Thoughts on the diagnosis and management of interstitial lung diseases.

In this edition of the SMJ, Dr. Sonye Danoff and colleagues from the Johns Hopkins University School of Medicine present a review of the current evidence guiding the diagnosis and treatment of interstitial lung diseases. They appropriately emphasize the importance of early recognition and the need for close collaboration between internists and pulmonologists in the management of these complex patients. (1)

Interstitial lung diseases (ILDs) are a very heterogeneous group of disorders with distinct clinical courses, radiographic patterns and histology. We choose to place them under the same classification "umbrella" due to the common finding of varying degrees of inflammation and fibrosis in the interstitial space of the lungs. (2) The presentation of most ILDs is nonspecific and the key to the diagnosis is having a high degree of suspicion, along with a systematic approach to each case. Patients complaining of breathlessness with persistent cough can easily be mistaken for having heart disease, COPD or gastroesophageal reflux causing bronchospasm.

Most cases of ILDs will fall in the "idiopathic" category, but often, a careful clinical assessment that unveils a history of occupational and environmental exposures will yield the diagnosis. Typical examples would be ILD induced by different drugs, hypersensitivity pneumonitis and occupation-related conditions such as asbestosis and silicosis. Most cases of ILD related to connective tissue diseases (CTDs) will be recognized by the stigmata of the underlying autoimmune process as a detailed physical examination is performed. (3)

Plain chest x-rays are seldom helpful and a high resolution CT scan (HRCT) of the chest should be obtained whenever ILD is suspected. (4) HRCTs are performed with thin cuts over the lung parenchyma and both prone and supine views are usually obtained. No IV contrast is necessary. The HRCT frequently will show nonspecific patterns such as reticular markings, ground glass opacities, honeycombing and/or traction bronchiectasis, but rarely, the findings will be specific enough to yield a diagnosis such as the thin-walled parenchymal cysts of lymphangioleiomyomatosis.

A HRCT showing predominantly basilar pleural-based honeycombing may abrogate the need for a surgical lung biopsy in suspected cases of idiopathic pulmonary fibrosis (IPF). Unfortunately, about 30% of cases of IPF do not present with this so-called "typical" pattern. (5,6)

Transbronchial biopsies will rarely yield the diagnosis, except in cases of cancer with lymphatic dissemination or granulomatous inflammation. Surgical lung biopsy is the method of choice for the definitive diagnosis of ILDs, and video-assisted thoracoscopic procedures have become the most favored technique. (7,8) It is very important for the clinician to consider that the lung has a limited "repertoire" with which it responds to an injury. The classic "idiopathic interstitial pneumonia" patterns of usual interstitial pneumonia (UIP), nonspecific interstitial pneumonitis (NSIP), bronchiolitis obliterans with organizing pneumonia (BOOP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) and acute interstitial pneumonitis (AIP) are oftentimes also seen in cases of ILD related to CTD or drug toxicity.

Furthering Dr. Danoff's recommendations, very close collaboration among clinicians, radiologists and lung pathologists is absolutely vital so the appropriate correlations are made for a correct diagnosis. (9)

Most ILDs are treated with immunosuppressive therapies; however, there are very few well-conducted clinical trials in this field to justify such an approach. Innumerable small studies utilizing lymphocyte-inhibiting agents such as azathioprine or cyclophosphamide for ILDs related to CTDs have been reported with variable degrees of success. (3) The Scleroderma Lung Study reported a modest, albeit significant benefit with a regimen utilizing cyclophosphamide and corticosteroids for six months. (10) Corticosteroids may benefit patients with acute hypersensitivity pneumonitis and cryptogenic organizing pneumonia. (11)

In 2000, a joint American Thoracic Society/European Respiratory Society (ATS/ERS) statement on IPF made clear that no specific treatment could be recommended. A regimen that included prednisone and azathioprine was suggested as first-line therapy, but practitioners were cautioned that this was not supported by large, well-controlled, clinical trials. (12) Subsequently, large controlled studies utilizing agents such as [gamma]-interferon-1b, (13) N-acetylcysteine (14) and the antifibrotic agent pirfenidone (15) failed to show clear benefit. Recognizing the lack of evidence-based therapies for IPF, the National Institutes of Health established the IPF Clinical Research Network (IPFnet) in 2005. The IPFnet has the mission of developing better treatments for IPF, and its 12 centers expect to start recruiting patients in 2007. Until a treatment shows clear benefit in a large randomized and placebo-controlled trial, patients with IPF should be promptly referred to specialized tertiary centers to be considered for enrollment in clinical studies.

Many cases of ILD are progressive, with slow destruction of the lung architecture and ultimate loss of function. IPF is a progressive disease with 50% mortality within the first three years of diagnosis. The rate at which it progresses is not predictable; thus, it is important to emphasize that patients younger than age 65 and without significant comorbidities should be referred for lung transplant evaluation soon after diagnosis.

Lung transplantation, however, is a very costly option and available to a select few. (16) As their diseases progress, patients will become increasingly breathless, deconditioned and depressed. It is important to recognize these problems and utilize strategies aimed at decreasing morbidity while increasing quality of life, such as supplemental oxygen and rehabilitation. Patients that are terminally ill will not benefit from mechanical ventilation and open discussions about end-of-life care, along with referral to a hospice program, should be undertaken. (17,18)

In summary, the management of ILDs is challenging and dependent on a multidisciplinary team. The promise of successful treatments with immunosuppression is almost always unrealistic. More research is needed to further our understanding of the mechanisms of lung fibrosis before more effective therapies can be developed.

References

1. Danoff S. A clinician's guide to the diagnosis and treatment of interstitial lung diseases. South Med J 2007;100:579-587.

2. Leslie KO, Wick MR. Practical Pulmonary Pathology--A Diagnostic Approach. Philadelphia, Elsevier Inc., 2005.

3. Freemer M, King TE Jr, Connective tissue diseases. In: Schwartz MI, King TE (ed). Interstitial Lung Disease, 4th ed. Hamilton, BC Decker, Inc., 2003.

4. Orens JB, Kazerooni EA, Martinez FJ, et al. The sensitivity of high-resolution CT in detecting idiopathic pulmonary fibrosis proved by open lung biopsy. A prospective study. Chest 1995;108:109-115.

5. Hunninghake GW, Zimmerman MB, Schwartz DA, et al. Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001;164:193-196.

6. Flaherty KR, Thwaite EL, Kazerooni EA, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax 2003;58:143-148.

7. Lettieri CJ, Veerappan GR, Helman DL, et al. Outcomes and safety of surgical lung biopsy for interstitial lung disease. Chest 2005;127:1600-1605.

8. Rena O, Casadio C, Leo F, et al. Videothoracoscopic lung biopsy in the diagnosis of interstitial lung disease. Eur J Cardiothorac Surg 1999;16:624-627.

9. Flaherty KR, King TE Jr, Raghu G, et al. Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis? Am J Respir Crit Care Med 2004;170:904-910.

10. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006;354:2655-2666.

11. Schwartz MI, King TE (eds). Interstitial Lung Disease, 4th ed. Hamilton, BC Decker Inc, 2003.

12. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000;161:646-664.

13. Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004;350:125-133.

14. Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2229-2242.

15. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005;171:1040-1047.

16. Orens JB, Estenne M, Arcasoy S, et al. International guidelines for the selection of lung transplant candidates: 2006 update-a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006;25:745-755.

17. Saydain G, Islam A, Afessa B, et al. Outcome of patients with idiopathic pulmonary fibrosis admitted to the intensive care unit. Am J Respir Crit Care Med 2002;166:839-842.

18. Blivet S, Philit F, Sab JM, et al. Outcome of patients with idiopathic pulmonary fibrosis admitted to the ICU for respiratory failure. Chest 2001;120:209-212.

Joao A. de Andrade, MD

From the University of Alabama School of Medicine, Department of Medicine, Birmingham, AL.

Reprint requests to Joao Alberto M. de Andrade, MD, University of Alabama School of Medicine, Department of Medicine, Birmingham, AL 35249. Email: [e-mail]