Diffuse panbronchiolitis in children misdiagnosed as asthma: A case report

Abstract

BACKGROUND

Diffuse panbronchiolitis (DPB) is a rare, chronic inflammatory lung disease marked by chronic cough, breathlessness, and preceding sinusitis. Symptoms often persist for years and can be misdiagnosed as asthma, particularly in children. This report describes a DPB case resolved with long-term azithromycin therapy, emphasizing the need for a timely and accurate diagnosis.

CASE SUMMARY

A 12-year-old girl, diagnosed with asthma at age five and managed with inhaled corticosteroids and long-acting beta-2 agonists, developed a history of chronic productive cough and chronic sinusitis for a year. On examination, she exhibited wheezing and coarse crackles. Despite receiving treatment for an asthma exacerbation, her symptoms did not improve. A chest X-ray revealed reticulonodular infiltration in both lower lungs, prompting further evaluation with high-resolution computed tomography (HRCT). The HRCT confirmed centrilobular nodule opacities, a 'tree-in-bud' pattern, and non-tapering bronchi, suggesting DPB. Elevated cold hemagglutinin titers at 128 further supported the diagnosis. Her cough and sinusitis resolved within a month after starting azithromycin therapy, chosen for its anti-inflammatory and immunomodulatory effects. Follow-up HRCT scans after 1 year of continuous treatment showed complete normalization.

CONCLUSION

This case highlights the importance of early diagnosis and prompt treatment in achieving favorable outcomes for DPB.

Key Words: Asthma; Bronchiolitis; Children; Diffuse panbronchiolitis; Macrolides; Wheeze; Case report

Core Tip: Diffuse panbronchiolitis presents progressively worsening symptoms such as chronic cough, shortness of breath during exertion, and persistent sinus infections. Often misdiagnosed as asthma, the condition can be identified through purulent sputum history or squawks detected during auscultation. Prompt and accurate diagnosis ensures effective treatment and improved clinical outcomes.

INTRODUCTION

Diffuse panbronchiolitis (DPB) is a rare chronic lung disease of unknown origin, characterized by persistent cough, exertional dyspnea, and chronic sinusitis[1]. DPB is most prevalent in Asian populations, particularly in Japan and Korea, likely due to genetic or environmental factors[2]. While the cause remains unclear, it may involve genetic predisposition or immune system imbalances[3]. DPB primarily affects individuals aged 20 to 40, but pediatric cases, which account for 13%, are often misdiagnosed as asthma[2]. Early diagnosis is critical to prevent mismanagement and ensure effective treatment. Long-term macrolide therapy, including erythromycin, clarithromycin, and azithromycin, has proven effective, even with dosage adjustments in children[4-6]. For instance, a 12-year-old girl misdiagnosed with asthma fully recovered after treatment with azithromycin. This case highlights the limited understanding of DPB management in children and underscores the need for further research and awareness.

CASE PRESENTATION

Chief complaints

Productive cough and chronic sinusitis persisting for a year.

History of present illness

A 12-year-old girl experienced a persistent productive cough and chronic sinusitis for a year. Despite her symptoms, she did not report fever or blood-tinged sputum. She was initially treated at a provincial hospital for an asthma flare-up with inhaled bronchodilators and corticosteroids. However, her symptoms persisted, resulting in her referral to our hospital.

History of past illness

She was diagnosed with asthma at age five and managed her symptoms using inhaled corticosteroids and long-acting beta-2 agonists.

Personal and family history

She had no history of exposure to the offending antigens and denied vaping electronic cigarettes. There was no family history of cystic fibrosis, primary ciliary dyskinesia, immunodeficiency, or autoimmune disorders.

Physical examination

The physical examination showed normal vital signs, including a temperature of 36.5°C, blood pressure of 105/63 mmHg, pulse and respiratory rates of 100 beats per minute and 20 breaths per minute, respectively, and an oxygen saturation of 96% on room air. Examination of the nasal cavity revealed swelling, reddened mucosa, and a whitish discharge. Lung auscultation revealed bilateral wheezing and coarse crackles at the lung bases, while other findings were unremarkable.

Laboratory examinations

Spirometry indicated an FEV1/FVC ratio of 81%. Pulmonary tuberculosis was ruled out with negative results for the tuberculin skin test, sputum acid-fast bacillus smear, and culture. Blood chemistry and immunological profiles, including IgG, IgM, IgA, and IgE, were normal, ruling out primary immune deficiency. However, a 128-fold increase in cold agglutinin levels was observed in her serum. Flexible bronchoscopy and bronchoalveolar lavage (BAL) showed a normal airway structure. Cytology revealed 1720 nucleated cells per cubic millimeter, comprising 80% neutrophils, 2% lymphocytes, and 18% alveolar macrophages. Furthermore, Pseudomonas aeruginosa was identified in the BAL fluid at over 100000 colony-forming units per millimeter.

Imaging examinations

Paranasal sinus X-rays (Figure 1) showed opacification in the maxillary sinuses with bilateral air-fluid levels. A chest radiograph (Figure 2) revealed reticulonodular infiltrates in both lower lungs. High-resolution computed tomography (HRCT) (Figure 3A) demonstrated centrilobular nodules, a "tree-in-bud" pattern, and non-tapering bronchi indicative of inflammatory bronchiolitis.

Figure 1  Film paranasal sinus showed mucoperiosteal thickening in the right maxillary sinus and total opacification in the left maxillary sinus.

Figure 2  Chest radiograph showed reticulonodular infiltration in both middle to lower lung zones.

Figure 3 Chest high-resolution computed tomography under maximum intensity projection. A: Before treatment, showed multiple centrilobular nodules with a tree-in-bud pattern; B: 10 months after treatment showed complete resolution of abnormal findings.

FINAL DIAGNOSIS

The diagnosis of DPB was confirmed using clinical features and the authoritative diagnostic criteria established by the Ministry of Health and Welfare of Japan. This patient met the following major criteria: (1) Persistent cough, sputum production, and exertional dyspnea; (2) A history of recurrent chronic sinusitis; and (3) Bilateral diffuse nodular shadows observed on imaging. The diagnosis was further supported by two minor criteria: (1) Coarse crackles, occasional wheezing, rhonchi, or squawks; and (2) Elevated cold hemagglutinin titers.

TREATMENT

Treatment began with a 2-week course of levofloxacin, followed by long-term azithromycin therapy at a dosage of 500 mg administered orally once daily. One month into treatment, productive cough and sinusitis symptoms were fully resolved. After symptom resolution, azithromycin was continued, while the doses of inhaled fluticasone-salmeterol and intranasal fluticasone furoate were gradually reduced.

OUTCOME AND FOLLOW-UP

After 1 year of treatment, chest HRCT (Figure 3B) revealed normal findings. Azithromycin was continued for 2 years without any adverse effects, and no symptoms recurred during the 2 years following its discontinuation.

DISCUSSION

DPB, a rare condition first described in Japan in the 1960s[7], is characterized by cough, shortness of breath, and chronic sinusitis[8]. Diagnosis requires three major criteria: (1) Persistent cough, sputum production, and exertional dyspnea; (2) History of recurrent chronic sinusitis; and (3) Bilateral diffuse nodular shadows on imaging. Additionally, at least two minor criteria must be present to confirm diagnosis. Minor criteria include: (1) Coarse crackles, occasional wheezing, rhonchi, or squawks; (2) Abnormal FEV1/FVC and partial oxygen pressure; and (3) Elevated cold hemagglutinin titers. It is essential to rule out differential diagnoses, including tuberculosis, primary ciliary dyskinesia, cystic fibrosis, and immunodeficiency, as these conditions are more common and share overlapping clinical and radiographic features.

The exact cause of DPB remains unknown; however, genetic, environmental, and systemic factors are thought to contribute to its development. Genetic predisposition, particularly in Japan, has been linked to specific markers like HLA-B54 haplotypes[9]. Additionally, Pseudomonas aeruginosa has been identified as a major factor contributing to persistent airway inflammation and structural lung damage[10]. In this case, Pseudomonas aeruginosa persisted until long-term macrolide therapy and targeted antibiotics were administered, effectively controlling the disease.

DPB is mainly diagnosed in middle-aged adults but can also affect children, often misdiagnosed as asthma[2,6]. Males account for 64% of cases, with diagnoses ranging from ages 10 years to over 70 years[2]. Pediatric cases are frequently identified after persistent asthma symptoms are reevaluated, with diagnostic delays of 6 months to 12 years. In adolescents and adults, symptoms arise only after significantly small airway involvement, as bronchioles contribute less to total airway resistance than young children[11].

Diagnosing DPB is challenging in clinical practice due to the lack of a definitive diagnostic test. However, clinical symptoms like chronic productive cough and exertional dyspnea can suggest DPB. These symptoms, while suggestive, are also seen in more common conditions like bronchiectasis and asthma. Symptoms often persist for years before diagnosis. In many cases, chronic sinusitis precedes pulmonary symptoms by several years[2]. On physical examination, findings such as wheezing and crackles further support the suspicion of DPB. Wheezing is primarily expiratory, while inspiratory crackles are typically heard at the lung bases.

When asthma is initially suspected in patients with these symptoms, a lack of improvement following a course of systemic corticosteroids should prompt further evaluation. This evaluation should include consideration of DPB. The presence of purulent sputum or squawks, uncommon asthma findings, can guide clinicians toward diagnosing DPB correctly. Squawks are abnormal lung sounds, described as short inspiratory wheezes, and are associated with conditions like hypersensitivity pneumonitis, pneumonia, and interstitial lung disease[12]. While rare in children, these findings provide a useful distinction between DPB and asthma, aiding in accurate diagnosis.

Although sputum cultures were inconsistently reported, Pseudomonas aeruginosa was frequently identified. It had also been detected in a previously documented pediatric case[5]. Pulmonary function tests often showed a mixed obstructive pattern with occasional restrictive features. Mild hypoxemia was commonly observed alongside a reduced diffusing capacity (DLCO) in measured cases. Radiologic findings complemented these results, often revealing diffuse small nodules on chest X-rays. HRCT scans of the chest consistently showed multiple centrilobular nodules and a characteristic tree-in-bud appearance. Dilated bronchioles and bronchiectasis were also frequently observed[2].

Lung biopsies in patients with DPB revealed fine nodules primarily located in the centrilobular regions. These nodules comprised thickened respiratory bronchiole walls with infiltration of lymphocytes, plasma cells, and histiocytes. A key histopathological feature was the accumulation of foamy histiocytes in the walls of the respiratory bronchioles and alveolar ducts[13]. If characteristic findings of DPB are observed on HRCT scans, a trial of azithromycin may be initiated without requiring biopsy confirmation.

Early diagnosis of DPB is crucial to prevent severe complications, including bronchiectasis and respiratory failure. Because DPB symptoms often persist for long periods before diagnosis, patients were initially treated with asthma medications. However, antibiotics targeting bacteria like Pseudomonas aeruginosa had little to no impact on disease progression. The standard treatment involves long-term macrolide therapy, with doses and durations customized for each patient[1,2]. Macrolides are thought to treat DPB through several mechanisms. These include reducing mucus hypersecretion, inhibiting neutrophil accumulation in the mucosal epithelium, and suppressing lymphocyte activity[14].

Erythromycin is a primary treatment for DPB, significantly enhancing lung function, radiographic outcomes, and survival rates. However, its use is limited by side effects such as gastrointestinal discomfort, liver dysfunction, and frequent dosing[15-18]. The first pediatric DPB case involved a 13-year-old girl with progressive disease over 12 years who showed significant improvement during a 6-month erythromycin regimen (5-10 mg/kg/day)[19]. Similarly, a 13-year-old boy experienced marked recovery within 4 weeks of erythromycin (500 mg/day), allowing discontinuation of other therapies, with maintenance treatment (500 mg every other day) sustaining his recovery for another year[20]. In contrast, a 16-year-old boy experienced persistent symptoms and lifestyle disruptions despite erythromycin treatment (200-400 mg/day), suggesting the need for alternative macrolides like clarithromycin[21]. Pediatric case series further indicate improved outcomes with switching to clarithromycin in some patients[6]. However, for those with severe lung impairment or advanced disease, such as a 12-year-old girl who deteriorated despite clarithromycin (250 mg/day), treatment responses were minimal, reflecting irreversible damage[4].

Azithromycin, a macrolide with fewer side effects and infrequent dosing, is an effective treatment for DPB[22-25]. Studies in China show it improves symptoms, lung function, and chest HRCT findings[24,25]. In Li et al's study[25], 27.5% of patients fully recovered, 70.6% improved, and the 5-year survival rate was 94.1%. This was achieved with a regimen starting with intravenous azithromycin (500 mg daily for 1-2 weeks), followed by oral doses (500 mg daily for 3 months) and tapering to three times weekly for up to 12 months. Hui et al[24] confirmed significant lung function improvements and HRCT findings, including reductions in nodular shadows and bronchial wall abnormalities after 6 months of azithromycin treatment.

The effectiveness of azithromycin in treating childhood DPB remains unclear, requiring further study. A previous case of a 10-year-old boy showed that early azithromycin treatment, an initial dose of 500 mg, 250 mg daily for 2 weeks, and 500 mg 3 times/week for 3 years, resolved symptoms and normalized lung function for a year after stopping therapy[5]. However, he experienced a relapse 3 years later, marked by severe rhinosinusitis and pulmonary symptoms, both resolved with azithromycin[2]. However, our reported case using a higher dosage also showed a positive outcome without relapse. Despite these results, the optimal dosage and duration to prevent relapses remain uncertain, emphasizing the need for further research. Early treatment is vital to prevent chronic airway inflammation and irreversible damage.

Conducting a high-quality randomized controlled trial (RCT) for DPB is challenging due to specific limitations inherent to rare diseases. The main challenge is the difficulty in recruiting enough participants because DPB is a rare condition with low prevalence. Ethical concerns also limit new trials, particularly when comparing macrolides to placebo or no treatment. Macrolides have already shown effectiveness in non-RCT studies and are recommended in current guidelines. Therefore, current evidence supports initiating macrolide therapy when DPB is diagnosed and continuing treatment for at least 6 months[17]. Future multi-center studies are needed to confirm the efficacy and safety of azithromycin in treating DPB and improve the research findings' applicability and generalizability.

CONCLUSION

We emphasize the importance of early diagnosis and treatment of DPB, particularly in cases of difficult-to-manage asthma or recurrent/chronic sinopulmonary symptoms, especially when purulent sputum is present, as early intervention leads to better outcomes. In addition, childhood DPB can be effectively managed with azithromycin, which has shown positive results without adverse effects. Further research is needed to determine the ideal treatment duration and assess the long-term effects of therapy.

ACKNOWLEDGEMENTS

The authors would like to express gratitude to the patient and the staff of the Radiology Department, Faculty of Medicine Siriraj Hospital, Mahidol University, for chest imaging and to Siriraj Medical Research Center (SiMR) for publication support.