HIV-Associated Pneumonias
by Matthew Fei, MD and Laurence Huang, MD
Respiratory symptoms, including cough, shortness of breath, labored breathing, and chest pain, are common complaints in the setting of HIV infection. The spectrum of respiratory infections ranges from mild, self-limited viral upper respiratory infections to severe, life-threatening pneumonias requiring urgent hospitalization and treatment. In the United States, bacterial pneumonia and Pneumocystis pneumonia (PCP) are the two most common HIV-associated pneumonias. Although less common in the U.S., tuberculosis (TB) is the leading HIV-associated pneumonia worldwide.
While the overall incidence of opportunistic infections has decreased since the introduction of highly active antiretroviral therapy (HAART) in 1996, HIV-associated pneumonias remain a significant source of illness, and any respiratory complaint that may be due to pneumonia must be taken seriously. This review focuses on the most common HIV-related pulmonary infections—bacterial pneumonia, Pneumocystis pneumonia, and tuberculosis—and will provide an overview of the epidemiology, characteristic clinical and chest radiograph findings, diagnosis, treatment, and prevention of these pneumonias.
Epidemiology
Following the introduction of HAART and the use of preventive antibiotics for PCP, the prevalence of different HIV-associated pneumonias has changed. From the beginning of the HIV/AIDS epidemic through the early 1990s, PCP was the most common pneumonia seen in most U.S. institutions. At San Francisco General Hospital (SFGH), for example, approximately 25 cases of PCP were diagnosed monthly in 1992. In the mid-1990s, HAART became available and cases of PCP declined. Today, bacterial pneumonia is the most common HIV associated pulmonary infection seen at SFGH, with significantly fewer cases of PCP—roughly three or four cases per month. (Unfortunately, over 20% of the people diagnosed with PCP at SFGH in the post-HAART era are unaware of their HIV positive status at the time of presentation with PCP, emphasizing the need for early HIV testing.)
Globally, TB is the major pulmonary infection associated with the HIV epidemic. In sub-Saharan Africa, TB is probably the most common pulmonary complication of HIV infection: approximately one-third of persons with TB in Africa are also HIV positive. In contrast, as reported in the January 2002 issue of AIDS, TB accounted for less than 5% of pneumonias in a prospective study of 230 people admitted with HIV and pneumonia to an academic medical center in Atlanta, Georgia.
Risk for HIV-Associated Pneumonias
The relative health of the immune system, as measured by the CD4 cell count, is the most important factor in assessing the risk for various opportunistic pulmonary infections (Table 1).Typically, the severity of HIV infection can be stratified by CD4 cell count into several stages: above 500, 200–500, 50–200, and below 50 cells/mm3. A CD4 cell count above 500 cells/mm3 is indicative of a relatively intact immune system, and is typically seen in early HIV infection or after initiation of HAART and successful immune reconstitution. A CD4 cell count between 200 and 500 cells/mm3 signals immune suppression. When the CD4 cell count decreases below 200 cells/mm3, HIV infection has progressed to AIDS as defined by the U.S. Centers for Disease Control and Prevention (CDC).
Table 1. HIV-Associated Opportunistic Respiratory Infections
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RISK INCREASED AT
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INFECTION
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Any CD4 cell count
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Bacterial pneumonia (community-acquired pneumonia)
Tuberculosis
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CD4 <200 cells/mm3
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Pneumocystis pneumonia
Cryptococcus neoformans pneumonia, usually associated with disseminated disease
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CD4 <100 cells/mm3
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Toxoplasma gondii pneumonia, usually associated with disseminated disease
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CD4 <50 cells/mm3
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Endemic fungal pneumonia: Histoplasma capsulatum or Coccidioides immitis pneumonia, usually associated with disseminated disease
Cytomegalovirus pneumonia
Mycobacterium avium complex pneumonia, usually associated with disseminated disease
Aspergillus species pneumonia
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Among the various opportunistic pulmonary infections, bacterial pneumonia and TB are unique in that HIV infection increases the risk of contracting both illnesses even if the CD4 cell count is relatively preserved (above 500 cells/mm3). In addition, the overall risk of contracting bacterial pneumonia or TB increases as the CD4 cell count decreases. In contrast, pulmonary infections such as PCP, fungal pneumonias, Toxoplasma gondii pneumonia, and cytomegalovirus (CMV) pneumonia are typically seen only in the setting of severe immune suppression, after the CD4 cell count falls below 200 cells/mm3.
In addition to the CD4 cell count, several key factors increase and decrease the likelihood of pulmonary infection. Injection drug use increases the risk of bacterial pneumonia. A prior diagnosis of PCP is a significant risk factor for subsequent PCP infection, while prophylactic use of trimethoprim-sulfamethoxazole (TMPSMX, Septra, Bactrim) when the CD4 cell count falls below 200 cells/mm3 substantially decreases the risk of subsequent PCP. Cigarette smoking has been linked to increased risk of bacterial pneumonia and TB in both HIV positive and HIV negative individuals.
HIV infection is a risk factor for progression of latent tuberculosis infection (LTBI) to active tuberculosis disease. LTBI indicates prior infection with Mycobacterium tuberculosis and is defined by a positive purified protein derivative (PPD) skin test (which involves injecting 0.1 ml of sterile M. tuberculosis proteins under the skin of the forearm and assessing for swelling at the injection site 48 to 72 hours later), along with a normal chest radiograph (X-ray) and no symptoms con cerning for active TB. HIV positive individuals who have LTBI face a 10% per year risk of progressing from latent to active tuberculous disease, compared with an approximately 10% lifetime risk in the general population. Thus, all HIV positive persons are advised to be screened annually for LTBI, and those diagnosed with LTBI should receive therapy.
Symptoms
While there is no one sign or symptom that indicates a pulmonary infection, a cluster of complaints that suggests the need for further evaluation includes the presence of fever, cough, fatigue, or shortness of breath. Chest pain worsened by breathing or a decrease in the ability to exercise or perform usual daily activities are concerning as well. The duration and acuity of symptoms is important to note (Table 2). For example, bacterial pneumonia classically presents with the rapid onset of fevers, chills, cough, and shortness of breath over the course of three to five days, whereas PCP typically presents with the sub-acute, gradual progression of fever, cough, and shortness of breath over the course of two to four weeks. The production or non-production of sputum (material discharged from infected airways) is also noteworthy. While PCP typically causes a dry, non-productive cough, bacterial pneumonia is often associated with the production of thick, purulent (puscontaining) sputum. These observations, however, are generalizations, and exceptions to the rule can and do occur. For example, cases of PCP have presented with a productive cough (though usually of thin, clear sputum), and bacterial pneumonia can on occasion present with a sub-acute onset of symptoms over one week or more.
Table 2. Signs and Symptoms of Common HIV-Associated Pulmonary Infections
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CLINICAL FEATURES
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BACTERIAL PNEUMONIA
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PNEUMOCYSTIS PNEUMONIA
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TUBERCULOSIS
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Organisms
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Streptococcus pneumoniae, Haemophilus species, Pseudomonas aeruginosa, and others
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Pneumocystis jirovecii
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Mycobacterium tuberculosis
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Signs and symptoms
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Cough with purulent sputum, fever, chills
Acute onset, symptoms <1 week
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Nonproductive cough, shortness of breath, fever
Gradual onset, symptoms >2 weeks
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Cough, fever, night sweats, weight loss, swollen lymph nodes
Gradual onset, symptoms >2 weeks
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The presence of non-pulmonary signs and symptoms must also be noted, as these can be related to a primary pulmonary infection. Prolonged fevers over weeks to months, drenching night sweats, loss of appetite, and weight loss are commonly seen in the setting of active tuberculosis, Mycobacterium avium complex (MAC) that is disseminated (spread to other organs besides the lungs), and endemic fungal infections such as Coccidioides immitis (the causal pathogen of “Valley Fever,” common to the California Central Valley and the American Southwest). The common portal of entry for these organisms is the lungs, and disseminated infection can present with pneumonia. Confusion and headache may indicate both neurologic and pulmonary involvement by the fungus Cryptococcus neoformans. Blurry vision and abdominal pain may herald concurrent CMV infections of the eye, gastrointestinal tract, and lung. Finally, it must be emphasized that two or more opportunistic infections may present concurrently in the setting of HIV infection, especially with advanced immune suppression. For example, simultaneous infection with two different entities—such as PCP and bacterial pneumonia—may occur. The following sections discuss in more detail the three most common HIV-associated pulmonary infections: bacterial pneumonia, PCP, and TB.
Bacterial Pneumonia
HIV positive persons are at greater risk for bacterial pneumonia than are HIV negative individuals. Bacterial pneumonia is a frequent complication of HIV infection, and it often precedes other opportunistic infections. In many people, bacterial pneumonia may be the first manifestation of undiagnosed HIV infection.
Epidemiology
In HIV positive people, bacterial pneumonia is frequently recurrent; in fact, recurrent bacterial pneumonia, defined as two or more episodes within 12 months, became an AIDS-defining illness in the CDC’s 1993 Expanded Surveillance Case Definition for AIDS Among Adolescents and Adults. Persons with multiple episodes of bacterial pneumonia may develop bronchiec tasis (permanent destruction and dilatation of the bronchial airways) and other irreversible damage to their lungs.
In 1995, the Pulmonary Complications of HIV Infection Study group (PCHIS) published a paper describing the increased risk of bacterial pneumonia in the setting of HIV infection. The PCHIS was a multicenter study with six sites across the United States, one of which was SFGH. The study authors found that the rate of bacterial pneumonia was higher in the HIV positive population, even when the CD4 cell count was greater than 500 cells/mm3. In addition, the rate of bacterial pneumonia increased as the CD4 cell count declined. In this study, the incidence of bacterial pneumonia among injection drug users was significantly higher than the rates found among both female heterosexuals and men who had sex with men. Among persons with CD4 cell counts less than 200 cells/mm3, those who smoked cigarettes had a higher incidence of bacterial pneumonia compared with non-smokers.
Etiology
Many bacterial pathogens have the potential to cause HIV-associated pneumonia. Studies have found that two of the most common bacteria are Streptococcus pneumoniae and Haemophilus influenzae. “Atypical” organisms, such as Mycoplasma, Legionella, and Chlamydophila, can also cause pneumonia. Pseudomonas aeruginosa and Staphylococcus aureus are both reported as community-acquired pathogens seen with an increased frequency in HIV positive persons. However, it is not uncommon to never identify the infectious organism despite culturing samples of blood and sputum. In the aforementioned Atlanta study, which investigated the microbiologic cause of 230 cases of HIV-associated pneumonia, the authors were unable to isolate the causative organism in 33% of cases. Nevertheless, in the majority of cases of “culture-negative” bacterial pneumonia, symptomatic improvement and recovery occur with antibiotics appropriate for the diagnosis of bacterial pneumonia.
Clinical and radiographic presentation
The clinical and radiographic presentation of bacterial pneumonia in HIV positive persons is similar to that in HIV negative individuals. Persons with pneumonias due to Streptococcus pneumoniae and Haemophilus species characteristically present with an acute onset (three to five days) of symptoms, including fevers, chills, rigors, chest pain, cough productive of purulent sputum, and dyspnea (labored breathing). The patient’s white blood cell (WBC) count is usually elevated. Persons with bacterial pneumonia characteristically present with unilateral (on one side only), focal (having a clear focus), segmental (located in a specific segment of the lungs), or lobar (located in a specific lobe, or side, of the lungs) consolidation on chest radiograph (Figure 1). However, the frequency of these typical radiographic findings may depend on the underlying bacterial pathogen. HIV positive persons may present with multifocal or multilobar involvement and with parapneumonic effusions— accumulations of fluid between layers of the membrane that lines the lung and the chest wall—more frequently than HIV negative individuals.
Figure 1: Chest radiograph of an HIV positive individual with a CD4 cell count above 200 cells/mm3, revealing right upper lobe consolidation. Sputum and blood cultures were positive for Streptococcus pneumoniae. Courtesy of Laurence Huang, MD.
Diagnosis
The evaluation for bacterial pneumonia typically involves an attempt to isolate the infectious pathogen in cultures of blood, sputum, and potentially other sterile areas such as pleural fluid (fluid accumulating in the pleural space, which surrounds the lungs in the chest cavity). While it is quite uncommon for PCP to disseminate and cause infection outside of the lung, pathogens responsible for bacterial pneumonia can often invade the lung barrier to gain access to the normally sterile bloodstream. From there, these bacteria can cause widespread infections of not only the blood (bacteremia) but also the heart valves (endocarditis), the pleural space (empyema), and the tissue layer surrounding the brain, or meninges (meningitis). In the setting of disseminated disease, the sequelae of infection can be quite morbid—long-term neurologic defects following S. pneumoniae meningitis are seen up to 25% of the time, and surgical replacement of infected heart valves is required in some instances of endocarditis.
Treatment
Treatment approaches for bacterial pneumonia differ based on whether the illness is severe enough to warrant hospital admission. Outpatient treatment for mild cases of bacterial pneumonia can be accomplished and usually involves seven to ten days of oral antibiotics. In the hospital setting, intravenous antibiotics are typically administered. The U.S. Public Health Service and Infectious Diseases Society of America recommend that HIV positive persons with suspected or confirmed bacterial pneumonia and who are being treated as inpatients should receive an intravenous betalactam antibiotic plus either a macrolide or doxycycline. The preferred betalactam antibiotics are ceftriaxone (Rocephin), cefotaxime (Calforan), or ampicillin (Omnipen, Polycillin, Principen).
Prevention
Because of the increased risk of disseminated disease with bacterial pneumonia, it is recommended that all HIV positive adults with a CD4 cell count greater than 200 cells/mm3 receive the 23-valent polysaccharide pneumococcal vaccine (PPV). The PPV works by stimulating an antibody response against sugars in the protective capsule of S. pneumoniae. The PPV may lose some efficacy if given after the CD4 cell count falls below 200 cells/mm3, as a protective immune response may fail to mobilize. In these persons, revaccination may be considered if the CD4 cell count rises above 200 cells/mm3, as a result of HAART.
Pneumocystis Pneumonia
Pneumocystis pneumonia (PCP) is caused by the fungal pathogen Pneumocystis jirovecii (formerly known as P. carinii). PCP is the most common AIDS-defining opportunistic infection in the United States and typically causes disease only when the CD4 cell count falls below 200 cells/mm3. PCP research has been hampered by the inability to culture this organism.
Epidemiology
On the basis of antibody testing, it is believed that the majority of people are infected with Pneumocystis early in childhood. The conventional theory is that PCP results from reactivation of this latent childhood infection, but studies suggest that PCP may also result from a recent exposure and infection. The route of transmission of PCP and its natural reservoir are incompletely understood, though a respiratory route of infection has been implicated in well-controlled animal studies. Currently, there is evidence that person-to-person transmission does occur, and recent molecular studies have shown that the organism can reside in the lungs without causing symptoms (referred to as “colonization”). The significance of colonization is unknown. Nevertheless, unlike management of TB, respiratory isolation for PCP is not routinely recommended at this time.
Clinical and radiographic presentation
The clinical presentation of PCP in HIV positive persons differs from the presentation in other immuno-compromised persons; in general, HIV positive individuals present with a sub-acute onset (two to four weeks) and a longer symptom duration. Classically, PCP presents with fever, cough, and shortness of breath. The cough is usually dry and non-productive unless a concurrent bacterial infection is present. The cough may be exacerbated by deep breathing and occasionally accompanied by “chest tightness.” Symptoms are often subtle at the onset but are gradually progressive and may be present for weeks and occasionally months before diagnosis.
No current laboratory test is specific for PCP. The serum lactate dehydrogenase (LDH) is usually found to be elevated; however, the LDH can be elevated in response to a variety of pulmonary and non pulmonary conditions. On chest radiograph, persons with PCP characteristically present with bilateral (on both sides), reticular (network-like), or granular (grainy-looking) opaque areas, or opacities (Figure 2).
Figure 2. Chest radiograph of an HIV positive person with a CD4 cell count below 200 cells/mm3, demonstrating the characteristic bilateral granular opacities of PCP.
Bronchoscopy with bronchoalveolar lavage fluid microscopic examination revealed Pneumocystis cysts and trophic forms. Courtesy of Laurence Huang, MD.
Occasionally, persons with PCP may have a normal or minimally abnormal chest radiograph and may undergo high-resolution computed tomography (HRCT) of the chest for further evaluation. On chest HRCT, persons with PCP characteristically present with bilateral, patchy areas called “ground-glass” opacities (Figure 3).
Figure 3: Chest high-resolution computed tomography (HRCT) scan of an HIV positive person with a CD4 cell count below 200 cells/mm3 whose chest radiograph was normal. Chest HRCT scan revealed the characteristic patchy ground-glass opacities of PCP. Induced sputum microscopic examination revealed Pneumocystis cysts and trophic forms. Courtesy of Laurence Huang, MD.
Diagnosis
There is no universally agreed-upon approach to the management of HIV positive persons with suspected PCP. Many institutions treat persons with suspected PCP based solely on the patients’ symptoms and chest radiographic presentation, while other institutions (such as SFGH) pursue a definitive microscopic diagnosis. Because Pneumocystis cannot be cultured, the diagnosis of PCP relies on microscopic examination of the characteristic cysts and/or trophic forms (different stages of the pathogen’s life cycle) on respiratory specimens that have been stained to make their microscopic structures more clearly visible. Typically, these respiratory specimens are obtained from sputum induction (a procedure to stimulate sputum production through the inhalation of hypertonic saline mist) or bronchoscopy with bronchoalveolar lavage (BAL; a procedure, performed by a pulmonary specialist, in which a fiberoptic bronchoscope is passed into the throat and wedged deep into an airway, saline is instilled, and fluid is aspirated back and sent for study). Several studies have examined the utility of applying a sensitive and specific molecular assay (e.g., polymerase chain reaction, or PCR) to a simple, non-invasive, 60-second procedure called oropharyngeal washing (OPW) to collect specimens for PCP diagnosis. However, although results indicate that PCR with OPW is a sensitive and specific test for PCP, it is mainly a research tool at present.
Treatment
Unfortunately, the health consequences of PCP infection can be severe. Outpatient treatment may be appropriate in cases of mild infection but most people with PCP require hospitalization and close observation. Indications for hospital admission include low oxygen saturation of the blood, severe shortness of breath, and persistent or worsening symptoms de- spite the use of appropriate oral PCP treatment. In the HIV positive population, PCP remains the most common reason for respiratory failure and need for mechanical ventilation (“breathing machine”). While the number of PCP infections has declined substantially since the introduction of PCP prophylaxis and HAART, mortality from severe PCP requiring admission to an intensive care unit and subsequent mechanic