriginal populations seem to be particularly susceptible to postadenovirus BO (5,6).
In the case of our patient, infection and recurrent aspirations are potential etiologies.BO as a sequela to adenovirus (types 3, 7 and 21), influenza A, measles and mycoplasma infections has been well documented (7)(8)(9)(10).Our patient had previously documented RSV bronchiolitis; however, we do not know whether other viruses, such as adenovirus, were tested for.Although RSV infection alone has not been reported to cause BO, coinfection with RSV and adenovirus has been described as a precursor to BO (11).Our patient also had serological evidence of previous EBV infection.The association of EBV infection with BO in immunocompetent, nontransplant, pediatric patients has not been reported.Adult studies (12) have suggested an association between EBV infection and idiopathic pulmonary fibrosis.In immunocompetent children, pulmonary parenchymal involvement in acute EBV infection is thought to be uncommon, although there have been a few case reports (13,14) linking EBV infection with interstitial lung disease in infancy.Whether EBV was the pathogen or a 'passenger' is not clear.
Histology provides the gold standard for diagnosing BO.The characteristic patchy lesions make sampling by transbronchial biopsy difficult.The diagnostic yield using open lung biopsy or video-assisted thoracoscopy is far superior (2,15).HRCT is another useful tool for diagnosing BO, with the sensitivity and specificity reported to be 80% to 93% and 80% to 94%, respectively (16)(17)(18).The characteristic 'mosaic pattern' results from gas trapping distal to the narrowed bronchioles, leading to parenchymal distortion and subsequent decreased perfusion to areas with bronchiolar obstruction.However, it should be noted that neither the pathological changes (19,20) nor the extent of abnormalities on HRCT (21) correlates well with the functional impairment of the patients.The clinical course of BO is not well documented in the literature because no prospective longitudinal studies have been performed.In one retrospective series of postinfectious BO patients (aged two to nine years) (22), 23% of patients went into remission and 68% had persistent symptoms 3.5 years later.Infectious exacerbations associated with BO are a major cause of morbidity and mortality (23).The severity of the illness, as marked by the presence of hypoxemia and pulmonary hypertension, is generally associated with poor survival in children with pILD (24).
The treatment of idiopathic BO is supportive.Supplemental oxygen, bronchodilators and corticosteroids are the mainstay of therapy, although there have been no controlled trials on the use of steroids in children with BO.In the postlung transplantation population, where recurrent rejection, and EBV and CMV infections are thought to be risk factors for developing BO, treatment strategies include augmentation of immunosuppression (using cyclosporin A, azathioprine and OKT3), early aggressive treatment of infections and prophylaxis for CMV and EBV infection using gancyclovir (25).Lung transplantation is an option for end-stage lung disease.
From the practical point of view, the treatment options for our patient remain a dilemma.Oxygen therapy, systemic corticosteroids and hydroxychloroquine have not produced substantial improvement.Pulse intravenous steroid therapy is an option but must be used cautiously in the face of pulmonary hypertension, and is unlikely to have a large additional benefit with the extensive fibrosis already present.Lung transplantation is an option which can potentially provide an improvement in function and quality of life for a finite period of time.The timing of transplantation is debatable because the natural history of this disease is not well understood.The present case illustrates our current lack of understanding of rare morbid lung diseases in children.Further research is necessary to determine the pathogenesis, natural history and new treatment options for these conditions.

ACKNOWLEDGEMENTS:
The authors thank Dr Ernest Cutz and Dr Gino Somers for their assistance in providing the pathology print.

SUPPORT:
The Cross Canada Pediatric Respiratory Group wishes to acknowledge AstraZeneca for their ongoing support of this program.The assistance provided in the establishment and development of these rounds, the first of this nature in the world, is greatly appreciated by the pediatric respiratory community.
) was performed and showed diffuse changes suggestive of pILD.Her sweat test, immune workup (including immunoglobulin [Ig] subclasses, functional antibody studies, T and B cell markers and stimulation tests) and HIV serology were negative.Sputum culture and nasopharyngeal swab for respiratory viruses were also negative.Serology was positive for Epstein-Barr virus (EBV) viral capsid antigen and EBV nuclear antigen IgG, indicating past EBV infection.Her first spirometry test showed what initially appeared to be a restrictive pattern (forced vital capacity was 41% predicted and forced expiratory volume in 1 s was 39% predicted).She was unable to perform lung volume tests at that time.The echocardiogram showed bowing of the right atrial septum to the left, and a right ventricle-right atrium gradient of 40 mmHg, indicating pulmonary hypertension.
pILD masquerading as difficult asthma Can Respir J Vol 12 No 6 September 2005 319

Figure 2 )Figure 3 )
Figure 2) High-resolution computed tomography showing diffuse ground glass opacities involving both lungs with gas trapping and marked interstitial thickening involving the lobular septae

TABLE 1
Etiologies of bronchiolitis obliterans