Chest
Volume 122, Issue 6, December 2002, Pages 2150-2164
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Lymphoid Interstitial Pneumonia: A Narrative Review

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Lymphoid interstitial pneumonia (LIP) is regarded as both a disease and a nonneoplastic, inflammatory pulmonary reaction to various external stimuli or systemic diseases. It is an uncommon condition with incidence and prevalence rates that are largely unknown. Liebow and Carrington originally classified LIP as an idiopathic interstitial pneumonia in 1969. Although LIP had since been removed from that category, the most recent consensus classification sponsored by the American Thoracic Society and the European Respiratory Society recognizes that some cases remain idiopathic in origin, and its clinical, radiographic, and pathologic features warrant the return of LIP to its original classification among the idiopathic interstitial pneumonias. LIP also belongs within a spectrum of pulmonary lymphoproliferative disorders that range in severity from benign, small, airway-centered cellular aggregates to malignant lymphomas. It is characterized by diffuse hyperplasia of bronchus-associated lymphoid tissue. The dominant microscopic feature of LIP is a diffuse, polyclonal lymphoid cell infiltrate surrounding airways and expanding the lung interstitium. Classically, LIP occurs in association with autoimmune diseases, most often Sjögren syndrome. This has led to consideration of an autoimmune etiology for LIP, but its pathogenesis remains poorly understood. Persons who are seropositive for HIV, and children in particular, are at increased risk of acquiring LIP. Some studies suggest causal roles for both HIV and Epstein-Barr virus. The incidence of LIP is approximately twofold greater in women than men. The average age at diagnosis is between 52 years and 56 years. Symptoms of progressive cough and dyspnea predominate. There is great variability in the clinical course of LIP, from resolution without treatment to progressive respiratory failure and death. Although LIP is often regarded as a steroid-responsive condition, and oral corticosteroids continue to be the mainstay of therapy, response is unpredictable. Approximately 33 to 50% of patients die within 5 years of diagnosis, and approximately 5% of cases of LIP transform to lymphoma.

Section snippets

Biology of Lung Lymphoid Tissue

This section reviews the distribution and function of mucosal-associated lymphoid tissue (MALT) in both healthy and antigen-challenged human lungs. It details the potential of the lung to formulate an immune response to inhaled and circulating antigen, and outlines how lymphoid interstitial pneumonia (LIP) is a morphologic manifestation of this response.

Lymphocytes

Lymphoid tissue is uncommon in normal adult human lungs,1 but is frequently observed in other mammalian groups such as rats, rabbits, and sheep (Fig 1). In nonsmoking adults, the majority of lung lymphoid tissue is contained in poorly organized aggregates predominantly located at bronchial divisions and adjacent to distal respiratory bronchioles.2 Additionally, small numbers of lymphoid cells are occasionally found scattered beneath and between cells composing bronchial walls.3 These cells and

Lymphoepithelium

Overlying and intricately associated with BALT is a specially adapted pseudostratified mucosal layer of attenuated epithelial cells with few ciliated and rare goblet cells (Fig 1),10 but increased numbers of cells with surface microvilli.11 The mucosa surface appears dome shaped and is infiltrated by T cells with CD8+ cells outnumbering CD4+ cells. This compilation of specialized epithelium, underlying BALT, and nearby efferent lymphatic vessels that drain to hilar nodes comprise what was

BALT Proliferations

The deposition of inhaled antigen on airway lymphoepithelium initiates T-cell and B-cell effector mechanisms that serve to prevent infection and also to protect the lung from excessive local parenchymal injury by down-regulating both nonspecific and immune-mediated inflammation.9 Antigen-presenting cells in the lung process inhaled antigens and induce naïve T cells to accumulate, develop antigen specificity, and proliferate.15 In the central processing phase, preactivated intra-alveolar

LIP as Diffuse BALT Hyperplasia

While this conceptual model of BALT hyperplasia provides a basis for characterizing and understanding an entire spectrum of lymphoid processes evolving in the lung,1 many questions remain. For example, why do these processes occur in some people and not others with similar clinical characteristics? Why does proliferation, at times, cease in its earliest stage23 as localized, airway-centered aggregates, while at other times there is progression to widespread interstitial processes such as LIP,

Autoimmune Mechanisms

Associations with numerous autoimmune phenomena have raised concern that LIP is itself an autoimmune disease24; however, theories on its pathogenesis have mainly focused on the role of viral infections.

Viral Infection

Because LIP occurs in varied clinical settings, including infection and immune system dysfunction, it is thought to represent a nonspecific response to multiple stimuli.25 In the first published study of LIP after its initial description in 1966, Liebow and Carrington26 suggested many

Clinical Features

The majority of patients with LIP are female. The onset of symptoms ranges from 40 to 70 years of age (mean age at diagnosis, 52 to 56 years). There is no race preponderance in children with LIP; however, the majority of HIV-positive adults with LIP are black, while most HIV-negative adults with LIP are white.24,26 Respiratory symptoms are present in the majority of patients at the time of diagnosis and include progressive dyspnea and dry cough.26,54,88 Systemic symptoms such as fever, night

Chest CT

As with other diffuse interstitial lung diseases, chest high-resolution CT is the radiographic procedure of choice to define the pulmonary opacities in LIP. CT is also able to confirm the absence of lymphadenopathy, as is the case in the majority of patients with LIP. Thickened bronchovascular bundles, nodules of varying sizes, and ground-glass opacities are common90 (Fig 2). Johkoh et al91 reported areas of ground-glass attenuation in 22 of 22 patients; the distribution showing bilateral

Pathologic Features

Microscopically, LIP is characterized by diffuse interstitial cellular infiltrates, which expand and widen interlobular and alveolar septae (Fig 4). The infiltrates are generally polymorphous, and are composed of an admixture of small mature lymphocytes, immunoblasts, plasma cells and histiocytes, including epithelioid and giant cell types. In the majority of cases, lymphocytes predominate over plasma cells. Cases with numerous plasma cells are associated with elevated serum gammaglobulin

Diagnosis, Treatment, and Prognosis

Although the lymphocytic infiltration of LIP can sometimes be observed on transbronchial biopsy specimens, the definitive diagnosis requires thoracoscopic or open-lung biopsy specimens.15,108 As previously discussed, immunohistochemical studies are required to establish the polyclonal nature of the infiltrate. An exception to this rule occurs in HIV-positive children; their radiographic pattern and symptoms are sufficiently distinctive that the diagnosis of LIP can be made confidently without

Conclusion

LIP is an interesting and complex polyclonal, inflammatory, lymphoid proliferation originating from hyperplasia of BALT, in which peribronchiolar and interstitial lymphocytes accumulate in response to various stimuli, including inhaled antigen. Although some cases remain idiopathic, LIP is usually found in association with one of several associated diseases or conditions. Features of progressive dyspnea and cough in the setting of bilateral reticulonodular CXR infiltrates, or thin-walled cysts

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