eMedicine Specialties > Pulmonology > Interstitial Lung Diseases

Lymphocytic Interstitial Pneumonia

Author: Jussi J Saukkonen, MD, Assistant Professor, Department of Internal Medicine, Division of Pulmonary/Critical Care Medicine, Boston University School of Medicine, Boston Medical Center
Contributor Information and Disclosures

Updated: Jan 17, 2008

Introduction

Background

Lymphocytic interstitial pneumonia (LIP) is a syndrome of fever, cough, and dyspnea, with bibasilar pulmonary infiltrates consisting of dense interstitial accumulations of lymphocytes and plasma cells.

LIP may be associated with autoimmune and lymphoproliferative disorders, including rheumatoid arthritis, Hashimoto thyroiditis, myasthenia gravis, pernicious anemia, autoerythrocyte sensitization syndrome, chronic active hepatitis, common variable immunodeficiency, Sjögren syndrome,1 allogeneic bone marrow transplantation, lupus, and lymphoma. Pseudolymphoma represents a localized masslike variant of LIP.

LIP is also associated with infection via human immunodeficiency virus (HIV) type 1, Epstein-Barr virus, and human T-cell leukemia virus (HTLV) type 1.

Pathophysiology

Patients may have symptoms related to the above disorders.

HIV-related LIP may be part of a continuum of lymphocytic infiltrative disorders, such as pulmonary lymphoid hyperplasia in children and radiographically clear lymphocytic alveolitis in adults. Patients positive for HLA-DR5 and HLA-DR6 alleles are predisposed to developing a diffuse visceral lymphocytosis syndrome with LIP.

LIP has been reported to occur as part of immune reconstitution syndrome.2

Frequency

United States

LIP is an uncommon disease. However, LIP is found in 22-75% of pediatric patients with HIV who have pulmonary disease. In contrast, among adult patients with HIV, LIP accounts for only 3% of HIV-related pulmonary pathology.

International

Small series have been reported in Europe, southwestern Japan, Africa, and the Caribbean basin.

Mortality/Morbidity

Mortality and morbidity data are inexact because of the lack of reported follow-up and the rarity of the disease.

  • In the population who does not have HIV infection, half the patients improve with treatment but relapse is common. End-stage fibrosis may follow despite treatment. In the past, high mortality was reported in older patients.
  • Patients with HIV-associated LIP display slower decline in CD4+ T-cell counts and longer survival than individuals who have HIV infection but do not have LIP.
  • Patients with HIV infection but not LIP generally respond to treatment.

Race

  • LIP has been found in every race and HIV risk group. Whether racial or geographic predispositions are crucial remains unclear.
  • Many reports describe HIV and HTLV type 1–associated LIP among individuals of African ancestry.3
  • LIP appears to cluster in southwestern Japan, where HTLV type 1 is endemic.

Sex

  • LIP is more common in women when not associated with HIV infection.
  • HIV-associated sicca syndrome occurs most often in males.4

Age

  • Most cases not associated with HIV occur in the fourth and seventh decades of life, at an average age of 56 years.
  • LIP is common only in children with HIV. In children with HIV infection, LIP has been designated an AIDS-defining illness by the US Centers for Disease Control and Prevention.

Clinical

History

Symptoms are gradually progressive, often accompanied by constitutional symptoms such as dyspnea and chronic cough.

  • Pleuritic chest pain and hemoptysis are infrequent.
  • Sicca syndrome symptoms may include xerophthalmia and xerostomia.4

Physical

Manifestations of associated diseases may be present. Physical findings vary in children and adults, as follows.

  • Children
    • Generalized lymphadenopathy
    • Hepatosplenomegaly
    • Parotid enlargement
    • Clubbing
    • Wheezing (occasional)
  • Adults
    • Generalized lymphadenopathy
    • Rales
    • Hepatosplenomegaly and parotid enlargement - Present in approximately one third of adult patients

Causes

Lymphocytic interstitial pneumonia (LIP) may result from an in situ lymphoproliferative response to chronically presented viral antigens or cytokines and/or recruitment of circulating lymphocytes. Mutations of the B-cell CLL/lymphoma 6 (BCL-6 or zinc finger protein 51) gene have been associated with LIP and mucosa-associated lymphoid tissue (MALT) lymphoma.5 Viruses (alone or in combination) may be responsible. Potential candidates include the following:

  • Epstein-Barr virus
    • Epstein-Barr virus (EBV) DNA is detected in pediatric LIP lung biopsy specimens when accompanied by evidence of primary or reactivated EBV infection at the time of biopsy.
    • Elevated titers of antibodies directed against EBV have been reported in adult patients with LIP.
  • HTLV type 1
    • This is associated with a spectrum of pulmonary lymphoproliferative syndromes, including LIP.
    • Serologic and molecular studies have correlated HTLV type 1 infection with LIP.
    • The viral transactivating protein p40Tax activates the genes for interleukin-2 (IL-2) and its receptor's high-affinity alpha chain.
    • Lymphocyte proliferation driven by IL-2 may cause lymphoproliferative pulmonary lesions related to HTLV type 1.
  • HIV type 1
    • The nef gene product induces an LIP-like syndrome in a transgenic mouse model.
    • Expression of interleukin-18 (IL-18) and IFN-gamma-inducible chemokines IP-10 and Mig is increased in LIP tissues compared with controls.6
    • The beta-chemokines RANTES, MIP1-alpha and MIP1-beta, chemotactic for T cells are increased in pediatric LIP lesions compared with controls.6
    • Infiltrating B cells are polyclonal.
    • Infiltrating T cells in HIV-related LIP are more commonly oligoclonal expansions than in HIV-negative LIP.7
    • BCL-6 mutations in HIV-associated LIP do not show features of immunoglobulin variable heavy chain (IgV[H]) hypermutations, while HIV-negative LIP BCL-6 mutations do.
    • The immune dysregulation of HIV-associated LIP appears to be a different type than in HIV-negative LIP.

More on Lymphocytic Interstitial Pneumonia

Overview: Lymphocytic Interstitial Pneumonia
Differential Diagnoses & Workup: Lymphocytic Interstitial Pneumonia
Treatment & Medication: Lymphocytic Interstitial Pneumonia
Follow-up: Lymphocytic Interstitial Pneumonia
Multimedia: Lymphocytic Interstitial Pneumonia
References
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References

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  2. Ingiliz P, Appenrodt B, Gruenhage F, Vogel M, Tschampa H, Tasci S, et al. Lymphoid pneumonitis as an immune reconstitution inflammatory syndrome in a patient with CD4 cell recovery after HAART initiation. HIV Med. Sep 2006;7(6):411-4. [Medline].

  3. Rio B, Louvet C, Gessain A, Dormont D, Gisselbrecht C, Martoia R, et al. [Adult T-cell leukemia and non-malignant adenopathies associated with HTLV I virus. Apropos of 17 patients born in the Caribbean region and Africa]. Presse Med. Apr 21 1990;19(16):746-51. [Medline].

  4. Couderc LJ, D'Agay MF, Danon F, Harzic M, Brocheriou C, Clauvel JP. Sicca complex and infection with human immunodeficiency virus. Arch Intern Med. May 1987;147(5):898-901. [Medline].

  5. Kurosu K, Weiden MD, Takiguchi Y, Rom WN, Yumoto N, Jaishree J, et al. BCL-6 mutations in pulmonary lymphoproliferative disorders: demonstration of an aberrant immunological reaction in HIV-related lymphoid interstitial pneumonia. J Immunol. Jun 1 2004;172(11):7116-22. [Medline].

  6. Teruya-Feldstein J, Kingma DW, Weiss A, Sorbara L, Burd PR, Raffeld M, et al. Chemokine gene expression and clonal analysis of B cells in tissues involved by lymphoid interstitial pneumonitis from HIV-infected pediatric patients. Mod Pathol. Oct 2001;14(10):929-36. [Medline].

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Further Reading

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Keywords

lymphocytic interstitial pneumonia, LIP, lymphoid interstitial pneumonitis, lymphoid pneumonitis, plasma cell interstitial pneumonitis, pulmonary interstitial infiltration, pseudolymphoma, autoimmune disorders, lymphoproliferative disorders, human immunodeficiency virus, HIV-related LIP, HIV-associated LIP, HIV, AIDS, Epstein-Barr virus, EBV, human T-cell leukemia virus, HTLV type 1, HIV type 1, rheumatoid arthritis, Hashimoto thyroiditis, myasthenia gravis, pernicious anemia, autoerythrocyte sensitization syndrome, chronic active hepatitis, common variable immunodeficiency, Sjögren syndrome, allogeneic bone marrow transplantation, lupus, lymphoma, B-cell CLL/lymphoma 6, BCL-6, zinc finger protein 51

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Contributor Information and Disclosures

Author

Jussi J Saukkonen, MD, Assistant Professor, Department of Internal Medicine, Division of Pulmonary/Critical Care Medicine, Boston University School of Medicine, Boston Medical Center
Jussi J Saukkonen, MD is a member of the following medical societies: American Thoracic Society
Disclosure: Nothing to disclose.

Medical Editor

Stephen P Peters, MD, PhD, Professor, Department of Medicine, Wake Forest University
Stephen P Peters, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Thoracic Society, and Sigma Xi
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Daniel R Ouellette, MD, FCCP, Associate Professor of Medicine, Wayne State University School of Medicine; Consulting Staff, Pulmonary Disease and Critical Care Medicine Service, Henry Ford Health System
Daniel R Ouellette, MD, FCCP is a member of the following medical societies: American College of Chest Physicians and American Thoracic Society
Disclosure: Boehringer Ingleheim Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching

CME Editor

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine
Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians
Disclosure: Nothing to disclose.

Chief Editor

Zab Mosenifar, MD, Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center; Professor of Medicine, David Geffen School of Medicine at UCLA
Zab Mosenifar, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, and American Thoracic Society
Disclosure: Nothing to disclose.

 
 
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