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