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Lymphoid Interstitial Pneumonia*: A Narrative Review FREE TO VIEW

Jeffrey J. Swigris, DO; Gerald J. Berry, MD; Thomas A. Raffin, MD, FCCP; Ware G. Kuschner, MD, FCCP
Author and Funding Information

*From the Division of Pulmonary and Critical Care Medicine (Drs. Swigris and Raffin), Stanford University, Stanford, CA; the Department of Pathology (Dr. Berry), Stanford University, Stanford, CA; and Veterans Affairs Palo Alto Health Care System (Dr. Kuschner), Palo Alto, CA.

Correspondence to: Jeffrey J. Swigris, DO, Stanford University Medical Center, Division of Pulmonary and Critical Care Medicine, 300 Pasteur Dr, Stanford, CA 94305-5236, e-mail: jjswig@pol.net



Chest. 2002;122(6):2150-2164. doi:10.1378/chest.122.6.2150
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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.

Figures in this Article

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.

Lymphoid tissue is uncommon in normal adult human lungs,1but 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.3These cells and other “preactivated” lymphocytes that reside alongside the alveolar lumen act as a kind of “lymphoid first defense” against inhaled antigen.4The mechanism by which circulating lymphoid cells initially populate these areas involves the contact of cell surface “homing receptors,”5 such as integrins, onto specific intrapulmonary vascular adhesion molecules,4 such as addressins on postcapillary venular endothelial cells or high endothelial venules.6Approximately 60% of lung lymphoid cells are B cells, and the rest are T lymphocytes.7In total, the constellation of unencapsulated lymphoid follicles, cellular collections, and loosely distributed mucosal lymphocytes constitute the bronchus-associated lymphoid tissue (BALT) or “pulmonary microtonsils.” Some investigators have placed the lymphoid aggregates found along the pleura and septae within this category, although these sites lack an epithelial component. BALT is more frequently and easily identified in neonates and infants than adults.8 BALT can remain as these simple collections of cells sparsely populating areas of bronchi, or it can be driven to dense proliferation encompassing entire airway walls and/or the lung interstitium. In such states, where BALT activity is stimulated, distinct lymphoid follicles with germinal centers are formed and become increasingly conspicuous.

BALT plays an essential role in the prevention of infection by inhaled microorganisms, by serving as the pulmonary site for secondary lymphoid differentiation, where naïve lymphocytes initially contact inhaled antigen to become antigen-specific memory or immune-effector cells.4 Once primed by antigen, memory cells circulate throughout the BALT compartment and the remaining lung parenchyma, awaiting exposure to the same provoking antigen.4 The complex interaction of lymphocytes with fibroblasts, dendritic cells, epithelial cells, and macrophagic cells requires various types of lymphocytes, including antigen-reactive, effector, and regulatory B-cell and T-cell lymphocytes.9

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),10but increased numbers of cells with surface microvilli.11The 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 formerly known as the “pulmonary sump,”12 an environment tailored to inhaled antigen-host immune interactions.

Inhaled antigens are most likely to be deposited on and adhere to mucosa at sites of airway branching and, not surprisingly, where BALT is most dense. The reason for the deposition in these areas is twofold: first, because of their mid-lumen position impaction is more likely to occur at airway branch points; and secondly, the unique airway cell surface in these areas is ideal for antigen adherence and absorption. In addition to these functions, the lymphoepithelium takes part in antigen transport and processing.13 It promotes antigen contact with antigen-presenting cells and then allows their transport across the epithelial surface to BALT.4 Interestingly, despite its integral role in pulmonary immune surveillance, BALT does not express the secretory component of IgA and differs from other mucosa-associated lymphoid tissues such as those in the GI tract (gut-associated lymphoid tissue).14

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 lymphocytes undergo clonal expansion.4 Local interstitial lymphocytes respond similarly once antigen is presented by antigen-presenting cells, such as interdigitating and follicular dendritic cells and macrophages.4 In the effector phase, T cells and B cells migrate into areas of ongoing inflammation or infection,1618 populate surrounding BALT compartments, and proliferate along with locally activated cells.10 Lung high endothelial venules help traffic in memory T cells,19 similarly to how circulating naïve lymphoid cells are initially recruited into the BALT compartment, in a process utilizing numerous lymphocyte (including leukocyte function-associated antigen 1 and integrins4) and endothelial ligands (including vascular cell adhesion molecule 120and others21). Cytokines released from active, proliferating cells induce subpopulations of lymphocytes to enlist either immune-effector (eg, cytotoxicity, Ig synthesis) or immune-modulator functions. Finally, circulating monocytes and blood lymphocytes are recruited into the milieu to further heighten the immune response.

It is the extent of immune activation and nature of the lymphoid proliferation, which results in a continuum of morphologic patterns, from localized benign hyperplasia to diffuse malignant neoplasms. Localized or nodular lymphoid proliferations in the lung include intrapulmonary lymph nodes, pulmonary hyalinizing granuloma, plasma cell granuloma-histiocytoma complex (inflammatory myofibroblastic tumor), Castleman disease, nodular amyloidosis/light-chain deposition disease, and nodular lymphoid hyperplasia (pseudolymphoma).22 LIP is a manifestation of benign diffuse lymphoid proliferation in the lung.

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, or further still, a malignant lymphoma? Multiple factors, including unique host susceptibility and host immune dysregulation, are likely involved.

Presently, the entire continuum of small lymphocytic proliferations in the lung is thought to arise from BALT.10,22 Conventional terminologies have provided suitable pathologic descriptions of these proliferations, but have failed to capture the essential feature of BALT as their tissue origin. New terminology based on the extent and location of lymphoid proliferation, with emphasis on BALT as the source, has been proposed19 and widely (though not universally) accepted.1,10,22 The spectrum of acquired benign diffuse proliferations of BALT now includes follicular bronchitis/bronchiolitis (FBB), diffuse lymphoid hyperplasia, and 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.25In the first published study of LIP after its initial description in 1966, Liebow and Carrington26 suggested many possibilities for these stimuli, including viral agents, either by their direct action on lungs or by their inducing failure in lung immune surveillance mechanisms. Since then, studies have attempted to delineate the association between LIP and viral infection, but inconsistencies have precluded the establishment of a well-defined relationship.

Epstein-Barr Virus:

Epstein-Barr virus (EBV) DNA has been found in the lung tissue specimens of some, but not all,27patients with LIP. For example, Barberà et al28detected EBV in open-lung biopsy specimens in 9 of 14 patients with LIP using in situ hybridization. Using the same method, another study detected EBV DNA in 80% of lung specimens from HIV-positive children with LIP. Some of these patients also had serologic evidence of acute EBV infection.29 Kaan et al30showed concurrently increased levels of EBV latent membrane protein 1, and the human apoptosis-inhibiting proto-oncogene bcl-2 in the lungs of patients with LIP. EBV latent membrane protein 1 up-regulates bcl-2, and high levels of bcl-2, which confer a survival advantage for lymphocytes in other lymphoproliferative disorders, could enhance tissue lymphocyte accumulation and survival in LIP as well. Kramer et al31 found significantly higher levels of anti-EBV antibodies (indicating primary or reactivated EBV infection) in HIV-positive adults with LIP compared to HIV-positive adults without LIP. Similar findings have also been found in many HIV-positive children with LIP.22,39

These data suggest EBV infection plays a role in some cases of LIP, but not all. Even in instances where EBV antigen or antibody is found in the lung, there are likely other adjunctive mechanisms, including a dysregulated host immune system, driving or allowing cellular proliferation.

HIV:

HIV antigen and antibody have been found in BAL and lung tissue specimens of some HIV-positive patients with LIP.3334 Chayt et al35 reported a significantly increased number of cells expressing human T-lymphotropic virus (HTLV) type III RNA in HIV-positive patients with LIP compared to HIV-positive patients with lung pathology other than LIP. Many of these cells were lymphocytes, but those of the macrophage-monocyte lineage also labeled positively. They concluded that each infected cell housed from 30 to 50 copies of HTLV-III (HIV) RNA.

HIV can induce proliferation of BALT in vitro,3637 and animal data convincingly display a relationship between HIV and LIP. Transgenically infected mice, expressing entire HIV-1 coding sequences in their CD4+ T lymphocytes and other cells, acquire many characteristic pathologic manifestations of HIV infection, including the lung lesions of LIP.38

It appears that a transient lymphocytic alveolitis may develop in every HIV-positive patient group.39 Agostini et al4 identified a model of lung immune response to HIV, which may, in part, explain the progressive evolution of LIP in some of these patients. After infection with HIV, it appears alveolar macrophages recruit CD8+ T cells into the lung from secondary lymphoid tissues.40These cells have a number of highly specialized functions, including lysis of certain HIV-infected cells.41Coincident with HIV disease progression is a complex series of immune cellular events favoring viral replication.42 For example, as interactions with antigen presenting cells ensue, intrapulmonary CD8+ T cells, themselves, may become infected with HIV, thus losing their cytotoxic ability.40 Additionally, certain cytokines released in response to HIV have paradoxical effects of promoting viral replication and down-regulating cytotoxic T lymphocytes.39 In response, activated alveolar macrophages recruit and activate more immunocompetent cells to combat the enlarging antigen load, thus increasing the density of the cellular infiltrate.

Simultaneous infection with EBV and HIV may amplify the risk of development of LIP. B lymphocytes infected with EBV are very susceptible to HIV infection in vitro and could enhance intrapulmonary replication of HIV. This would result in further interstitial lymphocyte proliferation via mechanisms explained above.43

Evidence to support the association of LIP with viral infections other than EBV or HIV comes from a Japanese study in which five of six patients with LIP tested seropositive for antibodies to HTLV-1. No patients in the study had antibodies to HIV or EBV.44

Underlying Conditions or Diseases

LIP is often seen in conjunction with systemic diseases, most notably HIV infection (or AIDS) and Sjögren syndrome,45although some cases remain idiopathic. Associations with common variable immunodeficiency4647 have been reported and LIP can be a late complication of allogeneic bone marrow transplantation, occurring between 200 days and 400 days after transplant.4849 There is a case report of a 10-year-old girl with cough and dyspnea, in which the lung biopsy revealed both LIP and pulmonary alveolar microlithiasis.50There are also reports of LIP occurring in the setting of Legionella pneumonia,51diphenylhydantoin use,52and pulmonary alveolar proteinosis.53

Autoimmune Diseases:

One of the most common (25% of LIP cases) associations of LIP is with Sjögren syndrome; 1% of Sjögren patients acquire LIP during the course of their disease.24,54As shown in Table 1 , LIP occurs in the setting of other autoimmune diseases, including systemic lupus erythematosus,57 rheumatoid arthritis, juvenile rheumatoid arthritis,58 autoimmune thyroiditis,26 myasthenia gravis,26,59 hemolytic26 and pernicious60anemia, the autoerythrocyte sensitization syndrome,61chronic active hepatitis,6263 celiac sprue,64 and primary biliary cirrhosis.24,62

HIV:

HIV infection represents another common association with LIP. Many believe LIP represents a specific lung reaction to HIV.35,6566 Why only some HIV-infected patients acquire hyperplasia of BALT, such as FBB (which has a propensity to occur in similar clinical settings as LIP) or LIP, is unknown. LIP is particularly common in HIV-infected children, wherein 16 to 50% of HIV-infected children acquire it, most often in the second or third year of life.6768 In this group, LIP is strongly associated with progression to AIDS, and has been considered an AIDS-defining illness in those < 13 years old since 1987.69LIP is listed in clinical category B according to the current HIV classification system for this age group.70

In HIV-positive adults, a nonspecific interstitial pneumonitis is much more common than LIP. LIP still occurs, albeit far less frequently than in the HIV-positive pediatric population.7173 Early reports of adult HIV-positive LIP showed it occurs predominantly in African-Caribbean or African-American population.34,7475 The clinical and radiologic findings are less specific than in children, and infectious etiologies must be excluded. A thoracoscopic lung biopsy is often required for this purpose.

Diffuse Infiltrative Lymphocytosis Syndrome:

A subset of HIV-positive patients have a unique sicca syndrome with increased circulating CD8+ cells, CD8+ T cells infiltrating tissues diffusely, parotid enlargement, and lymphadenopathy, which Itescu et al76named diffuse infiltrative lymphocytosis syndrome (DILS). In one study of 523 HIV-positive outpatients, the prevalence of DILS was between 3% and 4% and even higher among African-American patients. Nearly 50% of patients with DILS acquire LIP.7779

Similarities between DILS and Sjögren syndrome include xerostomia, xerophthalmia, lymphocytic infiltration of the salivary glands, and a propensity to acquire LIP. Key discriminating features include the following: the extraglandular manifestations of DILS are caused by CD8+ rather than CD4+ T-lymphocyte infiltrates, the low frequency of autoantibodies in DILS (ie, anti-Ro/SS-A and anti-La/SS-B antibodies), the strong association with human leukocyte antigen (HLA)-DR5, and HIV positivity.76,80

Having HLA-DR5 confers a relative risk of 16.9 times for DILS in HIV-positive black patients, while this association is lacking in HIV-positive white patients.76However, there is an increased frequency of HLA-DRw6 or HLA-DR7 in white patients with DILS. One study showed an increased incidence of DILS in patients who acquire HIV by male-to-male transmission.77

Like the lung in HIV-positive LIP, the extrapulmonary lymphocytic infiltration of DILS is thought to be a host immune response; HIV antigen is fueled, genetically determined,81and modulated by the major histocompatibility complex (MHC).82This is, in part, supported by the finding that some circulating83 and intrapulmonary41 CD8+ lymphocytes are cytotoxic to HIV-infected host cells, and are able to directly suppress viral replication in a process utilizing MHC surface markers.79,84

The lymphocytic infiltrates of DILS affect different organs including the GI mucosa, liver and portal triads, and kidneys, possibly inducing renal insufficiency and type 4 renal tubular acidosis. Other sites of involvement are the CNS, causing cranial neuropathies, and lymphocytic meningitis.8586 Some patients with DILS and LIP respond to treatment with corticosteroids or other immunosuppressive agents. Although antiretroviral therapy is proven beneficial, it appears that patients with DILS (including those with LIP) have an AIDS-free survival advantage, compared to HIV-positive patients without DILS, independent of whether antiretroviral agents are instituted.77,80 Two possible explanations are (1) the ability of infiltrating cytotoxic CD8+ cells to lower antigen burden; and (2) the possibility that certain MHC alleles, such as DRB1*1102, which encodes for DR5, or DRB1*1301, which encodes for DR6, play roles in a process that suppresses viral replication and delays the emergence of cytopathic HIV strains.87

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 sweats, and weight loss are less common. The mean time from presentation to diagnosis can exceed 15 months.54

Pediatric patients with LIP usually present in their second or third year with lung infiltrates, respiratory distress, and failure to thrive.15 Some symptoms, like bronchospasm and cough, may be present before any detectable radiographic abnormality.89

Lung auscultation often reveals bibasilar crackles.26 Clubbing is usually absent.24,26,54 Extrapulmonary lymphatic involvement, including peripheral or mediastinal lymphadenopathy or splenomegaly, is not common in LIP (except in cases of DILS) and suggests alternative diagnostic considerations.24,26 Pulmonary function studies usually show a restrictive ventilatory defect with a decreased carbon monoxide diffusing capacity and variable degrees of hypoxemia.24,54

Approximately 80% of patients with LIP have serum dysproteinemias, most commonly polyclonal hypergammaglobulimia.24,26,62 The significance of this finding is not known. In their original case series of 18 patients, Liebow and Carrington26 reported 12 patients with hypergammaglobulinemia and 5 patients with hypogammaglobulinemia.

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 (95%), diffuse (64%), patchy (23%), and peripheral (14%) patterns. Centrilobular nodules were also observed in 100% of cases, subpleural nodules in 86%, patchy bronchovascular bundle thickening in 86%, interlobular septal thickening in 82%, and 1- to 30-mm cysts in 68%. In comparing CT findings of patients with LIP to those of patients with lymphoma, Honda et al92found cysts in 82% of patients with LIP, but in only 2% of patients with lymphoma. Airspace disease, large nodules, and pleural effusions were rare in their patients with LIP. Other studies have confirmed the high frequency of cysts in LIP.9394 Ichikawa et al95noted cysts of LIP primarily deep within the lung parenchyma throughout the mid-lung zones, in contrast to the pleural-based, basilar zones in usual interstitial pneumonia. They postulate the cysts in LIP result from the lymphocytic infiltrate compressing bronchioles, causing stenosis or obstruction and subsequent postobstructive bronchiolar ectasia. Diffuse bronchiectasis, with all its classic CT features, is an increasingly reported finding in HIV-positive children with LIP.9697

Chest Radiography

Although not specific for LIP, the chest radiograph (CXR) is classically described as having bilateral, predominantly lower zone, reticular or reticulonodular opacities (Fig 3 ). While this pattern may be observed in other entities, such as Pneumocystis carinii pneumonia, miliary tuberculosis, or cytomegalovirus pneumonitis, a distinguishing feature of the infiltrates of LIP is their indolence, chronicity, and lack of response to treatment that would be expected to resolve other pulmonary processes.66 Coarse reticulonodular and more consolidative opacities can occur, but pleural effusions are rare.

Oldham et al98 reviewed the CXRs of 14 adult and 2 pediatric HIV-positive patients with LIP. They classified the radiographs into three categories based on severity: a type 1 LIP CXR had reticular or finely reticulonodular interstitial opacities with nodules < 3 mm; type 2 CXRs had coarse reticulonodular interstitial opacities with nodules between 3 mm and 5 mm; and type 3 LIP CXRs had findings of either type 1 or 2 plus at least one area of patchy alveolar opacity. A fourth radiographic pattern, focal alveolar consolidation resembling pneumonia, has recently been added to the original three.66 Although small, their study found a statistically significant (p < 0.001) increased mean survival in patients with a type 3 CXR (19 months) compared to a type 1 CXR (7 months). Thus, they equated more severe infiltrates on CXR with a stronger immune system (ie, less immunosuppression) and the ability to mount a more vigorous response to HIV. Laboratory data to support these findings (eg, increased CD4 counts in those with type 3 CXR compared to type 1 CXR) were not provided, and there were not enough patients with type 2 CXRs to draw conclusions about that group. In pediatric HIV-positive LIP, Prosper and colleagues,99validated the correlation of CXR infiltrate resolution with increasing severity of immunosuppression and declining CD4 lymphocyte counts. One patient was able to be weaned off oral glucocorticoids, and had clearing of her CXR as her CD4 count decreased from 418 to < 200 cells per microliter. Accordingly, the consensus has been that cases of HIV-positive LIP, in which radiographic resolution occurs in the absence of antiretroviral or corticosteroid therapy, should be perceived as a herald of worsening immunosuppression. A more recent retrospective analysis of 20 HIV-positive children with LIP has emphasized that spontaneous clinical and radiographic resolution without immune deterioration also occurs.100 Of 13 children with complete CXR resolution, CD4 counts remained unchanged from baseline in 11 children. The two patients with significant reductions in CD4 counts corresponding to improvements in their CXR were in clinically stable condition, and their CD4 counts increased over the following year without reoccurrence of LIP.

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 levels.26 Noncaseating granulomas are sometimes observed, but are loosely arranged in contrast to the “hard” granulomas of sarcoidosis.22 Reactive lymphoid follicles are found along the peribronchiolar regions in the majority of cases often with infiltration of lymphocytes into the bronchiolar epithelium.62 Interstitial fibrosis and honeycomb change are reported in advanced cases.54,101 While the predominant changes are centered on the pulmonary interstitium, secondary findings within alveolar airspaces can include collections of proteinaceous fluid, mononuclear inflammatory cells, foamy macrophages, or giant cells (Fig 5 ).

The interstitial lymphoid cells are mainly T cells and polytypic plasma cells, whereas polyclonal B cells are located in peribronchial germinal centers.1,10,62,102 The cells reside and also proliferate in these respective areas.19 This cellular organization, identical to that seen in hyperplastic peripheral lymph nodes, suggests the LIP lung behaves as a giant lymph organ.19,102 Similar cellular features have also been seen in the salivary glands of patients with Sjögren syndrome.26

Reactive lymphoid follicles are seen in both LIP and FBB, and the morphologic distinction is sometimes difficult62 and often subjective. As mentioned previously, both can be seen in similar clinical settings including connective tissue disorders, drug reactions and immunodeficiency states. Like Katzenstein,22 we recognize infiltrates confined to the peribronchiolar tissues as FBB and require diffuse expansion of alveolar septa for the diagnosis of LIP.

There are subtle differences in the immunophenotypic patterns of LIP in HIV-negative vs HIV-positive patients. In HIV-associated LIP, CD8+ T cells predominate,81,103 whereas in HIV-negative patients B cells are more numerous (in peribronchiolar areas and lymphoid follicles) and T cells are confined to the alveolar interstitium and areas surrounding lymphoid follicles. Further, bronchiolitis obliterans organizing pneumonia is rarely, if ever, present in cases of LIP,22,26 but Travis et al71 showed foci of proliferative obliterative bronchiolitis in one HIV-positive patient with LIP.

The histopathologic differential diagnosis of LIP includes a variety of infectious, inflammatory, and neoplastic processes (Table 2 ). In immunocompromised patients, histochemical stains (eg, Gomori-methenamine silver) must exclude pneumonitis such as P carinii. Viral pneumonia can also mimic LIP, including EBV-associated infections such as infectious mononucleosis or posttransplant lymphoproliferative disorders. Like LIP, the histopathologic findings in hypersensitivity pneumonitis (HP) [or extrinsic allergic alveolitis] include mononuclear bronchiolitis, cellular interstitial pneumonitis, and poorly formed granulomas (Fig 6 ). In general, HP is patchy in distribution and lacks the intense interstitial infiltrates of LIP. In some cases of HP, the inflammation can be prominent and the distinction between these entities may require the clinical exclusion of inhaled antigens and drugs. The cellular variant of nonspecific interstitial pneumonia demonstrates a mild-to-moderate interstitial expansion by lymphocytic or lymphocytoplasmic cells and not the dense infiltrates of LIP. It should be recognized that nonspecific interstitial pneumonia and LIP represent lesions along a morphologic spectrum and that some overlap can exist.

LIP must be distinguished from pulmonary involvement by low-grade malignant lymphoproliferative diseases, such as small lymphocytic lymphoma/chronic lymphocytic leukemia, lymphoplasmacytoid lymphoma, mantle cell lymphoma, and extranodal marginal zone lymphoma of MALT type.104Diagnostic features suggesting lymphomatous involvement include a monotonous population of lymphoid cells centered on pulmonary lymphatics in the bronchovascular bundles, subpleural and interlobular septa, pleural infiltration including parietal pleural fibroadipose tissues, the presence of eosinophilic intranuclear inclusions within plasmacytoid cells indicating Ig-secreting cells producing monoclonal proteins (called Dutcher bodies) and the formation of parenchymal nodules (Fig 7 ).105 Reactive germinal centers may be observed in both LIP and pulmonary low-grade lymphomas. Paraffin section immunohistochemical molecular techniques are currently available that allow accurate classification of malignant lymphoproliferative disorders of the lung.106More than 80% of primary pulmonary lymphomas are of the extranodal marginal zone type (called MALTomas). They usually present as single or multiple parenchymal consolidations centered on lymphatics, but can occasionally show a prominent interstitial distribution. Unlike small lymphocytic lymphoma/chronic lymphocytic leukemia that shows mature-appearing small lymphocytes, the composition in MALToma can include centrocyte-like cells, monocytoid cells, and plasmacytoid cells. Demonstration of light chain restriction by immunohistochemistry or flow cytometry is observed in > 50% of cases. The application of antibody panels allows discrimination of MALToma from LIP and from the other malignant lymphomas. Extranodal marginal zone lymphoma expresses B-cell–associated antigens CD20+, CD19+, and CD79a+, and is in most cases CD5-, CD10-, CD23-, CD43+/-, cyclin D1-, and BCL2-. This immunophenotypic profile distinguishes them from small lymphocytic lymphoma/chronic lymphocytic leukemia (CD20weak+, CD19+, CD79a+, CD5+, CD23+, CD43+), mantle zone lymphoma (CD5+, CD10-, CD23-, CD43+, cyclin D1+, BCL2+), and small cleaved cell lymphoma (CD20+, CD19+, CD79a+, CD10+, BCL2+).107

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 invasive procedures.68 In any case, when a histopathologic diagnosis of LIP is made, an investigation for potential associated conditions should be performed.

Controlled treatment trials have not been reported, and current therapeutic regimens are based largely on anecdotal experience. In the majority of published reports, corticosteroids have been the primary therapy, but other immunosuppressive agents, such as cyclophosphamide and chlorambucil, have been used.24 The results have been variable. Some patients improve without therapy while others progress to advanced interstitial fibrosis despite immunosuppression. Schwarz109 recommends a regimen similar to one recommended for the treatment of idiopathic bronchiolitis obliterans organizing pneumonia; prednisone, 0.75 to 1.0 mg/kg/d (based on the patient’s ideal weight and not to exceed 100 mg/d), is instituted for 8 to 12 weeks or until stabilization. Once the patient is in clinically stable condition, the dose is slowly tapered to 0.25 mg/kg/d and kept at that dose for another 6 to 12 weeks. Although the data are somewhat dated, approximately 50 to 60% of patients have responded to corticosteroids with symptomatic or radiographic stabilization or improvement.26 Koss et al54 noted that 4 of 13 patients treated with corticosteroids had complete clinical resolution after a mean follow-up period of 59 months. Over 82 months, four other patients in that series treated with corticosteroids remained in clinically and radiographically stable condition.

Single and multidrug antiretroviral therapy has resulted in clinical and radiographic resolution of LIP in some HIV-positive patients.110Newer approaches have been reported,111 including the successful treatment of LIP in a 35-year-old HIV-positive man using a three-nucleoside analog regimen. There was a marked decline in viral load, increase in CD4 count, and both radiographic and clinical resolution of pulmonary parenchymal disease.

As in the case with therapy, prognosis is variable and often unpredictable from clinical, morphologic, and radiographic parameters.26,54 Stabilization or resolution of disease is reported in some patients, but in others there is progressive decline in pulmonary function and development of honeycomb lung. In general, death occurs in approximately 33 to 50% of patients within 5 years of diagnosis.26,62 In one published series, 5 of 13 patients treated with corticosteroids died after a mean of only 8.6 months from the time of diagnosis.24 This may in part be due to the older average age of this group of patients. Among the survivors, two patients had complete radiographic resolution of disease, four patients had mild improvement, and two patients remained clinically and radiographically unchanged at a median follow-up of 44 months. Another series reported similar findings with 5 of 13 patients dying while undergoing treatment with corticosteroids.54 Of the remaining eight patients in that series, four patients had dramatic improvement and four patients had stabilization of LIP.

Most patients die of infectious complications related to immunosuppression, progressive pulmonary fibrosis, or transformation to malignant lymphoma.112113 In the past, LIP had been reported to progress to malignant lymphoma in up to 30% of cases. In retrospect, many of these cases were reclassified by immunohistochemical or molecular techniques as malignant lymphoma from the outset and were not LIP.104,114 The risk of transformation to malignant lymphoma is not known but is likely infrequent. A more recent and realistic estimate is closer to 5% of patients with LIP acquire malignant, low-grade, B-cell lymphoma.10,25,54 Reports of survival in children with HIV and LIP have varied. One study showed a significantly decreased mean survival of 33 months compared to HIV-positive children without LIP,68,115while other reports indicate a substantially better prognosis for these children compared to HIV-positive children with other AIDS-defining illnesses.116118 Mortality in HIV-positive adults is not adversely affected by LIP and, as previously discussed, the subset of patients with LIP and DILS live longer than HIV-positive adults without LIP.80

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 on high-resolution CT in a patient with Sjögren syndrome, should raise suspicion for the diagnosis. The pathogenesis of LIP is poorly understood. Some suggest viral infection may play an integral role. There has been little progress in the management of LIP and much about its cause and prognosis remains to be elucidated.

Abbreviations: BALT = bronchus-associated lymphoid tissue; CXR = chest radiograph; DILS = diffuse infiltrative lymphocytosis syndrome; EBV = Epstein-Barr virus; FBB = follicular bronchitis/bronchiolitis; HLA = human leukocyte antigen; HP = hypersensitivity pneumonitis; HTLV = human T-lymphotropic virus; LIP = lymphoid interstitial pneumonia; MALT = mucosal-associated lymphoid tissue; MHC = major histocompatibility complex

Figure Jump LinkFigure 1. Top: Low-power magnification of BALT in bronchiolar division point of normal ovine lung tissue. Unencapsulated collections of lymphoid cells including a small follicular structure are present (hematoxylin-eosin, original × 150). Bottom: High-power magnification showing intramucosal lymphocytes and aggregates within the lamina propria and submucosal tissues (hematoxylin-eosin, original × 400).Grahic Jump Location
Table Graphic Jump Location
Table 1. Diseases Associated With LIP
* 

Thirty-nine percent of LIP cases are associated with autoimmune diseases; 25% are found in patients with Sjögren syndrome. Between 1% and 2% of HIV-positive adults have LIP. The association of LIP with other diseases mentioned here are far less frequent. Percentages do not add up to 100 because study data are incomplete.

 

Compiled data from Yousem et al,23 Fishback and Koss,25 and Bakhos et al,53 which do not include data on HIV.

Figure Jump LinkFigure 2. High-resolution chest CT scans in two cases of LIP. Top: Multiple central and peripheral parenchymal and subpleural nodules of varying size and definition in a 36-year-old, HIV-negative woman. Bottom: Bilateral patchy ground-glass opacities and ill-defined centrilobular nodules affecting all lobes in a 41-year-old, HIV-positive man (courtesy of Ann Leung, MD).Grahic Jump Location
Figure Jump LinkFigure 3. CXR in LIP. Left: Posteroanterior CXR of a 39-year-old, HIV-negative woman, which demonstrates typical bilateral lower zone coarse reticulonodular opacities (courtesy of Paul Stark, MD). Right: Lateral view of the CXR from the same patient.Grahic Jump Location
Figure Jump LinkFigure 4. Low-power magnification of LIP showing expansion of alveolar interstitium by mononuclear inflammatory cell infiltrates. The alveolar airspaces display variable degrees of distortion and collapse (hematoxylin-eosin, original × 60). The infiltrates (insert) are composed of an admixture of cell types including small lymphocytes, plasma cells, and histiocytes (hematoxylin-eosin, original × 400).Grahic Jump Location
Figure Jump LinkFigure 5. LIP arising in an HIV-positive patient with an underlying connective tissue disorder. The airspaces display secondary changes ranging from compression by the interstitial infiltrates to proteinaceous fluid and macrophage collections (hematoxylin-eosin, original × 100). In this case the polyclonal septal infiltrates (insert) contain fewer plasma cells (hematoxylin-eosin, original × 400).Grahic Jump Location
Table Graphic Jump Location
Table 2. Histopathologic Features That Distinguish LIP, HP, and Small Lymphocytic/Lymphocytoplasmic Lymphoma/Extranodal Marginal Zone Lymphoma (MALToma)*
* 

WDL = small lymphocytic/lymphocytoplasmic lymphoma.

Figure Jump LinkFigure 6. The histopathologic features of HP share some features of LIP, but the infiltrates are patchy in distribution and generally less intense, as shown in this low-power view (hematoxylin-eosin, original × 100). The loosely formed granulomas of hypersensitivity pneumonitis (insert) are within the interstitial spaces (hematoxylin-eosin, original × 400).Grahic Jump Location
Figure Jump LinkFigure 7. Pulmonary involvement by small lymphocytic lymphoma showing the classic nodular collections of neoplastic cells along a lymphatic distribution (hematoxylin-eosin, original × 60). High-power magnification (insert) shows a monotonous population of small lymphocytes (hematoxylin-eosin, original × 400).Grahic Jump Location
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Figures

Figure Jump LinkFigure 1. Top: Low-power magnification of BALT in bronchiolar division point of normal ovine lung tissue. Unencapsulated collections of lymphoid cells including a small follicular structure are present (hematoxylin-eosin, original × 150). Bottom: High-power magnification showing intramucosal lymphocytes and aggregates within the lamina propria and submucosal tissues (hematoxylin-eosin, original × 400).Grahic Jump Location
Figure Jump LinkFigure 2. High-resolution chest CT scans in two cases of LIP. Top: Multiple central and peripheral parenchymal and subpleural nodules of varying size and definition in a 36-year-old, HIV-negative woman. Bottom: Bilateral patchy ground-glass opacities and ill-defined centrilobular nodules affecting all lobes in a 41-year-old, HIV-positive man (courtesy of Ann Leung, MD).Grahic Jump Location
Figure Jump LinkFigure 3. CXR in LIP. Left: Posteroanterior CXR of a 39-year-old, HIV-negative woman, which demonstrates typical bilateral lower zone coarse reticulonodular opacities (courtesy of Paul Stark, MD). Right: Lateral view of the CXR from the same patient.Grahic Jump Location
Figure Jump LinkFigure 4. Low-power magnification of LIP showing expansion of alveolar interstitium by mononuclear inflammatory cell infiltrates. The alveolar airspaces display variable degrees of distortion and collapse (hematoxylin-eosin, original × 60). The infiltrates (insert) are composed of an admixture of cell types including small lymphocytes, plasma cells, and histiocytes (hematoxylin-eosin, original × 400).Grahic Jump Location
Figure Jump LinkFigure 5. LIP arising in an HIV-positive patient with an underlying connective tissue disorder. The airspaces display secondary changes ranging from compression by the interstitial infiltrates to proteinaceous fluid and macrophage collections (hematoxylin-eosin, original × 100). In this case the polyclonal septal infiltrates (insert) contain fewer plasma cells (hematoxylin-eosin, original × 400).Grahic Jump Location
Figure Jump LinkFigure 6. The histopathologic features of HP share some features of LIP, but the infiltrates are patchy in distribution and generally less intense, as shown in this low-power view (hematoxylin-eosin, original × 100). The loosely formed granulomas of hypersensitivity pneumonitis (insert) are within the interstitial spaces (hematoxylin-eosin, original × 400).Grahic Jump Location
Figure Jump LinkFigure 7. Pulmonary involvement by small lymphocytic lymphoma showing the classic nodular collections of neoplastic cells along a lymphatic distribution (hematoxylin-eosin, original × 60). High-power magnification (insert) shows a monotonous population of small lymphocytes (hematoxylin-eosin, original × 400).Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Diseases Associated With LIP
* 

Thirty-nine percent of LIP cases are associated with autoimmune diseases; 25% are found in patients with Sjögren syndrome. Between 1% and 2% of HIV-positive adults have LIP. The association of LIP with other diseases mentioned here are far less frequent. Percentages do not add up to 100 because study data are incomplete.

 

Compiled data from Yousem et al,23 Fishback and Koss,25 and Bakhos et al,53 which do not include data on HIV.

Table Graphic Jump Location
Table 2. Histopathologic Features That Distinguish LIP, HP, and Small Lymphocytic/Lymphocytoplasmic Lymphoma/Extranodal Marginal Zone Lymphoma (MALToma)*
* 

WDL = small lymphocytic/lymphocytoplasmic lymphoma.

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