Lymphoid Interstitial Pneumonitis

Background

Lymphoid interstitial pneumonitis (LIP) is a polyclonal polymorphic B-cell lymphoproliferative disorder occurring as a common pulmonary complication in pediatric AIDS patients.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/Immunohistochemistry/Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

SYNONYMS LIP

INCIDENCE 75% of cases of pediatric AIDS

DISEASE ASSOCIATIONS CHARACTERIZATION

CONNECTIVE TISSUE DISEASE

Atypical lymphoid infiltrates arising in cutaneous lesions of connective tissue disease.

Magro CM, Crowson AN, Harrist TJ.

Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Pathology Services, Inc., Cambridge, Massachusetts, USA.
Am J Dermatopathol. 1997 Oct;19(5):446-55. Abstract quote
Atypical lymphoid infiltrates occurring in the setting of connective-tissue disease (CTD) comprise malignant neoplasms of B-cell or T-cell phenotypes and various reactive lymphoid hyperplasias, such as myoepithelial sialadenitis, lymphocytic thyroiditis, and lymphocytic interstitial pneumonitis.

We describe 17 patients with atypical lymphoid infiltrates arising in cutaneous lesions of CTD, the spectrum of which included lupus erythematosus, dermatomyositis, relapsing polychondritis, and lichen sclerosus et atrophicus.

There were two principal categories, pseudolymphoma and malignant lymphoma, the former representing 15 of the 17 cases. The clinical and histologic features and possible pathogenetic mechanisms are discussed.

THYMIC CYST

Multilocular thymic cyst. A novel thymic lesion associated with human immunodeficiency virus infection.

Mishalani SH, Lones MA, Said JW.

Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Arch Pathol Lab Med 1995 May;119(5):467-70 Abstract quote

Thymic involvement is an important feature of human immunodeficiency virus-related disease in the pediatric population. The most common lesions are thymic involution or atrophy, thymitis (thymic lymphoid hyperplasia), and dysinvolution with loss of Hassall's corpuscles.

We report a case of an unusual form of thymic enlargement in a human immunodeficiency virus-infected boy. In addition to lymphoid hyperplasia similar to that associated with human immunodeficiency virus infection in lymph nodes and other sites, the thymus was characterized by multilocular cysts with squamous epithelial lining (multilocular cystic lesion of the thymus).

Multilocular thymic cysts in children with human immunodeficiency virus infection: clinical and pathologic aspects.

Kontny HU, Sleasman JW, Kingma DW, Jaffe ES, Avila NA, Pizzo PA, Mueller BU.

Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1182, USA.

J Pediatr 1997 Aug;131(2):264-70 Abstract quote

BACKGROUND: Children with human immunodeficiency virus (HIV) infection have an increased susceptibility to severe and unusual infections, malignancies, and disorders characterized by abnormal lymphoproliferation (e.g., lymphoid interstitial pneumonitis). We report a novel disease entity associated with pediatric HIV infection that is characterized by massive enlargement of the thymus as a result of lymphoid hyperplasia and multicystic changes.

METHODS: Eight patients with HIV infection and cystic enlargement of the thymus are subject of this report. The status of their HIV disease and its clinical and radiologic manifestations at the time of diagnosis of the mediastinal mass are described. Tissue specimens were obtained from six patients and examined by microscopy and immunohistochemistry. The specimens were also evaluated for the evidence of HIV and Epstein-Barr virus by in situ hybridization.

RESULTS: Patients were between 2.1 and 12.1 years of age, with CD4+ cell counts between 102 and 733 cells/mm3. In all eight cases an anterior mediastinal mass was discovered incidentally on radiography of the chest, and computed tomography of the chest revealed a multicystic appearance. Histologic examination demonstrated distortion of the thymic architecture by focal cystic changes, lymphoid follicular hyperplasia, diffuse plasmacytosis, and multinucleated giant cells. In situ hybridization revealed HIV particles on the surface of follicular dendritic cells. Further, results of in situ hybridization for EBV were positive in lymphoid cells from biopsy samples of four patients. The patients were followed between 8 months and 4.8 years. In five patients the mass either decreased in size or resolved completely.

CONCLUSIONS: We describe a series of children with HIV infection and multilocular thymic cysts. We hypothesize that aberrant immunoregulation in these HIV-infected children leads to follicular hyperplasia and multicystic changes in the thymus, causing massive enlargement. EBV infection might also contribute to the pathogenesis of this process. Because none of our patients had symptoms from the mass, and there was no evidence of malignancy in the examined biopsy samples, it seems prudent to manage such children with careful follow-up examinations.

PATHOGENESIS CHARACTERIZATION

Aberrant expression of immunoglobulin heavy chain genes in Epstein-Barr virus-negative, human immunodeficiency virus-related lymphoid interstitial pneumonia.

Kurosu K, Yumoto N, Rom WN, Jaishree J, Nakata K, Kuriyama T, Mikata A, Weiden MD.

Department of Medicine, Shimizu Kohsei Hospital, Shimizu City, Shizuoka, Japan.

Lab Invest 2000 Dec;80(12):1891-903 Abstract quote

The two-step polymerase chain reaction (PCR) and sequencing analysis was used to analyze the immunoglobulin heavy chain variable (Ig V(H)) genes of open-chest biopsy or autopsy samples from five patients with Epstein-Barr virus-negative human immunodeficiency virus (HIV)-related lymphoid interstitial pneumonia (LIP), and the results were compared with those for Ig V(H) genes from five HIV-negative LIP patients.

The findings of this study are consistent with the different immunological situations of HIV-related and HIV-negative LIP. (a) The Ig V(H)3 subgroup was underexpressed in three of five cases of HIV-related LIP. In contrast, none of the HIV-negative cases showed this abnormality. Because the Ig V(H)3 subgroup encodes the largest portion of Ig V(H) genes, a depletion of B cells expressing Ig V(H)3 genes reflects a major alteration in the B-cell compartment. (b) All HIV-related LIP cases demonstrated two or three oligoclonal populations. HIV-negative cases showed minor monoclonal or polyclonal populations, but not oligoclonal ones. These oligoclonal populations suggest the coexistence of several occult clonal B-cell populations in HIV-related LIP. (c) Some oligoclonal clones in HIV-related LIP showed mutated framework regions not demonstrated in HIV-negative clones. This degree of variation exceeds the usual mutation rate for frameworks, suggesting a role for framework residues in antigen binding. (d) The frequency of D-D fusions of minor oligoclonal clones (HIV-related LIP) is higher than that of minor monoclonal clones (HIV-negative LIP).

Such D-D fusions may enhance the probability of expression of antibodies capable of binding HIV glycoproteins.

Chemokine Gene Expression and Clonal Analysis of B Cells in Tissues Involved by Lymphoid Interstitial Pneumonitis from HIV-Infected Pediatric Patients

Julie Teruya-Feldstein, M.D., Douglas W. Kingma, M.D., Andrew Weiss, M.D., Lynn Sorbara, Ph.D., Parris R. Burd, Ph.D., Mark Raffeld, M.D., Brigitta U. Mueller, M.D., Giovanna Tosato, M.D. and Elaine S. Jaffe, M.D.

Laboratory of Pathology (JTFDWK, AW, LS, MR, ESJ), Hematopathology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Center for Biologics Evaluation and Research (PRB, GT), Food and Drug Administration, Bethesda, Maryland; and Texas Children�s Cancer Center (BUM), Houston, Texas

Mod Pathol 2001;14:929-936 Abstract quote

Lymphoid interstitial pneumonitis (LIP), a frequent pulmonary complication in HIV-infected pediatric patients, is characterized histologically by marked infiltration of lymphoid cells.

We sought to evaluate the nature and pathogenesis of the lymphoid infiltrates and to examine the relationship of LIP to pulmonary MALT lymphoma that has been described in pediatric HIV positive patients.

To examine the potential contribution of chemokines and cytokines to the inflammatory cell recruitment in tissues involved by lymphoid interstitial pneumonitis from HIV-infected pediatric patients, RNA was extracted from paraffin-embedded tissues from five lung biopsies in four pediatric HIV-positive patients and from five control, normal lung biopsies in five HIV-negative patients and was analyzed by semiquantitative RT-PCR for the expression of cytokines (TNF-, GM-CSF, IFN-, IL-4, IL-6, IL-10, and IL-18) and chemokines (IP-10, Mig, regulated upon activation, normal T expressed and secreted [RANTES], and MIP1- and �) after normalization for G3PDH. Expression of IL-18 was increased, as well as expression of IFN-�inducible chemokines IP-10 and Mig in LIP tissues compared with controls. RANTES and MIP1- and -� were also increased in pediatric LIP lesions compared with controls. In contrast, expression of TNF-, GM-CSF, IL-10, and IL-6 was variable in LIP tissues and controls. In addition, clonality of the B-cell population was evaluated by VDJ-PCR. A polyclonal B-cell population was shown in all five biopsies from five patients with LIP; and in one patient with concurrent LIP and MALT lymphoma, a band of increased intensity was observed in the LIP biopsy that was identical in size to the monoclonal band in the concurrent MALT lymphoma biopsy.

These results provide evidence of high-level expression of certain chemokines in lymphoid interstitial pneumonitis tissues and suggest that chemokines and cytokines may play an important role in the recruitment of inflammatory cell infiltrates into these tissues. In addition, LIP may represent an early stage of MALT lymphoma or an immunologic response to a chronic antigenic stimulus that may provide a milieu or microenvironment for the evolution of a monoclonal B-cell population.

LABORATORY/RADIOLOGIC CHARACTERIZATION

RADIOLOGIC

Radiographic patterns of PLH/LIP in HIV positive children.

Marquis JR, Berman CZ, DiCarlo F, Oleske JM.

Department of Radiology, Children's Hospital of New Jersey, Newark 07107.
Pediatr Radiol. 1993;23(4):328-30. Abstract quote
A retrospective study was performed of the radiographic patterns of the lungs in children being followed in the Children's Hospital Aids Program (CHAP).

The most consistent finding was a diffuse reticulonodular pattern in the lungs. In addition, lung consolidation, either isolated or in combination with nodules, was noted. There was variation in presentation of the nodules, and prominent linear patterns were frequently encountered. Biopsy specimens of the lungs of these patients demonstrated a correlation between the presence of PLH/LIP and the various radiographic patterns.

The lymphoid infiltration of PLH was occasionally observed in a circumferential peri-bronchiolar pattern suggesting an association with the prominent linear patterns on the films.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

General

VARIANTS

A case of lymphoid interstitial pneumonia in a 3-month-old boy not associated with HIV infection: immunohistochemistry of lung biopsy specimens and serum transforming growth factor-beta 1 assay.

Koga M, Umemoto Y, Nishikawa M, Nakashima K, Ishihara T, Furukawa S.

Department of Pediatrics, Yamaguchi University School of Medicine, Ube, Japan.

Pathol Int 1997 Oct;47(10):698-702 Abstract quote

The case of a 3-month-old boy with lymphoid interstitial pneumonia (LIP) is reported.

He had cough and tachypnea, his weight gain was poor and a chest radiograph showed microgranular shadows in almost all lung areas. Histological investigations revealed severe cellular infiltration by a variety of lymphoid and plasma cells with lymphoid follicle formation in the alveolar walls and also around the bronchioles. Foamy macrophages, a few lymphocytes and exudate filled the alveolar spaces. Epithelial cells lining the air spaces expressed human leukocyte antigen (HLA)-DR. Lymphocytes and macrophages in the alveolar spaces expressed transforming growth factor (TGF)-beta strongly. Serum TGF-beta 1 concentrations were measured eight times during the course of his illness. They exceeded the upper end of the normal range in four samples and were within it in the others.

These results suggested that dysfunction of the immune system, especially abnormal expression of HLA-DR in non-immune cells and exaggerated production of TGF-beta played important roles in the pathogenesis of LIP in this patient.

HISTOLOGICAL TYPES CHARACTERIZATION

General

Pulmonary disease in children with acquired immune deficiency syndrome and AIDS-related complex.

Rubinstein A, Morecki R, Silverman B, Charytan M, Krieger BZ, Andiman W, Ziprkowski MN, Goldman H.

J Pediatr 1986 Apr;108(4):498-503 Abstract quote

Two major pulmonary diseases were defined on the basis of lung biopsies in 15 children with acquired immune deficiency syndrome (AIDS) or AIDS-related complex.

Pneumocystis carinii pneumonia was observed in eight children, and pulmonary lymphoid hyperplasia in six. One child had nonspecific interstitial pneumonitis. Children with P. carinii pneumonia had more severe hypoxemia, with higher alveolar-arterial oxygen gradients, and higher isomorphic elevations of serum lactate dehydrogenase. Clinically, children with pulmonary lymphoid hyperplasia were older, and had digital clubbing, parotid gland enlargement, and elevated serum IgG levels. Results of serologic assays and lung tissue analysis were suggestive of persistent Epstein-Barr virus infection exclusively in patients with pulmonary lymphoid hyperplasia.

Recognition of the clinical and laboratory findings characteristic of each entity may assist in the differential diagnosis without the need of surgical biopsy.

Role of tissue diagnosis in pulmonary involvement in pediatric human immunodeficiency virus infection.

Izraeli S, Mueller BU, Ling A, Temeck BK, Lewis LL, Chang R, Shad AT, Pass HI, Pizzo PA.

Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Pediatr Infect Dis J 1996 Feb;15(2):112-6 Abstract quote

BACKGROUND: Pulmonary complications occur commonly during HIV infection. The aim of this study was to evaluate the clinical value of lung tissue examination in the diagnosis and treatment of pulmonary disorders in children with HIV infection.

METHODS: The medical records of 347 children enrolled between January, 1990, and April, 1994, into various antiretroviral therapy protocols were reviewed to identify patients who underwent a lung biopsy.

RESULTS: Fourteen patients underwent diagnostic lung biopsies on 16 separate occasions. The most common radiologic findings were nodular infiltrates which were localized in 7 patients and diffuse in 6. Eight patients presented with fever and progressive respiratory distress unresponsive to empiric therapy, whereas the rest had progressive nodular infiltrates. The pathologic diagnoses included opportunistic infection in 7 patients, lymphocytic interstitial pneumonitis in 5, non-Hodgkin's lymphoma in 3 and interstitial fibrosis in 1. The biopsy led to a major change in the treatment of 7 patients which resulted in a significant improvement of the pulmonary process in all of them. In an additional patient the excisional biopsy proved curative.

CONCLUSIONS: When patients are selected appropriately, lung biopsy might have a significant impact on therapy and outcome in HIV-infected children with pulmonary infiltrates.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

The spectrum of mucosa-associated lymphoid tissue lesions in pediatric patients infected with HIV: A clinicopathologic study of six cases.

Joshi VV, Gagnon GA, Chadwick EG, Berard CW, McClain KL, Leach CT, Jenson HB, Murphy SB.

Department of Pathology and Laboratory Medicine, East Carolina University School of Medicine, Greenville, North Carolina, USA.

Am J Clin Pathol 1997 May;107(5):592-600 Abstract quote

Mucosa-associated lymphoid tissue (MALT) lesions in nonimmunocompromised individuals include reactive lymphoid proliferations and both low- and high-grade lymphoid neoplasms. These lesions occur at extranodal mucosal sites, such as the gastrointestinal tract, bronchus, salivary gland, and other locations. The spectrum of MALT lesions in children with HIV infection had not been previously described.

In this study, six cases that demonstrated the spectrum of MALT lesions in pediatric patients, aged 28 months to 23 years, who had HIV infection were described.

Half the patients acquired the infection perinatally, and half acquired it by transfusion. Mucosal sites of involvement included the salivary gland (4 patients), bronchiolar mucosa (2 patients), and oropharyngeal mucosa (1 patient). One patient had lesions in lung and oropharynx sequentially; all others had involvement of solitary sites. The histologic diagnoses included myoepithelial sialadenitis (MESA), MESA with low-grade MALT lymphoma, typical low-grade MALT lymphoma, diffuse large cell lymphoma (DLCL), and atypical pulmonary lymphoid hyperplasia and lymphoid interstitial pneumonitis complex. The two cases of high-grade DLCL were confined to mucosal sites (tonsil and parotid); in one of these patients, a previous biopsy specimen showed a MALT lesion with low-grade features. In two cases, quantitation of the Epstein-Barr virus (EBV) genome by the polymerase chain reaction showed a very high copy number in peripheral blood mononuclear cells but a low copy number in the MALT lesion, which suggested that MALT lesions may not be directly associated with EBV infection. Two patients who had high-grade tumors (DLCL) were successfully treated with chemotherapy and radiation therapy. The remaining patients, all of whom had low-grade MALT lesions, received either corticosteroids or alpha-interferon or no specific therapy; in all patients, the lesions followed an indolent clinical course.

Clinicians and pathologists should be alert to the possibility that MALT lesions, including MALT lymphomas, may be present in children who have AIDS.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSIS

GENERAL

Lymphoid interstitial pneumonia: a narrative review.

Swigris JJ, Berry GJ, Raffin TA, Kuschner WG.

Division of Pulmonary and Critical Care Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA 94305-5236, USA.
Chest. 2002 Dec;122(6):2150-64. Abstract quote
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 Sjogren 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.

TREATMENT

ANTI-RETROVIRAL THERAPY

Improvement of symptomatic human immunodeficiency virus-related lymphoid interstitial pneumonia in patients receiving highly active antiretroviral therapy.

Dufour V, Wislez M, Bergot E, Mayaud C, Cadranel J.

Service de Pneumologie et de Reanimation Respiratoire, Hopital Tenon, Paris, France.
Clin Infect Dis. 2003 May 15;36(10):e127-30. Abstract quote
To analyze the impact of highly active antiretroviral therapy on lymphoid interstitial pneumonia (LIP), we reviewed the medical files of 5 human immunodeficiency virus (HIV)-infected patients in whom LIP was diagnosed during 1996-2001 who had never previously received antiretroviral treatment.

Patients were mildly immunosuppressed at the time of diagnosis of LIP but had high plasma HIV loads and marked circulating and pulmonary CD8 hyperlymphocytosis.

All patients improved clinically, radiologically, and functionally; improvement was accompanied by a drastic reduction in the virus load and an increase in the CD4 lymphocyte count.

CYCLOSPORINE

Lymphoid interstitial pneumonitis associated with common variable hypogammaglobulinaemia treated with cyclosporin A.

Davies CW, Juniper MC, Gray W, Gleeson FV, Chapel HM, Davies RJ.

Osler Chest Unit, Churchill Hospital, Oxford Radcliffe Trust, Oxford OX3 7LJ, UK.

Thorax 2000 Jan;55(1):88-90 Abstract quote

Lymphoid interstitial pneumonitis (LIP) is a rare clinicopathological entity that may be associated with common variable immune deficiency (CVID) and may lead to respiratory failure and death. Some patients may respond to prolonged corticosteroid treatment.

We hypothesised that, in view of the predominant T cell nature of LIP, cyclosporin A would be a more appropriate choice of immunosuppressive agent and report the first case of its successful use in a woman with LIP associated with CVID.

Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.

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Last Updated 5/25/2003

DISEASE ASSOCIATIONS	CHARACTERIZATION
CONNECTIVE TISSUE DISEASE
Atypical lymphoid infiltrates arising in cutaneous lesions of connective tissue disease. Magro CM, Crowson AN, Harrist TJ. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Pathology Services, Inc., Cambridge, Massachusetts, USA.	Am J Dermatopathol. 1997 Oct;19(5):446-55. Abstract quote Atypical lymphoid infiltrates occurring in the setting of connective-tissue disease (CTD) comprise malignant neoplasms of B-cell or T-cell phenotypes and various reactive lymphoid hyperplasias, such as myoepithelial sialadenitis, lymphocytic thyroiditis, and lymphocytic interstitial pneumonitis. We describe 17 patients with atypical lymphoid infiltrates arising in cutaneous lesions of CTD, the spectrum of which included lupus erythematosus, dermatomyositis, relapsing polychondritis, and lichen sclerosus et atrophicus. There were two principal categories, pseudolymphoma and malignant lymphoma, the former representing 15 of the 17 cases. The clinical and histologic features and possible pathogenetic mechanisms are discussed.
THYMIC CYST
Multilocular thymic cyst. A novel thymic lesion associated with human immunodeficiency virus infection. Mishalani SH, Lones MA, Said JW. Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.	Arch Pathol Lab Med 1995 May;119(5):467-70 Abstract quote Thymic involvement is an important feature of human immunodeficiency virus-related disease in the pediatric population. The most common lesions are thymic involution or atrophy, thymitis (thymic lymphoid hyperplasia), and dysinvolution with loss of Hassall's corpuscles. We report a case of an unusual form of thymic enlargement in a human immunodeficiency virus-infected boy. In addition to lymphoid hyperplasia similar to that associated with human immunodeficiency virus infection in lymph nodes and other sites, the thymus was characterized by multilocular cysts with squamous epithelial lining (multilocular cystic lesion of the thymus).
Multilocular thymic cysts in children with human immunodeficiency virus infection: clinical and pathologic aspects. Kontny HU, Sleasman JW, Kingma DW, Jaffe ES, Avila NA, Pizzo PA, Mueller BU. Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1182, USA.	J Pediatr 1997 Aug;131(2):264-70 Abstract quote BACKGROUND: Children with human immunodeficiency virus (HIV) infection have an increased susceptibility to severe and unusual infections, malignancies, and disorders characterized by abnormal lymphoproliferation (e.g., lymphoid interstitial pneumonitis). We report a novel disease entity associated with pediatric HIV infection that is characterized by massive enlargement of the thymus as a result of lymphoid hyperplasia and multicystic changes. METHODS: Eight patients with HIV infection and cystic enlargement of the thymus are subject of this report. The status of their HIV disease and its clinical and radiologic manifestations at the time of diagnosis of the mediastinal mass are described. Tissue specimens were obtained from six patients and examined by microscopy and immunohistochemistry. The specimens were also evaluated for the evidence of HIV and Epstein-Barr virus by in situ hybridization. RESULTS: Patients were between 2.1 and 12.1 years of age, with CD4+ cell counts between 102 and 733 cells/mm3. In all eight cases an anterior mediastinal mass was discovered incidentally on radiography of the chest, and computed tomography of the chest revealed a multicystic appearance. Histologic examination demonstrated distortion of the thymic architecture by focal cystic changes, lymphoid follicular hyperplasia, diffuse plasmacytosis, and multinucleated giant cells. In situ hybridization revealed HIV particles on the surface of follicular dendritic cells. Further, results of in situ hybridization for EBV were positive in lymphoid cells from biopsy samples of four patients. The patients were followed between 8 months and 4.8 years. In five patients the mass either decreased in size or resolved completely. CONCLUSIONS: We describe a series of children with HIV infection and multilocular thymic cysts. We hypothesize that aberrant immunoregulation in these HIV-infected children leads to follicular hyperplasia and multicystic changes in the thymus, causing massive enlargement. EBV infection might also contribute to the pathogenesis of this process. Because none of our patients had symptoms from the mass, and there was no evidence of malignancy in the examined biopsy samples, it seems prudent to manage such children with careful follow-up examinations.

HISTOLOGICAL TYPES	CHARACTERIZATION
General
Pulmonary disease in children with acquired immune deficiency syndrome and AIDS-related complex. Rubinstein A, Morecki R, Silverman B, Charytan M, Krieger BZ, Andiman W, Ziprkowski MN, Goldman H.	J Pediatr 1986 Apr;108(4):498-503 Abstract quote Two major pulmonary diseases were defined on the basis of lung biopsies in 15 children with acquired immune deficiency syndrome (AIDS) or AIDS-related complex. Pneumocystis carinii pneumonia was observed in eight children, and pulmonary lymphoid hyperplasia in six. One child had nonspecific interstitial pneumonitis. Children with P. carinii pneumonia had more severe hypoxemia, with higher alveolar-arterial oxygen gradients, and higher isomorphic elevations of serum lactate dehydrogenase. Clinically, children with pulmonary lymphoid hyperplasia were older, and had digital clubbing, parotid gland enlargement, and elevated serum IgG levels. Results of serologic assays and lung tissue analysis were suggestive of persistent Epstein-Barr virus infection exclusively in patients with pulmonary lymphoid hyperplasia. Recognition of the clinical and laboratory findings characteristic of each entity may assist in the differential diagnosis without the need of surgical biopsy.
Role of tissue diagnosis in pulmonary involvement in pediatric human immunodeficiency virus infection. Izraeli S, Mueller BU, Ling A, Temeck BK, Lewis LL, Chang R, Shad AT, Pass HI, Pizzo PA. Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.	Pediatr Infect Dis J 1996 Feb;15(2):112-6 Abstract quote BACKGROUND: Pulmonary complications occur commonly during HIV infection. The aim of this study was to evaluate the clinical value of lung tissue examination in the diagnosis and treatment of pulmonary disorders in children with HIV infection. METHODS: The medical records of 347 children enrolled between January, 1990, and April, 1994, into various antiretroviral therapy protocols were reviewed to identify patients who underwent a lung biopsy. RESULTS: Fourteen patients underwent diagnostic lung biopsies on 16 separate occasions. The most common radiologic findings were nodular infiltrates which were localized in 7 patients and diffuse in 6. Eight patients presented with fever and progressive respiratory distress unresponsive to empiric therapy, whereas the rest had progressive nodular infiltrates. The pathologic diagnoses included opportunistic infection in 7 patients, lymphocytic interstitial pneumonitis in 5, non-Hodgkin's lymphoma in 3 and interstitial fibrosis in 1. The biopsy led to a major change in the treatment of 7 patients which resulted in a significant improvement of the pulmonary process in all of them. In an additional patient the excisional biopsy proved curative. CONCLUSIONS: When patients are selected appropriately, lung biopsy might have a significant impact on therapy and outcome in HIV-infected children with pulmonary infiltrates.

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	LIP
INCIDENCE	75% of cases of pediatric AIDS

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
General
VARIANTS
A case of lymphoid interstitial pneumonia in a 3-month-old boy not associated with HIV infection: immunohistochemistry of lung biopsy specimens and serum transforming growth factor-beta 1 assay. Koga M, Umemoto Y, Nishikawa M, Nakashima K, Ishihara T, Furukawa S. Department of Pediatrics, Yamaguchi University School of Medicine, Ube, Japan.	Pathol Int 1997 Oct;47(10):698-702 Abstract quote The case of a 3-month-old boy with lymphoid interstitial pneumonia (LIP) is reported. He had cough and tachypnea, his weight gain was poor and a chest radiograph showed microgranular shadows in almost all lung areas. Histological investigations revealed severe cellular infiltration by a variety of lymphoid and plasma cells with lymphoid follicle formation in the alveolar walls and also around the bronchioles. Foamy macrophages, a few lymphocytes and exudate filled the alveolar spaces. Epithelial cells lining the air spaces expressed human leukocyte antigen (HLA)-DR. Lymphocytes and macrophages in the alveolar spaces expressed transforming growth factor (TGF)-beta strongly. Serum TGF-beta 1 concentrations were measured eight times during the course of his illness. They exceeded the upper end of the normal range in four samples and were within it in the others. These results suggested that dysfunction of the immune system, especially abnormal expression of HLA-DR in non-immune cells and exaggerated production of TGF-beta played important roles in the pathogenesis of LIP in this patient.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS
GENERAL
Lymphoid interstitial pneumonia: a narrative review. Swigris JJ, Berry GJ, Raffin TA, Kuschner WG. Division of Pulmonary and Critical Care Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA 94305-5236, USA.	Chest. 2002 Dec;122(6):2150-64. Abstract quote 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 Sjogren 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.
TREATMENT
ANTI-RETROVIRAL THERAPY
Improvement of symptomatic human immunodeficiency virus-related lymphoid interstitial pneumonia in patients receiving highly active antiretroviral therapy. Dufour V, Wislez M, Bergot E, Mayaud C, Cadranel J. Service de Pneumologie et de Reanimation Respiratoire, Hopital Tenon, Paris, France.	Clin Infect Dis. 2003 May 15;36(10):e127-30. Abstract quote To analyze the impact of highly active antiretroviral therapy on lymphoid interstitial pneumonia (LIP), we reviewed the medical files of 5 human immunodeficiency virus (HIV)-infected patients in whom LIP was diagnosed during 1996-2001 who had never previously received antiretroviral treatment. Patients were mildly immunosuppressed at the time of diagnosis of LIP but had high plasma HIV loads and marked circulating and pulmonary CD8 hyperlymphocytosis. All patients improved clinically, radiologically, and functionally; improvement was accompanied by a drastic reduction in the virus load and an increase in the CD4 lymphocyte count.
CYCLOSPORINE
Lymphoid interstitial pneumonitis associated with common variable hypogammaglobulinaemia treated with cyclosporin A. Davies CW, Juniper MC, Gray W, Gleeson FV, Chapel HM, Davies RJ. Osler Chest Unit, Churchill Hospital, Oxford Radcliffe Trust, Oxford OX3 7LJ, UK.	Thorax 2000 Jan;55(1):88-90 Abstract quote Lymphoid interstitial pneumonitis (LIP) is a rare clinicopathological entity that may be associated with common variable immune deficiency (CVID) and may lead to respiratory failure and death. Some patients may respond to prolonged corticosteroid treatment. We hypothesised that, in view of the predominant T cell nature of LIP, cyclosporin A would be a more appropriate choice of immunosuppressive agent and report the first case of its successful use in a woman with LIP associated with CVID.