eMedicine Specialties > Pulmonology > Interstitial Lung Diseases

Lymphocytic Interstitial Pneumonia

Jussi J Saukkonen, MD, Assistant Professor, Department of Internal Medicine, Division of Pulmonary/Critical Care Medicine, Boston University School of Medicine, Boston Medical Center

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.

Differential Diagnoses

Other Problems to Be Considered

Angioimmunoblastic lymphadenopathy
Benign lymphocytic angiitis
Granulomatosis
Nonspecific interstitial pneumonitis
Plasma cell interstitial pneumonitis
Interstitial lung disease

Workup

Laboratory Studies

• Laboratory tests are nonspecific.
• The most essential items are the chest radiograph, measurement of gas exchange, and histology.
• Serum protein electrophoresis: Polyclonal hypergammaglobulinemia is common.
• Lactate dehydrogenase
  • In pediatric patients with LIP and HIV, lactate dehydrogenase (LDH) may be elevated to 300-500 IU/L, approximately half the levels seen in Pneumocystis carinii pneumonia.
  • This measurement is not helpful in adults.
• Serologic testing: Test for HIV type 1, HTLV type 1, EBV, and rheumatoid factor.

Imaging Studies

• Chest radiograph
  • Bibasilar interstitial or micronodular infiltrates (see Media File 1) with coalescence into an alveolar pattern are present.
  • In adults, honeycombing is present in up to one third of cases. Hilar adenopathy and pleural effusion are uncommon.
  • Similar infiltrates are seen in children, often with mediastinal widening and hilar enlargement denoting pulmonary lymphoid hyperplasia.
• CT scan
  • This reveals the extent of the disease.
  • It may demonstrate bronchiectasis.
  • It also demonstrates the degree of fibrosis.
  • Findings may be used to follow disease progression.
  • Long-term follow-up may show the development of fibrosis, bronchiectasis, micronodules, bullae, and/or cystic changes.

Other Tests

• Pulmonary function testing
  • This usually demonstrates restriction with a reduced or normal diffusion capacity.
  • Obstructive airway disease has been reported occasionally.
• Arterial blood gas measurement: This may be helpful in assessing the severity of illness, but the findings are nonspecific. Findings include the following:
  • Partial pressure of oxygen (PO₂) measurement is normal.
  • Profound hypoxemia and/or an increased alveolar to arterial (A-a) oxygen gradient is present.
  • Pulse oximetry is used for screening, but it may not detect an A-a gradient. It should be checked at rest and following exercise.

Procedures

• Bronchoscopy with transbronchial biopsy
  • Generally, this is diagnostic if multiple biopsies are obtained from several affected subsegments.
  • Exact sensitivity and specificity of transbronchial biopsy is not reported.
  • Open lung biopsy is the criterion standard. It may be required in the face of nonspecific or equivocal findings, as with extensive fibrosis.

Histologic Findings

Histology shows alveolar septal and intra-alveolar infiltration by small, mature, noncleaved polyclonal lymphocytes and plasma cells. Lymphoid follicles or micronodules also may be present. No intrapulmonary lymphadenopathy, vasculitis, or necrosis is observed. Extensive areas of interstitial fibrosis may be present. Noncaseating granulomata have been reported.

Treatment

Medical Care

• Asymptomatic and physiologically unaffected patients may not require treatment.
• Symptomatic patients may require supportive care and immunosuppressives, chiefly corticosteroids. Occasionally, cytotoxic therapy has been used. No controlled treatment trials have been reported. Consider oxygen supplementation based on blood gas and/or exercise oximetry findings.
• Antibiotics are used for associated pulmonary infections.
• In pediatric patients with HIV, empiric treatment for LIP often is initiated based on the findings of subacute dyspnea, mild hypoxemia, and clubbing.
• LIP has been reported to improve with the use of zidovudine alone. Instances of resolution with highly active antiretroviral therapy (HAART) have been reported.²
• Bronchodilators may be used for associated wheezing.

Consultations

• Consultation with a pulmonologist or thoracic surgeon may be necessary to obtain transbronchial biopsy or open lung biopsy, respectively.
• In cases associated with HIV infection, consultation with a specialist familiar with HIV care is recommended.

Activity

• Activity may be limited by exercise-induced oxygen desaturation.
• Perform exercise oximetry to determine if supplementary oxygen is needed.

Medication

Medications should be used in patients who are symptomatic or physiologically compromised. Carefully weigh risks and benefits of immunosuppressive therapy in these patients.

HAART may result in improvement or resolution of LIP in some instances.²

One report describes dramatic improvement in LIP associated with common variable immunodeficiency treated with intravenous immunoglobulin without steroids.⁸

Corticosteroids

Used when patient is symptomatic and/or has physiologic compromise due to LIP. Risks of infection, osteoporosis, hyperglycemia, weight gain, dermatologic changes, and other potential toxicities should be weighed against any potential benefit.

Prednisone (Deltasone, Orasone, Sterapred)

For use as immunosuppressant in autoimmune disorders. By reversing increased capillary permeability and suppressing PMN activity, may decrease inflammation.
Doses on lower end of range are prescribed for at least 1 mo and tapered as tolerated. More than 50% respond. In some instances, chronic low-dose suppressive therapy required.

Dosing

Adult

0.5-1 mg/kg/d PO

Pediatric

Administer as in adults

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity, viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, fungal or tubercular skin infections, GI disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Alkylating agents

Are used when disease is refractory to corticosteroid therapy. Should be considered only in cases clearly unresponsive to corticosteroids used in high dosage. Should only be prescribed by physicians familiar with usage and toxicities. Generally prescribed for several weeks at a time; disease manifestations and complete blood count should be monitored.

Chlorambucil (Leukeran)

Reportedly given in pre-HIV era to patients with LIP refractory to corticosteroids. Anecdotal results, efficacy unclear.

Dosing

Adult

0.1 mg/kg/d PO

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; previous resistance to medication

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Causes infertility, is carcinogenic, and causes myelosuppression; lowest possible doses should be used; monitor CBC for neutropenia, lymphopenia, anemia, and thrombocytopenia; dosage is decreased or discontinued if counts fall below normal values; if rash develops, discontinue drug because it may cause severe Stevens-Johnson syndrome; potentially epileptogenic medication and should be administered with care to patients with history of seizure disorder, head trauma, or who receive other epileptogenic agents; monitor for GI bleeding or symptoms

Follow-up

Further Inpatient Care

• Exclude pulmonary infections.
• The presence of adequate oxygenation should be ascertained. Arrange for ambulatory supplementary oxygen if necessary.
• If a transbronchial or open lung biopsy has been performed, postprocedure pneumothorax should be excluded or demonstrated to be small and stable by expiratory chest radiographs.

Further Outpatient Care

• Periodically perform pulse oximetry at rest and with exercise.
• Encourage consistent use of a standardized exercise course such as a long corridor or several flights of steps.
• Obtain periodic chest radiographs and/or chest CT scan.
  • Assesses for improvement on therapy
  • Helps detect exacerbation of LIP or other pulmonary pathology, notably infections
  • Assesses for residual fibrosis
• Determining if remaining respiratory compromise is related to pulmonary fibrosis or some other pulmonary pathology is critical.
• Obtain clinical reevaluation, radiography, and/or chest CT scan if patient continues to require high-dose steroids.
• A change in sputum may be the only sign of infection.

Inpatient & Outpatient Medications

• After the first month of therapy and if disease activity allows it, gradually taper prednisone dosage. Use the lowest possible dose to suppress this chronic interstitial pneumonitis.
• Monitor patient for signs of infection and other toxicities of corticosteroid or immunosuppressive therapy.

Transfer

• Adequate gas exchange and a stable airway are required.
• Appropriate medical records and copies of actual chest radiographs should be transferred.

Complications

• Bronchiectasis has been associated with LIP. Whether this is due to LIP or the frequent bacterial infections these patients experience remains unclear.
• Bronchitis and pneumonia commonly occur in these patients, with or without bronchiectasis or cystic changes.
• Pulmonary fibrosis may be a long-term complication. Generally, it is indolent.
• Respiratory failure has been reported, especially in the pediatric population.
• Malignant transformation to lymphoma or association with lymphoid malignancy has been reported.

Prognosis

• Clinical course is variable. The duration is 1 month to 11 years. It often is stable for months without treatment, and sometimes it improves spontaneously.
• Symptoms often are recurrent and occasionally may lead to end-stage fibrosis or bronchiectasis.
• Mortality data are inexact due to lack of reported follow-up and the anecdotal nature of reports.

Patient Education

• Instructions to patients should include relating all potential toxicities of corticosteroids, including aseptic necrosis of the femoral head, infections, weight gain, hyperglycemia, and other adverse effects.
• Instruct patients to seek medical attention for increased dyspnea or change in sputum.

Multimedia

Media file 1: Chest radiograph of lymphocytic interstitial pneumonia in an adult who is HIV positive and has exertional dyspnea, demonstrating characteristic fine bibasilar interstitial markings

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].

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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

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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