2001 - A Young Lady With Progressive Dyspnea
Dr. Edwin POON, Dr. MT CHEUNG, Dr. KH FUNG, Dr. SW PANG, Department of Medicine, Department of Radiology, Department of Pathology, Pamela Youde Netherzole Eastern Hospital
Case Report
The patient was a 37 year-old lady, non-smoker / non-drinker. She was working as a clerk. She presented to the Medical Department of the Pamela Youde Nethersole Eastern hospital on the 151February 2000. She enjoyed good past health and a chest radiograph (CXR) taken in 1998 for insurance purposes was normal. She had no significant family history, no regular medications and no allergies. She complained of intermittent cough since July 1999 productive of yellowish sputum and worse at night. She had exertional dyspnoea with a deterioration in exercise tolerance over six months to one 'flight of stairs' recently. She admitted to weight loss of twenty pounds over six months, with night sweating and amenorrhoea. She was diagnosed as asthma by her GP and treated with oral steroids, theophylline and salmeterol / fluticasone accuhaler. With worsening symptoms of increasing cough and dyspnea for three days in late January 2000, and a CXR by her GP showing bilateral lower zone shadows, she was referred to the Accident and Emergency department on the 151 February 2000. Physical examination on admission showed no palor, jaundice, cyanosis, clubbing or cervical lymphadenopathy. She was mildly tachypnoeic at rest (20 breaths/min, oxygen saturation-Sa02 95% on room air), blood pressure 140170mmHg, tachycardia -120/min. and low-grade fever 37.6 C. Chest auscultation revealed bilateral lower zone fine inspiratory and expiratory crepitations with no wheezes. Cardiovascular and abdominal examination were otherwise unremarkable. (CXR - Fig.l) The initial impression given by the admitting medical officer was atypical pneumonia. Routine blood tests, erythrocyte sedimentation rate, arterial blood gases, blood cultures, atypical pneumonia titres, theophylline level and thyroid function were taken and sputum was saved for gram stain, culture and acid fast bacilli. Clarithromycin 500mg BD was initially started orally along with nebulised bronchodilators.
Blood tests
- Hb 13.6 g/dL MCV 84 fL
- WCC 13.0 Neut 10.2 Ly 1.7 Eos 0.13
- Plt 64 with clumping ESR 47
- L/RFT normal Albumin 44 g/L
- Glucose 4.5 mmol/L
ABG lL 02 :
- pH 7.38
- pC02 6.2 kPa
- p02 11.8kPa
- HC03 27 mmol/L
- Sa02 96%
On Day 2, her oxygen saturations deteriorated; Sa02 was maintained at 93% with oxygen (02) at two litres per minute (LPM). There was no improvement with bronchodilators. Bedside spirometry showed:
PEFR - 138 l/min, FEV1 - 0.46 1,FVC - 0.86 1.
The CXR was reviewed and the differential diagnosis included interstitial lung disease histocytosis X, LAMS, IPF etc.) and viral infection. Blood for antinuclear factor (ANF), rheumatoid factor (RF), complement, antiDs- DNA, C-reactive protein, cold agglutinin and immunoglobulin pattern was saved. High resolution computerized tomography (HRCT) of the thorax was booked and formal spirometry was performed.
Spirometry / bronchodilator response:
PFR 127 (37%) 128 (37%)
FEV1 0.57 (22%) 0.42 (16%)
FVC 0.91 (30%) 0.74 (24%)
Ratio 0.63 (73%) 0.57 (66%)
HRCT thorax showed diffuse interstitial involvement of undetermined nature, (Fig. 2) and our patient was planned for thoracoscopic lung biopsy.
- IgA 6.1 (0.68-3.78)
- IgG 16.9 (6.94-16.18)
- IgM 1. 68 (0.60-2.63)
- Atypical pneumonia serology negative
- C3 C4, ANA, RF and anti D/ENA negative
- Cold Agglutinin 1:80 (1 :<40)
- CRP <4
Thoracoscopic lung biopsy was performed, complicated by persistent air leak and left pneumothorax. Our patient developed sputum retention post operatively with respiratory distress and desaturation requiring re-intubation and sedation. Improvement with chest physiotherapy and sputum clearance allowed extubation and the chest drain was subsequently removed, with a small residual apical pneumothorax. The lung biopsy result showed diffuse panbronchiolitis. Low dose oral erythromycin (250mg bd) was started. Antituberculous drugs (HRMZ) were also started because the biopsy also showed caseating granuloma. The ENT department was consulted and there was no evidence of sinusitis. Our patient was discharged home on Day 20 with long term oxygen therapy (LTOT) 3-5 LPM. She desaturated with minimal exertion requiring 5-7 min to recover and her ambulatory state was poor being mainly chairbound.
Progress after discharge:
The course of antituberculous treatment (9/12) was well tolerated and completed. She developed four further episodes of pneumothorax; left pleurodesis was performed in May 2000 and left pleurectomy in June 2000. Clinical (symptoms and signs - Fig. 5), lung function (Fig. 6) and radiographic (Figs. 7 & 8) progress was made after initiation of erythromycin 250mg bd.
Panbronchiolitis (DPB)
DPB is a unique chronic obstructive lung disease of obscure etiology. It is an idiopathic condition characterized by chronic inflammation exclusively located in the region of the respiratory bronchiole. DPB was identified at the end of 1960s, first described by Yamanaka. 1969 criteria (as marked by an asterisk*) were developed in collaboration with the Japanese Ministry of Health and Welfare (Table 1). The condition is largely restricted geographically to the Far East; primarily Japan, and is rare elsewhere. It is reported to be more prevalent in men and most subjects have never smoked. With a peak incidence in fifth and sixth decades it can occur at any age of adult life. Both genetic and environmental influences are important. A specific infectious agent has not been found, nor any identifiable aetiology. There is an increased incidence of HLA- Bw54; this allele being rare except in Japanese, Chinese, and Korean populations, suggesting some genetic component. A small number of familial cases have been reported, with a high incidence of chronic parasinusitis affecting other family members.
Diffuse Panbronchiolitis - Differential diagnosis of clinical features
- Sinopulmonary syndromes
- Bronchiolitis
- Cryptic cases of obstructive lung disease
- COrD
- Bronchiectasis
- Primary ciliary dyskinesia
- Cystic fibrosis
- Wegener's granulomatosis
- Malignant lymphoma
- Lymphocytic interstitial pneumonia
Clinical presentation (* 1969 diagnostic criteria)
DPB is a distinct clinicopathological entity characterized by chronic cough with copious mucopurulent sputum, exertional dyspnoea*. Chronic sinusitis* is commonly found (75% of Japanese patients) - part of a spectrum of sinobronchial syndrome. Either crackles or wheezes* may be heard on chest auscultation. The natural history is rapidly progressive respiratory failure leading to cor pulmonale and ultimately to death. DPB has been reported complicating ulcerative colitis and adult T-cell leukemia.
Investigation
There is no specific diagnostic serology. Elevated cold agglutinin titre* (> x 64) with negative mycoplasma serology may be found and a change in titre may reflect response to treatment. Serum IgA may be increased (IgG subclass deficiency. RF (40%) or ANA positivity, increased ESR and CRP may also be found. Sputum cultures may be positive for H. influenza or P. aeruginosa; reflecting early and later stages of disease respectively. HLA Bw54 is associated with a relative risk of 13 times in the affected population. Blood gas often shows hypoxaemia; PaO2 < 80mmHg (with hypercarbia in terminal stages). Some series report an increase in CD4/CD8 ratio. Lung function test* typically shows obstructive +/- restrictive defects; obstruction is more resistant to bronchodilators than that of COAD. Diffusion capacity variably decreased.
Radiological Classification (Figs. 9 & 10) and Clinico-radiological Correlation (Fig. 11)
Radio-pathological Correlation
• Nishimura K et al. Radiology 1992; 184: 779-785
Lesions are predominantly in a centrilobular distribution. Nodules correspond to chronic inflammatory & fibrotic lesions in and around membranous & respiratory bronchioles, adjacent alveolar ducts and alveoli. Branching structures correspond to widening of bronchiolar lumina, wall thickening and intraluminal secretions. Dilated bronchi and wall thickening are common outside secondary lobules. Thickened bronchial walls may be due to secretions and peripheral hypoattenuation is due to hyperinflation in peripheral zones.
Lung Biopsy
Lung biopsy is generally recommended to confirm the diagnosis because there are no other specific findings. (Lung biopsy may not be necessar;} in countries where the prevalence of DPB is high. In this setting, the clinical, physiologic and radiographic features of DPB are typical and specific enough to warrant a presumptive diagnosis and a therapeutic trial of erythromycin.
Histology (Figs. 3,4 & 12 and compare with Fig. 13- constrictive bronchiolitis) Chronic inflammation is localized mainly in the respiratory bronchioles and adjacent centrilobular regions, with infiltration of plasma cells and lymphocytes, lymphoid follicle is occasionally observed. Small conducting airways sometimes show luminal stenosis or dilation, with subepithelial infiltration of plasma cells and lymphocytes, and fibrotic and elastolytic lesions. Foamy macrophage accumulate in the wall of respiratory bronchioles, adjacent alveolar duct, and alveoli, with infiltration of lymphoid cells (unit lesion of panbronchiolitis). Lesions may extend to the more proximal bronchioles, leading to secondary bronchiectasis in advanced stages. No significant lesions are found in the alveolar areas away from the centrilobular lesion.
Histology - Differential diagnosis of unit lesion
- Bronchiolitis
- Cystic fibrosis
- Bronchiectasis
- Aspiration pneumonia
- Extrinsic allergic alveolitis
- Wegener'sgranulomatosis
- Bronchocentric granulomatosis
- Malignant lymphoma
- MIwata et al. Hum Path 1994, 25(4): 357-63
Treatment
DBP is fatal if untreated with a 42% 5-yr survival rate (25% at 10yrs). Corticosteroids offer no significant improvement in morbidity and mortality. Other treatments that have been tried including beta-lactams, aminoglycosides and newer quinolones have not been useful. Erythromycin (EM) has changed DPB from a fatal disease to curable one; first noted in 1982 in a case report followed by controlled trials with the 5-yr-survival rate improving to 92%. EM at low dose 400- 600mg is recommended for at least 6 months. HRCT response to treatment showed decreased nodular opacities, peri-airway thickening and mucus plugging in several series. A clinical trial of the efficacy of EM was reported in 1984. A retrospective analysis of 595 patients registered with the Ministry of Health & Welfare of Japan from 1970 to 1990 showed improvement of survival in patients with DPB treated with low dose EM (Fig. 14).
Erythromycin has specific effects in DBP - anti-inflammatory/ immunomodulatory rather than via antibacterial activity (serum and sputum EM levels well below MIC of common organisms). However, the mechanism is still largely unknown. There is inhibition of neutrophil accumulation/ chemotaxis - marked reduction of neutrophil numbers in BALF. EM reduces the pulmonary levels of interleukin -6 and -8 and leukotriene B4, which are potent chemotactic agents; reducing neutrophil influx into the lesions, and neutrophil elastase release. There is acceleration of neutrophil apoptosis and lymphocyte proliferation is dose-dependently inhibited by EM. There is normalization of CD4+/CD8+ ratio with EM in animal models of chronic pseudomonas infection and macrophage differentiation and proliferation is accelerated. There is inhibition of hypersecretion - EM dose dependently inhibits ion transport when attached to the mucosa by blocking the chloride channel and there is decrease IL-8 induced goblet cell secretion: both combining a “drying effect” of EM in various chronic suppurative diseases. EM interfere with the formation of P. aeruginosa biofilms- preventing its persistence and reducing both H. influenza, and P. aeruginosa in sputum cultures. Other macrolide antibiotic (clarithromycin, azithromycin, roxithromycin) have also been reported to be effective. For resistant cases, inhalation of indomethacin and oxitropium bromide might be effective in reducing sputum production. Routine use of heta-2 agonists or ipratropium bromide is encouraged to promote bronchodilation and mucociliary clearance, and treatment of coexisting sinus disorders may help alleviate airways disease.
In a recent local series by Tsang et al., some atypical features were noted including a lower prevalence of HLA-Bw54 (most possess HLA-A2, HLA DR9 and HLA- Bw55), no IgG subclass deficiency in some patients nor increase in IgA, normal or low CD4/CD8 ratio, absence of cold haemagglutinin and RF, and positive c-ANCA(which was negative for anti-PR3).
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