Lymphocytic Interstitial Pneumonia 

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. Dysproteinemia has been reported in association with LIP.^{[2, 3]}

LIP is also associated with infection via human immunodeficiency virus (HIV) type 1,^{[4, 5, 6]} Epstein-Barr virus, and human T-cell leukemia virus (HTLV) type 1.

Laboratory test results are nonspecific for LIP. The most essential items in the workup are the chest radiograph, measurement of gas exchange, and histology.

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. Oxygen supplementation may be considered on the basis of blood gas and/or exercise oximetry findings.

For other discussions on pneumonia, see the following:

• Mycoplasma Pneumonia
• Bacterial Pneumonia
• Viral Pneumonia
• Imaging Pneumocystis Carinii Pneumonia
• Community-Acquired Pneumonia
• Nosocomial Pneumonia
• Aspiration Pneumonia
• Pneumocystis (carinii) jiroveci Pneumonia
• Fungal Pneumonia
• Pneumonia, Immunocompromised
• Nursing Home Acquired Pneumonia
• Chlamydial Pneumonias
• Ventilator-Associated Pneumonia
• Imaging Typical Bacterial Pneumonia
• Imaging Atypical Bacterial Pneumonia
• Imaging Viral Pneumonia

HIV-related lymphocytic interstitial pneumonia (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.^[7]

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.^[8] Viruses (alone or in combination) may be responsible.^{[9, 10, 11]} Potential candidates include Epstein-Barr virus (EBV), human T-lymphotropic virus 1 (HTLV-1), and HIV-1.

Epstein-Barr virus

DNA from EBV 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-1

HTLV-1 is associated with a spectrum of pulmonary lymphoproliferative syndromes, including LIP. Serologic and molecular studies have correlated HTLV-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-1.

HIV-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.^[12] The beta-chemokines RANTES, MIP1-alpha and MIP1-beta, chemotactic for T cells, are increased in pediatric LIP lesions compared with controls.^[12]

Infiltrating B cells are polyclonal. Infiltrating T cells in HIV-related LIP are more commonly oligoclonal expansions than in HIV-negative LIP.^[13]

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.

Lymphocytic interstitial pneumonia (LIP) is an uncommon disease. In the United States, however, it 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. Small series have been reported in Europe, southwestern Japan, Africa, and the Caribbean basin.

Most cases of LIP 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, lymphocytic interstitial pneumonia has been designated an AIDS-defining illness by the US Centers for Disease Control and Prevention.

LIP is more common in women when not associated with HIV infection. HIV-associated sicca syndrome occurs most often in males.^[14]

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-1–associated LIP among individuals of African ancestry.^[15] LIP appears to cluster in southwestern Japan, where HTLV-1 is endemic.

The clinical course of LIP 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 and morbidity data are inexact because of the lack of reported follow-up, the anecdotal nature of reports, 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.

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. Patients should be instructed to seek medical attention for increased dyspnea or change in sputum.

Patient 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.^[14]

Physical examination

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

Physical examination findings in children may include the following:

• Generalized lymphadenopathy
• Hepatosplenomegaly
• Parotid enlargement
• Clubbing
• Wheezing (occasional)

Physical examination findings in adults may include the following:

• Generalized lymphadenopathy
• Rales
• Hepatosplenomegaly and parotid enlargement: present in approximately one third of adult patients

Complications

Bronchiectasis has been associated with lymphocytic interstitial pneumonia (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.

The differential diagnosis of LIP includes the following:

• Acute Respiratory Distress Syndrome
• Hypersensitivity Pneumonitis
• Lymphomatoid Granulomatosis
• Pneumocystis Carinii Pneumonia
• Bacterial Pneumonia
• Fungal Pneumonia
• Viral Pneumonia
• Pulmonary Edema, Cardiogenic
• Pulmonary Fibrosis, Idiopathic
• Pulmonary Fibrosis, Interstitial (Nonidiopathic)

Other problems to be considered include the following^{[16, 17, 18]} :

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

Laboratory test results are nonspecific for lymphocytic interstitial pneumonia (LIP). Serum protein electrophoresis commonly shows polyclonal hypergammaglobulinemia. In pediatric patients with LIP and HIV, lactate dehydrogenase (LDH) levels 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 for HIV-1, HTLV-1, EBV, and rheumatoid factor should be carried out.

Chest radiography

Bibasilar interstitial or micronodular infiltrates with coalescence into an alveolar pattern are present (see the image below).

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.

Computed tomography

Computed tomography (CT) scanning 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.^{[19, 20]}

Arterial blood gas measurement

Arterial blood gas measurement may be helpful in assessing the severity of illness, but the findings are nonspecific.

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.

Pulmonary function testing

Pulmonary function testing usually demonstrates restriction with a reduced or normal diffusion capacity. Obstructive airway disease has been reported occasionally.

Generally, bronchoscopy with transbronchial biopsy 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.

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.

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.

In pediatric patients with HIV, empiric treatment for lymphocytic interstitial pneumonia (LIP) often is initiated based on the findings of subacute dyspnea, mild hypoxemia, and clubbing.

Medications should be used in patients who are symptomatic or physiologically compromised.

Corticosteroids

Corticosteroids are used if the 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.

One report describes dramatic improvement in LIP associated with common variable immunodeficiency treated with intravenous immunoglobulin without steroids.^[21]

Alkylating agents

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

Other agents

Antibiotics are used for associated pulmonary infections.

LIP has been reported to improve with the use of zidovudine alone. Highly active antiretroviral therapy (HAART) may result in improvement or resolution of LIP in some instances.^[7]

Bronchodilators may be used for associated wheezing.

Oxygen supplementation

Activity may be limited by exercise-induced oxygen desaturation. Perform exercise oximetry to determine if supplementary oxygen is needed. Consider oxygen supplementation based on blood gas and/or exercise oximetry findings.

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.

Steps for inpatients

Steps for inpatients include the following:

• Exclude pulmonary infections.
• Determine whether oxygenation is adequate. Arrange for ambulatory supplementary oxygen if necessary.
• If a transbronchial or open lung biopsy has been performed, either exclude postprocedure pneumothorax or demonstrate that it is small and stable by means of expiratory chest radiographs.

Steps for outpatients

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, which are used for the following purposes:

• To assess for improvement on therapy
• To help detect exacerbation of lymphocytic interstitial pneumonia or other pulmonary pathology, notably infections
• To assess for residual fibrosis

Make every attempt to determine if remaining respiratory compromise is related to pulmonary fibrosis or some other pulmonary pathology.

Obtain clinical reevaluation, radiography, and/or chest CT scan if the patient continues to require high-dose steroids. A change in sputum may be the only sign of infection.

Modification of medication regimen

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

Evaluation for transfer

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