Acute Primary Human Immunodeficiency Virus Infection

The time from acquisition of HIV infection to development of detectable antibodies (the “window” period) usually is about 6 to 8 weeks. For 30% to 70% of people who become infected, a seroconversion illness is typical. Antibodies to HIV antibody normally are detectable within 2 to 3 weeks of onset of these symptoms, though this can take longer. HIV RNA in peripheral blood is detectable before the appearance of antibodies and often is used to confirm infection.

The nonspecific features of primary “seroconversion” HIV infection usually are self-limiting, and the infection typically mimics a flu-like illness or glandular fever. Nearly all persons with primary HIV infection spontaneously recover within 4 weeks, irrespective of their acute symptoms. A small proportion develop persistent (symmetric) generalized lymphadenopathy. The prognosis for this group is no different from that for asymptomatic HIV-positive persons.

Chronic Human Immunodeficiency Virus Infection

Although a proportion of HIV-seropositive persons remain completely well without ART for an extended period (approximately 20%, after 10 years), many infected persons have minor symptoms and signs suggesting immune dysfunction. Oral candidiasis and constitutional symptoms (e.g., malaise, idiopathic fever, night sweats, diarrhea, weight loss) are the strongest clinical predictors of progression to AIDS.

The term AIDS was originally created as an epidemiologic tool to capture specific clinical presentations, which early in the HIV epidemic appeared to suggest significant immune deficiency. Over the past 30 years, the definition has been modified to incorporate the expanding spectrum of diseases affecting HIV-infected patients, including cervical carcinoma and recurrent bacterial pneumonia (see Box 29-2). The 1993 CDC classification included an immunologic criterion for AIDS (CD4⁺ count below 200 cells/µL or CD4⁺ percentage less than 14% of total lymphocytes) regardless of clinical symptoms (see Table 29-2). These data are used to define a point at which the risk for severe opportunistic infection rises dramatically.

Apart from cervical carcinoma, AIDS indicator diseases differ little between men and women. Injection drug users in the United States and the United Kingdom have a high incidence of recurrent bacterial pneumonia and tuberculosis. Geographic differences occur that reflect the opportunistic pathogens present in the local environment (e.g., histoplasmosis or visceral leishmaniasis usually are found only in patients from endemic areas). In the developed world, survival differences after an AIDS diagnosis mainly arise from variation in ease of access to and provision of medical care. It is clear that better treatment outcomes are associated with specialist care provided by treatment centers with extensive experience in the management of HIV-infected persons.

In countries in which ART is available, the spectrum of HIV-related disease has changed over the past 30 years. In the HIV Outpatient Study (HOPS), a prospective multicenter observational study in the United States, between 1994 and 2007, opportunistic infections associated with very low CD4⁺ counts (e.g., cytomegalovirus retinitis, Mycobacterium avium complex [MAC] infection) declined rapidly after introduction of ART and stabilized at low levels during the period 2003 to 2007. In the EuroSIDA cohort (a pan-European prospective study of HIV infection), between 1994 and 2004, opportunistic infections were observed less frequently over time, and malignant disease, such as non-Hodgkin lymphoma, increased as an AIDS-defining event.

Although death rates have fallen in ART-treated populations, there has been a rise in the proportion of non-AIDS deaths. In some series, this category accounts for a majority of events. Causes include liver disease (often due to viral hepatitides) and cancer, as well as cardiovascular disease and drug-related toxicity. In such circumstances, AIDS deaths usually occur among patients who have not accessed medical care regularly and who present with advanced HIV disease.

A new manifestation of opportunistic infection has been described in patients commencing ART. The immune reconstitution inflammatory syndrome (IRIS) (the pathogenesis of which is discussed later under treatment for tuberculosis) may cause severe if temporary clinical illness as the patient’s immunity recovers. Patients appear to experience a relapse of their original (and often incompletely treated) disease. IRIS often is seen in MAC infection, tuberculosis, hepatitis B, CMV retinitis, and herpesvirus infection. In the developed world, metabolic complications of ART, such as ischemic heart disease, hypertension, diabetes, and cerebrovascular disease, are increasingly encountered by clinicians providing care. A significant number of persons receiving ART also experience drug toxicity. An increasing number of patients also are surviving to manifest symptoms associated with chronic hepatitis B and C virus infection. HIV-associated nephropathy (often with chronic kidney disease) is common among black Africans and is a significant cause of long-term morbidity.

Bronchitis

The clinical presentation in bronchitis mimics that in bacterial exacerbations of chronic obstructive lung disease; most patients have a productive cough and fever. The pathogens commonly identified are similar to those in the general population (e.g., Streptococcus pneumoniae and Haemophilus influenzae). However, patients with advanced disease may be infected with Pseudomonas aeruginosa or Staphylococcus aureus. Response to appropriate antibiotic therapy in conventional doses is good, although relapses are common.

Bronchiectasis

Bronchiectasis is increasingly recognized in HIV-infected patients with advanced HIV disease and low CD4⁺ lymphocyte counts. It probably arises secondary to recurrent bacterial, mycobacterial or P. jirovecii infections. The diagnosis most often is made by high-resolution (thin-section) computed tomography (CT) scanning (Figure 29-2). Its prevalence has not been accurately determined, although with improved survival from both opportunistic infections and HIV disease, it can be expected to be increasingly common in clinical practice. The pathogens isolated in patients with bronchiectasis are those seen in bronchitis. In addition, Burkholderia cepacia and Moraxella catarrhalis have been described.

Figure 29-2 Computed tomography scan of thorax showing widespread bronchiectasis in a patient with a previous history of multiple episodes of bacterial pneumonia.

Pneumonia

Community-acquired bacterial pneumonia occurs more frequently in HIV-infected patients than in the general population. It is especially common in HIV-infected injecting drug users. The spectrum of bacterial pathogens is similar to that in non–HIV-infected persons (see Box 29-1). S. pneumoniae is the most commonly identified pathogen, followed by H. influenzae. HIV-infected patients with S. pneumoniae–related pneumonia frequently are bacteremic. In one study, the rate of pneumococcal bacteremia in HIV-infected patients was 100 times that for an HIV-negative population. More recent work has confirmed this to be the case for all causes of HIV-related bacterial pneumonia. Typically, blood cultures have a 40-fold increased pick-up rate in HIV-positive patients. The widespread use of ART has led to some decrease in rates of bacterial pneumonia and bacteremia, although they are still considerably higher than in a non–HIV-infected population.

Bacterial pneumonia has a similar presentation in HIV-infected patients and in uninfected persons. Chest radiographs frequently are atypical in appearance, mimicking that in PCP in up to half of the cases (Figure 29-3). By contrast, radiographic lobar or segmental consolidation also may be seen in a wide range of bacterial organisms (Figure 29-4); these include S. pneumoniae, P. aeruginosa, H. influenzae, and M. tuberculosis. PCP also may manifest with lobar or segmental consolidation. In patients with more advanced HIV disease and low CD4⁺ lymphocyte counts, P. aeruginosa and S. aureus also can cause pneumonia.

Figure 29-3 Chest radiograph showing bilateral, diffuse, interstitial infiltrates mimicking the changes of Pneumocystis jirovecii pneumonia. The etiologic agent was Streptococcus pneumoniae.

Figure 29-4 Chest radiograph showing lobar consolidation. The etiologic agent was Salmonella choleraesuis.

Complications of bacterial pneumonia are frequent, and pleural effusions are twice as likely in HIV infection (often occurring with S. aureus infection); empyema and intrapulmonary abscessation are present in up to 10% of patients. Inevitably, the mortality rate is high (approximately 10%).

Other Bacterial Infections

Tuberculosis

HIV infection is associated with a 20- to 40-fold increased risk for development of active tuberculosis disease in a person with latent tuberculosis infection (LTBI) over that in noninfected subjects. Taken together with its ability to infect both the immunocompromised and the immunocompetent, tuberculosis is perhaps therefore the single most important disease associated with HIV infection. It is estimated that each year, 1.1 million new cases of active tuberculosis occur in HIV-infected patients. Accordingly, tuberculosis is a major cause of HIV-related morbidity and mortality. It also is a clear driver in both resource-rich and poor countries for the current overall increase in tuberculosis rates. Where HIV infection is endemic, tuberculosis control at a population level is almost impossible if treatment for both infections is not available.

In the United Kingdom, many centers routinely offer HIV antibody testing to all patients with tuberculosis, regardless of risk factors for HIV infection. In the United States, the CDC now recommends HIV testing as a routine part of health care for all patients 13 to 64 years of age seeking medical services. The benefit of treating HIV co-infection is indisputable. Moreover, strategies that reduce high-risk behavior and cut ongoing HIV transmission can be introduced. Unfortunately, offering HIV testing in tuberculosis clinics has not been routine practice in many countries, and integration with HIV infection–related services is poor. This disconnect leads to both diagnostic delay of HIV infection and potentially suboptimal, uncoordinated care, with potentially disastrous outcomes.

Active tuberculosis can occur at any stage of HIV infection and, unlike almost every other HIV-related infection, may do so despite effective ART. In the United States, the United Kingdom, and most European countries, reporting of tuberculosis in both HIV-infected and non–HIV-infected patients is mandatory.

Clinical disease in HIV-infected patients may arise in several different ways: by reactivation of latent tuberculosis, by rapid progression of pulmonary infection, and by reinfection from an exogenous source.

Pulmonary disease is the most common presentation, and clinical manifestations are determined by the patient’s level of immunity. For example, persons with reasonably well-preserved CD4⁺ counts exhibit clinical features similar to those of “normal” adult postprimary disease (Table 29-3). Signs and symptoms typically include weight loss, fever with sweats, cough, sputum, dyspnea, hemoptysis, and chest pain. These patients may have no clinical features to suggest associated HIV infection. The chest radiograph frequently shows upper lobe consolidation, and cavitary change is common (Figure 29-5). If performed, the tuberculin skin test (TST), using purified protein derivative (PPD), usually gives a positive result, and the likelihood that spontaneously expectorated sputum or BAL fluid will be smear-positive for acid-fast bacilli is high.

Table 29-3 Tuberculosis and Human Immunodeficiency Virus (HIV) Infection

Figure 29-5 Chest radiograph showing pathologic changes of pulmonary tuberculosis in early-stage human immunodeficiency virus infection. Upper lobe infiltrates and cavities are seen.

In persons with advanced HIV disease (i.e., low CD4⁺ lymphocyte counts and clinically apparent immunosuppression), it may be difficult to diagnose tuberculosis. The clinical presentation here often is with nonspecific symptoms. Fever, weight loss, fatigue, and malaise may be mistakenly ascribed to HIV infection itself. In this context, pulmonary tuberculosis is often similar to primary infection, with the chest radiograph showing diffuse or miliary-type shadowing (Figure 29-6), hilar or mediastinal lymphadenopathy, or pleural effusion; cavitation is unusual, with no upper zone chest radiographic predominance. In up to 10% of patients, the chest radiograph may appear normal; in others, the pulmonary infiltrate can be bilateral, diffuse, and interstitial in pattern, thus mimicking PCP. Hilar lymphadenopathy and pleural effusion also may be manifestations of pulmonary Kaposi sarcoma or lymphoma, with which M. tuberculosis may coexist. The TST result usually is negative, and spontaneously expectorated sputum and BAL fluid samples often are smear-negative (although they are culture-positive).

Figure 29-6 Chest radiograph showing pathologic changes of miliary tuberculosis. The patient’s CD4⁺ count was 80 cells/µL.

In addition to pulmonary tuberculosis, extrapulmonary disease occurs in a high proportion of HIV-infected persons with low CD4⁺ lymphocyte counts (less than 150 cells/µL). Mycobacteremia and generalized lymph node infection (Figure 29-7) are common, but involvement of bone marrow, liver, pericardium, meninges, and brain also has been described.

Figure 29-7 Photomicrograph of mediastinal lymph node showing necrotic tissue surrounded by areas of poorly developed granulomatous inflammation (left inset). A Ziehl-Neelsen stain showed numerous acid-fast bacilli (right inset).

(Reproduced from Miller RF, Shahmanesh M, Talbot MD, et al: Progressive symptoms and signs following institution of highly active antiretroviral therapy and subsequent antituberculosis therapy: immune reconstitution syndrome or infection? Sex Transm Infect 82:111–116, 2006.)

Evidence of extrapulmonary tuberculosis should be sought in any HIV-infected patient with suspected or confirmed pulmonary tuberculosis, by culture of stool, urine, and blood or bone marrow. Traditional solid phase culture and speciation techniques may take 6 to 10 weeks. Liquid culture methods (e.g., BACTEC, Becton Dickinson, Towson, Maryland) that detect early growth provide a faster diagnosis (usually in 2 to 3 weeks). Molecular diagnostic tests using M. tuberculosis genome detection (e.g., by polymerase chain reaction [PCR]) offer the possibility of yet more rapid diagnosis (within hours). The original concerns that “high-tech” systems may not be practical in a field setting are now being challenged. The World Health Organization (WHO) has endorsed the Xpert TBRIF assay, which is portable and simple to use with sputum samples. This kit is expensive, however, although it may be of use in high-prevalence tuberculosis/HIV infection settings, in which prompt treatment initiation is critical to infection control. Current data suggest that such tests are of value, although less sensitive in HIV-infected subjects (in whom sputum samples generally have a lower bacterial load). The availability of simple but highly sensitive and specific methods that utilize the inoculation of large quantities of the sample (e.g., sputum) onto microscopic plates with subsequent rapid detection (in days) of both mycobacterial growth and resistance patterns (i.e., microscopic observation drug susceptibility [MODS] assay) is of great potential significance.

Until the results of culture and speciation are known, acid-fast bacilli identified in respiratory samples, biopsy tissue, an aspirate, or blood in an HIV-infected patient, regardless of the CD4⁺ lymphocyte count, should be regarded as being M. tuberculosis, and conventional antituberculosis therapy should be commenced. If culture fails to demonstrate M. tuberculosis and instead another mycobacterium (see later) is identified, then the treatment regimen can be modified.

Drug-Resistant Tuberculosis

Multiple drug–resistant (MDR) tuberculosis—that is, disease caused by M. tuberculosis strains resistant to isoniazid and rifampicin (rifampin), with or without other drugs—is now an important clinical problem in HIV-infected patients in the United States, where it is responsible for approximately 3% of all cases of tuberculosis in this population. Outbreaks of MDR tuberculosis have occurred in both HIV-infected and non–HIV-infected persons in the United States in prison facilities, hostels, and hospitals. Similar incidents also have been documented among HIV-infected patients in Europe. Inadequate treatment (including case management and supervision of medication) of tuberculosis and poor patient compliance with antituberculosis therapy are the most important risk factors for development of MDR tuberculosis. Other cases have arisen through exogenous reinfection of profoundly immunosuppressed HIV-infected patients who are already receiving treatment for drug-sensitive disease.

Despite antituberculosis therapy, the median survival in HIV-infected persons with MDR tuberculosis initially was only 2 to 3 months. Recently this has improved, largely because of an increased awareness of the condition with early initiation of suitable therapy as determined by drug sensitivity testing.

The advances in molecular diagnostics are not confined to rapid mycobacterial speciation. Commercial kits are available which can detect the commonest mutations that confer rifampicin and isoniazid resistance with good sensitivity. These are of great potential value in infection control in tuberculosis-endemic areas. They can guide initial therapy, assess for resistance in unexpected poor clinical response and significantly improve treatment outcomes. Next generation tests will also incorporate drug resistance profiles for other important agents such as fluoroquinolones.

Extensively Drug-Resistant Tuberculosis

Extensively drug-resistant (XDR) tuberculosis—that is, M. tuberculosis resistant to isoniazid and rifampicin (rifampin), plus any fluoroquinolone and one or more of the three injectable second-line drugs (capreomycin, kanamycin, and amikacin)—is an increasing clinical problem. Originally described in South Africa in association with HIV infection, XDR tuberculosis has now been identified worldwide. The current picture mirrors early reports of MDR tuberculosis in HIV infection in that mortality is very high among HIV-infected patients: In the original South African study from KwaZulu Natal, survival was less than 3 weeks from the time of receipt of the first sputum sample. Earlier suspicion and prompt initiation of therapy have improved survival, although the outcome often is poor and treatment is extremely expensive.

Infections Due to Mycobacteria Other Than Tuberculosis

Pneumocystis jirovecii Pneumonia

The development of PCP is largely related to underlying states of immunosuppression induced by malignancy or treatment thereof, organ transplantation, or HIV infection. In 2011 in the United States, the United Kingdom, Europe, and Australasia, PCP was largely seen only in HIV-infected persons unaware of their serostatus or in those reported to be intolerant of or noncompliant with anti–P. jirovecii prophylaxis and ART.

P. jirovecii originally was regarded as a protozoan, as suggested by its morphology and the lack of response to antifungal agents such as amphotericin B. The organism is now thought to be a fungus. The demonstration of antibodies against P. jirovecii in most healthy children and adults suggests that infection is acquired in childhood and persists in the lungs in a dormant phase. Subsequent immunosuppression (e.g., as a result of HIV infection) allows the fungus to propagate in the lung, causing clinical disease. This “latency hypothesis,” however, is challenged by several observations: P. jirovecii cannot be identified in the lungs of immunocompetent persons; “case clusters” of PCP in health care facilities suggest recent transmission; different genotypes of P. jirovecii are identified in each episode in HIV-infected patients who have recurrent PCP; genotypes of P. jirovecii in patients who have PCP correlate with place of diagnosis and not with their place of birth, suggesting infection has been recently acquired. Taken together, these data suggest that PCP arises by reinfection from an exogenous source.

The clinical presentation of PCP is nonspecific, with onset of progressive exertional dyspnea over days or weeks, together with a dry cough, with or without expectoration of minimal quantities of mucoid sputum. Patients often report an inability to take a deep breath, which is not due to pleurisy (Table 29-4). Fever is common, yet patients rarely complain of temperature-related signs and symptoms including sweats. In HIV-infected patients, the presentation usually is more insidious than in those receiving immunosuppressive therapy. The median time to diagnosis from onset of symptoms is more than 3 weeks in those with HIV infection, compared with less than 1 week in non–HIV-infected patients. In a small proportion of HIV-positive patients, the disease course of PCP is fulminant, with an interval of only 5 to 7 days between onset of symptoms and progression to development of respiratory failure. In others, it may be much more indolent, with respiratory symptoms that worsen almost imperceptibly over several months. Rarely, PCP may manifest as a fever of undetermined origin without respiratory symptoms.

Table 29-4 Clinical Presentation in Pneumocystis jirovecii Pneumonia

Clinical examination usually is remarkable only for the absence of physical signs; occasionally, fine, basal, end-inspiratory crackles are audible. Features that would suggest an alternative diagnosis include a cough productive of purulent sputum or hemoptysis, chest pain (particularly pleural pain), and signs of focal consolidation or pleural effusion (see Table 29-4). Of note, infection with more than one pathogen occurs in almost one fifth of these patients, so symptoms may be related to infection with any of several agents.

The chest radiographic appearance in PCP typically is unremarkable initially. Later, diffuse reticular shadowing, especially in the perihilar regions, is seen and may progress to widespread alveolar consolidation that resembles that in untreated pulmonary edema or with presentation late in disease. At this stage, the lung may be grossly consolidated and almost airless (Figure 29-8). Up to 20% of chest radiographs are atypical in appearance, showing lobar consolidation, honeycomb lung, multiple thin-walled cystic air spaces (pneumatoceles), intrapulmonary nodules, cavitary lesions, pneumothorax, and hilar and mediastinal lymphadenopathy. Predominantly apical changes, resembling those of tuberculosis, may occur in patients with PCP that developed subsequent to anti–P. jirovecii prophylaxis with nebulized pentamidine (Figure 29-9). All of these radiographic changes are nonspecific; similar changes occur with other pulmonary pathogens, including pyogenic bacterial, mycobacterial, and fungal infection, as well as Kaposi sarcoma and nonspecific interstitial pneumonitis. Respiratory symptoms in an immunosuppressed, HIV-infected patient with a normal-appearing chest radiograph should not be discounted, however, because radiographic abnormalities may not appear until 2 to 3 days later.

Figure 29-8 Chest radiograph showing diffuse bilateral interstitial infiltrates in a patient with severe Pneumocystis jirovecii pneumonia.

Figure 29-9 Chest radiograph showing upper lobe infiltrates in a patient with Pneumocystis jirovecii pneumonia. The patient had received nebulized pentamidine.

The diagnosis of PCP is made by demonstration of the organism in induced sputum, BAL fluid, or lung biopsy material using histochemical or immunofluorescence techniques.

Molecular detection tests for P. jirovecii using a variety of primers have been reported using BAL fluid, induced sputum and oropharyngeal wash (OPW) specimens. In general PCR-based tests have increased sensitivity, but a reduced specificity when compared to visualization of the organism using histochemical stains. This reduced specificity results from the finding that P. jirovecii DNA may be detected in respiratory samples from HIV-infected patients who do not have PCP (such as with tuberculosis or bacterial pneumonia) but are colonized with the organism. One study compared two PCR-based assays; these had sensitivities of 97% and 98%, but specificities were only 68% and 66%. The sensitivity of molecular detection techniques is lower if OPW rather than BAL fluid is used.

Candidal Infection

In contrast with infections of the oropharynx and esophagus, candidal infection of the trachea, bronchi, and lungs is rare in HIV-infected patients, as are candidemia, disseminated candidiasis, and deep focal candidiasis. The clinical presentation of pulmonary candidal infection has no specific features. Chest radiography is equally nonspecific—the radiographic appearance may be normal or show patchy infiltrates. Isolation of Candida from sputum may simply represent colonization and does not mean that the patient has candidal pneumonia. Indirect evidence may be obtained from positive cultures or rising antibody titers. However, in HIV-infected patients a high antibody titer alone is a less reliable indicator, and antibodies may be absent in proven cases of invasive candidal infection. Some correlation occurs between identification of large quantities of Candida species in BAL fluid and Candida spp. as the cause of pneumonia. Definitive diagnosis is made by lung biopsy.

Aspergillus Infection

Unlike in patients immunosuppressed and rendered neutropenic by systemic chemotherapy, infection with Aspergillus species is relatively rare in HIV-positive patients. Risk factors for aspergillosis are neutropenia, which commonly is drug-induced (e.g., in chemotherapy), and use of corticosteroids. Fever, cough, and dyspnea are the most common presenting manifestations, but pleuritic chest pain and hemoptysis are found in approximately one third of patients.

Patterns of pulmonary disease include cavitating upper lobe disease, focal radiographic opacities resembling bacterial pneumonia, bilateral diffuse and patchy opacities (nodular or reticular-nodular in pattern), pseudomembranous aspergillosis (which may obstruct the lumen of airways), and tracheobronchitis. Diagnosis of pulmonary aspergillosis is made by the identification of fungus in sputum, sputum casts, or BAL fluid in association with respiratory tract tissue invasion (Figure 29-10). Serum (1,3)-β-D-glucan levels may be elevated (see further on).

Figure 29-10 Bronchoalveolar lavage fluid containing Aspergillus fumigatus organisms.

Cryptococcal Infection

Infection may manifest in one of two ways: either as primary cryptococcosis or complicating cryptococcal meningitis as part of disseminated infection with cryptococcemia, pneumonia, and cutaneous disease (umbilicated papules mimicking molluscum contagiosum) (Figure 29-11). Primary pulmonary cryptococcosis presents in a very nonspecific way and is frequently indistinguishable from other pulmonary infections. In disseminated infection, the presentation frequently is overshadowed by headache, fever, and malaise (caused by meningitis). The time to onset may range from only a few days to several weeks. Examination may reveal skin lesions, lymphadenopathy, and meningism. In the chest, signs may be absent or crackles may be audible. Arterial blood gas analysis may reveal normal findings or show hypoxemia. The most common abnormality on the chest radiograph is focal or diffuse interstitial infiltrates. Less frequently, masses, mediastinal or hilar lymphadenopathy, nodules, and effusion are noted.

Figure 29-11 Skin changes in disseminated cryptococcosis. The multiple, umbilicated lesions resemble those of molluscum contagiosum.

The diagnosis of cryptococcal pulmonary infection (Figure 29-12) is made by identification of Cryptococcus neoformans (by staining with India ink or mucicarmine, and by culture) in sputum, BAL fluid, pleural fluid, or lung biopsy tissue. Cryptococcal antigen may be detected in serum using the cryptococcal latex agglutination (CrAg) test. Titers usually are high but may be negative in primary pulmonary cryptococcosis, in which case BAL fluid (CrAg) is positive. In patients with disseminated infection, C. neoformans also may be cultured from blood and cerebrospinal fluid.

Figure 29-12 Bronchoalveolar lavage fluid containing Cryptococcus neoformans organisms.

Endemic Mycoses

The endemic mycoses caused by Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatitidis are found in HIV-infected patients living in North America (especially the Mississippi and Ohio River valleys). Histoplasmosis also is found in Southeast Asia, the Caribbean Islands, and South America. Coccidioidomycosis is endemic in the southwest United States (southern California), northern Mexico, and in parts of Argentina and Brazil. Blastomycosis has a similar distribution, with an extension north into Canada.

Histoplasmosis

Progressive, disseminated histoplasmosis in patients with HIV typically manifests with a subacute onset of fever and weight loss; approximately 50% of patients have mild respiratory symptoms with a nonproductive cough and dyspnea. Hepatosplenomegaly frequently is noted on examination, and a rash (similar to that produced by Cryptococcus spp.) may be seen. Rarely, the presentation may be rapidly fulminant, with clinical features of the sepsis syndrome including anemia or disseminated intravascular coagulation. The chest radiograph may be normal in appearance (in up to one third of patients), although characteristic abnormalities consist of bilateral, widespread nodules 2 to 4 mm in size (Figure 29-13). Other radiographic features are nonspecific and include interstitial infiltrates, reticular nodular shadowing, and alveolar consolidation. The diagnosis is made reliably by identification of the organism in Wright-stained peripheral blood or by Giemsa staining of bone marrow, lymph node, skin, sputum, BAL fluid, or lung tissue. It is important that identification be confirmed by detection of H. capsulatum var. capsulatum polysaccharide antigen by radioimmunoassay, which has a high sensitivity. False-positive results are possible in patients infected with Blastomyces and Coccidioides spp. Testing for Histoplasma antibodies by complement fixation or immunodiffusion techniques may give a negative result in immunosuppressed, HIV-positive patients. Serum (1,3)-β-D-glucan levels may be elevated (see further on).

Figure 29-13 Chest radiograph showing pathologic changes of histoplasmosis.

Penicillium marneffei Infection

P. marneffei infection is particularly common in Southeast Asia. Most HIV-infected patients present with disseminated infection and solitary skin or oral mucosal lesions, or with multiple infiltrates in the liver or spleen, or bone marrow (leading to presentation with pancytopenia). Pulmonary infection has no specific clinical features, and chest radiographs may be normal-appearing or show diffuse, small nodular infiltrates. Diagnosis is made by identifying the organism in bone marrow, skin biopsy specimens, blood films, or BAL fluid. The differential diagnosis for P. marneffei infection includes both PCP and tuberculosis.

Community-Based Respiratory Viral Infections

Influenza A

HIV-infected persons do not have a greater incidence of influenza A but may be at increased risk for more severe disease. This susceptibility is due to associated medical comorbid conditions.

HIV-infected patients with seasonal or H1N1 influenza typically present with an acute respiratory illness (e.g., coryzal symptoms) with fever, headache, and myalgia. Vomiting and diarrhea occur more often with H1N1 influenza than with seasonal influenza. Some patients with seasonal or H1N1 influenza may not have fever. Careful clinical assessment, together with awareness of local surveillance data on circulating influenza viruses and other community-prevalent respiratory pathogens, is important in the differential diagnosis for patients presenting with an influenza-like illness. In some HIV-infected patients, especially those with low CD4⁺ cell counts (less than 100 cells/µL), the illness may progress rapidly (Figure 29-14) and can be complicated by secondary bacterial pneumonia. The diagnosis is made by detection of viral antigen or RNA, or by culture of nasopharyngeal aspirate or nasal swab.

Figure 29-14 Chest radiograph showing pathologic changes of severe H1N1 influenza.

Leishmaniasis

Pulmonary involvement with Leishmania spp. may rarely occur as part of the syndrome of visceral leishmaniasis in HIV-infected patients. Patients usually have advanced HIV disease with CD4⁺ lymphocyte counts below 300 cells/µL and present with fever, splenomegaly, and leukopenia. Respiratory symptoms often are absent. Diagnosis of visceral leishmaniasis most often is made by staining and culture of splenic or bone marrow aspirate. Occasionally the parasite is found by chance in a skin or rectal biopsy specimen or BAL fluid taken for other purposes. The chest radiograph may be normal in appearance or show reticular-nodular infiltrates.

Toxoplasmosis

Toxoplasma gondii infection in HIV-infected patients usually occurs as a result of reactivation of latent, intracellular protozoa acquired in a primary infection. Toxoplasmic pneumonia frequently manifests with nonproductive cough and dyspnea. Chest radiographic abnormalities include diffuse interstitial infiltrates indistinguishable from those of PCP (Figure 29-16), as well as micronodular infiltrates, a coarse nodular infiltrate, cavitary change, and lobar consolidation. The diagnosis is made by hematoxylin-eosin or Giemsa staining of BAL fluid, which reveals cysts and trophozoites of T. gondii. Staining of BAL fluid is not always positive; the diagnostic yield is increased either by staining of transbronchial biopsy material or by performing PCR assay to detect T. gondii DNA in BAL fluid.

Figure 29-16 Chest radiograph showing pathologic changes of Toxoplasma gondii pneumonia. The diffuse bilateral infiltrates resemble those in P. jirovecii pneumonia.

(Reproduced from Miller RF, Lucas SB, Bateman NT: Disseminated Toxoplasma gondii infection presenting with a fulminant pneumonia, Genitourin Med 72:139–143, 1996.)

Strongyloidiasis

The nematode Strongyloides stercoralis is endemic in warm countries worldwide. In immunosuppressed patients, the organism has an increased ability to reproduce parthenogenetically in the gastrointestinal tract without the need for repeated exposure to new infection—so-called autoinfection. This enhanced reproductivity results in a great increase in worm load, and a hyperinfective state ensues; massive acute dissemination with S. stercoralis may occur in the lungs, kidneys, pancreas, and brain. Although infection with S. stercoralis is more severe in immunocompromised patients, it is no more common in patients who have HIV infection. Presentation with hyperinfection may be with fever, hypotension secondary to bacterial sepsis, or disseminated intravascular coagulation. The clinical features of respiratory S. stercoralis infection are very nonspecific. S. stercoralis in sputum or BAL fluid (Figure 29-17) may be identified in HIV-positive patients in the absence of symptoms elsewhere; this can predate disseminated infection and as such requires prompt treatment.

Figure 29-17 Bronchoalveolar lavage fluid sample containing an adult Strongyloides stercoralis roundworm.

Lactate Dehydrogenase

In an HIV-infected patient who presents with an acute or subacute pneumonitis, an elevated serum lactate dehydrogenase (LDH) level is strongly suggestive of PCP. In interpreting such results, it is important to recognize that other pulmonary disease processes (e.g., pulmonary embolism; nonspecific pneumonitis; fungal, bacterial, and mycobacterial pneumonia) and extrapulmonary disease (Castleman disease and lymphoma) also may cause elevations of LDH and may need to be considered in the correct clinical context.

Plasma or Serum S-Adenosylmethionine

The rationale behind use of the plasma or serum S-adenosylmethionine (SAM or AdoMet) assay is that Pneumocystis was thought to be unable to metabolize SAM, because it lacks a SAM synthetase and therefore scavenges this from its host. According to this hypothesis, patients with PCP might be expected to have low SAM levels. Some studies have shown that plasma AdoMet levels can be used to distinguish HIV-infected patients with PCP from those with other-cause pneumonia (e.g., bacterial pneumonia or tuberculosis) and found no overlap in AdoMet levels between those with and those without PCP. Another study that measured serum AdoMet reported overlapping levels in HIV-infected patients with PCP and other-cause pneumonia. Currently measurement of serum or plasma AdoMet is not used for diagnosis of PCP.

Serum (1,3)-β-D-Glucan

In all fungi, including Pneumocystis, (1,3)-β-D-glucan is a cell wall component. Serum (1,3)-β-D-glucan levels are higher in patients with PCP (with or without underlying HIV infection) when compared to patients without PCP. The sensitivity and specificity of this assay are maximal using a cutoff of 100 pg/mL (for diagnosis of PCP). Because serum (1,3)-β-D-glucan levels may be elevated in pneumonia caused by several fungal pathogens, this test does not permit discrimination among potential etiologic disorders (e.g., PCP, Aspergillus infection, histoplasmosis). Additionally, case reports of false-positive results in patients with pulmonary infection due to P. aeruginosa further limit diagnostic utility. Among patients with confirmed PCP, use of serum (1,3)-β-D-glucan levels to monitor response to therapy requires further evaluation.

From the preceding discussion, it is evident that noninvasive tests cannot reliably distinguish the different infecting agents from each other but may be useful in excluding acute opportunistic disease. Thus, the clinician is left with either proceeding to diagnostic lung fluid or tissue sampling (using either induced sputum collection or bronchoscopy and BAL with or without transbronchial biopsy) (Table 29-5) or treating an unknown condition empirically. ART also has altered the investigation of respiratory disease. The numbers of invasive procedures performed are falling, and such procedures tend to be used in patients not taking antiretroviral drugs (usually to exclude PCP), or in whom no response to empirical antibiotic therapy (regardless of the CD4⁺ count) has been observed.

Trimethoprim-Sulfamethoxazole

Several drugs are effective in the treatment of PCP. TMP-SMX is the drug of first choice (Tables 29-7 and 29-8). Overall, it is effective in 70% to 80% of patients when used for first-line therapy. Adverse reactions to TMP-SMX are common and usually become apparent between days 6 and 14 of treatment. Neutropenia and anemia (in up to 40% of patients), rash and fever (up to 30%), and biochemical abnormalities of liver function (up to 15%) are the most frequent adverse reactions. Hematologic toxicity induced by TMP-SMX is neither attenuated nor prevented by coadministration of folic or folinic acid. Furthermore, the use of these agents may be associated with reduced therapeutic success. During treatment with TMP-SMX, monitoring with full blood counts, liver function testing, and measurements of urea and electrolytes at least twice weekly is indicated.

Table 29-8 Treatment Schedules for Pneumocystis jirovecii Pneumonia*

CDC, Centers for Disease Control and Prevention; NIH, National Institutes of Health; IDSA, Infectious Diseases Society of America.

* NOTE: None of these regimens for adjuvant glucocorticoids therapy have been compared in prospective clinical trials.

It is not known why HIV-infected patients, especially those with higher CD4⁺ counts, experience such a high frequency of adverse reactions to TMP-SMX. The optimal strategy for management of an HIV-infected patient who has PCP and who becomes intolerant of high-dose TMP-SMX has not been established. Many physicians advocate “treating through” minor rash, often adding an antihistamine and a short course of oral prednisolone (30 mg every 24 hours, tapering to zero over 5 days).

Other Therapeutic Agents

If treatment with TMP-SMX fails, or is not tolerated by the patient, several alternative therapies are available (see Tables 29-7 and 29-8).

General Management of Pneumocystis jirovecii Pneumonia

Mild PCP may be treated on an outpatient basis with oral TMP-SMX if the patient is able to manage at home, is willing to attend the outpatient clinic for regular review, and exhibits clinical and radiographic evidence of recovery. If the patient is intolerant of oral TMP-SMX despite clinical recovery, either the drug is switched to an intravenous formulation or the regimen may be changed to oral clindamycin plus primaquine. All patients with moderate and severe PCP should be hospitalized and given intravenous TMP-SMX or intravenous clindamycin and oral primaquine (plus adjuvant steroids). Patients with moderate or severe disease who show clinical and radiographic response by days 7 to 10 of therapy may be switched to oral TMP-SMX to complete the remaining 14 days of treatment. If the patient has failed to respond within 7 to 10 days or deteriorates before this time, while receiving TMP-SMX, then treatment should be changed to clindamycin and primaquine, or intravenous pentamidine.

Deterioration in the Patient with Pneumocystis jirovecii Pneumonia

Deterioration in a patient who is receiving anti–P. jirovecii therapy may occur for several reasons (Table 29-9). Before deterioration is ascribed to treatment failure necessitating a change in therapy, these alternatives should be evaluated carefully. It also is important to consider treating for any copathogens present in BAL fluid and to perform bronchoscopy if the diagnosis was made empirically, and to repeat the procedure or carry out open lung biopsy to confirm that the diagnosis is correct.

Table 29-9 Causes of Clinical Deterioration in a Human Immunodeficiency Virus (HIV)-Infected Patient with Pneumocystis jirovecii Pneumonia

Overlapping Toxicity

In the developed world, isoniazid-related peripheral neuropathy is rare in HIV-negative subjects taking pyridoxine. The nucleoside reverse transcriptase inhibitors (RTI) didanosine and stavudine, which are now less rarely used in the United States and the United Kingdom, but which frequently are seen in the developing world can also cause a painful peripheral neuropathy. This complication develops in up to 30% of patients if stavudine and isoniazid are coadministered. Rash, fever, and biochemical hepatitis are common adverse events with rifamycins, pyrazinamide, and isoniazid (occurring more frequently in patients with tuberculosis who have HIV infection with hepatitis C coinfection). The non-nucleoside RTI drugs (e.g., nevirapine) have a similar toxicity profile. If treatment for both HIV and tuberculosis is coadministered, then ascribing a cause may be problematic.

Drug-Drug Interactions

Drug-drug interactions between medications used to treat tuberculosis and HIV infection occur because of their common pathway of metabolism, through the hepatic cytochrome P-450 enzyme system. Rifampin is a potent inducer of this enzyme (rifabutin less so), which may result in subtherapeutic levels of non-nucleoside RTI and protease inhibitor antiretroviral drugs, with the potential for inadequate suppression of HIV replication and the development of resistance to HIV. In addition, the protease inhibitor class of antiretroviral drugs inhibits the metabolism of rifamycins, which leads to increases in their plasma concentration and is associated with increased drug toxicity. The non-nucleoside RTI drugs are inducers of this enzyme pathway. Coadministration of rifabutin with efavirenz requires an increase in the dose of rifabutin to compensate for the increase in its metabolism induced by efavirenz (see later). The newer classes of ART such as integrase inhibitors (e.g., raltegravir) or second-generation non-nucleoside RTI (e.g., rilpivirine) also are significantly affected by rifamycins.

Type and Duration of Therapy for Tuberculosis

The optimal duration of treatment of tuberculosis, using a rifamycin-based regimen, in a patient who has HIV infection is unknown. Current recommendations from the BHIVA and the ATS/CDC/Infectious Diseases Society of North America (IDSA) are to treat tuberculosis in HIV-infected patients in the same way as for the general population (i.e., for 6 months for drug-sensitive pulmonary tuberculosis). In addition, ATS/CDC/IDSA guidelines recommend that treatment be extended to 9 months in patients who have cavitation on the original radiograph, continuing clinical signs, or a positive culture after 2 months of therapy.

Risk for development of rifampin monoresistance in HIV-infected patients receiving the drug has been reported. This association is especially strong if intermittent regimens are used and may be related to a lack of efficacy of the other drugs present in the combination (e.g., intermittent isoniazid). Hence, daily medication regimens are recommended and should be closely supervised in all HIV-positive patients. In clinical practice, rifabutin usually is given thrice weekly with ritonavir-boosted protease inhibitors. This regimen appears generally to achieve adequate rifamycin levels, although therapeutic drug failure and rifamycin resistance have recently been reported in patients who demonstrated appropriate adherence to prescribed treatment. Some clinicians now routinely prescribe daily rifabutin at its thrice-weekly dose and monitor drug levels. Little additional toxicity is reported, although the regimen is more expensive and has not been fully evaluated.

Directly observed therapy (DOT) is an important although fairly labor-intensive strategy that has the support of the WHO. It is of undoubted value in populations at risk for nonadherence, such as substance abusers, the homeless, and people with mental health problems, and can be integrated with addressing other health care needs. This approach can help to offset what might appear punitive to persons in DOT programs.

Timing of Initiation of Antiretroviral Therapy for Tuberculosis

Recent data are available that can guide the optimal time to start ART in patients being treated for tuberculosis. Initial decision analysis showed that early treatment with antiretroviral therapy led to a marked reduction in further opportunistic disease. Against this was balanced the risk of needing to discontinue antituberculosis therapy or ART because of drug toxicity or drug-drug interactions. IRIS was reported to be more likely if these treatments were started at the same time.

These findings have now been confirmed in several studies from around the world, predominantly in developing nations. In essence, deferred ART (i.e., given at least 8 weeks after starting antituberculosis therapy) was associated with significantly increased mortality, when compared to treatment started within 4 weeks. Although IRIS was several times more frequent in the latter population, its morbidity generally was manageable and mortality was low. The survival benefit of early treatment was most pronounced in post hoc analyses in subjects with the lowest CD4⁺ counts (that is, less than 50 cells/µL).

Delaying the start of antiretroviral therapy can simplify patient management and may reduce or prevent adverse drug reactions and drug-drug interactions; plus also reduce the risk of IRIS. Based on current guidance for general ART initiation, patients with CD4⁺ counts above 350 cells/µL, who are at low risk of HIV disease progression or death during 6 months of treatment for tuberculosis, could defer ART until treatment for tuberculosis is completed or well under way. In these patients, the CD4⁺ count should be closely monitored. In patients who have CD4⁺ counts of 349 to 100 cells/µL, many centers currently delay starting ART until after the first 2 months of treatment for tuberculosis have been completed, and patients are given concomitant PCP prophylaxis. In those with CD4⁺ counts below 99 cells/µL, ART is started as soon as possible after initiation of treatment for tuberculosis.

Two options exist for starting antiretroviral therapy in a patient already being treated for tuberculosis. First, the rifampin-based regimen is continued and ART is commenced—for example, with a combination of two nucleoside RTIs and a non-nucleoside RTI such as efavirenz (if the patient weighs more than 60 kg, the efavirenz dose often is increased to 800 mg given once daily, to compensate for rifampin-induced metabolism of efavirenz). Alternatively, the rifampin is stopped and rifabutin is started: Antiretroviral therapy is given, with a combination of two nucleoside RTI drugs and either a single ritonavir-boosted protease inhibitor or a non-nucleoside RTI. Here the dose of rifabutin is adjusted to take into account the pharmacokinetic effect of the coadministered drug. With a boosted protease inhibitor, it usually is prescribed at a dose of 150 mg thrice weekly, and with efavirenz, it is increased to 450 mg once a day, although as discussed earlier, some centers will use 150 mg rifabutin once daily.

Immune Reconstitution Inflammatory Syndrome

Before the advent of ART, physicians treating patients with tuberculosis recognized that an apparent response to the antimycobacterial treatment would sometimes be followed by a short period of clinical deterioration. This paradoxical reaction (in the context of overall treatment response) was seen as an interesting and probably immune-based phenomenon directed against residual mycobacterial antigen, of generally little consequence. The widespread introduction of ART has led to an increased awareness by clinicians of similar but generally more severe events in HIV-infected persons. In the context of HIV infection, a reaction of this type is now termed immune reconstitution inflammatory syndrome (IRIS), or immune reconstitution disease.

Such reactions can manifest in a number of ways, and in association with a range of opportunistic conditions. Perhaps the most common of these is similar to a paradoxical reaction. In this instance, after initiation of ART in a patient being treated for tuberculosis, for example, the original symptoms and signs or new features develop. These often are of an inflammatory nature and may be associated with marked radiographic changes. Manifestations of IRIS may include fever, dyspnea, lymphadenopathy, effusions, parenchymal pulmonary infiltrates, or expansion of cerebral tuberculomas. This form of IRIS is seen most frequently with disease due to mycobacteria (commonly M. tuberculosis or MAC), fungi (notably, Cryptococcus), and viruses (hepatitis viruses and Herpesviridae).

IRIS develops in up to one third of HIV-infected patients being treated for tuberculosis when ART is started. The median time to onset of tuberculosis-related IRIS is about 4 weeks from beginning antituberculosis treatment or 2 weeks from commencing ART. It appears to be more likely in patients who have disseminated tuberculosis (and hence presumably more stimulating antigen present as well as more potential for significant inflammatory reactions); and a lower baseline blood CD4⁺ count. A rapid fall in HIV load as well as a large increase in CD4⁺ counts in response to ART may also predict IRIS; as might circulating inflammatory cytokines such as interferon-γ or markers such as C-reactive protein. The relationship between early use of ART and low blood CD4⁺ counts suggests that care must be taken when antiretrovirals are started in patients with tuberculosis at sites where rapid expansion of an inflammatory mass could be life-threatening. Examples of this are cerebral, pericardial, or peritracheal disease (Figure 29-20).

Figure 29-20 Chest radiograph (A) and CT scan (B) showing massive mediastinal lymphadenopathy in a patient with IRIS due to Mycobacterium tuberculosis.

(Reproduced from Buckingham SJ, Haddow LJ, Shaw PJ, Miller RF: Immune reconstitution inflammatory syndrome in HIV-infected patients with mycobacterial infections starting highly active anti-retroviral therapy, Clin Radiol 59:505–513, 2004.)

An important point is that IRIS currently is a diagnosis of exclusion. No specific laboratory test is available to assist with this, and it should be made only after progressive or (multi)drug-resistant tuberculosis, poor drug adherence (to either antituberculosis or antiretroviral agents) and drug absorption, or an alternative pathologic process has been excluded as an explanation for the presentation. Criteria have been drawn up that seek to provide clinical diagnostic guidelines (Box 29-4).

The mechanism leading to IRIS is unclear. It is not due to failure of treatment of tuberculosis or to another coexistent disease process, and if anything it is most likely to represent an exuberant and uncontrolled response to mycobacterial antigens (from both dead and alive organisms).

Current treatments include nonsteroidal antiinflammatory drugs and glucocorticoids. The latter are undoubtedly effective although they can lead to hyperglycemia and hypertension. Recurrent aspiration of lymph nodes or effusion also may be needed. Although IRIS often is self-limiting, it may persist for several months. Rarely, temporary discontinuation of ART is required. In this situation there may be precipitous falls in CD4⁺ counts, and patients are at risk of other opportunistic infections.

Attention also has focused on an issue of possibly greater concern—the form of IRIS referred to as the “unmasking phenomenon”: In some persons with presumably latent tuberculosis infection who start ART, systemic active (and often infectious) tuberculosis develops within a 3-month period. Although the patient’s disease probably would have manifested in time anyway, and some reported cases may in fact represent progression of previously subclinical tuberculosis, reflecting ascertainment bias, the current view is that this phenomenon is real and constitutes an adverse effect of ART. In view of the fact that persons most at risk live in countries with limited facilities for pre-ART screening, this issue has major implications for ART rollout programs in resource-poor areas. It has led to heightened need for intensified screening using simple algorithms that seek to exclude mycobacterial infection and disease before institution of ART. One consequence of this added awareness is the increased use of regimens to treat LTBI, plus the increased detection of subclinical active tuberculosis cases.

Trimethoprim-Sulfamethoxazole

As with treatment strategies, TMP-SMX is the drug of choice for prophylaxis of PCP (Table 29-13). It has the advantages of being highly effective for both primary and secondary prophylaxis (with the 1-year risk of PCP during therapy with this agent being 1.5% and 3.5%, respectively). It is cheap, can be taken orally, acts systemically, and provides some cross-prophylaxis against other infections, such as toxoplasmosis and infections due to Salmonella spp., staphylococci, and H. influenzae. Its main disadvantage is that adverse reactions are common (see earlier), occurring in up to 50% of patients taking the prophylactic dose.

Table 29-13 Primary and Secondary Prophylaxis Regimens for Pneumocystis jirovecii Pneumonia

* 160 mg trimethoprim plus 800 mg sulfamethoxazole.

† 80 mg trimethoprim plus 400 mg sulfamethoxazole.

The standard dose of TMP-SMX is one double-strength tablet (containing 160 mg of trimethoprim plus 800 mg of sulfamethoxazole) per day. Other regimens have been tried; these include one “double-strength” tablet thrice weekly and one single-strength tablet per day. In general, when used for primary prophylaxis, these regimens are tolerated well (if not better than the standard) and appear to be as efficacious as one double-strength tablet per day. The data are less clear in secondary prophylaxis, in which subjects are at a much higher risk for recurrent PCP. Attempts to desensitize patients who are intolerant of TMP-SMX have met with some success.

Dapsone

In patients who cannot tolerate TMP-SMX, dapsone is a safe and inexpensive alternative. It has been studied in a number of trials as both primary and secondary prophylaxis and is effective at an oral dose of 100 mg/day. When combined with pyrimethamine (25 mg three times per week), it provides a degree of cross-prophylaxis against toxoplasmosis. Before starting dapsone, patients are tested for glucose-6-phosphate dehydrogenase deficiency.

Pentamidine

Nebulized pentamidine has largely fallen from use as a prophylactic agent. Initial advantages included better clinical tolerance and efficacy similar to that of TMP-SMX for primary preventive therapy. The associated breakthrough rate for this agent, however, is higher in patients who have lower CD4⁺ counts (i.e., below 100 cells/µL) and in those who take it as secondary prophylaxis. Other disadvantages include delivery equipment costs and complexity (alveolar deposition is crucial, so the nebulizer system used is important), the risk of transmission of respiratory disease (e.g., tuberculosis) to other patients and staff during the nebulization procedure, altered clinical presentation of PCP during pentamidine therapy (increased frequency of radiographic upper zone shadowing, increased incidence of pneumothorax), and a lack of systemic protection against Pneumocystis and other infectious agents. In addition, an acute bronchoconstriction effect during nebulization has been noted. Long-term follow-up studies have not demonstrated any significant negative effect on lung function.

Atovaquone

Atovaquone oral suspension is used as a second-line prophylactic agent in patients intolerant of TMP-SMX. It appears to be similar in efficacy to dapsone (given together with weekly pyrimethamine), with a reduced incidence of side effects, of which the most frequent are rash, fever, and gastrointestinal disturbance.

Predictors of Pneumocystis Prophylaxis Failure

A low blood CD4⁺ count (less than 50 cells/µL) is the current best laboratory predictor of prophylaxis failure. This correlation is not particularly surprising because the median blood CD4⁺ count of subjects not on prophylaxis who develop PCP is below 50 cells/µL. Persistent fever of unknown cause is an important clinical risk factor for PCP. Used as preventive therapy, TMP-SMX significantly reduces the chance for development of Pneumocystis. It is therefore vital that subjects who are most vulnerable be encouraged to use this drug on a regular basis.