Lymphoid interstitial pneumonia

INTRODUCTION — 

Lymphoid interstitial pneumonia (LIP) is an uncommon form of interstitial lung disease in adults characterized histopathologically by lymphocytic, plasma cell, and other lymphoreticular cell infiltration of the interstitium and alveolar spaces [1,2]. First described in 1966 by Carrington and Liebow [3], LIP is one entity within a spectrum of lymphoproliferative disorders that can involve the lung. Many cases previously diagnosed as LIP are now considered cellular nonspecific interstitial pneumonia (NSIP) [4].

The etiology, clinical manifestations, diagnosis, and treatment of LIP will be reviewed here. The pathologic classification of idiopathic interstitial pneumonias and an approach to the evaluation and diagnosis of interstitial lung disease are discussed separately. (See "Idiopathic interstitial pneumonias: Classification and pathology" and "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)

The American Thoracic Society (ATS) and European Respiratory Society (ERS) statement on the classification of idiopathic interstitial pneumonias, as well as other ATS guidelines, can be accessed through the ATS website at www.thoracic.org/statements.

CLASSIFICATION — 

The lung is occasionally the primary organ of involvement in a variety of lymphoproliferative disorders [5]:

●Lymphoid interstitial pneumonia (LIP)

●Pseudolymphoma

●Lymphomatoid granulomatosis

●Angioimmunoblastic T cell lymphoma (angioimmunoblastic lymphadenopathy)

●Primary pulmonary lymphoma

LIP represents a benign polyclonal proliferation (usually of mature B or T cells) that can either diffusely involve the lung or be a focal process. Focal LIP is probably the same entity as pseudolymphoma of the lung, given the very similar histology and clinical outcomes of the two disorders [6]. Identifying the infiltrate as a monoclonal proliferation of lymphocytes implies a malignant population rather than LIP [1,5]. Other features of LIP may include type II cell hyperplasia, occasional noncaseating granulomas, and germinal centers [3].

ASSOCIATED DISEASES — 

The cause of lymphoid interstitial pneumonia (LIP) is unknown. It likely involves derangements in the immune system or manifestations of an underlying infection (especially viral). LIP is associated with multiple autoimmune and infectious diseases, although familial forms and isolated idiopathic cases also occur (table 1).

Most frequent associations — Among non-HIV-infected patients, the most common associated conditions are hypergammaglobulinemia, Sjögren's disease, other autoimmune conditions, and hypogammaglobulinemia with relative incidences of about 40, 30, 15, and 8 percent, respectively [1,7-9]. Among HIV-infected adults, LIP was an uncommon complication prior to the widespread use of antiretroviral therapy (ART); since then, it has become even less frequent.

In children, LIP is most frequently associated with perinatally acquired HIV, juvenile idiopathic arthritis, and a variety of inborn errors of immunity.

Idiopathic — Less than 20 percent of cases of LIP have no apparent underlying cause [9].

Rheumatic diseases — LIP is frequently associated with rheumatic diseases and processes associated with autoantibody production (especially those with dysproteinemias), including (among others) Sjögren's disease, rheumatoid arthritis, systemic lupus erythematosus, juvenile idiopathic arthritis, celiac sprue, myasthenia gravis, pernicious anemia, chronic active hepatitis, and biliary cirrhosis (table 1) [6,10-12]. LIP may precede or follow the diagnosis of the underlying process [6].

Sjögren's disease is associated with one-fourth of reported cases of LIP in adults, often with a marked monoclonal or polyclonal gammopathy. (See "Interstitial lung disease associated with Sjögren's disease: Clinical manifestations, evaluation, and diagnosis".)

Immunodeficiency/dysregulation — A form of lymphocytic interstitial pneumonitis, known as granulomatous and lymphocytic interstitial lung disease (GLILD), has been described in patients with common variable immunodeficiency (CVID) [13]. The etiology of GLILD is unknown, but it may be related to human herpes virus type 8 (HHV8) infection. On histopathology, follicular bronchiolitis may accompany GLILD. (See "Pulmonary complications of primary immunodeficiencies", section on 'Interstitial diseases'.)

In addition to CVID, GLILD has also been reported in patients with other immunodeficiencies, such as hypomorphic mutations in recombination-activating gene 1 (RAG1), haploinsufficiency of cytotoxic T lymphocyte antigen-4 (CTLA4), and deficiency in lipopolysaccharide responsive beige-like anchor protein (LRBA). LIP may also arise due to immune dysfunction caused by pathogenic variants in other genes, including STAT3 and GATA2. (See "Classification of diffuse lung disease (interstitial lung disease) in infants and children", section on 'Lymphoid interstitial pneumonia'.)

IgG4-related disease can also demonstrate an LIP pattern on histopathology. (See 'Differential diagnosis' below and "Clinical manifestations and diagnosis of IgG4-related disease", section on 'Other manifestations'.)

Viral infections — LIP has been frequently associated with viruses that lead to or result from immune dysregulation. Most notably, LIP has a highly increased incidence in persons infected with HIV, especially among children [14-16]. LIP occurs in 25 to 40 percent of children with untreated perinatally acquired HIV and usually presents in the second or third year of life. LIP is less common in adults with HIV infection, particularly in those treated with antiretroviral therapy. LIP can be seen in 27 to 59 percent of HIV-infected patients with diffuse infiltrative lymphocytosis syndrome (DILS), which usually presents with salivary gland enlargement and xerostomia [17]. (See "Evaluation of pulmonary symptoms in persons with HIV" and "Pediatric HIV infection: Epidemiology, clinical manifestations, and outcome".)

Human T-lymphotropic virus type I (HTLV-I), a retrovirus, has also been implicated in LIP in Japanese patients [18]. (See "Human T-lymphotropic virus type I: Virology, pathogenesis, and epidemiology".)

Improvement of LIP with antiretroviral therapy alone has led some to theorize that either HIV viral replication itself may be driving the proliferation of immune cells or that HIV-related immunosuppression has allowed another virus, such as Epstein-Barr virus (EBV) to promote lymphocyte proliferation [19,20]. In situ hybridization studies of biopsy specimens of patients with LIP (both with and without HIV) show a significant increase in the presence of the EBV genome compared to other chronic lung disease specimens [21]. Serologic evidence of recrudescent or primary EBV infection has been observed in children and adults with LIP [22,23].

Other — Rare cases of LIP have been reported in patients with use of the medication diphenylhydantoin, benign hypergammaglobulinemic purpura of Waldenström, pulmonary amyloidosis, and surfactant protein C deficiency [6].

CLINICAL MANIFESTATIONS

Symptoms — Fewer than 5 percent of patients are asymptomatic at presentation. Cough (71 percent of cases) and dyspnea (61 percent), slowly progressive over months to years (mean duration before diagnosis = 19 months), are the most common presenting symptoms of lymphoid interstitial pneumonia (LIP) [3,6,9].

Other symptoms and signs include:

●Weight loss (16 percent)

●Fevers (10 percent)

●Pleuritic chest pain (6 percent)

●Fatigue

●Arthralgias

In a case series from an HIV endemic setting, 32 patients with definite or probable LIP were described [24]. Definite LIP occurred most commonly (85 percent) in young female patients (median age 34 years) in the setting of a median CD4 count of 194 cells/mL. Among those with definite LIP, the predominant symptom was cough (90 percent), which was productive in 64 percent; mild to moderate dyspnea was present in 70 percent.

Physical examination — Examination of the chest reveals crackles in most patients. Digital clubbing is seen in 10 percent of cases, and cyanosis is found rarely. Other findings often depend upon another underlying disease process (especially Sjögren's disease) and include hepatosplenomegaly, lymphadenopathy, parotid gland enlargement, and arthritis [6]. (See "Clinical manifestations of Sjögren's disease: Extraglandular disease".)

In the case series of 32 adults with HIV-associated definite or probable LIP mentioned above, approximately 60 percent had bibasilar crackles and 20 percent had clubbing [24]. Other case reports have noted fever and weight loss [2,20,25-27].

EVALUATION — 

The presence of lymphoid interstitial pneumonia (LIP) is usually suspected in the patient with an associated rheumatic disorder (eg, Sjögren's disease) and characteristic radiographic findings (see 'Chest imaging' below) [28]. The evaluation of patients with LIP is similar to that of patients with other suspected interstitial lung diseases. Initial evaluation is focused on determining whether an underlying systemic process is the cause of the pulmonary abnormality. (See 'Associated diseases' above and "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)

Laboratory — In patients without known rheumatic disease who present with new onset of ILD, the evaluation follows that of interstitial lung disease (ILD) in general, which includes serologic testing (eg, antinuclear antibody, rheumatoid factor) and testing for HIV infection (algorithm 1). Additional serologic tests are based on the clinical features and results of initial testing. In patients with symptoms suggestive of Sjögren's disease, we also obtain anti-Ro/SSA and anti-La/SSB antibodies, quantitative immunoglobulin levels, and serum protein electrophoresis. Similarly, if rheumatoid arthritis is suspected, anti-cyclic citrullinated antibodies are obtained. (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Laboratory tests' and "Interstitial lung disease associated with Sjögren's disease: Clinical manifestations, evaluation, and diagnosis", section on 'Laboratory'.)

In adults who are HIV positive, the onset of LIP does not correlate with CD4 count, although LIP is more closely associated with immunodeficiency in children. (See "Pediatric HIV infection: Epidemiology, clinical manifestations, and outcome".)

Laboratory abnormalities in idiopathic LIP generally reflect the state of the underlying disease. Up to three-fourths of patients have a serum protein abnormality [1,6]. Polyclonal gammopathy is the most common dysproteinemia in this setting, but monoclonal gammopathy can also occasionally be seen. In children, hypogammaglobulinemia may be identified [6,29]. (See "Pulmonary complications of primary immunodeficiencies", section on 'Interstitial diseases'.)

Chest imaging — LIP has a varied radiographic appearance [30]; basilar reticular opacities or nodular densities may be seen on the chest radiograph (image 1). As the disease progresses, alveolar spaces become involved, and a mixed pattern of ground glass and consolidative opacities appears. Air bronchograms may be seen in larger, mass-like lesions. Nodular disease seems to be more common in patients with HIV [5,8].

High-resolution computed tomography (HRCT) should be obtained to establish the extent and location of lung involvement, define the hilar anatomy, and identify any pleural involvement. Ground-glass attenuation, centrilobular nodules, and interstitial thickening are frequently seen with a lower lobe predominance [31]. These findings are similar to those of nonspecific interstitial pneumonia (NSIP) [31,32]. Lung cysts occur in 68 to 82 percent of patients with LIP (image 1), whereas they are rare in NSIP and pulmonary lymphoma and can help distinguish LIP from these entities [10,31,33,34]. The cysts in LIP tend to be discrete and peribronchovascular in distribution [35].

Pleural thickening and effusions are rare in LIP, as are hilar and mediastinal lymphadenopathy. These findings may suggest an underlying malignant process.

Pulmonary function tests — Complete lung function testing (spirometry, lung volumes, diffusing capacity) and resting and exercise pulse oximetry are obtained in virtually all patients with suspected ILD.

In patients with LIP, pulmonary function testing characteristically shows reduced lung volumes (eg, forced vital capacity [FVC], total lung capacity [TLC]) and diffusing capacity (DLCO) without airflow obstruction. In one case series, the mean DLCO was 62 percent of predicted [9]. Marked hypoxemia can occur in advanced disease [36]. (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Pulmonary function testing'.)

Bronchoalveolar lavage — Bronchoalveolar lavage (BAL) may be performed in patients with ILD to exclude infection, specific occupational causes of ILD, chronic eosinophilic pneumonia, and malignancy (algorithm 1). (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Role of bronchoalveolar lavage' and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

BAL is less helpful in securing a diagnosis of LIP, as the BAL findings are not specific. The total BAL cell count is increased compared with normal; a BAL lymphocytosis of approximately 30 percent has been reported [9]. The proportion of B and T lymphocytes varies among studies [9,28,37]. BAL lymphocytosis is also seen in hypersensitivity pneumonitis, sarcoidosis, and chronic beryllium disease. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Lymphocytic BAL'.)

Lung biopsy — As the clinical features, radiographic appearance, and BAL findings are not specific for LIP, a definitive diagnosis requires a surgical lung biopsy [4,6]. Surgical lung biopsy via video-assisted thoracoscopic surgery (VATS) or thoracotomy is preferred over transbronchial biopsy as the small size of a transbronchial specimen is often insufficient for diagnosis. Transbronchial cryobiopsy is a less invasive diagnostic option in centers of expertise with this technique. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

PATHOLOGIC FINDINGS — 

The histopathology of lymphoid interstitial pneumonia (LIP) is characterized by an interstitial infiltrate of lymphocytes, plasma cells, and histiocytes (table 2) [1,4,38]. Germinal centers and multinucleated giant cells with noncaseating granulomas may also be found (picture 1A-C) [1]. According to the American Thoracic Society/European Respiratory Society (ATS/ERS) classification, the characteristic feature of LIP is extensive alveolar septal infiltration. However, the cellular infiltrate may sometimes appear along the bronchi and vessels (picture 2). This localization differentiates LIP from diffuse lymphoid hyperplasia, which predominantly affects areas of the interstitium other than alveolar septa (eg, bronchovascular bundles and interlobular septa) [4,31].

The histopathology of granulomatous and lymphocytic interstitial lung disease (GLILD), a variant of LIP that may develop in patients with common variable immunodeficiency (CVID), often shows both peribronchiolar and diffuse interstitial infiltration; more than 90 percent of patients will also have granulomas [13]. (See "Pulmonary complications of primary immunodeficiencies", section on 'Interstitial diseases'.)

Demonstration of the polyclonality of the infiltrates (usually B cells) distinguishes LIP from pulmonary lymphoma. T cell-predominant infiltrates have been reported in some patients with HIV, although no clear pattern of cell type is known [1,16,36]. Mutations in the noncoding regulatory (promoter) regions of B cell lymphoma 6 (BCL-6) gene have been identified in several pulmonary lymphoproliferative disorders, including mucosa-associated lymphoid tissue (MALT) lymphoma, HIV-related, Epstein-Barr virus (EBV)-related, and virus-negative lymphocytic interstitial pneumonia (LIP) [39]. (See "Diffuse large B cell lymphoma and other large B cell lymphomas: Presentation, diagnosis, and classification", section on 'BCL6 alterations' and "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

It is essential to establish the benign nature of the lesion. Features suggesting malignant transformation include lymphangitic or bronchovascular distribution, monoclonality, hilar or pleural involvement, bronchial wall infiltration, and loss of germinal center architecture [6,40].

DIAGNOSIS — 

The diagnosis of lymphoid interstitial pneumonia (LIP) is generally established by a lung biopsy that demonstrates extensive alveolar septal infiltration with lymphocytes, plasma cells, and histiocytes (table 2) [38]. Since LIP is a benign disorder, the lymphocytic infiltrate, usually B cells, must be polyclonal. (See 'Pathologic findings' above and "Interpretation of lung biopsy results in interstitial lung disease", section on 'Lymphoid interstitial pneumonia'.)

An exception to the need for a lung biopsy is in HIV-positive children, as the clinical presentation and radiographic findings are considered sufficiently diagnostic to make a lung biopsy unnecessary. (See "Pediatric HIV infection: Epidemiology, clinical manifestations, and outcome", section on 'Selected AIDS-defining conditions'.)

A presumptive diagnosis of LIP can also be made in patients with Sjögren’s disease who demonstrate classic imaging findings (thin-walled perivascular cysts and either ground-glass opacities or poorly defined centrilobular or subpleural nodules). (See "Interstitial lung disease associated with Sjögren's disease: Clinical manifestations, evaluation, and diagnosis", section on 'Lymphoid interstitial pneumonia'.)

Once the diagnosis of LIP is suspected (based on imaging or biopsy), the specific disease association should be identified (table 1). The patient’s medication list should be reviewed for the use of phenytoin. Valuable tests include the following (if not already performed):

●Serum protein electrophoresis (SPEP)

●Serum immunoglobulin (Ig)G4 level (consistent with IgG4-related disease if ≥2 times the upper limit of normal) (see "Clinical manifestations and diagnosis of IgG4-related disease")

●HIV-1/2 immunoassay (see "Screening and diagnostic testing for HIV infection in adults", section on 'Overview of available tests')

●Antinuclear antibody (ANA)

●Anti-Ro/SSA and anti-La/SSB antibodies (see "Diagnosis and classification of Sjögren's disease", section on 'Serologic and other laboratory testing')

●Rheumatoid factor

Granulomatous and lymphocytic interstitial lung disease (GLILD) is characterized by granulomatous and lymphoproliferative (eg, lymphoid interstitial pneumonia [LIP], follicular bronchiolitis) histopathologic patterns in the lung. GLILD occurs in the context of common variable immunodeficiency (CVID) or another primary immunodeficiency, such as hypomorphic mutations in recombination-activating gene 1 (RAG1), haploinsufficiency of cytotoxic T lymphocyte antigen-4 (CTLA4), and deficiency in lipopolysaccharide responsive beige-like anchor protein (LRBA). (See "Pulmonary complications of primary immunodeficiencies", section on 'Interstitial diseases' and "Classification of diffuse lung disease (interstitial lung disease) in infants and children", section on 'Lymphoid interstitial pneumonia'.)

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of lymphoid interstitial pneumonia (LIP) includes pseudolymphoma, lymphomatoid granulomatosis, follicular bronchiolitis, primary pulmonary lymphoma, bronchocentric granulomatosis, IgG4-related disease, hypersensitivity pneumonitis, and nonspecific interstitial pneumonia.

A clinical setting of underlying rheumatic disease (particularly Sjögren's disease), common variable immunodeficiency, or HIV infection all favor the diagnosis of LIP.

Features that help distinguish LIP from other disorders are discussed below:

●Lymphoma – On histology, lymphomas are characterized by monoclonality, lymphangitic or bronchovascular distribution, hilar or pleural involvement, bronchial wall infiltration, and loss of germinal center architecture. Antibody panels can also be used to differentiate lymphoma from LIP. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)", section on 'Immunophenotype'.)

●Pulmonary amyloidosis (AL type) – Pulmonary amyloidosis has been described in a case series of eight patients with primary Sjögren's disease who presented with cough and dyspnea [41]. The main CT findings were cysts and multiple nodules; no patients had reticular opacities, septal thickening, or consolidation. All patients had anti-SS-A/Ro and anti-SS-B/La antibodies. Amyloid can be confirmed by Congo red staining (showing green birefringence under polarized light) and immunohistochemistry of lung biopsy samples. Three of these patients also had mucosa-associated lymphoid tissue (MALT) lymphoma. (See "Interstitial lung disease associated with Sjögren's disease: Clinical manifestations, evaluation, and diagnosis", section on 'Pulmonary nodular amyloidosis'.)

●Hypersensitivity pneumonitis – The pathologic appearance of LIP and hypersensitivity pneumonitis is similar, although the latter tends to be more patchy and consistently associated with loose noncaseating granulomas [2]. Hypersensitivity pneumonitis is more likely in patients with a history of exposure to agents known to be associated with the disorder, and findings on HRCT are usually upper and mid-lung zone predominant [42]. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Epidemiology, causes, and pathogenesis".)

●Lymphomatoid granulomatosis and follicular bronchiolitis – Although similar clinically and with overlapping radiologic features, characteristic histologic patterns distinguish LIP from lymphomatoid granulomatosis and follicular bronchiolitis. (See "Pulmonary lymphomatoid granulomatosis" and "Overview of bronchiolar disorders in adults", section on 'Follicular bronchiolitis'.)

●IgG4-related disease – IgG4-related disease is associated with various patterns on HRCT, including rounded or diffuse ground-glass opacities and solid nodules [43]. In addition, sicca symptoms can be seen with both Sjögren's disease and IgG4-related disease, thus making it essential to exclude this diagnosis in patients with suspected LIP. In IgG4-related disease, the serum IgG4 level is elevated in approximately 85 percent of affected patients. Flow cytometry demonstrating elevation in blood plasmablasts also strongly suggests IgG4-related disease. The diagnosis is established by demonstration of IgG4 staining on histopathology. (See "Clinical manifestations and diagnosis of IgG4-related disease".)

●Pulmonary infections – In HIV-infected patients, infectious etiologies of diffuse pulmonary opacities (eg, Pneumocystis jirovecii pneumonia [PCP], cytomegalovirus, and mycobacteria) must be excluded. (See "Evaluation of pulmonary symptoms in persons with HIV" and "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV" and "Pediatric HIV infection: Epidemiology, clinical manifestations, and outcome".)

The differential diagnosis of granulomatous and lymphocytic interstitial lung disease (GLILD) includes sarcoidosis and hypersensitivity pneumonitis. However, sarcoidosis typically has normal or elevated serum immunoglobulin levels and may have a characteristic imaging pattern of bilateral symmetric hilar adenopathy, which is not typical of GLILD. Hypersensitivity pneumonitis is typically distinguished by normal immunoglobulin levels and a history of exposure to culprit antigens. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section on 'Diagnosis' and "Clinical manifestations and diagnosis of sarcoidosis", section on 'Diagnostic approach'.)

TREATMENT — 

Controlled clinical trials have not been reported for lymphoid interstitial pneumonia (LIP). Information on treatment comes from case reports and case series. The treatment of LIP differs depending on the severity of the patient's symptoms, the degree of functional impairment, and the presence or absence of an associated rheumatic disease, immunodeficiency, or HIV infection.

LIP in rheumatic disease — The treatment of patients with LIP complicating rheumatic disease (eg, Sjögren's disease, rheumatoid arthritis, systemic lupus erythematosus) is based on the severity of lung impairment, evidence of progression, and the treatment requirements of the underlying disease. Most patients with LIP associated with a rheumatic disease are symptomatic and have evidence of physiologic impairment. No clinical trials have been performed, but our experience suggests that such patients respond well to oral glucocorticoids, although some require an additional immunosuppressive agent.

Some patients will require treatment for extrapulmonary manifestations of their rheumatic disease, which may also treat their lung disease. Detailed discussions of the management of patients with specific rheumatic diseases are presented separately.

Sjögren’s:

●(See "Overview of the management and prognosis of Sjögren's disease".)

●(See "Interstitial lung disease associated with Sjögren's disease: Management and prognosis", section on 'Lymphoid interstitial pneumonia'.)

Rheumatoid arthritis:

●(See "General principles and overview of management of rheumatoid arthritis in adults".)

●(See "Systemic juvenile idiopathic arthritis: Treatment and prognosis".)

●(See "Interstitial lung disease in rheumatoid arthritis", section on 'Treatment'.)

Systemic lupus erythematosus:

●(See "Systemic lupus erythematosus in adults: Overview of the management and prognosis".)

●(See "Pulmonary manifestations of systemic lupus erythematosus in adults", section on 'Interstitial lung disease'.)

For most patients, the initial approach to therapy includes systemic glucocorticoids. Glucocorticoid-sparing immunosuppressants are appropriate for those who progress despite therapy, have side effects from therapy, or require prolonged treatment due to relapses.

●Initial regimen and taper – For symptomatic patients with either physiologic impairment at presentation or deterioration in lung function over time, we suggest initiating systemic glucocorticoid therapy. However, data are uncertain whether treatment alters the natural history of the disease [2,8,9]. We define physiologic impairment by a forced vital capacity (FVC) or diffusing capacity for carbon monoxide (DLCO) less than 70 percent of predicted (or z-score <-1.645) and deterioration in function by a decrease in FVC or DLCO by 10 percent or more.

Our initial regimen is oral prednisone (or the equivalent prednisolone dose) 0.25 to 0.5 mg/kg given once daily (based upon the patient's ideal body weight; not exceeding 60 mg/day). After 8 to 12 weeks, we evaluate response to therapy based on improvement in symptoms, radiographic appearance (ie, high resolution computed tomography [HRCT]), and physiologic parameters (ie, FVC, total lung capacity [TLC], DLCO). If the patient's condition is stable or improved, the dose is tapered (if necessary) over 6 to 8 weeks to 0.25 mg/kg daily. We typically maintain prednisone at that level for an additional 6 to 12 weeks and then taper further as tolerated.

In the most extensive reported series, 13 of 15 patients (three had idiopathic disease) were administered glucocorticoid therapy. Among the nine in whom the response could be evaluated, clinical improvement was noted in four, clinical stabilization in four, and disease progression in one. Median survival was approximately 12 years. Overall, about one-half appeared to respond with improvement or stabilization of disease [8,9].

●Duration of therapy – The proper length of therapy in patients who respond to treatment is unknown. We usually aim for a treatment course of at least six months to one year; discontinuing treatment prematurely is a relatively frequent cause of relapse in patients who have initially responded. Long-term treatment with low-dose therapy (less than 0.25 mg/kg per day) or a glucocorticoid-sparing agent may be required by a small number of patients. Alternate-day oral prednisone therapy is not recommended since no data are available to suggest that it is effective.

●Pneumocystis prophylaxis – We suggest Pneumocystis jirovecii pneumonia prophylaxis for any patient with LIP receiving moderate to high dose glucocorticoid (eg, prednisone 20 mg or more daily). (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

Management of other complications of chronic systemic glucocorticoids is discussed separately. (See "Major adverse effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)

●Refractory or persistent disease – About 20 percent of patients have progressive disease despite systemic glucocorticoid therapy. For these patients, those who experience side effects from the glucocorticoids, or those requiring long-term treatment using more than 5 to 10 mg/day of prednisone, we typically add another immunosuppressive agent. There is no clear consensus on the optimal agent to choose. However, several case reports and small patient series (usually including patients with rheumatic disease and heterogeneous associated diagnoses) have reported some success with azathioprine, cyclophosphamide, cyclosporine, or rituximab [2,9,44,45]. The use of these agents is described in the discussion of immunosuppressive therapy for nonspecific interstitial pneumonitis. (See "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Additional immunosuppressive drugs'.)

Idiopathic LIP — Most reported patients with idiopathic LIP have had significant respiratory symptoms or physiologic impairment at the time of diagnosis and will require therapy. For the occasional patient with idiopathic LIP who has minimal symptoms and mild disease (based on physiologic and radiographic studies), we suggest careful longitudinal clinical, functional, and radiological evaluation before drug treatment [2,9]. This approach is based on the observation that spontaneous remission is observed in a small percentage of such patients.

For symptomatic patients with physiologic impairment at presentation or deterioration in lung function over time, we suggest initiating systemic glucocorticoid therapy based on the experience with LIP associated with rheumatic disease. Some patients will also need an additional immunosuppressive agent [9,46]. (See 'LIP in rheumatic disease' above.)

GLILD in common variable immunodeficiency — Granulomatous and lymphocytic interstitial lung disease (GLILD) in the setting of common variable immunodeficiency can lead to progressive pulmonary fibrosis and respiratory failure if untreated. However, GLILD is often poorly responsive to glucocorticoid treatment, and the optimal treatment is unknown. Small numbers of patients with GLILD have been treated successfully with tumor necrosis factor-alpha antagonists, cyclosporine, or a combination of rituximab and an antimetabolite (either azathioprine or mycophenolate). The management of GLILD is discussed in more detail separately. (See 'Immunodeficiency/dysregulation' above and "Pulmonary complications of primary immunodeficiencies", section on 'Granulomatous and lymphocytic interstitial lung disease'.)

LIP in HIV infection — The approach to the management of LIP in HIV-infected patients varies based on the severity of disease and whether antiretroviral therapy (ART) is currently being administered.

●Patients not receiving ART – Among those who have not been previously treated with ART, we suggest initiating ART for symptomatic LIP, even though LIP is not technically an AIDS-defining illness [47,48]. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".) This is based on the following observations:

•Several case reports and a case series have described improvement in LIP after initiation of ART [20,48,49].

•The overall incidence of LIP is decreasing, which is temporally associated with the introduction of ART [50].

If ART therapy alone is inadequate, the addition of glucocorticoids may be effective [36,51,52]. We typically use the dosing regimen described above for LIP associated with rheumatic disease. However, the use of any agent that may lead to further immunosuppression in an already immunocompromised patient must be undertaken with caution and close surveillance.

●Patients currently receiving ART – Among HIV-infected patients who develop LIP or have progressive LIP despite being treated with ART, we assess whether the ART regimen is optimal and modify it, if necessary. If LIP progresses despite an optimal ART regimen, we suggest the addition of glucocorticoids based on personal experience and the response of HIV-infected patients with LIP to glucocorticoids in the pre-ART era [27,53,54]. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load".)

We suggest Pneumocystis prophylaxis in HIV-infected patients with LIP who require moderate- to high-dose glucocorticoid therapy (eg, prednisone 20 mg or more per day) in addition to those who meet other criteria for Pneumocystis prophylaxis. (See 'Idiopathic' above and "Treatment and prevention of Pneumocystis infection in patients with HIV", section on 'Antimicrobial prophylaxis'.)

PROGNOSIS — 

The natural history and prognosis of lymphoid interstitial pneumonia (LIP) are poorly understood. Possible outcomes include spontaneous resolution, stabilization of disease, resolution following treatment (eg, with glucocorticoids or other immunosuppressive agents), progression to lymphoma, or progression to pulmonary fibrosis with respiratory insufficiency and death [1,2,6,8,9].

Among 15 patients with LIP that was associated with rheumatic disease, idiopathic, or associated with hypogammaglobulinemia (but not HIV), the median survival was 11.5 years (with 13 of 15 receiving glucocorticoid therapy) [9]. Three patients progressed to end-stage lung disease; malignant transformation was not noted.

LONG-TERM COMPLICATIONS — 

Approximately 5 percent of patients with LIP develop lymphoma, with increased risk in patients with Sjögren's disease; however, it is unclear whether LIP undergoes malignant transformation or whether the lymphoma develops as a comorbid process [2,55-58]. Lymphomas arising in association with LIP lesions are typically well-differentiated and slow-growing mucosa-associated lymphoid tissue (MALT) lymphomas [11,57], which have a favorable prognosis.

Secondary infections are a serious and potentially fatal complication of either the primary immunologic abnormality (eg, HIV, hypogammaglobulinemia) or the immunosuppressive therapy [8,9,29]. Infections with both typical and atypical organisms occur.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Interstitial lung disease".)

SUMMARY AND RECOMMENDATIONS

●Definition – Lymphoid interstitial pneumonia (LIP) is a lymphoproliferative disorder of the lung characterized by infiltration of the interstitium and alveolar spaces by lymphocytes, plasma cells, and other lymphoreticular elements. (See 'Introduction' above and 'Classification' above.)

●Associated diseases – The specific etiology of LIP is unknown. Its association with autoimmune diseases (eg, Sjögren's disease, systemic lupus erythematosus) suggests an autoimmune etiology, and its association with HIV infection suggests a possible viral infectious etiology (table 1). (See 'Associated diseases' above.)

●Clinical manifestations – Clinical manifestations include cough, dyspnea, and, less commonly, weight loss and fever. Lung examination typically reveals crackles in affected areas. (See 'Clinical manifestations' above.)

●Chest imaging – On high-resolution chest CT, ground-glass attenuation, centrilobular nodules (single or multiple) or masses, mixed ground glass-consolidative opacities, and septal thickening are typical (image 1). Lung cysts are also common, especially in HIV-associated LIP. (See 'Chest imaging' above.)

●Pathologic findings – LIP represents a benign polyclonal proliferation (usually of mature B or T cells) that can involve the lung diffusely or focally. Germinal centers, noncaseating granulomas, and multinucleated giant cells may also be seen. As the disease progresses, fibrotic and cystic changes are seen along with loss of lung parenchyma. (See 'Classification' above and 'Pathologic findings' above.)

●Diagnosis – Open or thoracoscopic lung biopsy is often required to confirm the diagnosis, as biopsy specimens need to be large enough for the pathologist to define architectural elements and test for clonality. Imaging alone is sufficient in HIV-positive children and when characteristic in patients with Sjögren’s disease. (See 'Diagnosis' above.)

●Treatment

•Idiopathic or rheumatic disease-associated LIP – For patients with idiopathic or rheumatic disease-associated LIP who are asymptomatic and have mild disease (based on physiologic and radiographic studies), we suggest not initiating treatment (Grade 2C). We follow these patients with longitudinal assessments of clinical, functional, and radiologic parameters. (See 'Treatment' above.)

In adults with idiopathic or rheumatic disease-associated LIP who are symptomatic, have significant physiologic impairment, or demonstrate progressive disease on longitudinal assessment, we suggest treatment with oral glucocorticoids (Grade 2C) rather than no treatment or other immunosuppressants. We typically initiate oral prednisone (or the equivalent prednisolone dose) 0.25 to 0.5 mg/kg given once daily (based upon the patient's ideal body weight but not exceeding 60 mg/day). The course of therapy is usually 6 to 12 months, with tapering based on response. (See 'Treatment' above.)

For patients with idiopathic or rheumatic disease-associated LIP who do not respond to, are intolerant of, or require prolonged glucocorticoid therapy, we suggest adding an additional immunosuppressive agent (Grade 2C). Reasonable options include azathioprine, cyclophosphamide, cyclosporine, or rituximab. (See 'Treatment' above.)

Monitoring, prevention, and treatment of potential adverse side effects of glucocorticoids is vital for patients undergoing prolonged glucocorticoid therapy. (See "Major adverse effects of systemic glucocorticoids".)

•HIV-infected patients – In HIV-infected patients (including children) with symptomatic LIP and no other indication for antiretroviral therapy (ART), we suggest initiating ART (Grade 2C). We also suggest not initiating glucocorticoid therapy until after a trial of optimal ART (Grade 2C). For patients whose LIP progresses despite optimal ART, we follow the treatment protocol for glucocorticoid therapy outlined for LIP in rheumatic disease. (See 'Treatment' above.)

•Granulomatous lymphocytic ILD – Although often refractory to treatment, small numbers of patients with LIP histopathology in the setting of GLILD have been treated successfully with various immunomodulatory therapies. The management of GLILD is discussed in more detail separately. (See 'Immunodeficiency/dysregulation' above and "Pulmonary complications of primary immunodeficiencies", section on 'Granulomatous and lymphocytic interstitial lung disease'.)

•Prophylaxis – We suggest Pneumocystis prophylaxis is appropriate for patients receiving moderate to high doses of glucocorticoids, for patients on multiple agents, and for some patients with LIP and concomitant HIV. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis' and "Treatment and prevention of Pneumocystis infection in patients with HIV", section on 'Antimicrobial prophylaxis'.)

●Long-term complications – Malignant transformation of LIP to lymphoma may infrequently occur years after the initial diagnosis. Lymphomas arising from LIP lesions are associated with prolonged survival, as they are well-differentiated and slow-growing. (See 'Prognosis' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Karen A Fagan, MD, who contributed to earlier versions of this topic review.