(Chest. 2005;128:4008-4012.)
© 2005
American College of Chest Physicians
A 38-Year-Old Man With HIV Infection and Subacute Onset of Cough and Dyspnea*
Nawar Najjar, MD;
Amr El Gamal, MD;
Sahar Halabi, MD and
Vadim Leyenson, MD
* From the Department of Internal Medicine, St. Joseph Hospital, Chicago, IL.
Correspondence to: Amr El Gamal, MD, Department of Internal Medicine, St. Joseph Hospital, 2900 N Lake Shore Dr, Chicago, IL 60657; e-mail: gamalamr{at}yahoo.com
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Introduction
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A 38-year-old man with known HIV infection diagnosed 4 years prior to hospital admission presented with cough and clear sputum production of 10 weeks in duration. He received a 5-day course of levofloxacin with no significant improvement of his symptoms. Six weeks prior to hospital admission, he began to complain of fatigue and dyspnea on exertion. This became progressively worse over the last few days. He also noted to have a fever of 38.3°C. He has never been treated for HIV infection. He stopped smoking 2 years ago, after accumulating a 5-pack-year smoking history.
Examination revealed a well-built man with no acute distress. Temperature was 36.5°C, pulse rate was 86 beats/min, systolic/diastolic BP was 107/76 mm Hg, and respiratory rate was 18 breaths/min. Examination was remarkable for thrush and a nontender left submandibular lymph node. He had few crackles over the lung bases bilaterally. Cardiac and abdominal examinations were entirely normal.
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Laboratory Findings
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Laboratory findings included the following: WBC count, 4.9 x 103/µL; neutrophils, 48 x103/µL; lymphocytes, 26 x 103/µL; hematocrit, 41.4; platelets, 229 x 103/µL; and lactate dehydrogenase, 608 IU/L. Arterial blood gas analysis revealed pH 7.47; PCO2, 36 mm Hg; and PO2, 85 mm Hg while breathing room air. The chest radiograph is shown in Figure 1
, and CT of the chest is shown in Figure 2.
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What should be the next diagnostic test?
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What is the most likely diagnosis?
Diagnostic testing: Bronchoscopy and BAL
Findings of bacterial, fungal, and viral cultures, acid-fast bacilli stain and culture, as well as Legionella culture were all negative. Multiple transbronchial biopsy specimens were obtained. Flow cytometry revealed predominance of lymphocytes expressing CD8 marker (Table 1
).
Diagnosis: Lymphocytic interstitial pneumonitis
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Case Discussion
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Pulmonary infiltrates in patients with HIV infection encompass a broad spectrum of diagnostic possibilities, which include infectious (bacterial, viral, fungal) and noninfectious causes such as interstitial pneumonitis, and malignancy (Kaposi sarcoma, non-Hodgkin lymphoma). There are two distinct entities of interstitial pneumonitis in HIV, namely lymphocytic interstitial pneumonitis (LIP), manifesting as chronic pulmonary infiltrates in children with AIDS but rarely described in adults; and nonspecific interstitial pneumonitis, which is less clinically characterized than LIP and has been noted in both adults and children.
LIP is a rare lung disease that is characterized by infiltration of the interstitium and alveolar spaces by lymphocytes and plasma cells. This disease entity was first described in 1966; however, there has been a renewed interest in LIP due to its recognized association with AIDS, particularly in the pediatric population. This case illustrates the rare association of LIP with HIV infection in adults. Moreover, our patient had no evidence of immune system compromise secondary to HIV at the time of presentation.
LIP is classified as a form of idiopathic interstitial pneumonia by the American Thoracic Society/European Respiratory Society consensus statement of idiopathic interstitial pneumonias. The decision to retain LIP within the family of idiopathic interstitial pneumonias rather than the pulmonary lymphoproliferative diseases is due to the histologic appearance as a diffuse interstitial pneumonia, which may exist as an idiopathic, inflammatory, nonmalignant entity.
Idiopathic LIP presents more commonly in women, typically in the fifth decade; however, it can present at any age. Symptoms are generally poorly defined and are indistinguishable from other forms of idiopathic pneumonias. Patients present with a gradual onset of cough and dyspnea over 3 or more years. Constitutional symptoms such as fever, weight loss, and arthralgia are occasionally present. Bilateral basal crackles are common on clinical examination. Lymphadenopathy is not common, and its presence suggests an alternative diagnosis.
LIP may be associated with a number of lymphoproliferative and autoimmune disorders. The latter is reported to be present in 39% of LIP patients. Sjögren syndrome is noted in 25% of all cases of LIP. Furthermore, 1% of patients with Sjögren syndrome acquire LIP at some point in the course of their disease. According to Liebow et al, "other associations with LIP include dysproteinemia (monoclonal or polyclonal gammopathy is present in 75% of patients), myasthenia gravis, autoerythrocyte sensitization syndrome, chronic active hepatitis, primary biliary cirrhoses, and celiac sprue."
HIV infection is commonly associated with LIP in children, with an incidence ranging from 16 to 50%, in which it is considered an AIDS-defining illness. In adults with HIV, LIP is far less frequent and was found in < 5% of patients at necropsy. The association between LIP and HIV infection was first reported in the 1980s in several case reports. Whether or not LIP is caused by the lung immune response to the direct presence of HIV is still debatable. The pathogenesis of LIP in HIV remains unclear. HIV reverse transcriptase was simultaneously recovered from the serum and BAL fluid of a patient with AIDS and LIP. However, other studies reported the lack of HIV detection in BAL in four patients with HIV and LIP. Why only a minority of HIV patients acquire LIP is unknown; however, it seems that certain host factors, particularly human leukocyte antigen DR5, are concerned with the regulation of the immune response to HIV. Some reports suggested the association between HIV-positive status, human leukocyte antigen DR5, and the increase in the level of circulating CD8 lymphocytes with significant visceral infiltration, particularly the salivary glands, and the lungs, which is the most common manifestation of LIP. This association was named the diffuse infiltrative lymphocytic syndrome and is found only in a subset of HIV-positive patients.
Several studies investigated the role of infection with Epstein-Barr virus (EBV). The EBV genome was detected in the lung tissue of LIP using in situ hybridization and Southern blot hybridization. Furthermore, there is evidence that the viral latent membrane protein up-regulates the cellular proto-oncogene B-cell leukemia-2. This oncogene in turn inhibits apoptosis and transforms the lymphocytes. Co-infection with HIV and EBV may substantially increase the risk of development of LIP. In one study, HIV patients with LIP had significantly higher levels of anti-EBV antibodies compared to HIV patients without LIP.
Typical appearances on chest radiography are lower-zone reticular or reticulonodular shadowing, consolidation, or nodular infiltrates. In a study evaluating CT findings in LIP, all patients had bilateral ground-glass attenuation. The pattern was diffuse in 64%, patchy in 23%, and peripherally distributed in 14% of the patients. Bilateral centrilobular nodules were also noted in > 90% of patients and had a diffuse distribution in 86% of the patients, while patchy distribution was found in 14% of the patients. The next most common finding was interlobular septal thickening that was seen in 82% of the patients. Sixty-eight percent of patients had cystic air spaces, and a similar percentage had hilar or mediastinal lymphadenopathy or both. Less common findings were airspace consolidation, lung cysts, honeycombing, bronchiectasis, and pleural thickening (Table 2
).
The diagnosis of LIP can sometimes be made from transbronchial biopsy; however, the definitive diagnosis requires thoracoscopic or open-lung biopsy, as LIP has to be distinguished from other lymphoproliferative lung diseases. The main distinguishing feature is the illustration of polyclonal inflammatory nature of LIP, in contrast to the monotonous population of lymphoid cells in pulmonary lymphatics and bronchovascular bundles (Fig 3
). LIP may undergo spontaneous resolution, remission following treatment with corticosteroids or immunosuppressants, progression to lymphoma, or pulmonary fibrosis leading to respiratory failure and death.
Improvement in the manifestations of LIP in patients with HIV infection is closely related to the reduction in viral load and rise of the CD4+ count, hence a favorable response to antiretroviral therapy is expected. In a few case reports, zidovudine was used as a single agent or in combination with chloroquine with variable responses. Highly active antiretroviral therapy caused significant improvement in the clinical and radiologic findings in five patients with LIP and HIV who never had received antiretroviral agents. The present patient underwent transbronchial biopsy that demonstrated a predominance of CD8 lymphocytes and was started on HAART with initial improvement in both clinical and radiographic findings over a period of 2 months.
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Clinical Pearls
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- LIP is an interstitial lung disease with infiltration of the lung parenchyma with CD8 lymphocytes.
- LIP should be considered in the differential diagnosis of pulmonary infiltrates in adult patients with HIV, although it is seen more commonly in pediatric patients with HIV.
- Patients typically present with insidious onset of cough and dyspnea over months to years.
- Typical CT in findings in patients with LIP include bilateral ground-glass attenuation, diffuse bilateral small or large nodules, and interlobular septal thickening.
- A surgical or transbronchial lung biopsy is required to establish a diagnosis of LIP.
- LIP is associated with autoimmune disorders, with Sjögren syndrome being noted in 25% of all LIP cases.
- In addition to corticosteroids, treatment with HAART has been associated with a significant clinical and radiologic improvement in LIP in the HIV-positive patient.
Received for publication February 1, 2005.
Accepted for publication June 10, 2005.
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Suggested Readings
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- Carrington, CB, Liebow, AA Lymphocytic interstitial pneumonia [abstract]. Am J Pathol 1966;48,36a
- Crieco, MH, Chinoy-Acharya, P Lymphocytic interstitial pneumonia associated with the acquired immune deficiency syndrome. Am Rev Respir Dis 1985;131,952-955[Medline]
- Das, S, Miller, RF Lymphocytic interstitial pneumonitis in HIV infected adults. Sex Transm Infect 2003;79,88-93[Abstract/Free Full Text]
- Dean, NC, Golden, JA, Evans, LA, et al Human immunodeficiency virus recovery from bronchoalveolar lavage fluid in patients with AIDS. Chest 1988;93,1176-1179[Medline]
- Deheinzelin, D, Capelozzi, V, Kairalla, R, et al Interstitial lung disease in primary Sjogren’s syndrome. Am J Respir Crit Care Med 1996;154,794-799[Abstract]
- Dufour, V, Wislez, M, Bergot, E, et al Improvement of symptomatic human immunodeficiency virus-related lymphoid interstitial pneumonia in patients receiving highly active antiretroviral therapy. Clin Infect Dis 2003;15,36:127-130
- Hunninghake, GW, Zimmerman, MB, Schwartz, DA, et al Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001;164,193-196[Abstract/Free Full Text]
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Introduction
Laboratory Findings
