The diffuse parenchymal lung diseases (DPLDs), commonly referred to as interstitial lung diseases (ILDs), are a diverse group of pulmonary processes that involve the pulmonary interstitium and sometimes the alveoli. Most are insidious in onset, with cough and dyspnea being the predominant symptoms. This underscores the concept that not all cough and dyspnea are due to COPD. Many of these patients do have a strong history of smoking, and it is easy to mislabel them as COPD. The performance of pulmonary function testing in all patients with such a symptom complex is critical in differentiating COPD, which manifests with obstructive physiology, as opposed to the ILDs, which are usually accompanied by a restrictive picture.

Over the last several decades, understanding of the ILDs has increased significantly. In 1944, Louis Hamman and Arnold Rich published a report describing a fibrotic lung disease that was rapidly fatal.1 Fibrotic lung disease was not a new entity, but no classification or pathologic description was available.2 Averill Leibow, MD, a renowned pathologist published the first classification system for the interstitial lung diseases in 1975.3 Since then, other classification systems have been proposed. These culminated in the recent publication of a joint classification and nomenclature system for the idiopathic interstitial pneumonias (IIPs) by the American Thoracic Society and the European Respiratory Society.4 This classification of the IIPs as well as other common causes of ILD is shown in Table 1.

Defining the true incidence and prevalence of ILDs has been challenging.5 Many historical reviews did not differentiate between fibrotic lung diseases. Reviews of idiopathic pulmonary fibrosis (IPF), the most common of the idiopathic ILDs, show the incidence in the United States to be estimated at 6.8 to 16.3 per 100,000.6 With the publication of the joint ATS/ERS International Multidisciplinary Consensus Classification Statement, further reviews of incidence and prevalence will likely become more precise. In this latest classification, IPF is defined as a distinct clinical entity that is characterized pathologically by a pattern of injury referred to as usual interstitial pneumonia (UIP).

The clinical course of ILDs ranges from complete remission for cryptogenic organizing pneumonia (COP) and respiratory bronchiolitis interstitial lung disease (RB-ILD) to the rapidly progressive fatal course commonly seen in acute interstitial pneumonia (AIP). Idiopathic pulmonary fibrosis, the most common idiopathic ILD, unfortunately has a dismal prognosis independent of treatment. In a recent study from the Mayo Clinic, the median survival for patients with this condition was 2.8 years.7 Pulmonary fibrosis can often be seen in advanced cases of many ILDs, and can be difficult to differentiate from IPF in the late stages. Regardless of the underlying diagnosis, pulmonary fibrosis when present predicts a poor prognosis.8 Treatment of ILD can be subdivided into pharmacologic, surgical, and adjunctive measures.

Pharmacologic Therapy

With the prevailing hypothesis that ILDs were caused by inflammation, historical therapeutic regimens were centered on decreasing inflammation through immunosuppression. This is summarized in Table 2. The ILDs have varying responses to immunosuppressive therapy. While some studies have shown patients with IPF to have subjective and objective improvement with immunosuppressive therapy, this must be considered with an understanding of the high risks of side effects. In addition, many of the studies that attested to the potential utility of steroids were prior to the recent ATS/ERS classification of the IIPs. It is likely that many of the “responders” had other forms of IIP, such as COP or nonspecific interstitial pneumonia (NSIP), and not IPF as we understand it today. Corticosteroids have also been used to treat AIP, although there is no established benefit to this therapeutic approach.9 Steroids are currently considered effective initial therapy for NSIP, sarcoidosis, and COP. Additionally, corticosteroids have been considered effective secondary therapy for desquamatous interstitial pneumonia, pulmonary Langerhans cell histiocytosis, RB-ILD, and hypersensitivity pneumonitis. In treating ILDs, the addition of cytotoxic agents to achieve immunosuppression while decreasing the side effects of chronic corticosteroid use is common.

Idiopathic Pulmonary Fibrosis. IPF is the most common idiopathic ILD and has a poor prognosis. Historically, treatment of IPF was aimed at decreasing inflammation. Single agent corticosteroids have not proven to be effective for IPF. Additionally, several immunosuppressive agents have been utilized to augment corticosteroids and as steroid sparing agents. An alkylating agent, cyclophosphamide has not only failed to prove effective in treating IPF, it also has been insinuated as causing interstitial lung disease.10 Additionally, the side-effect profile of cyclophosphamide is considerable. There is data from a small study11 to suggest that azathioprine coupled with corticosteroids might be useful in IPF. However, this study was completed prior to our current definition and understanding of IPF and, therefore, could have included patients with other IIPs such as NSIP. Oral N-acetylcysteine (NAC), a potent antioxidant, has been studied in conjunction with corticosteroids and azathioprine. While no mortality benefit could be shown with NAC, corticosteroids, and azathioprine combination therapy, a decrease in lung function decline was noted. The low side-effect profile of NAC makes it an attractive agent. Colchicine inhibits collagen formation, which may slow the fibrotic process. However, colchicine has not been shown to improve mortality in IPF. Additionally, there was not significant difference in outcomes between colchicine and corticosteroids when compared. Likewise, interferon gamma-1b (IFN-1b), while showing initial promise in a number of studies, failed to show any mortality benefit in a definitive Phase-3 study of more than 800 patients. Pirfenidone is a unique compound with antifibrotic properties that has shown promise in human studies of IPF and is now being subjected to further definitive Phase-3 studies. Other drugs being studied for IPF include bosentan, imitinab mesylate, and sildenafil. While IPF is still not fully understood, recent advances have been made in the understanding of its pathogenesis and biology, which will allow for more rational targeted therapeutic trials. To facilitate enrollment and provide answers within the context of such studies, the referral of patients with IPF to centers participating in clinical trials should be a high priority.

Nonspecific Interstitial Pneumonia. NSIP, an idiopathic ILD that can present very similarly to IPF, is felt to be more responsive to therapy. There are two forms of NSIP, the more common fibrotic and the more treatment-responsive cellular variant. While not as prevalent as IPF, NSIP does respond to immunosuppression. Corticosteroids, cyclosporine, cyclophosphamide, azathioprine, and methotrexate have all been used with favorable results.12

Collagen Vascular Diseases. Collagen vascular diseases are associated with many pulmonary manifestations. ILDs commonly linked to collagen vascular disease generally carry a more favorable prognosis. Pathologically, these diseases can be associated with histologic patterns including most commonly NSIP, UIP, and COP. Therapy is guided by current recommendations for the underlying collagen vascular disease. Corticosteroids and other immunosuppressive therapy are often used with mixed responses.13

Cryptogenic Organizing Pneumonia. COP is a disease of histologic organizing pneumonia in which no infectious or other etiologic agents can be identified. Although no rigorous trials have evaluated the required dose and duration of therapy, the efficacy of corticosteroids in the treatment of COP is accepted.14 One recommended regimen is to begin with 1.0 to1.5 mg/kg/day of prednisone tapered over 3 to 6 months.15

Granulomatous Lung Disease. Sarcoidosis is a granulomatous disease that usually involves the lungs. Advanced stage sarcoidosis can progress to a diffuse lung disease often with pulmonary fibrosis. Therapy is centered on immunosuppression with corticosteroids.16 Other therapies, including chloroquine, methotrexate, and cyclosporine, have been evaluated.17-19 Another granulomatous disease of the lungs, hypersensitivity pneumonitis (HP), is often caused by inhalation of organic substances, frequently from bird excrement. The aggressive inflammatory process within the lungs usually responds to removal of the inciting substance. However, corticosteroids have been used for cases in which removal of the offending agent was not effective. While most patients improve, it remains unclear what the role of corticosteroid is for HP.20

Unusual Causes of Interstitial Lung Disease. Lymphangiomyomatosis (LAM) is a disease of females characterized by smooth muscle proliferation commonly involving the lungs. This proliferation is thought to be stimulated by estrogen, and, therefore, treatment has included hormonal manipulation. Patients are often managed with progesterone taken orally or given intramuscularly monthly or bimonthly. Progesterone and oophorectomy have been shown to be effective.21

Smoking-related interstitial lung diseases include RB-ILD, desquamative interstitial pneumonia (DIP), and pulmonary Langerhans cell histiocytosis (PLCH). All three might respond to smoking cessation, and this should be the first approach to treatment.22 In contrast to RB-ILD, DIP and PLCH often progress despite the cessation of smoking. Corticosteroids have been used in these entities when smoking cessation is not effective.23 Although corticosteroids have been used, the benefit remains unclear. Other immunosuppressive agents, including cyclophosphamide, vincristine, and chlorambucil, have been used for resistant cases, but their benefit is unclear.23

Surgical Therapy

The only surgical option for many ILDs is lung transplantation. In fact, transplantation might be the only therapeutic option for some patients with ILD. Lung transplantation, while effectively replacing the diseased lung(s), does so with risk and comorbidity. IPF is currently second only to COPD as an indication for lung transplantation. Transplantation options for ILD include both single lung transplantation and bilateral lung transplantation. However, for IPF, single lung transplantation is performed more often. The outcome of transplantation has improved, and the survival post transplantation is 86% at 3 months, 76% at 1 year, 60% at 3 years, 49% at 5 years, and 24% at 10 years.24 The survival in recent years has improved, such that the 1-year survival is now about 80%. A distribution of the diagnoses for which lung transplantation was performed from January 1995 to June 2004 is listed in Table 3.

As the clinical course of IPF is unpredictable, it is recommended that patients diagnosed with IPF be referred for transplant evaluation at the time of diagnosis.25 Guidelines26 for transplantation for IPF, diagnosed histologically or radiographically, are single breath diffusing capacity (DLco) <39%, desaturation <88% on six-minute walk test (6MWT), 10% decrease in the forced vital capacity (FVC) during 6 months of follow-up, or honeycombing on high-resolution CAT scan (fibrosis score >2). For histologically diagnosed NSIP, the guidelines for transplantation are DLco <35% predicted (or 15% decline in DLco in 6 months follow-up), or 10% decline in FVC in 6 months follow-up .

PLCH and LAM are cystic ILDs that are prone to pneumothoraces. Surgical therapy for these entities includes thoracotomy, video-assisted thoracoscopic surgery, or pleurodesis.23

Adjunctive Therapy

An initial step in treating ILD is to determine if there is a causative agent that can be withdrawn. Tobacco smoke, drugs, and inhaled organic substances are common agents linked to ILDs. Smoking tobacco products has been implicated as causing three specific ILDs: PLCH, DIP, and RB-ILD. Controversy exists over the interaction of smoking and idiopathic pulmonary fibrosis.23 For the three smoking-related ILDs, smoking cessation is the mainstay of therapy. In addition, it is recommended that physicians provide aggressive smoking cessation measures for all patients with ILD. Drug-induced ILD is a well-known entity. Withdrawal of the offending drug is paramount. Many inhaled organic substances have been linked to hypersensitivity pneumonitis. If HP is suspected, a thorough evaluation into possible causative substances should be performed. Complete isolation from the substance should be attempted.

It is not surprising that fibrotic lung diseases may lead to hypoxemia. Desaturation during a 6MWT has been shown to occur in 53% of patients with IPF and 36% of patients with NSIP and is an indicator of poor prognosis.27 Whether treatment of ILD-associated hypoxemia with supplemental oxygen improves outcomes is unknown. A Cochrane database review found no evidence that domiciliary supplemental oxygen therapy for ILD improved a patient’s quality of life or mortality.28 In 1980, the Nocturnal Oxygen Therapy Trial Group showed that supplemental oxygen therapy improved mortality in hypoxemic patients with chronic obstructive lung disease.29 A Cochrane database review from 2004 reviewing six randomized controlled trials reiterated this point.30 Thus, the evidence for the use of oxygen therapy for hypoxemia patients with ILD has been extrapolated from the chronic obstructive pulmonary disease patient population.

The recognition and treatment of associated comorbidities are important in the care of patients with ILD. Pulmonary hypertension (PH) has emerged as a common process accompanying fibrotic lung disease. Additionally, PH heralds an advanced form of ILD and predicts a poorer outcome.31 Patients with advanced forms of ILD should be screened for PH. However, whether the PH of IPF should be treated with available PH therapies, while a tempting intervention, remains to be proven in clinical trials. Gastroesophageal reflux disease often accompanies ILD and should be treated.32 Appropriate patients should also be considered for enrollment in a program of pulmonary rehabilitation.11

Conclusion

The ILDs have varied responses to therapy. The historical assumption that these were inflammatory processes led to treatment with immunosuppression. For most of these diseases, this is still a reasonable approach. However, decisions for therapy are commonly not guided by large randomized controlled trials due to the rarity of these processes. A diligent search for cause should be attempted, as withdrawal of an inciting agent can be quite effective. Smoking cessation should be a priority. Diagnosing and treating associated comorbid processes assist in the care and may improve the outcomes. Enrollment into pulmonary rehabilitation programs should be considered. Unfortunately, IPF, the most common idiopathic ILD, is unresponsive to current pharmacologic therapy. Many new agents are undergoing clinical trials for IPF. When IPF is diagnosed, patients should be referred to specialized centers and considered for enrollment in a clinical trial. Additionally, with the poor prognosis and frequent rapid deterioration of IPF, strong consideration should be made to refer for transplant evaluation.

Joel Anthony Nations, MD, is current fellow in the Pulmonary and Critical Care Fellowship program at the National Capital Consortium and is on active duty at the National Naval Medicine Center, Bethesda, Md; Steven D. Nathan, MD, is the director of the Advanced Lung Disease Program and the medical director of the Lung Transplant Program, Inova Fairfax Hospital, Falls Church, Va, and affiliate professor of Biomedical Sciences at George Mason University, Fairfax, Va.

The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the US Government.

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