A double blind randomised placebo controlled pilot study of oral co-trimoxazole in advanced fibrotic lung disease

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Abstract

Background: In 1996, clinical improvement with oral co-trimoxazole was noted in a patient with biopsy proven advanced fibrotic lung disease who was awaiting a lung transplant. Subsequently, 14 patients with end stage fibrotic lung disease also responded to oral co-trimoxazole.

This prompted a double blind randomised placebo controlled pilot study in patients with advanced stages of idiopathic interstitial pneumonias (IIP) to objectively measure benefit.

Patients: Twenty patients (aged 49–84 years; 11 males) with progressive fibrotic lung disease who had differing subtype diagnosis from CT scans of progressive fibrotic IIP, and showed oxygen desaturation on exertion were selected.

Method: A detailed assessment of arterial gases, lung function, and progressive shuttle-walking tests combined with oxygen saturation monitoring. Quality of life data was recorded. Randomisation was to co-trimoxazole or identical placebo for 3 months followed by 6 weeks of pulmonary rehabilitation before decoding. Placebo patients received active treatment upon decoding with continued follow up of all patients.

Main outcome measures:

Primary1. Shuttle walking test.
Secondary2. FVC and quality of life.
Results: Active treatment showed a significant improvement in shuttle walking test from 255 to 355 m (p=0.002) (95% CI 200–450) with reduced oxygen desaturations during exercise (p=0.003). FVC improved on treatment (+21%) from median 1.9 to 2.3 L (p=0.05) (95% CI 1.3–3.0) but TLC and DLCO were not significantly changed although stable at 12 months. The MRC 5 Point Dyspnoea Score showed improvement (p=0.05) at 3 months for the active group which was maintained at 12 months. The SGHRQ showed a significant reduction in symptom scores at 12 months (p=0.05). The placebo group showed no significant change in any parameters, but demonstrated identical improvement following oral co-trimoxazole. Serum vascular endothelial growth factor (VEGF) was reduced 50% in the active group at 3 months, but just failed to reach statistical significance. ‘Out of study’ HRCT scans in 12 patients showed significant reduction in ground glass changes (p=0.05) after 12 months of continuous co-trimoxazole treatment.

Conclusion: The findings of the pilot study show significant improvements in objective and subjective parameters which fulfil the ATS/ERS (2000) criteria of ‘a favourable response to treatment’.

Introduction

Idiopathic interstitial pneumonia (IIP) belongs to the group of interstitial lung diseases that result in pulmonary inflammation and fibrosis [1], [2]. The clinical picture is one of progressive dyspnoea and respiratory failure. The American Thoracic Society (ATS)/European Respiratory Society (ERS) reviewed and defined the clinical and pathological diagnosis and management of these diseases (joint statement February 2000) [3]. It clarified the main subtypes from biopsy or high resolution CT (HRCT) scanning of the chest. As less than 25% of the UK patients with IIP are biopsied, histological subtypes were often unknown [4], [5] and clinically indistinguishable [6]. Comparative studies show sufficient correlation to allow HRCT to replace biopsy in a high percentage of cases [7], [8]. Usual interstitial pneumonia (UIP) is the commonest sub type in the UK (mean survival of 5 years) [9], [10]. A recent Cochrane meta-analysis of IPF/UIP found no convincing evidence that immunosuppression with steroids and other agents resulted in disease regression or improved survival [11], [12]. UK studies demonstrated that 65% of patients receive these treatments despite the view of clinicians that their efficacy is poor [13], [14].

In 1996, a 50 year old man with advanced fibrotic lung disease awaiting lung transplant was admitted with severe hypoxaemia and dyspnoea. His past treatment included daily oral prednisolone and monthly pulsed methyl-prednisolone and cyclophosphamide. Despite this he had a progressive downhill course with dyspnoea at a few feet.

On admission, fevers with severe hypoxaemia and increased cough raised the possibility of infection with pneumocystis due from long-term immunosuppression. Bronchoscopy was impossible on clinical grounds so high dose oral co-trimoxazole was commenced. Oxygen requirements reduced from 15 L/min to zero within 7 days. At 14 days the patient was well with minimal exertional dyspnoea. Bronchoscopy then returned negative for pneumocystis on silver-stain. To date his clinical state remains stable on co-trimoxazole 480 mg od. In 2002 histological review of his biopsies from two reference centres gave different diagnoses (NSIP and DIP).

Between 1998 and 2000, 14 patients judged to be dying from end stage fibrotic IIP (CT diagnosis 50% UIP and 50% fibrotic NSIP) were admitted to St Helier Hospital on conventional steroid treatment. Treatment with co-trimoxazole was commenced on verbal consent, resulting in improvements within 5 days and discharged in 2 weeks. Doses of co-trimoxazole were gradually lowered in subsequent patients to reduce gastric fullness and dyspepsia. A single case report (1998) of desquamative interstitial pneumonitis recurring in a single lung transplant recipient which resolved on co-trimoxazole treatment was identified from the literature [15].

From our observations, a double blind randomised placebo controlled pilot study was designed. This study would examine IIP patients with progressive fibrotic lung disease of mixed subtypes where oxygen desaturation on exercise could be fully assessed by the shuttle walking test and other measures impossible for end stage patients. This publication describes the pilot study and includes ongoing follow up data ‘out of study’.

Section snippets

Method

This study was approved by the local regional ethical committee, with written informed consent from the patients and their general practitioners.

Results

Patient characteristics & HRCT patterns (Table 1): All sputum samples were negative for pneumocystis and common pathogens on culture.

Discussion

The pilot study was designed to test the observations that patients with progressive fibrotic lung disease (IIP) did improve with co-trimoxazole. The current study includes patients with IIP with of a variety of HRCT patterns (predominantly UIP and fibrotic NSIP). On clinical grounds all groups of patients were indistinguishable, but symptomatic with cough, poor life quality and alarming reductions in exercise tolerance with time.

The study findings demonstrate improvement in exercise capacity

Conclusion

This pilot study examines an antibiotic not previously used in the treatment of progressive fibrotic lung disease. The findings show significant improvements in objective and subjective parameters, which fulfil the ATS/ERS criteria of a response to treatment. Since patients with progressive fibrotic lung disease are clinically difficult for doctors to manage, co-trimoxazole may be an inexpensive and helpful agent; improving life quality and exercise capacity with benefit seen after 2 weeks.

Acknowledgements

The authors thank Peel Trust Fund for funding of oral co-trimoxazole and placebo tablets, R & D St Helier for funding out of study repeat HRCT scans only. The authors also thanks the Pharmacy for randomisation and drug issue and the patients for their good humour and reliable attendance on Saturday mornings. Thanks are also to Alex Nicholas (B.Sc., M.Sc.) and Rod Lunn (B.Sc., M.Sc.) for cytokine analysis and to Jenny Swallow for preparation of the manuscript. The authors gratefully acknowledges

References (30)

  • D.M. Hansell et al.

    CT evaluation of fibrosing alveolitis—applications and in sights

    J Thoracic Imaging

    (1996)
    D.M. Hansell et al.

    CT evaluation of fibrosing alveolitis—applications and in sights

    Eur Respir J

    (1998)
  • S.L.S. MacDonald et al.

    Nonspecific interstitial pneumonia and usual interstitial pneumonia: comparative appearances and diagnostic accuracy of thin section CT

    Radiology

    (2001)
  • K.R. Flaherty et al.

    Radiological versus histological diagnosis in UIP and NSIP: survival implications

    Thorax

    (2003)
  • R. Hubbard et al.

    Survival in patients with cryptogenic fibrosing alveolitis—a population based cohort study

    Chest

    (1998)
  • H.R. Davies et al.

    Immunomodulatory agents for idiopathic pulmonary fibrosis

    Cochrane Database Systematic Rev

    (2003)
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