Vanishing Lung Syndrome and HIV Infection

Abstract

Persons with HIV infection have a higher risk of infectious pulmonary complications, chronic obstructive pulmonary disease, lung cancer, pulmonary hypertension, and pulmonary fibrosis than individuals not infected with HIV. Herein, we describe the clinical course of a patient with longstanding and well-controlled HIV infection and multiple previous pneumothoraces who presented to medical attention with insidious onset of shortness of breath and was diagnosed with vanishing lung syndrome (VLS). The VLS or giant bullous emphysema is a distinct clinical syndrome characterized by large bullae, predominantly in the upper lobes, occupying at least one third of the hemithorax and compressing surrounding normal lung parenchyma. It is a progressive disorder that typically occurs in young men, the majority of whom are smokers. As people with HIV/AIDS are now surviving well into middle age and beyond, clinicians are more likely to encounter VLS and severe obstructive lung disease, which are potentially fatal but preventable conditions.

Introduction

HIV-associated morbidity and mortality have declined dramatically in resource-rich countries since the mid-1990s when highly active antiretroviral therapy (HAART) became widely available. ^1,2 Before the HAART era, the most common pulmonary conditions encountered in HIV-infected patients were infectious and included acute bronchitis, Pneumocystis jiroveci pneumonia, and bacterial pneumonia. ³ Recent studies suggest that nonopportunistic infectious pulmonary complications remain problematic and there is an increased risk of chronic obstructive pulmonary disease (COPD), lung cancer, pulmonary hypertension, and pulmonary fibrosis in people living with HIV/AIDS (PLWA) compared with individuals not infected with HIV. ^4,5 Herein, we describe the clinical course of a patient with HIV infection presenting with vanishing lung syndrome (VLS), a disorder marked by the insidious onset of prominent bullous changes in 1 or both lungs, which can culminate in life-threatening obstructive lung disease. ⁶

Case Report

A 39-year-old HIV-infected white man with a 15-pack-year history of cigarette smoking but no illicit recreational or intravenous drug use (IVDU) sought medical attention for worsening shortness of breath, productive cough, and back pain of 3 days’ duration. He had not experienced fevers or weight loss and denied palpitations or chest pain.

He had been diagnosed with AIDS greater than a decade ago but had been faithful in taking his antiviral tenofovir [TDF], lamivudine [3TC], atazanavir [ATV], and ritonavir [RTV]) without deviation and had consistently nondetectable HIV viral loads and a well-reconstituted immune status as reflected by CD4 counts typically greater than 350 cells/mm³.

His pulmonary history included 4 separate episodes of spontaneous pneumothoraces, the first occurring at age 15 years. In 2 instances, chest tube placement was necessary to re-expand his lungs. Right upper lobe blebectomy and talc pleurodesis was performed to treat the third instance 3 years ago (Figure 1A). A fourth intervention included video-assisted thoracic surgery with mechanical and talc pleurodesis to expand a left pneumothorax and occurred 1 year prior to the current encounter. Subsequent pulmonary function tests documented significant persistent dysfunction, including a forced vital capacity of 41% and diffusion capacity of 25% of predicted. He did not have a clinical history or histopathologic evidence of Pneumocystis jiroveci infections.

Figure 1.

A, Photomicrograph showing a large subpleural emphysematous bulla within which there are discontinuous fragments of alveolar septa (large straight arrows). Within the overlying pleura there is an associated pleural bleb (smaller curved arrow). B, Noncontrast computerized tomography of chest demonstrating extensive bullous lung disease, with markedly decreased left lung parenchyma due to massive expansion of bullae.

On physical examination, he was afebrile but diaphoretic, with a pulse rate of 104/min and respiratory rate of 26/min. He had diminished breath sounds in the left lower lung fields with slight expiratory wheezes. Laboratory assessment included a normal complete blood count and chemistry panel, an undetectable HIV viral load and a CD4 count of 414 cells/mm³. Arterial blood gas on 2 L of oxygen showed a pH of 7.45, PCO₂ of 36, PaO₂ of 63, and an A-a gradient of 105 mm Hg (normal, 5-15 mm Hg). No mutations for alpha-1-antitrypsin deficiency (AAT) were identified. Chest roentgenogram was initially interpreted as consistent with a new left pneumothorax, but a chest CT scan (Figure 1B) showed extensive and progressive bullous disease of the lung with decreased left lung parenchyma due to bullae expansion, otherwise known as VLS, and T7 to T8 compression fractures.

Consulting cardiothoracic and pulmonary teams recommended conservative management of his dyspnea. Despite treatment with bronchodilators, corticosteroids, and empiric antibiotics, he remained dependent on supplemental oxygen via nasal cannula. After experiencing new onset lower extremity weakness and worsening back pain on day 3 following hospitalization, he underwent a magnetic resonance imaging of the spine which revealed a T8 spinal tumor and multiple lumbar and thoracic osteoporotic compression fractures. He underwent a T8 laminectomy and resection of a schwannoma and a week later our interventional radiologists performed adjacent vertebroplasties of T7 and T10.

After a rehabilitation stay at a skilled nursing facility for several weeks he was discharged home, now too short of breath to carry out his activities of daily living without help from several friends and home health agencies, including palliative care. Owing to persistent respiratory symptoms from bullous emphysema, he is currently being evaluated for lung transplant; 2 transplant programs have already rejected his candidacy because of his HIV-seropositive status.

Discussion

The VLS or giant bullous emphysema is a distinct clinical syndrome characterized by large bullae predominantly in the upper lobes, occupying at least one third of the hemithorax and compressing surrounding normal lung parenchyma. ⁶ It is a progressive disorder that typically occurs in young men, the majority of whom are smokers. Treatment involves conservative management or surgical bullectomy, depending on the extent and location of the bullae and patient’s degree of limitation. ⁷

We believe that this is the first reported case of HIV-associated VLS. HIV infection accelerates the onset of cigarette smoke-induced emphysema. ⁸ In the Veterans Aging Cohort study, after adjusting for differences in age, smoking, race/ethnicity, and other potential confounders such as IVDU and alcohol abuse, PLWA were approximately 50% to 60% more likely to have COPD than HIV-negative patients. ⁹ Potential mechanisms of increased risk of emphysema with HIV infection include upregulation of matrix metalloproteases, lymphocytic alveolitis, and expression of interferon (IFN)-gamma, episodes of clinical pneumonia or colonization with respiratory organisms including Pneumocystis jiroveci and increased oxidative stress. ^10,11 Other causes for bullous lung disease include AAT deficiency, IVDU, connective tissue disease (cutis laxa, Marfan syndrome, Ehlers-Danlos syndrome), sarcoidosis, hypocomplementemic urticarial vasculitis, malnutrition, and rare metabolic disorders like Salla disease, a disorder of sialic acid metabolism and Menke syndrome, a genetic disorder affecting transport protein-mediated copper uptake from the intestine. ¹² Our patient did not have a history of IVDU, Pneumocystis jiroveci infection, AAT deficiency, or connective tissue disorders. Although his body mass index was chronically slightly depressed at 18.2 (normal, 18.5-25), his serum albumin was consistently within normal levels. His antiviral medications had remained constant for many years, and we were not able to identify a connection between the type of HAART and VLS. Consequently, it is most likely that his diagnosis of VLS is related to cigarette smoking and chronic HIV infection.

Pneumothorax is an uncommon but potentially fatal complication of HIV infection. In a prospective observational study of 599 consecutive HIV-infected patients who were hospitalized for a variety of reasons, 1.2% developed pneumothorax during their inpatient stay. ¹³ Pneumothorax was associated with a poor outcome, with an in-hospital mortality rate of 31% among patients with HIV infection and pneumothorax compared to 6% among HIV-seropositive patients who were hospitalized and did not develop pneumothorax.

Most cases of secondary pneumothorax in HIV-infected individuals occur in conjunction with bacterial or Pneumocystis jiroveci pneumonia. ^14,15 The exact mechanism behind the development of the pulmonary cysts and pneumothoraces sometimes seen in conjunction with Pneumocystis jiroveci is not yet known. The various mechanisms proposed include tissue invasion by the organism and subsequent necrosis of pulmonary parenchyma, overdistension of the lungs caused by obstructive bronchiolitis with inflammatory exudates in the small bronchioles acting as a ball valve, interstitial emphysema, and abnormal remodeling of pulmonary architecture due to interstitial fibrosis, and release of elastase and other proteolytic enzymes. ^{16 –18} Risk factors associated with spontaneous pneumothorax in conjunction with Pneumocystis pneumonia include history of cigarette smoking, pentamidine aerosol treatment, and detection of pneumatoceles by chest radiography. ¹⁹ In addition to trauma and iatrogenic causes (most notably in conjunction with central venous line placements), pneumothorax in PLWA has also been associated with pulmonary Kaposi sarcoma, ²⁰ bullous emphysema due to IVDU, ²¹ and fungal, viral, and mycobacterial infections. ¹⁴ Given our patient’s experience, giant bullous emphysema, otherwise known as VLS must also be considered in the differential diagnosis.

The prevalence of smoking among HIV-infected patients ranges from 40% to 70% in contrast to 21% among US adults. ²² As PLWA are now surviving well into middle age and beyond, clinicians are more likely to encounter VLS and severe obstructive lung disease, which are potentially fatal but preventable conditions. ²³ Chronic obstructive pulmonary disease is the most common noninfectious pulmonary disease in HIV-infected patients, with 16% carrying a baseline or incident diagnosis of COPD. ⁴ HIV-infected current smokers have an approximately 2-fold increased hazard for bacterial pneumonia compared with those who have never smoked, with a population-attributable risk percentage for pneumonia due to current smoking estimated at 25%. ^{24 –27} The added concern of malignancies of the head and neck, lung, and gastrointestinal system associated with smoking are also significant as are the enhanced risks of cardiovascular complications associated with this habit. ²⁷

Smoking cessation must be a priority goal addressed during our clinical encounters. HIV care providers may be less aware of smoking among their patients than general medicine providers and less confident in their ability to achieve smoking cessation in their patients, hence higher provider awareness of current smoking among HIV-infected patients and increased provider training in smoking cessation are desperately needed. ^28,29 Barriers to achieving smoking cessation include the high rates of IVDU, alcohol abuse, as well as mental health disorders which are prevalent in this diverse patient population. Available evidence suggests that smoking cessation interventions that have been employed in the general population including smoking cessation counseling and medications (eg, bupropion, varenicline, and nicotine replacement therapy) can also be effectively utilized in the setting of HIV infection. ^30,31 Smoking cessation treatment tailored to the special needs of individuals living with HIV/AIDS, such as counseling delivered by cellular telephone, can also significantly increase smoking abstinence rates over that achieved by usual care. ³²

Treatment of VLS includes conservative management or surgical bullectomy, based on the patient’s functional status and the extent and location of the bullae. ⁷ Our patient is also being evaluated for lung transplantation. HIV-infected patients are increasingly undergoing successful liver, kidney, and heart transplantation surgeries without disproportionate mortality compared with age-matched HIV-seronegative patients undergoing similar organ transplants for similar reasons. ³³ Lung transplantation in the backdrop of HIV infection is still considered a relative contraindication because of the increased risk of infectious complications and the interactions between HAART and immunosuppressive therapy, specifically between calcineurin inhibitors and protease inhibitors. ³⁴ As our patients’ pulmonary reserves continue to dwindle, we look to lung transplantation as a viable option, bolstered in part by 2 recent case reports describing good outcomes: one in a patient with HIV infection and cystic fibrosis and the second in a patient with HIV infection and severe interstitial pulmonary fibrosis and concomitant pulmonary hypertension. ^35,36

This case report which describes a rare but significant cause of life-threatening shortness of breath serves to underscore the importance of advising our patients not to smoke and to be mindful of pulmonary complications that are seen in the HAART era.