FINAL DIAGNOSIS: LYMPHOCYTIC INTERSTITIAL PNEUMONIA
Lymphocytic interstitial pneumonia (LIP) is a condition in which the lungs are diffusely infiltrated by benign lymphoid elements. The disease is more common in middle-aged women (1,2,3,4). Affected individuals generally have concurrent systemic disease, most frequently some form of immunologic dysfunction. An estimated one third of patients with LIP have manifestations of Sjögren's syndrome (5). Other associated autoimmune conditions include systemic lupus erythematosus (1,4), myasthenia gravis (3,6), pernicious anemia (7), and autoimmune hemolytic anemia (8). Cases of LIP in patients with chronic active hepatitis (4), and primary biliary cirrhosis (4) have also been described.
LIP has been associated with various immune deficiencies, including agammaglobulinemia (7), hypogammaglobulinemia (1,3 4, 9) and, as in the current case, with common variable immunodeficiency (10,11). There is a clear association between LIP and human immunodeficiency virus (HIV) infection in the pediatric population; with some 30 -50% of HIV positive children affected (12). The Centers for Disease Control (CDC) recognizes LIP as an AIDS-defining illness in HIV positive individual (13).
Patients typically present with cough, progressive dyspnea (3,4, 14,15), and/or chest pain (3,4,15). Fever, weight loss, and fatigue are other common manifestations (3,4). Bibasilar rales are a consistent finding on lung auscultation (1,3,4,16); wheezes and decreased breath sounds may also be present (4). However, in many instances, the physical findings are minimal (1) or the physical examination is normal (1,12).
The interstitial distribution of LIP is apparent on chest films, which characteristically show bilateral reticular to reticulonodular opacities, predominately in the lung bases (1,2,3,4,14,15,16,17). These opacities range from fine to coarse in texture(1,4). Patchy alveolar infiltrates may also be seen (2,3,12,16); occasionally, these nodular densities are less well defined and demonstrate a "fluffy" appearance (3,14). In cases of advanced disease with extensive interstitial fibrosis, chest films may show a honeycomb appearance (3, 4). Pulmonary function studies typically show evidence of restrictive lung disease (3,4,14,15) and decreased carbon monoxide diffusing capacity (3,14,16).
Arterial blood gases generally reveal hypoxemia (4, 16) and respiratory alkalosis (16). Dysproteinemia, a consistently noted abnormality, usually manifests as a polyclonal hypergammaglobulinemia on serum protein electrophoresis (1, 3, 4). The most frequently elevated immunoglobulin is IgG, followed by IgM and IgA (4). Monoclonal gammopathies (6,18,19) and hypogammaglobulinemias (3,4,16), although less common, have been reported. Proteinuria is typically not seen (1,3,4). Peripheral lymphocytosis has been observed in some cases (12).
Although clinical findings are supportive, a lung biopsy is requisite for a definitive diagnosis of LIP (3,12). Microscopic features range from diffusely distributed interstitial infiltrates of mature lymphocytes, plasma cells, and histiocytes (14,16) to more patchy, dense cellular infiltrates with lymphoid follicles and germinal centers; giant cells and histiocytes may also be seen (20). Noncaseating granulomas are reported in 20 -50% (2, 4) of cases. Other significant findings include type II pneumocyte hyperplasia and, in the end-stage lung, interstitial fibrosis (20).
The histologic differential diagnosis should include other disorders that are characterized by interstitial lymphoid proliferation. Pneumocystis carinii can precipitate a prominent lymphoplasmacytic infiltrate and may be erroneously diagnosed as LIP if it is not considered in the differential diagnosis or if organisms are not evident (20). With florid histiocytic proliferations and granulomatous inflammation, fungal and mycobacterial infections should be excluded. Thus it is important to obtain cultures and special stains for fungi and mycobacteria. Pseudolymphomas are characterized by prominent follicles, often with germinal centers, surrounded by dense collections of lymphocytes and plasma cells(17,20). Differentiating LIP from a low-grade lymphoma can also be challenging. Histologically, low-grade lymphomas consist of dense, monomorphic infiltrates (20). They tend to follow lymphatic routes (17) and spread more aggressively, sometimes invading the pleura or the bronchial cartilage (20). Although occasionally present, germinal centers are uncommonly seen in pulmonary lymphomas (14,17,20). Mitotic activity is a feature more suggestive of lymphoma (1). In cases of lymphoma, immunohistochemical stains may help demonstrate immunoglobulin light chain restriction and single cell lineage (21). Cellular lymphoplasmacytic interstitial infiltrates and sarcoid-like granulomas characterize hypersensitivity pneumonitis. However, the infiltrate is denser in LIP (22). In the later stages of LIP, there may be prominent interstitial fibrosis; differentiation from usual interstitial pneumonitis (UIP), which also occurs in connective tissue disease (23), can be extremely difficult, if not impossible. Dense chronic inflammatory interstitial infiltrates are also featured in follicular bronchitis and bronchiolitis. However, there is typically a peribronchial or peribronchiolar pattern of follicular lymphoid hyperplasia, with sparing of the interstitium in follicular bronchitis/bronchiolitis (15,17,21). In contrast to LIP, noncaseating granulomas are typically not seen (15).
There is wide variation in the response of LIP to treatment. Some patients clearly improve or stabilize with steroids, while others respond poorly, if at all (16). No treatment has consistently been effective, even when combined drug therapy has been applied.
The etiology of LIP remains unclear. The vast spectrum of disorders associated with this condition further complicates investigation. In 1973, Liebow and Carrington suggested multiple possible etiologies, including a viral agent (1). Since then, the immunosuppressed population - predominantly HIV patients and transplant recipients has significantly grown. It is well known that these patients are disproportionately susceptible to Epstein-Barr virus-associated lymphoproliferative conditions, including lymphoma and post-transplant lymphoproliferative disorder. Using in situ hybridization, Barbera et al. demonstrated Epstein-Barr virus (EBV) DNA in archival lung tissue of patients diagnosed with LIP (24). The prevalence of LIP among individuals with HIV has led some to focus on the virus itself. Some investigators have compared bronchoalveolar lavage fluids from HIV patients both with and without LIP. They detected HIV antigen in the lavage fluids of patients with LIP, while the fluids of those who did not have LIP were negative (25,26).
Because LIP is frequently associated with collagen vascular disease and other autoimmune disorders, some have suggested that circulating antibodies or immune complexes may play a role in its etiology (27). Using immunofluorescence, DeCoteau et al. detected linear deposits of IgG and IgA on the alveolar basement membranes in the lung tissue of a patient with LIP (27).
However, Levinson at al. challenged the idea of humoral autoimmune antibody-mediated mechanisms, particularly in patients with immunoglobulin deficiencies. They reported a case of LIP in a patient with agammaglobulinemia whose disease course rapidly progressed during a period of severe immunoglobulin deficiency. No circulating anti-lung antibodies were detected in her serum and her T-cell function was intact (7). Thus, they suggest that LIP may be the result of a T-cell-mediated mechanism (7). Findings in other studies support this hypothesis (5,11). Kohler and associates observed that 92% of the infiltrating lymphocytes were of T-cell origin in a woman who developed LIP associated with hypogammaglobulinemia (11). A predominance of proliferating CD9 cytotoxic/suppressor T-lymphocytes has been demonstrated in the lymphoid infiltrates of HIV patients with LIP (28) and some have noticed that the severity of LIP diminishes in HIV patients as their T cell counts decrease (12).
Lymphocytic interstitial pneumonia (LIP) remains poorly understood and there is much speculation about its etiology. Some propose that LIP may not be a distinct entity but, instead, a histopathologic manifestation that is common to a variety of immunologic conditions.
Contributed by Sonya Arnold, MD and Susan Hasegawa, MD, PhD