Chapter 48. AIDS in the Intensive Care Unit

• The acquired immunodeficiency syndrome (AIDS) is caused by chronic infection with the human immunodeficiency virus (HIV), which through its relentless replication causes progressive depletion of T-helper lymphocytes leading to severe cellular immunodeficiency.
• In the absence of treatment, after a variable period, usually years from infection, multiple opportunistic infections or neoplasms characteristic of AIDS develop. Despite substantial progress in antiretroviral therapy, cure of the disease remains elusive.
• HIV transmission is limited to sexual exposure (homosexual or heterosexual), exposure to blood or blood products (including transplanted organs), and perinatal exposure (transplacentally, at the time of delivery, or through lactation).
• HIV cannot be transmitted through casual contact. Universal precautions, however, should be implemented and enforced to minimize the risk of occupational exposure to HIV as well as other infectious agents. The rate of seroconversion following a single accidental needle stick or mucous membrane exposure appears to be well below 1%.
• Combination antiretroviral therapy has been shown to prolong survival as well as disease-free interval. The widespread availability of plasma viral load monitoring and increasing access to genotype resistance testing in developed countries have led to further optimization of therapy and hence further improvement in outcomes.
• Acute respiratory failure (ARF) secondary to Pneumocystis carinii pneumonia (PCP) is a frequent cause of ICU admission among HIV-infected individuals.
• PCP usually is diagnosed in the ICU using bronchoalveolar lavage (BAL). BAL fluid always should be processed to allow identification of P. carinii, fungi, common bacteria, mycobacteria, and viruses.
• PCP-related ARF should be treated aggressively with specific antimicrobials, adjunctive systemic corticosteroids, and oxygenation support.
• The mortality of PCP-related ARF has decreased substantially with the use of adjunctive systemic corticosteroids. Patients developing ARF despite corticosteroid treatment, however, continue to have a dismal prognosis.
• Initiation of highly active antiretroviral therapy or revision of a failing regimen should be delayed until completion of PCP therapy because of the risk of pulmonary deterioration related to PCP immune reconstitution syndrome.
• The issue of life support should be discussed early and reassessed frequently with HIV-infected individuals. ICU admission and life support, however, should be discouraged for patients with multiple life-threatening complications for which there is no effective therapy. Because the outlook of AIDS and its related diseases is changing rapidly, rigid policies regarding ICU eligibility should be strongly discouraged.

Human Immunodeficiency Virus Infection

The acquired immunodeficiency syndrome (AIDS) is caused by chronic infection with the human immunodeficiency viruses (HIV-1, HIV-2). Continuous HIV replication leads to progressive dysfunction and gradual depletion of the helper T-lymphocytes or CD4+ lymphocytes.1,2 It is clear, however, that HIV can infect other cells, including macrophages and B-lymphocytes. Eventually, this results in the development of the otherwise unusual opportunistic infections and neoplasms characteristic of AIDS.

The total number of people infected with HIV/AIDS globally as of December 2000 has been estimated to be 58 million, of whom 21.8 million have died since the beginning of the epidemic. The number of people in the United States living with HIV or AIDS was estimated to be 920,000 and 320,000, respectively.3

The proportion of AIDS cases requiring either hospitalization or admission to the ICU has declined since the introduction of highly active anti-retroviral therapy (HAART) in 1996. In recent years, HIV-related hospitalizations are less often due to opportunistic diseases compared with the pre-HAART era. Since the increase in HIV infection among injection drug users, a significant proportion of hospital admissions for HIV patients now are accounted for by other complications of injection drug use (e.g., liver disease from chronic hepatitis B and C, cellulitis, endocarditis etc.).

Transmission

The most common route of transmission of HIV remains sexual intercourse. It must be emphasized that homosexual and heterosexual transmission occurs, and in both cases, bidirectional transmission is possible.4 The second most prevalent form of transmission is through exposure to infected blood or blood products, including transplanted organs. Since the widespread adoption of HIV screening of donated blood, however, parenteral transmission of HIV is limited almost exclusively to intravenous drug use. Finally, the infection also can be transmitted perinatally. This refers to infection of offspring transplacentally, at the time of delivery, or through lactation.5

It is important to emphasize that HIV is not transmitted through casual contact. After a single accidental needle stick exposure to contaminated material, the rate of seroconversion is approximately 1 per 300 exposures, or 0.3 percent. This is particularly reassuring for the families and health care providers of AIDS patients. In the ICU setting, the “universal precautions” recommended for patients infected with the hepatitis B virus are sufficient to deal appropriately with HIV.6 Nevertheless, the risk of acquiring HIV infection in the workplace is real; this issue, therefore, should not be hidden but rather discussed openly, and health care institutions should adopt exemplary policies to deal fairly and compassionately with such occurrences. A case-control study conducted by the Centers for Disease Control and Prevention (CDC) showed that zidovudine use following accidental exposure to HIV in health care workers reduced the risk of transmission by approximately 80%.7 Consequently, the need for antiretroviral therapy immediately following accidental exposure to HIV should be evaluated on a case-by-case basis by qualified specialists. According to published guidelines, counseling and possibly combination antiretroviral therapy, depending on the details of the potential exposure, should be offered immediately to health care workers.8

Pathophysiology

HIV preferentially infects T-lymphocytes bearing the surface marker CD4, the so-called helper T cells or T4 cells. This tropism is mediated through a specific interaction between GP160, a viral envelope glycoprotein, and the CD4 molecule itself. HIV is also capable of infecting a number of other bone-marrow-derived cells, including monocytes, macrophages, Langerhans dendritic cells, microglial cells, B-lymphocytes, and bone marrow stem cells.9

Once within the cell, the viral ribonucleic acid (RNA) and reverse transcriptase are released. The reverse transcriptase generates a deoxyribonucleic acid (DNA) sequence complementary to the viral RNA, which then integrates into the host cell's genome to produce new viral particles, which in turn will infect other susceptible cells. Relentless HIV replication causes T4 cell dysfunction and death, leading to severe cellular immunodeficiency.9

Natural History

Acute HIV infection is associated with retrospectively identified transient symptomatic illness in 40% to 90% of patients.10 This is most often a nonspecific flulike illness often confused with acute infectious mononucleosis and characterized by fever (>80% to 90%), fatigue (>70% to 90%), rash (>40% to 80%), headache (32% to 70%), lymphadenopathy (40% to 70%), pharyngitis (50% to 70%), and aseptic meningitis (24%), as well as other symptoms. This usually benign and self-limited syndrome, also known as seroconversion illness, is believed to be an immune-complex-mediated phenomenon resulting from early antibody response to the infection by HIV. Typically, after a variable period (rarely less than 2 years) with few or no symptoms, progressive immunodeficiency develops, rendering the individual susceptible to the development of opportunistic infections, wasting, and/or neoplasms characteristic of AIDS. AIDS remains incurable despite considerable progress in antiretroviral therapy. The often-prolonged period of clinical latency is characterized by continued viral replication and decline of the immune system, as illustrated by the progressive destruction of the lymph node architecture.11

Surrogate Markers

A number of laboratory tests have been shown to correlate with prognosis among HIV-infected individuals. These tests generally are referred to as surrogate markers of disease progression.12 The CD4+ lymphocyte count traditionally has been the most commonly used surrogate marker. A range of 400 to 1400 cells/μL (0.40 to 1.40 × 109/L) is considered normal in most laboratories. The CD4 count usually is reported as a fraction and an absolute count. Although the absolute CD4 count is usually a good reflection of the degree of immunodeficiency in a given patient, it must be noted that under specific circumstances this may be misleading. It is therefore advisable to monitor the CD4 fraction to ensure that this is in general agreement with the absolute CD4 count. CD4 counts are used widely to guide therapeutic decisions regarding the use of antiretrovirals and preventive strategies, yet they are subject to considerable variability. CD4 counts show circadian variation, which is lowest in the morning and highest in the evening. In normal individuals, the evening CD4 cell count can be nearly double the morning nadir. Although this variation may be reduced in HIV-infected patients, specimens for CD4 counting should be collected in a standardized fashion. Other factors that may affect the count include acute infections such as common viral illnesses, certain pharmaceutical agents, stress, smoking, and exercise. The results also may be influenced by differing laboratory methodologies. Despite controlling the time of collection, HIV-infected individuals who are stable clinically will still show considerable variation in CD4 counts. Short-term CD4 count fluctuations of nearly 30% may occur that are not attributable to a change in disease status. In addition, correlation between CD4 count and clinical status can be quite different from one patient to the next. Overall, it is important to monitor the trends in CD4 counts over time to avoid placing too much emphasis on the specific number derived from a single determination. Despite these limitations, the CD4 count remains a valuable tool when attempting to establish the differential diagnoses in a given patient. For example, it would be very unusual (although still possible, particularly in the context of immune reconstitution syndromes) to have a case of PCP, Mycobacterium avium complex (MAC), or cytomegalovirus (CMV) disease with a CD4 count within the normal range.

Strong evidence has been generated regarding the prognostic value of viral load determinations in seroincidence and seroprevalent cohorts. In one such study, seroprevalent individuals who had high viral loads were shown to have a substantially worse prognosis with regard to survival. Whereas median survival was in excess of 10 years for individuals with a plasma viral load under 5000/mL, those with plasma viral loads over 34,000/mL had a median survival on the order of 3 years.13 These data were confirmed by the results of virologic studies within the AIDS Clinical Trials Group Protocol 175 (ACTG 175). This study demonstrated a 10-fold increase in the rate of death and progression to AIDS or death when individuals with lower viral loads (<5000 copies/mL) were compared with those with high loads (>54,000 copies/mL). In this study, CD4 counts and viral load were shown to be independent prognostic markers at enrollment. More important, decreases in viral load with treatment between weeks 0 and 8 were shown to be statistically significantly associated with improved survival and decreased progression to AIDS within this protocol. Of note, increases in CD4 counts with treatment, during the same period, failed to demonstrate a statistical association with clinical outcomes. These data strongly support the independent contribution that viral load determinations can have in terms of monitoring prognosis and response to antiretroviral therapy. Plasma viral load determinations should be obtained in tandem with CD4 counts. However, although viral load determinations play a major role in the management of HIV-infected individuals, this marker has no demonstrated role in the ICU care of HIV-infected individuals.

Antiretroviral Treatment

Combination therapy regimens have been shown to prolong survival and the disease-free interval substantially among HIV-infected individuals. More recently, a number of new drugs have been added to our therapeutic armamentarium. The currently available classes of antiretrovirals are the nucleoside or nucleotide reverse-transcriptase inhibitors (NRTIs, NtRTIs), nonnucleoside reverse-transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and fusion inhibitors. The NRTIs include zidovudine (AZT), didanosine (ddI), stavudine (D4T), lamivudine (3TC), abacavir, and tenofovir. The NNRTIs include nevirapine, delavirdine, and efavirenz. The protease inhibitors include indinavir, ritonavir, saquinavir (hard-gel [Invirase], soft-gel [Fortovase]), nelfinavir, amprenavir (and fos-amprenavir), atazanavir, tipranavir, and the coformulation of lopinavir plus ritonavir (known commercially as Kaletra). PIs are increasingly coadministered with low-dose ritonavir for the purpose of taking advantage of the drug interaction, which results in higher drug levels (pharmacologic boosting) of the coadministered PI. This applies to indinavir/ritonavir, saquinavir/ritonavir, amprenavir/ ritonavir, tipranavir/ritonavir, and lopinavir/ritonavir; such combinations are considered to count only as a single drug from the antiviral perspective. Currently, triple (or quadruple) drug combinations, including two nucleosides (zidovudine or stavudine plus lamivudine or didanosine) and a PI (or boosted dual PI combination) or NNRTI are recommended to achieve a greater level of suppression of viral replication.14 Recently, regimens containing both d4T and ddI have been associated with high rates of toxicity. Alternative NRTIs (or NtRTI) include abacavir and tenofovir, which cannot be given together due to a yet to be understood interaction that compromises their antiviral effect.

In the ICU, it is particularly important to be aware of the more prevalent adverse effects of these agents (Table 48-1). As patients are increasingly treated with multiple antiretroviral agents, often including experimental agents, it is important to remain open to the possibility of new and previously unrecognized adverse effects. Also, whenever antiretroviral therapy is discontinued, viral replication will rebound within days to weeks. Patients receiving combination therapy who develop an adverse effect or drug intolerance to one of the antiretrovirals precluding its continuation should be reviewed by an HIV specialist. Temporary interruption of one drug or part of the antiretroviral regimen in particular may seriously compromise the long-term efficacy of the regimen by promoting the development of resistance to the remaining agents in the regimen.14 Under these circumstances, interruption of the full antiretroviral regimen is a more appropriate strategy.

It is likely that as experience with some of the newer antiretroviral agents increases, new adverse effects and toxicities will be uncovered. Also, physicians should pay particular attention to possible drug interactions in these often heavily medicated patients.15 In particular, the profound effect of ritonavir on drug metabolism always should be kept in mind in this setting.

The Spectrum of Disease in the ICU

Although HIV-infected individuals develop many medical complications, those leading to ICU admission are few. The complications may be divided according to their relationship to the HIV infection. Causes of ICU admission unrelated to the HIV infection generally are similar to those found in non-HIV-infected individuals of comparable age and risk groups (i.e., young intravenous drug users or homosexual males in North America), and since HIV infection generally is asymptomatic early in its course, many patients with clinically unsuspected HIV infection are treated in ICUs and emergency rooms. Patients with these conditions usually respond to standard management, and their prognosis appears to be similar to that of non-HIV-infected patients who have the same condition unless there is concomitant severe immunodeficiency, in which case the prognosis tends to be determined by the severity of the immunodeficiency.

Of the causes of ICU admission related to the HIV infection, acute respiratory failure (ARF) secondary to Pneumocystis carinii pneumonia (PCP) is much less common than in previous years. However, it remains a problem among patients who have barriers to accessing medical care and others who are nonadherent or fail to respond to antiretrovirals and PCP prophylaxis. Various conditions, such as cerebral toxoplasmosis, bacterial pneumonia, disseminated infections (such as bacterial sepsis or mycobacterial infection), gastrointestinal bleeding, Kaposi's sarcoma, lymphoma, endocarditis, and cardiomyopathy account for other HIV-related ICU admissions. The broad differential diagnosis of opportunistic diseases should be kept in mind to avoid delays in diagnosis.16 Less frequently, a person with AIDS may be admitted to the ICU without prior knowledge of her or his HIV status. Certainly, the presence or history of minor or major opportunistic infections, wasting, otherwise unexplained extensive herpes zoster, or persistent generalized lymphadenopathy combined with a history (or clinical evidence) of high-risk activities will necessitate consideration of HIV infection and related diseases in the differential diagnosis. Also, a number of laboratory features found commonly among HIV-infected individuals can provide the initial basis for considering HIV infection within the differential diagnosis. Among them, lymphopenia, anemia, thrombocytopenia, and hypergammaglobulinemia are the most common. It must be emphasized, however, that HIV infection should not be diagnosed unless this has been confirmed using specific serologic tests, most commonly, enzyme-linked immunosorbent assay (ELISA) and Western blot.

Acute respiratory failure secondary to PCP remains a frequent cause of ICU admission among HIV-infected individuals. Despite this, the initial diagnostic workup of patients with acute pulmonary disease always should consider less frequent causes, among them fungal, bacterial, mycobacterial, and viral infections. Other infections that may mimic PCP both clinically and radiologically include various causes of “atypical” pneumonia (influenza, Mycoplasma pneumoniae), miliary tuberculosis, disseminated histoplasmosis, cryptococcosis, coccidioidomycosis, and acute respiratory distress syndrome (ARDS). Although severe acute respiratory syndrome (SARS) has not been reported in HIV-infected patients, its progression to diffuse pulmonary infiltrates in association with lymphopenia17 would resemble PCP in an HIV-positive patient. Among 19 AIDS patients hospitalized together with 95 SARS patients on the same floor of a hospital in the Province of Guangdong, none developed SARS, in contrast to 6 of 28 medical staff who did.18 This has raised the questions of whether HIV-1 interferes with SARS virus replication in the same host or combination antiretroviral regimens may prevent SARS.18 Although Kaposi's sarcoma (KS) can result in ARF, this seldom occurs in the absence of overt mucocutaneous disease. Progression to ARF in KS patients is usually a reflection of overwhelming disease.

Patients who have ARF present with varying degrees of hypoxemia, hypocapnia, and other nonspecific abnormalities related to the underlying HIV disease, as discussed earlier.19 If available, the CD4 count can aid in the differential diagnosis because the occurrence of PCP when the CD4 count is greater than 250 cells/μL would be unusual. An elevated lactic dehydrogenase (LDH) concentration in a patient with known HIV infection and respiratory distress is typical of PCP, and the LDH level tends to correlate with the severity of the episode. Furthermore, changes in the LDH level tend to parallel the course of PCP.23 However, an elevated LDH concentration is nonspecific because this enzyme also can be elevated in various other settings, including other pneumonias, pulmonary embolism, lymphoma, megaloblastic anemia, liver disease, shock liver, and hemolysis (commonly seen among HIV-infected patients receiving dapsone treatment or prophylaxis for PCP) or during long-term AZT therapy.

By the time ARF secondary to PCP requiring ICU admission develops, the chest radiograph usually has evolved to a diffuse alveolar pattern characteristic of ARDS. However, a careful review of previous radiographs can, at times, aid in the differential diagnosis, as shown in Table 48-2.20,21 The clinical, laboratory, and radiologic pattern is seldom specific enough to establish the diagnosis, which should be confirmed using appropriate laboratory examinations. This is particularly important when the patient does not yet carry a diagnosis of AIDS because of the serious prognostic and therapeutic implications of this diagnosis. If sputum is available, this should be cultured for bacteria, fungi, and mycobacteria. Blood cultures also should be obtained, and in selected patients, mycobacterial and fungal blood cultures should be obtained. The key to the etiologic diagnosis relies on obtaining tracheobronchial secretions.19 In the ICU setting, particularly in ventilated patients, bronchoscopic bronchoalveolar lavage (BAL) is the preferred approach. This should be performed by an experienced specialist. Bronchoscopy should be performed using appropriate cardiorespiratory monitoring, including pulse oximetry and an electrocardiogram (ECG).

The sensitivity of BAL for P. carinii and other treatable pathogens commonly found in AIDS patients exceeds 95%. BAL specimens should be concentrated to increase sensitivity. Aliquots should be referred for viral, bacterial, fungal, and mycobacterial studies. P. carinii screening should be requested specifically because this is not performed routinely in most laboratories. Sputum induction and transbronchial biopsies, although valuable techniques in the routine evaluation of less critically ill patients, are not recommended in critically ill and ventilated patients. In the few patients for whom the initial BAL does not provide a diagnosis, a transbronchial or open lung biopsy should be considered.20 However, the appropriateness of such intervention is best decided on a case-by-case basis after careful assessment of the general status of the patient, as well as the likelihood of diagnosing a treatable condition.

P. Carinii Pneumonia

P. carinii, recently reclassified as a fungus but having some properties of protozoa, is a ubiquitous organism that produces human disease throughout the world, usually in the setting of severe immunosuppression. Asymptomatic primary infection generally occurs early in life. Rarely, P. carinii can be found incidentally at autopsy in the absence of symptoms. It is not clear whether this represents late infection or early disease not yet manifested clinically.

PCP was the index disease that facilitated the clinical recognition of AIDS. Since then, it also has become the first major AIDS-related opportunistic infection for which development of effective therapy has led to important improvement in survival. Despite these advances, PCP remains a serious opportunistic infection among those infected with HIV, typically occurring among those who do not get tested for HIV or who have problems with access or adherence to antiretroviral and prophylactic therapies. PCP is generally a late event in the evolution of HIV infection, usually occurring when the CD4 count is below 200 cells/μL.22 Therefore, it is recommended that all HIV-infected individuals with CD4 counts below 200 cells/μL or those who have had an episode of PCP should receive lifelong PCP prophylaxis unless immune reconstitution occurs owing to antiretroviral therapy (sustained increase in absolute CD4 count to more than 200 cells/μL for at least 3 months)22 (Table 48-3).

Clinical and Radiologic Features

Dyspnea, nonproductive cough, and fever are the classic features of PCP. In critically ill patients, the physical examination usually demonstrates evidence of acute respiratory distress, with surprisingly few adventitious sounds on auscultation of the chest. Acute hypoxemic respiratory failure requiring mechanical ventilation has been reported to occur in as many as 20% of hospitalized patients.23 Most often this occurs within the first 3 days of starting antimicrobial therapy; less frequently acute hypoxemic respiratory failure develops as a complication of diagnostic bronchoscopy and rarely as the initial presentation to the emergency room.23

Clinically overt PCP usually develops over a period of several days to weeks, and in this time, the radiologic picture tends to progress from a normal chest radiograph to a diffuse bilateral interstitial pattern. Varying degrees of alveolar involvement can be seen; even frank consolidation may occur, as seen in Figs. 48-1, 48-2, and 48-3. A number of atypical radiologic presentations have been described, including cystic changes, pneumothoraces (Fig. 48-4), nodular or masslike opacities, and even cavities.20 Upper lung field involvement, as seen in Fig. 48-5, also has been recognized increasingly, particularly (but not exclusively) in the context of aerosol pentamidine prophylaxis. To what extent aerosol pentamidine prophylaxis is responsible for the apparent increased frequency of PCP-related pneumothoraces remains controversial.

Diagnosis

As discussed earlier, given the nonspecific nature of the clinical, laboratory, and radiologic picture of PCP, diagnostic confirmation is desirable. BAL is a rapid, safe, and effective means of obtaining tracheobronchial secretions to provide an adequate diagnostic specimen. Lung biopsy is seldom required to confirm the diagnosis of PCP. As seen in Fig. 48-6, the usual pathologic picture of PCP consists of a mild to moderate interstitial inflammatory reaction with predominance of lymphocytes and alveolar macrophages and the presence of a foamy alveolar exudate (as seen with hematoxylin and eosin [H&E] staining). The foamy appearance of the alveolar exudate is caused by the presence of the cystic form of the organism, which is not stained with H&E but can be easily recognized using readily available special stains (Fig. 48-7). As seen in Fig. 48-8, BAL allows clear identification of the organism if the specimen is concentrated and stained appropriately.19,20 The composition of the alveolar exudate has not been established conclusively. However, BAL studies suggest that this is an inflammatory exudate rich in immunoglobulins, macrophages, and suppressor cytotoxic lymphocytes.24 Although P. carinii infection usually is confined to the lungs, systemic pneumocystosis (involving liver, spleen, lymph nodes, adrenals, and eyes), has been reported occasionally.25 Polymerase chain reaction (PCR) methodology has been applied to the diagnosis of PCP using blood, sputum, and BAL but is not widely available and remains investigational.

PCP Immune Reconstitution Syndrome

Immune reconstitution syndrome (IRS; also known as immune reconstitution inflammatory syndrome) is the clinical deterioration or “paradoxical reaction” that may develop in almost any organ system as a result of augmented immune response to preexisting clinical or subclinical infection.26,27 Among HIV-negative patients, this phenomenon occurs occasionally during the course of chronic hepatitis B and during treatment for borderline lepromatous leprosy (reversal reaction, Lepra type I) or tuberculosis (e.g., central nervous system tuberculomas) and is due to improvement in cell-mediated immunity.28 A similar pathogenesis is believed to account for IRS among HIV-infected patients. IRS has been reported increasingly since the introduction of highly active antiretroviral therapy (HAART) in 1996. IRS has been described as both an unmasking of subclinical latent infection or a worsening of already documented preexisting disease. Most of the reports have been related to CMV retinitis, tuberculosis (TB), MAC, PCP, cryptococcosis, progressive multifocal leukoencephalopathy, and herpes zoster infection.

A diagnosis of IRS begins with a suspicion of clinical events occurring usually within weeks or months after initiating or revising an antiretroviral regimen. The differential diagnosis may include adverse drug effects and coexisting unrecognized infections (nosocomial or community-acquired). Some opportunistic infections show atypical features in the context of IRS, particularly MAC, CMV retinitis, and cryptococcal meningitis.29 The diagnosis cannot be made without convincing evidence of a response to the antiretroviral regimen (e.g., ≥1 log10 reduction in HIV RNA and usually a CD4 increase). For preexisting opportunistic infections (e.g., TB), the diagnosis of IRS is one of exclusion. In contrast, MAC IRS is usually an unmasking of subclinical infection, and when the organism is recovered from a normally sterile body site, the diagnosis is established. It is important to make the diagnosis of IRS in order to avoid inappropriate therapy (e.g., chemotherapy for suspected multidrug resistant TB).

Initiation of combination antiretrovirals during therapy for PCP has been associated with a paradoxical worsening of the pulmonary infiltrates and lung function in up to 5% to 18% of patients.30 Among the 17 patients with PCP immune reconstitution syndrome reported to date, the clinical worsening was observed 3 to 17 days after starting the antiretroviral regimen. Flow cytometry of BAL specimens in such patients may show a higher CD4/CD8 ratio than usually observed in PCP owing to an influx of CD4 cells during immune reconstitution.31 Transbronchial lung biopsy may reveal a prominent alveolar infiltrate consisting of lymphocytes, macrophages, and neutrophils with few or no demonstrable PCP organisms.32 The diagnosis is established by endoscopy and transbronchial biopsy in order to demonstrate the above-mentioned findings and exclude other possible opportunistic diseases. Any diagnosis of IRS should be supported by evidence of a virologic (HIV viral load reduction of usually ≥1 log10) and/or immunologic (CD4 count increase) response to the antiretroviral regimen. Some patients with PCP IRS have developed respiratory failure and appeared to respond to systemic corticosteroids. The incidence of this complication may be reduced by delaying the initiation of antiretrovirals until after PCP therapy has been completed because reported cases usually have developed within the first few weeks following the dagnosis of PCP.

Management

Trimethoprim-sulfamethoxazole (TMP-SMX) is effective against P. carinii, as well as various gram-negative and gram-positive bacterial organisms. TMP-SMX is administered intravenously or orally at a dose of 15 and 75 mg/kg daily, respectively, in three divided doses for 14 to 21 days. Poor tolerance of TMP-SMX among HIV-infected patients is a significant problem, with adverse drug reactions occurring in 60% to 100% of patients. These include rash, fever, liver dysfunction, renal dysfunction, leukopenia, thrombocytopenia, hyponatremia, anemia, and gastrointestinal upset. Less common but at times severe are mucocutaneous reactions, occurring generally at the end of the first week of treatment. A number of reports have documented successful desensitization of TMP-SMX-allergic patients using progressively larger doses of the drug. Hypersensitivity-type reactions such as fever or rash also can be treated with diphenhydramine or corticosteroids.33,34

Pentamidine isethionate was used initially for the treatment of African trypanosomiasis. Since 1958, it has been known to be effective against P. carinii. Pentamidine usually is administered intravenously once daily at a dose of 4 mg/kg diluted in 250 mL of 5% dextrose and water for 14 to 21 days. Adverse reactions are common, occurring in up to 100% of patients in some series. Common adverse drug reactions include renal and liver dysfunction, neutropenia, thrombocytopenia, hyponatremia, rash, fever, and gastrointestinal upset. Hypotension is commonly associated with pentamidine infusion. This can be minimized by administering the drug slowly over several hours; if severe or long-lasting hypotension occurs, this should be treated supportively because it is readily reversible. Occasionally, carbohydrate metabolism abnormalities (hypo- or hyperglycemia) may develop, including insulin-dependent diabetes mellitus. Ventricular arrhythmias and pancreatitis also have been reported. Finally, observations suggest an increased risk of pancreatitis among patients receiving didanosine and systemic pentamidine concomitantly. Coadministration of these two drugs therefore is contraindicated. Owing to delayed elimination of intravenous pentamidine, ddI should not be coadministered for several weeks after stopping IV pentamidine. Because adverse reactions to pentamidine are related to its systemic concentration, and because of its poor absorption through the alveolar surface, aerosol therapy has been investigated. In a pilot study, a high cure rate with no significant systemic toxicity was achieved using 5 mg/kg daily via a nebulizer in a highly selected group of patients with mild PCP. The only reported adverse effects were cough and bronchospasm in the majority of patients; however, these adverse effects were easily prevented by premedication with a β2-agonist bronchodilator. However, because of variable efficacy and increasing concern regarding the possibility of uneven drug distribution, early relapse, and extrapulmonary pneumocystosis, aerosol pentamidine therapy is not recommended; it should be reserved for use as a prophylactic agent only.35–37

Dapsone (DPS), a sulfone used for the treatment of leprosy and dermatitis herpetiformis, has been shown to be effective against P. carinii, particularly when DPS, 100 mg by mouth daily, is combined with trimethoprim (TMP), 320 mg by mouth q8h (or 15 mg/kg daily, divided q8h). DPS-TMP has been shown to have similar efficacy and better tolerability than TMP-SMX.38 Adverse reactions are common, including hemolytic anemia with methemoglobinemia, thrombocytopenia, neutropenia, liver dysfunction, rash, and gastrointestinal upset, which often interferes with oral administration. The DPS-induced methemoglobinemia and hemolytic anemia are particularly severe among individuals with glucose-6-phosphate dehydrogenase deficiency. It is also important to note that the hemolytic anemia will produce an increase in LDH that should not be misinterpreted as a sign of worsening PCP.19

Atovaquone, a newly developed hydroxynaphthoquinone, has been shown to be a useful second-line agent for the treatment of PCP. Although slightly less effective than TMP-SMX, atovaquone has shown similar efficacy to IV pentamidine, with a very favorable safety profile. This agent is available only in an oral formulation. Furthermore, the drug is not to be used in the presence of moderate to severe diarrhea. For these reasons, atovaquone does not lend itself well to use in the critical care setting.39

Clindamycin-primaquine also has been shown to be effective in the treatment of PCP. This regimen usually is reserved for those who fail or are intolerant to TMP-SMX and IV pentamidine. Clindamycin is given orally or intravenously at doses of 450 to 600 mg four times daily, and primaquine is given orally at a dose of 15 to 30 mg daily.40 Finally, trimetrexate has failed to find a place in the therapeutic armamentarium against PCP despite early favorable reports.41

Prospective, randomized placebo-controlled studies have demonstrated a beneficial short-term effect of adjunctive corticosteroid therapy,42 which prevents the characteristic early deterioration in gas exchange seen in untreated patients and results in a faster resolution of the episode (as measured by respiratory rate, temperature, heart rate, PaO2, and LDH). Adjuvant corticosteroids also have been shown to decrease mortality significantly among patients with PCP-related ARF in a prospective, placebo-controlled trial.43 Systemic corticosteroids are recommended routinely as adjuvant therapy for moderate and severe PCP if no contraindications are present.44 A regimen consisting of oral prednisone 40 mg twice daily for the initial 7 days followed first by 40 mg orally daily for 7 days and then by 20 mg orally daily for the final 7 days is recommended.44 Corticosteroids should be started early in the course of the disease, and to this end, a PaO2 threshold of 70 mm Hg has been proposed.44 It must be emphasized that adjuvant corticosteroid therapy should be continued while patients are on anti-PCP antimicrobials to avoid the rapid deterioration often seen following premature discontinuation of adjuvant corticosteroids. Adjuvant corticosteroids also may exert a similarly beneficial effect even among patients with milder forms of PCP.45

The initial selection of the antimicrobial agent usually occurs outside the ICU. Patients with mild to moderate PCP generally are started on dapsone-trimethoprim or TMP-SMX orally. If there is a concern regarding superimposed bacterial infection, additional antibacterial coverage should be added for community-acquired pneumonia.46Pentamidine generally should be reserved for in-patients with PCP and documented intolerance to TMP-SMX. If the patient is first diagnosed in the ICU, TMP-SMX intravenously generally will be the preferred antimicrobial. Corticosteroids should be started at once in any patient whose PaO2 is below 70 mm Hg while breathing room air. Response to antimicrobials generally is slow, and significant improvement usually does not occur until after 5 to 7 days.33 With the use of adjunctive corticosteroids, however, significant improvement can be observed within the first 3 days of treatment.42 Patients who fail to improve within the first 5 days of therapy should be reviewed thoroughly to rule out potential intercurrent infections (such as ventilator-associated pneumonia) or other complications, including pneumothorax and fluid volume overload. Evidence of P. carinii resistance to sulfamethoxazole has been demonstrated in patients with prior sulfonamide exposure by the presence of mutations in the gene of sulfamethaxazoles' target enzyme, dihydropteroate synthase (DHPS).47 The results of studies that have evaluated the clinical significance of such mutations are conflicting. A retrospective Danish study suggested that DHPS mutations are predictive of mortality,48 whereas another did not confirm this prediction.49 Lack of improvement within 7 days of therapy generally is interpreted as a failure of treatment and therefore an indication for a trial of the alternative agent. A change in antimicrobial also would be warranted if severe adverse reactions develop despite the use of adjunctive corticosteroids. There is no evidence of increased efficacy, but there is increased toxicity when combining TMP-SMX with pentamidine. However, when switching from TMP-SMX to pentamidine, it may be advisable to administer both drugs for a few days until therapeutic levels of pentamidine can be expected in lung tissue.

Prognosis

Untreated, PCP is universally fatal. With the use of appropriate antimicrobials, overall mortality of AIDS-related PCP is below 10%. However, the mortality clearly increases with the severity of the episode.21,23,44 The expected mortality of a mild first episode of PCP, therefore, usually is negligible. In addition, young age and early diagnosis have been correlated with better outcome.21,23,50 The mortality of ARF secondary to AIDS-related PCP appears to be changing. In the early days of the epidemic, mortality was greater than 80% in most series.51,52 Mortality has been reduced to less than 50% with the addition of systemic corticosteroids.23,43,44 However, if PCP-related ARF develops despite early intervention with maximal therapy, including corticosteroids and appropriate antimicrobial agents, the prognosis appears to be dismal, with a mortality greater than 90% in some series.53

Mycobacterium Tuberculosis (MTb)

Tuberculosis occurs with varying degrees of frequency among HIV-infected individuals, reaching 20% in some series. Because the risk of developing tuberculosis is proportional to the risk of developing it prior to the acquisition of HIV, its incidence in North America is greatest among intravenous drug users, blacks, and Latin Americans. Tuberculosis usually develops within the year prior to the diagnosis of other AIDS-defining conditions. Either pulmonary or disseminated tuberculosis in an HIV-infected individual is diagnostic of AIDS according to the CDC classification of HIV disease.

The symptoms of tuberculosis in the context of HIV generally are nonspecific. This is particularly the case because “classic” tuberculosis symptoms such as fatigue, malaise, weight loss, fever, and night sweats are extremely common, even in moderately advanced stages of HIV disease. In contrast to the immunocompetent host, in the context of HIV disease, reactivating tuberculosis usually has radiologic features similar to those of primary tuberculosis, including hilar and/or mediastinal adenopathy, middle and lower lung infiltrates, pleural effusions, or a miliary pattern. Apical infiltrates or cavities are seen only in a minority of patients. As many as 9% of patients with CD4 counts of less than 200 cells/μL have a normal chest x-ray with a positive sputum culture for MTb.54 Furthermore, PCP is diagnosed simultaneously in as many as 25% of the cases of tuberculosis. Prospective tuberculin skin testing (PPD) is useful among HIV-infected individuals because tuberculosis develops more frequently in patients known to have a previously positive test; however, at the time of diagnosis of AIDS, at least 30% of patients are anergic. MTb usually can be diagnosed with smear and culture of sputum or BAL. Of particular note is the diagnostic yield of blood culture (2% to 12%) in some patients. Rapid diagnostic tests have been approved for the detection of M. tuberculosis RNA or DNA in respiratory tract specimens within 24 hours. Such tests are particularly useful in the management of selected patients who are positive or negative for an acid-fast bacilli smear, particularly for those with an intermediate pretest probability of having tuberculosis.55 Treatment guidelines for tuberculosis have been revised recently by the American Thoracic Society (ATS) and the CDC. Tuberculosis (i.e., first-line antituberculous drug–susceptible) in HIV-infected adults should be treated with isoniazid (plus pyridoxine), rifampin, pyrazinamide, and ethambutol for the initial 2 months (initial phase) of therapy. Ethambutol and pyrazinamide are then discontinued. The continuation phase of treatment consists of isoniazid (plus pyridoxine) and rifampin for 4 more months (total 6 months). Patients who respond slowly to treatment should have the continuation phase of treatment increased to 7 months (total 9 months, or 6 months after documented culture conversion). During the continuation phase, treatment may be administered either on a daily basis or three times weekly. However, twice-weekly therapy is not recommended, particularly for those with CD4 counts of less than 100 cells/μL.56 Numerous significant drug interactions have been identified between rifamycins and many antiretrovirals, except for NRTIs and NtRTIs. Patients with CD4 counts of less than 300 cells/μL likely will require concurrent antituberculous and antiretroviral therapy. Those with CD4 counts between 200 and 300 cells/μL should be considered for antiretroviral therapy. Rifabutin may be substituted for rifampin and has the advantage of being associated with fewer and less profound antiretroviral drug interactions.56,57

A high proportion of patients with multi-drug-resistant tuberculosis (MDR-TB) have been HIV-infected. MDR-TB should be suspected in patients with persistent fevers after 14 days of therapy, particularly in areas of high prevalence.58 Persistent fevers also have been associated with extensive pulmonary or miliary disease in cases of non-MDR-TB. In contrast to previous reports, HIV-infected patients with MDR-TB had survival rates similar to those with non-MDR-TB when an early diagnosis was established and treatment was initiated with a regimen containing at least two drugs to which the isolate was susceptible in vitro.58 Expert consultation is recommended for the management of patients with suspected or proven drug-resistant TB. Principles of therapy include the use of at least three previously unused drugs, not limiting regimens to three drugs if other active unused drugs are available (since four- to six-drug regimens appear to be more effective), using directly observed therapy (DOT), and avoiding intermittent therapy except possibly for injectable drugs after the first 2 to 3 months.56 MTb IRS is important to consider in the differential diagnosis of any HIV+ patient who appears to worsen during the course of therapy for MTB.

M. Tuberculosis Immune Reconstitution Syndrome

M. tuberculosis immune reconstitution syndrome (MTb-IRS) is a paradoxical worsening of the signs and symptoms of tuberculosis during the course of antituberculous therapy. This phenomenon was reported occasionally in the pre-AIDS era and considered to be a consequence of resolution of mycobacterial-induced suppression of cell-mediated immunity. MTb-IRS has been reported to occur in up to 36% of HIV-infected patients who initiate HAART.59 MTb-IRS is important to consider in the differential diagnosis of any HIV+ patient who appears to worsen during the course of therapy for MTb infection. The manifestations may include fever, worsening pulmonary infiltrates, lymphadenopathy, and CNS granulomas. Case reports suggest a possible benefit of systemic corticosteroids for the management of moderate to severe IRS related to MTb and IRS related to other organisms. The diagnosis of MTb-IRS is one of exclusion, including consideration of coexisting opportunistic infections and also multi-drug-resistant MTb.

Among tuberculosis patients with advanced HIV disease (CD4 count <200 cells/μL), HAART recipients have improved 12-month survival compared with historic controls in the pre-HAART era (95% versus 85%).60 However, problems related to polypharmacy and overlapping drug toxicities argue against the simultaneous initiation of antituberculous and antiretroviral therapy. Consequently, a more appropriate time to begin HAART may be after 4 to 8 weeks of antituberculous therapy56; furthermore MTb-IRS may be less likely to occur then.61

MAC disease is usually disseminated (90%) and occurs later than MTb in the course of HIV infection, typically when the CD4 lymphocyte count has fallen below 50 cells/μL. A number of nonspecific symptoms, signs, and routine laboratory abnormalities are encountered frequently in patients with MAC, including fever (87%), night sweats (78%), diarrhea (47%), weight loss (38%), anemia (hemoglobin = 8.5 g/dL; 85%), and elevated serum alkaline phosphatase levels (53%).62 Clinical and radiologic evidence of lower respiratory tract involvement (4% to 10%) is usually absent. Occasional patients have few or no symptoms in the face of MAC bacteremia.

The diagnosis is established by isolating the organism from blood (mycobacterial blood culture, using radiometric broth or lysis-centrifugation method) or less often from tissue biopsy (e.g., bone marrow, liver) or other normally sterile body fluids. Recovery of the organism from sputum, BAL, bowel, or stool specimens may represent colonization or localized or disseminated disease. In a prospective study, multivariate analysis identified three independent predictors of mycobacteremia in patients with CD4 counts of less than 50 cells/μL: (1) fever for 30 days during the previous 3 months, (2) serum albumin concentration of less than 3.0 g/dL, and (3) hematocrit of less than 30%.63 When applied prospectively to a validation set, the presence of at least one of the three predictors provided a sensitivity of 94%, a specificity of 42%, and a positive predictive value of 30%.

Significantly improved survival (median = 8.6 versus 5.2 months) and eradication of mycobacteremia was demonstrated with a three-drug combination of clarithromycin, ethambutol, and rifabutin (versus a four-drug regimen of ciprofloxacin, rifampin, ethambutol, and clofazimine) in a prospective, randomized trial.64 Adverse effects of rifabutin included uveitis, which occurred much less often at a daily dose of 300 mg (6%) compared with 600 mg (38%).64 Results from a randomized trial of combination therapy for MAC bacteremia indicated a survival benefit for a regimen containing clarithromycin 500 mg bid compared with 1000 mg bid.65 In a randomized trial, Chaisson and coworkers66 reported higher mortality among patients receiving clofazimine (61%) compared with placebo (38%, p = 0.032) in combination with clarithromycin and ethambutol.

Rifabutin does not need to be added to clarithromycin-ethambutol for treatment of AIDS-related MAC bacteremia, as outlined below. No clinical or microbiologic benefit was associated with the addition of rifabutin (versus placebo) to a clarithromycin-ethambutol regimen in AIDS-related MAC bacteremia. Among those who responded to therapy, subsequent development of clarithromycin resistance occurred in 2% (1 of 44) and 14% (6 of 42) who received rifabutin and placebo, respectively (p = 0.055).67 However, the significance of the protective effect of rifabutin on subsequent clarithromycin resistance is doubtful in the HAART era because long-term survival and subsequent MAC bacteremia relapses are related primarily to immune reconstitution rather than continued clarithromycin susceptibility of the MAC isolate.

Primary prophylaxis of MAC is indicated for patients with CD4 counts below 50 cells/μL. A randomized comparative study indicated that azithromycin 1200 mg once weekly is a more effective prophylactic than rifabutin 300 mg daily,68 in addition to being less expensive and less problematic with respect to drug interactions. Clarithromycin is also effective for MAC prophylaxis; however, when breakthrough mycobacteremia occurs, 29% to 58% of MAC isolates are clarithromycin-resistant. MAC drug resistance has not been a problem among failures of rifabutin prophylaxis and was observed in only 11% of azithromycin failures.68 The interest in preserving clarithromycin as an active drug for treatment of MAC bacteremia provides the rationale for restricting its use as an alternative prophylaxis drug. Primary prophylaxis for MAC bacteremia may be discontinued if there is a sustained rise in the CD4 count to more than 100 cells/μL for at least 3 months22 (see Table 48-3).

Cytomegalovirus (CMV) Disease

CMV isolation from pulmonary secretions in AIDS patients appears to have little prognostic value, even when corticosteroids are added to the treatment of PCP. Patients with confirmed PCP respond to anti-Pneumocystis treatment whether or not CMV is also recovered in BAL specimens.69 However, the prominent role of CMV as a gastrointestinal or ocular pathogen among these patients is clearly recognized.

CMV pneumonitis in the context of AIDS should be diagnosed only if hypoxemia and diffuse pulmonary infiltrates coexist with evidence of CMV cytopathic effect (i.e., intranuclear and intracytoplasmic inclusions) in lung tissue and with histologic absence of other likely causes to explain the pulmonary disorder.70 Unfortunately, CMV blood and urine cultures have poor diagnostic and predictive value in the setting of HIV disease, and the likelihood of a positive result correlates inversely with CD4 count.71 CMV disease usually is treated with ganciclovir or foscarnet, as outlined in Table 48-4. Long-term maintenance therapy is required for CMV retinitis but may not always be needed in gastrointestinal disease. In the context of AIDS, CMV disease tends to occur at a late stage, usually when the CD4 count is less than 50 cells/μL. Mean survival with intravenous or oral ganciclovir maintenance therapy following an episode of CMV retinitis is approximately 13 months without HAART.72

Other Causes of Pulmonary Infiltrates

Bacterial pneumonias tend to occur with increased frequency among HIV-infected individuals. Community-acquired pneumonias usually are caused by Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, or gram-negative bacilli. Legionella pneumonitis, contrary to early reports, occurs infrequently among HIV-infected individuals. Clinical features of community-acquired bacterial pneumonia are indistinguishable from those described in the immunocompetent host. Chest radiographs usually demonstrate segmental or lobar consolidation. Treatment of bacterial infections is included in Table 48-4.73,74

Nosocomial pneumonias among HIV-infected individuals are indistinguishable from those occurring in other hospitalized patients. These are usually caused by gram-negative organisms and tend to have a high mortality despite appropriate therapy.

Ventilator-associated pneumonia (VAP) may complicate the course of HIV-infected patients who require mechanical ventilation. There is an increasing frequency of S. aureus (methicillin-resistant S. aureus [MRSA] or methicillin-sensitive S. aureus [MSSA]) as the cause of VAP. In addition, aerobic gram-negative bacilli remain common causes of VAP. The other diagnosis to consider in patients who have pulmonary infiltrates and who require mechanical ventilation is ventilator-associated lung injury. The details of mechanical ventilation are discussed in Chaps. 36 and 38. HIV-infected patients who have acute lung injury (diffuse bilateral infiltrates, PaO2/FiO2 <300 mm Hg, and no cardiac cause of pulmonary edema) should receive lung-protective ventilation.75

Fungal pneumonias are a rare cause of respiratory failure among HIV-infected individuals. Disseminated infection is often present. Aspergillosis, cryptococcosis, histoplasmosis, and coccidioidomycosis are encountered most frequently and usually are associated with advanced HIV disease. Although reported rarely in AIDS prior to 1990, invasive aspergillosis had an incidence estimated to be between 0.9% and 8.6% among patients with AIDS in the pre-HAART era.76 Respiratory tract syndromes caused by Aspergillus spp. in AIDS include invasive pulmonary aspergillosis, obstructing bronchial lesions, and tracheobronchitis. The presenting symptoms frequently are cough and fever; less common complaints include dyspnea, chest pain, and hemoptysis.76 A common radiologic finding in AIDS-related invasive pulmonary aspergillosis is a thick-walled cavity.77

Candidiasis of the trachea, bronchi, or lungs, despite being recognized by the CDC as an AIDS-defining condition, is a very infrequent problem among these patients. Treatment of fungal disease is outlined in Table 48-4.78–81

Kaposi's sarcoma (KS) involves the lungs in up to 25% of patients with mucocutaneous KS. Clinically significant pulmonary KS without obvious mucocutaneous involvement is rare. Pulmonary KS often is indistinguishable from other HIV-related pulmonary diseases. Cough and dyspnea are common presenting features. Fever, wheezing, hoarseness, and even upper airway obstruction can occur. Sputum production usually is scant or absent. Hemoptysis, however, is relatively frequent. Chest radiograph usually shows nodular opacities of varying sizes coexisting with varying degrees of interstitial disease. Pleural and nodal involvement is also frequent. Bronchoscopic evaluation usually helps to rule out a superimposed treatable HIV-related disease in patients with pulmonary KS. It also may allow visualization of the characteristic red-violaceous lesions in the endobronchial tree. Although biopsy of these lesions at times can provide diagnostic confirmation, this is rarely required. No definitive therapy is currently available for the treatment of systemic KS, although significant improvement has been observed among some patients treated with HAART. Interferon has been used with some limited success for the treatment of early disease. Radiation therapy and chemotherapy have had some success in providing palliation. Given the poor prognosis of KS-related ARF at this time, these patients are unlikely to benefit from ICU support.82

Neurologic disease secondary to opportunistic infection or neoplasm may be associated with a depressed level of consciousness and occasionally precipitate ICU consultation and care. Often the neurologic disease may be a concomitant problem in patients requiring ICU care for other reasons.

The most frequently encountered neurologic syndromes in HIV-infected patients are meningitis, dementia, encephalopathy, focal neurologic deficits, myelopathy, peripheral neuropathy, and myopathy.83,84 The various etiologic agents responsible for these syndromes, in addition to key points of clinical presentation and diagnostic evaluation, are summarized in Table 48-5. In general, most of the treatable infections complicating AIDS produce either meningitis or progressive focal neurologic deficits owing to localized inflammatory lesions in the brain, and both these syndromes usually are associated with headache. However, most of the causes of diffuse brain involvement are not associated with headache. A suggested sequence of investigations in the HIV-infected patient with headache or CNS dysfunction is outlined in Fig. 48-9. Antimicrobial therapy is outlined in Table 48-4.85–88

Meningitis

The clinical presentation of both acute and chronic meningitis is little different in the AIDS patient from that seen in the immunocompetent host; presentation includes headache, fever, and nuchal rigidity of variable duration and severity.

The most important cause of meningitis in the HIV-infected patient is Cryptococcus neoformans. Uncommon etiologies include Mycobacterium tuberculosis,89,90 Coccidioides immitis,91 Histoplasma capsulatum, Treponema pallidum (syphilis), Listeria monocytogenes, and the usual causative agents of bacterial meningitis (pneumococcus, meningococcus, Haemophilus influenzae). Antimicrobial therapy is outlined in Table 48-4. HIV-related aseptic meningitis may occur at the time of seroconversion but is more common later in the course of HIV disease, when both acute and chronic presentations have been described. The role of antiretroviral therapy for HIV-related aseptic meningitis has not been evaluated.

Diffuse Brain Disease (Dementia and Encephalopathy)

AIDS dementia complex (ADC) appears to be caused by chronic HIV infection of the CNS. Patients with ADC manifest varying degrees of impaired cognition, behavior, and motor function but usually remain alert. In contrast, the diffuse encephalopathies associated with toxic and metabolic disorders, CNS toxoplasmosis, lymphoma, or viral infection (e.g., herpes simplex or CMV) usually result in impairment of cognition associated with a disturbance in the level of consciousness. Patients with ADC should be treated with combination antiretroviral therapy. There is evidence that antiretroviral therapy can both prevent and ameliorate ADC. Zidovudine (AZT) has been associated with sustained improvement in neurologic performance in up to 50% of patients.92 The role of other antiretroviral agents in the management of ADC has not been determined; however, in a meta-analysis of clinical trials of patients switching from AZT to didanosine (ddI), there was no evidence of any increase in the incidence of ADC during ddI therapy. Despite the absence of definitive clinical trials clarifying the efficacy of HAART for the prevention or treatment of ADC, extrapolation from the monotherapy trials and anecdotal experience supports this approach. Although unproven, improved clinical response may be associated with regimens that include drugs that have good brain penetration (AZT, abacavir, stavudine, and nevirapine).

Focal Neurologic Disease

Patients presenting with focal neurologic deficits should have urgent magnetic resonance imaging (MRI) or a computed tomographic (CT) head scan with contrast material, which usually yields evidence of CNS toxoplasmosis (Fig. 48-10), lymphoma (Fig. 48-11), or progressive multifocal leukoencephalopathy (PML). Occasional cases of subacute focal brain disease may be caused by aspergillosis, cryptococcoma, tuberculoma, varicella-zoster virus infection, or herpes simplex encephalitis. The abrupt onset of focal neurologic deficit suggests either a seizure or vascular disorder. Patients with a CT scan or MRI compatible with toxoplasmosis should be treated empirically (see Table 48-4). The diagnosis of toxoplasmosis usually is presumptive on the basis of a clinical and radiologic response to empirical therapy, without brain biopsy. Early brain biopsy should be considered for patients with mass lesion(s) who are unlikely to have toxoxplasmosis based on the combination of neuroimaging findings, toxoplasma serology, and whether the patient developed the lesions while taking TMP-SMX or dapsone prophylaxis (see Fig. 48-9). Corticosteroids should be avoided unless there is life-threatening cerebral edema and the risk of brain herniation. Since lymphoma may respond transiently to corticosteroids, coadministration with empirical toxoplasmosis therapy may confound the assessment of response to therapy and reduce the diagnostic yield of brain biopsy. Those who are not responding to empirical therapy, particularly when associated with negative serum serology (IgG) for toxoplasmosis, should be considered for brain biopsy.93 Although less responsive to therapy, some patients with CNS lymphoma may have a significant response to radiotherapy and chemotherapy. HAART has been associated with improved clinical course and survival time in HIV-related PML for the subset of patients having relatively high CD4 counts and low spinal fluid JC viral load at the time of diagnosis.94 JC viral load in spinal fluid usually becomes undetectable for PML patients who respond to HAART. A possible role for cidofovir in the management of PML has been suggested by observational studies.95 Neurosyphilis is responsible only occasionally for focal neurologic deficit, but it is important to consider this treatable condition.86

Myelopathy, Peripheral Neuropathy, and Myopathy

Vacuolar myelopathy is slowly progressive and characterized by diffuse involvement of the spinal cord in HIV-infected individuals. A clinically indistinguishable presentation may be seen in human T-cell lymphotropic virus 1 (HTLV-1) infection. In contrast, a much less common form of myelopathy has a more rapid onset and is associated with segmental pathology of the spinal cord (transverse myelitis). The etiologic agents for this latter condition include lymphoma, varicella-zoster virus (VZV) infection, CMV infection, and toxoplasmosis. CMV occasionally may cause a subacute progressive polyradiculopathy96; patients present with sacral sensory loss, urinary retention, and flaccid paraparesis within days to weeks. The cerebrospinal fluid (CSF) is markedly abnormal in CMV polyradiculopathy, with a polymorphonuclear pleocytosis, hypoglycorrhachia, and elevated protein. CMV may be cultured or demonstrated by PCR from the CSF, but treatment should be started empirically with ganciclovir. Herpes zoster may result in a painful radiculopathy that persists long after resolution of the dermatomal vesicular lesions. However, postherpetic neuralgia is less common in HIV-infected patients.

Peripheral neuropathy may occur at any time during the course of HIV infection. During seroconversion or the latent period (usually CD4 count >500 cells/μL), an inflammatory demyelinating neuropathy may occur with a presentation similar to that of the Guillain-Barré syndrome. This neuropathy may respond to corticosteroids, intravenous immune globulin, or plasmapheresis. Later in the course of HIV infection, an axonal neuropathy, possibly caused by HIV, results in a painful distal neuropathy that is predominantly sensory. Treatment is symptomatic with analgesics or pain-modifying agents (e.g., gabapentin, amitriptyline, or carbamazepine). A similar picture may be caused by drugs, particularly didanosine (ddI), or stavudine (d4T).

AZT has been associated with myopathy, which may present with asymptomatic elevation in the creatine kinase (CK) level or progressive myalgia and weakness, particularly in the proximal leg muscles. AZT should be discontinued in symptomatic patients, and clinical improvement and a decrease in the CK level usually occur within 2 weeks.97 Muscle biopsy should be considered if the myopathy persists after withdrawal of AZT. If muscle biopsy shows significant inflammatory infiltrates but no opportunistic pathogens or mitochondrial changes, then an immune-mediated myopathy should be suspected. HIV-1-associated myopathy may be mediated by an immune mechanism, and some patients have responded to corticosteroids.97

Candidiasis

Although candidiasis is the most common opportunistic fungal infection in AIDS, most such infections are limited to mucosal disease involving the oropharynx, esophagus, or vagina. Treatment therefore is aimed at control of symptoms, as outlined in Table 48-4. Deep Candida infections (e.g., endophthalmitis or vertebral osteomyelitis) and disseminated candidiasis are encountered rarely in the setting of HIV infection, and in such instances, the usual risk factors for invasive candidiasis often can be identified. These include granulocytopenia, immunosuppressive therapy, prolonged vascular catheterization, recent surgery (e.g., gastrointestinal, cardiac), broad-spectrum antibiotic use, and intravenous drug abuse. Management of candidemia includes removal of any potentially infected vascular catheters and careful assessment for the presence of metastatic sites of infection such as endophthalmitis. Antifungal treatment options for candidemia and other invasive forms of candidiasis include fluconazole,80,81 amphotericin B, lipid formulations of amphotericin B, and caspofungin, as outlined in Table 48-4.

Cryptococcosis

Although less common now since the introduction of HAART, cryptococcosis occurred in approximately 5% to 10% of individuals at some point during the course of HIV infection in the pre-HAART era (i.e., before 1996). Cryptococcal disease in AIDS usually presents as a subacute to chronic meningitis. However, up to 9% of patients with AIDS-related cryptococcosis develop ARF, which in one series was associated with a 100% mortality rate.98 The diagnosis of cryptococcal ARF often is not considered before death, but a serum cryptococcal antigen titer is a rapid and sensitive screening test. Predictors of ARF in AIDS-related cryptococcosis are African-American ethnicity, serum LDH concentration of more than 500 IU/L, interstitial infiltrates, and cutaneous lesions.98 The duration of symptoms before presentation varies from a few days to several weeks. It is important to note that the diagnosis of meningitis may be overlooked because headache and other neurologic symptoms may be mild or absent. Furthermore, meningeal signs are present in only a minority of cases. Other presentations of cryptococcosis include skin lesions and unexplained fever.99

An elevated opening pressure at lumbar puncture is common in cryptococcal meningitis. However, the abnormalities in CSF cell count and glucose and protein concentrations may be minimal or absent despite positive results for India ink smear, fungal culture, and cryptococcal antigen. The CSF white blood cell count usually is less than 20/μL and predominantly lymphocytic. The CSF glucose concentration is usually normal but may be low. The serum cryptococcal antigen determination provides a rapid, noninvasive test that is particularly helpful in identifying the HIV-positive patient with extrapulmonary cryptococcal disease.99 The organism may be cultured from spinal fluid, blood, urine, sputum, and skin lesions. Patients with C. neoformans isolated from an extraneural site should be investigated for the presence of disseminated disease, including a lumbar puncture, even in the absence of headache or neurologic symptoms.

A suggested sequence of investigations in the HIV-infected patient with headache or CNS dysfunction is outlined in Fig. 48-9. An HIV-infected patient presenting with an illness compatible with cryptococcosis whose serum cryptococcal antigen titer is positive (except if the titer is 1:8 or less, which may represent a false-positive result) should be started on antifungal therapy before completion of the investigations if there are delays involved in obtaining a CT head scan (or MRI) or contraindications to performing a lumbar puncture (e.g., mass lesion or shift on CT head scan or coagulopathy). Initial treatment of AIDS-related cryptococcal meningitis (see Table 48-4) should be initiated with amphotericin B at 0.7 mg/kg per day (plus flucytosine) rather than with fluconazole.100,101 The role of flucytosine in the management of AIDS-related cryptococcal meningitis has been controversial, although in a recent randomized trial the addition of flucytosine to amphotericin B was associated with improved CSF sterilization at 2 weeks of treatment (confirmed by multivariate analysis) and fewer subsequent relapses. However, there was no survival benefit.102 The best-studied alternative treatment is liposomal amphotericin B, which appears to be of equal efficacy but is better tolerated than amphotericin B.103 Similar results were obtained with liposomal amphotericin at 3 or 6 mg/kg per day compared with conventional amphotericin B at 0.7 mg/kg per day.103 Limited human and animal studies provide evidence of delayed CSF sterilization with amphotericin B–lipid complex (Ablecet), arguing against its use in the management of cryptococcal meningitis.104 Investigational approaches to salvage therapy include high-dose fluconazole (800 to 1200 mg/d) plus 5-flucytosine (100 to 150 mg/kg per day divided q6h).105 Increased intracranial pressure is common, and its documentation and management should not be overlooked.106 Usually this entails serial lumbar punctures or placement of a CSF shunt in order to reduce intracranial pressure. After a clinical response has been obtained (usually after 2 to 3 weeks), patients should be switched to oral fluconazole at 400 mg daily in order to complete 10 weeks of therapy.102 Thereafter, the fluconazole dosage is reduced to 200 mg daily and continued lifelong as suppressive therapy, unless the patient undergoes immune reconstitution with antiretroviral therapy (see Table 48-3).107 An unacceptably high relapse rate has been observed during suppressive therapy with itraconazole at 200 mg daily (24%) compared with fluconazole at 200 mg daily (4%).108 Despite its importance for initial diagnosis, the serum cryptococcal antigen titer has not been helpful in assessing either the response to initial treatment or a suspected relapse of cryptococcal meningitis.109

IRS (immune reconstitution syndrome) has been described in patients with cryptococcosis who subsequently receive HAART. Presentations may include pulmonary or soft tissue lesions that often are culture-negative but demonstrate organisms consistent with cryptococcus on smear or histology.110 Others may experience an exacerbation of cryptococcal meningitis associated with a negative CSF culture and a higher than usual CSF pleocytosis.111 Cryptococcal meningitis also may be unmasked by HAART-induced immune reconstitution. HAART may precipitate symptomatic disease in those with latent CNS cryptococcal infection. Cryptococcal meningitis IRS exacerbation may respond to systemic corticosteroids, according to anecdotal reports. Antiretroviral therapy should be interrupted for life-threatening IRS and possibly reintroduced at a later date along with corticosteroid coadministration.

Histoplasmosis

In North America, histoplasmosis is usually restricted geographically to the endemic zone extending from Mexico and Texas up through the central United States (especially the Mississippi Valley area) and into eastern Canada. Most patients with histoplasmosis will have a history of exposure to endemic areas. Although less common at present, during the pre-HAART era (before 1996), histoplasmosis occurred in 2% to 5% of HIV-infected patients in endemic areas but in as many as 25% in certain cities. Although over 90% of cases have occurred in patients whose CD4 count was less than 100 cells/μL, histoplasmosis was the first AIDS-defining illness in half the cases.

Histoplasmosis in the context of AIDS is almost always a disseminated infection. The clinical presentation is usually that of a nonspecific febrile illness often accompanied by other features such as pulmonary infiltrates, hepatosplenomegaly, lymphadenopathy, pancytopenia, and liver enzyme elevations.112 The spectrum of disease ranges from a nonspecific febrile illness (often with constitutional and/or respiratory symptoms) to a syndrome resembling septic shock (10% of patients) with respiratory and multiorgan failure. Chest radiographs reveal diffuse infiltrates (interstitial or reticulonodular) in approximately half the patients, but radiologic findings are normal in one-third of patients.113 A rapid presumptive diagnosis can be obtained by demonstrating the organism in a buffy coat smear (30% sensitivity), bone marrow biopsy, or occasionally other tissues. The small intracellular yeast forms may be seen within leukocytes. The diagnosis is confirmed by fungal culture (blood, bone marrow, respiratory tract specimens, lymph node, or skin biopsy), although a positive result may take several weeks. Complement-fixation titers are negative in up to 30% of non-AIDS patients with histoplasmosis. Similarly, in AIDS patients, a negative serology for histoplasmosis does not reliably exclude the disease. However, antigen detection in serum and urine is rapid and reliable,114 but the test is not widely available, and specimens must be sent to the reference laboratory. A helpful clue to the diagnosis of disseminated histoplasmosis is the presence of a markedly elevated serum LDH concentration (>600 IU in 73% of patient in one series),115 which also may be seen in AIDS-related disseminated toxoplasmosis. Therapy is outlined in Table 48-4. A prospective, double-blind study in moderate to severe AIDS-related disseminated histoplasmosis demonstrated greater efficacy and significantly increased survival with liposomal amphotericin B (3 mg/kg per day) compared with conventional amphotericin B (0.7 mg/kg per day) as induction therapy.116 Itraconazole is effective therapy for patients with mild to moderate disease.

Coccidioidomycosis

The endemic zone for coccidioidomycosis in North America is limited to the southwestern United States and extends into northern Mexico. Coccidioidomycosis is an important opportunistic infection in endemic areas, occurring in 6% of HIV-infected patients in Arizona during the pre-HAART era (before 1996).91 Most patients have a CD4 count of less than 250 cells/μL at the time of diagnosis. This infection should be considered in HIV-infected individuals who have history of exposure to endemic areas and who present with a compatible illness. Clinical features are nonspecific and may include fevers, dyspnea, focal or diffuse pulmonary infiltrates, meningitis, skin lesions, arthritis, and lymphadenopathy. Some patients have fevers and weight loss with no focal lesions.117 The most common clinical presentations include diffuse or focal pulmonary infiltrates and meningitis. The diagnosis is made by histologic examination and fungal culture of respiratory secretions, tissue biopsies (skin or lymph node), spinal fluid, and blood. The characteristic coccidioidal spherules may be identified using lactophenol cotton blue stain, Gomori's silver methenamine stain, or Papanicolaou's stain. The CSF characteristics in coccidioidal meningitis usually include a pleocytosis of greater than 50 cells/μL that consists of predominantly lymphocytes. The CSF glucose concentration is low, and the protein concentration is elevated. Serology for coccidioidomycosis is positive in approximately 90% of HIV-related cases.117 Positive CSF serology (complement fixation) for C. immitis usually indicates the presence of coccidioidal meningitis. Therapy is outlined in Table 48-4. Fluconazole represents an important advance in the therapy of coccidioidomycosis because of the efficacy and lower side-effect profile of fluconazole compared with amphotericin B. Lifelong suppressive azole therapy is required in coccidioidal meningitis.118–120 Survival is shortest among patients with diffuse pulmonary disease.

Resuscitation and supportive care of AIDS patients in the ICU includes airway protection, noninvasive ventilation, mechanical ventilation, cardiovascular monitoring and support, gastrointestinal and nutritional management, and psychological supportive care. Airway assessment is important in patients who have a depressed level of consciousness, usually because of neurologic problems or systemic sepsis, and in patients who have acute respiratory failure. Detailed discussion of the management of acute hypoxemic respiratory failure is presented in Chap. 38. In general, patients with arterial hypoxemia require supplemental high-flow, high-concentration oxygen. If hypoxemia is refractory to supplemental oxygen, then mask continuous positive airway pressure (CPAP) of 5 to 10 cm H2O may improve arterial hypoxemia and decrease respiratory rate in alert patients who are able to protect their airway.123 Mask CPAP has been used for up to 11 days. Pneumothorax occurs infrequently, in approximately 5% of patients.121 Mask CPAP also allows speech and therefore ongoing discussion regarding prognosis and therapeutic options. Noninvasive ventilation using BiPAP also may preclude the need for intubation and mechanical ventilation. Endotracheal intubation and mechanical ventilation are indicated in patients who require airway protection, or who do not respond to CPAP or BiPAP. Assist-control ventilation with positive end-expiratory pressure is usually necessary for PCP patients who require mechanical ventilation.

In patients who meet the criteria of acute lung injury (ALI),75 lung-protective ventilation with a tidal volume of 6 mL/kg of ideal body weight is recommended because this decreases the mortality of ALI from 40% to 30% (ARDSnet). It is recommended to use the ARDSnet protocol, which includes titration of positive end-expiratory pressure (PEEP) and FiO2 according to a simple algorithm. Use of higher PEEP generally is not recommended because of the risk of barotrauma (especially in PCP) and because a randomized, controlled trial of higher PEEP versus “usual” PEEP (ALVEOLI trial, in press at present time) found no significant improvement in mortality.

Critically ill AIDS patients may develop cardiovascular instability. Systemic arterial catheterization is appropriate for continuous arterial pressure monitoring and arterial blood gas determinations. Hypotension may be caused by hypovolemia, autonomic neuropathy, pentamidine, or septic shock. Hypovolemia may be caused by increased insensible fluid losses, diarrhea, and inadequate intake. Autonomic neuropathy occurs in some AIDS patients and appears to explain the occasionally sudden fatal hypotension and bradycardia.122 The hypotension that may occur during infusion of pentamidine can be minimized by administering the drug slowly over 4 hours, as described earlier. Hypotension in critically ill AIDS patients may be the result of septic shock owing to bacterial sepsis (e.g., pneumococcus, H. influenzae, Staphylococcus, or enteric gram-negative bacilli), PCP, or other systemic fungal infection such as histoplasmosis. Patients who have PCP, similar to patients who have bacterial sepsis, have tachycardia, decreased systemic vascular resistance, increased cardiac output, and hypotension.123 The clinical approach to management is similar to that for other critically ill patients, detailed in Chap. 46. The evaluation of adrenal insufficiency and use of corticosteroids for septic shock124 are relevant; furthermore, patients with PCP or suspected PCP should be treated with hydrocortisone, as discussed earlier.

HIV-positive patients who have severe sepsis in the ICU may be eligible for consideration of treatment with recombinant human activated protein C (rhAPC). This treatment option is discussed in more detail in Chap. 46. A large, pivotal randomized clinical trial showed that rhAPC decreased mortality of severe sepsis from 31% to 25%.125 RhAPC is approved for treatment of patients who have severe sepsis and who are at high risk of death (defined as an APACHE II score >25 or organ system failure involving two or more organs). End-stage disease and end-stage HIV were exclusions in the pivotal trial. However, we recommend consideration of rhAPC in HIV-positive patients admitted to the ICU who have at least an otherwise moderately good prognosis.

Enteropathy, malnutrition, and weight loss are very common gastrointestinal problems in AIDS patients. Up to 30% of AIDS patients have multiple gastrointestinal pathogens.126 The causes of common gastrointestinal problems in AIDS patients are listed in Table 48-6, and their treatment is outlined in Table 48-4. Esophagitis may be caused by Candida, CMV, and herpes simplex virus (HSV). Candida esophagitis usually presents with dysphagia, but marked odynophagia suggests either HSV or CMV esophagitis. Oropharyngeal and esophageal Candida infection rarely gives rise to deep visceral involvement or disseminated candidiasis. Diarrhea occurs in about 50% of AIDS patients and is caused by gastrointestinal infections, AIDS-associated enteropathy, and much less commonly, gastrointestinal neoplasms. Gastroenteritis may be secondary to Cryptosporidium, Giardia, Isospora, Salmonella, MAC, and CMV. Cryptosporidium and Microsporidia may cause severe diarrhea, and although specific antimicrobial therapy for cryptosporidiosis has not been proved effective, clinical and microbiologic resolution has been reported anecdotally in association with HAART-induced immune reconstitution. Enterocolitis may be the result of infection with Shigella, Campylobacter, Entamoeba histolytica, and CMV. Finally, sexually transmitted proctitis caused by gonorrhea, syphilis, Chlamydia, or HSV may produce severe rectal symptoms accompanied by frequent small-volume stools associated with blood and mucus. Clostridium difficile colitis also should be considered in patients treated recently with antibacterial agents. Others have diarrhea caused by AIDS-associated enteropathy,127 which may represent an unidentified infectious cause, possibly HIV or an autoimmune disorder.

AIDS patients with esophageal symptoms and thrush may be treated empirically with fluconazole 100 to 200 mg daily. If there is no response, then esophagoscopy and biopsy should be performed. Investigation of diarrhea includes examination of stool for ova and parasites, stool culture and C. difficile toxin assay, and occasionally, flexible sigmoidoscopy and upper gastrointestinal endoscopy.128 The treatment of critically ill AIDS patients who have diarrhea includes bowel rest, antimicrobial therapy for isolated pathogens126,129 (see Table 48-4), intravenous fluid and electrolytes, symptomatic antidiarrheal therapy, and nutritional therapy. Antimotility agents should be avoided when certain enteric pathogens (e.g., Salmonella, Shigella, E. histolytica, and C. difficile) are suspected. Total parenteral nutrition may be necessary in critically ill patients who have significant diarrhea because enteral nutrition frequently exacerbates the diarrhea. Malnourished AIDS patients who are critically ill and do not have diarrhea often respond adequately to enteral nutrition supplemented as appropriate with potassium, magnesium, calcium, and phosphate.

AIDS patients, family, and friends also may suffer important emotional and psychological problems that require counseling, psychological support, and the empathy of health care workers. In many communities with a high prevalence of AIDS patients, active peer support groups may be extremely helpful. In addition, family physicians and referring specialists who have long-term care relationships with patients can provide valuable support to the critical care team.

The two fundamental issues determining ICU eligibility in a patient with AIDS are the patient's prognosis and the patient's wishes regarding life support. Concerning prognosis, it is necessary to assess both the prognosis of the acute illness necessitating life support and the prognosis of the underlying HIV disease. Prior to the development of AIDS, the prognosis of HIV disease generally was dictated by the CD4 count and the remaining antiretroviral treatment options available. A prognostic staging system had been suggested for patients with AIDS.130 Various clinical and laboratory abnormalities were scored, and higher scores were associated with shorter survival times. Although this information had been useful in the assessment of eligibility of AIDS patients for life support in the ICU,131 its applicability in the setting of HAART is unclear.

As in any other critical illness, it is of utmost importance to involve the patient or those close to the patient, whenever possible, in discussions regarding the appropriateness of ICU admission and life support. Often the issue of life support has been considered previously, and the patient has already made his or her wishes known to primary physicians, friends, or relatives.132 ICU admission and life support generally are inappropriate for patients with life-threatening complications for which there is no particularly effective therapy (e.g., high-grade lymphoma). It is reasonable, however, to offer ICU admission and life support to patients with an acceptable quality of life who have a potentially reversible acute illness.133

In every instance, clear goals of ICU admission should be established with the patient, family, and treating physicians. Obviously, a lucid, well-informed patient and his or her family may refuse life support. Finally, it must be emphasized that the outlook of AIDS and its related conditions has improved considerably. For this reason, rigid policies regarding ICU admission are undesirable, and detailed evaluation of each situation on a case-by-case basis is required. For patients who still have antiretroviral therapy options and in whom there is some expectation of partial immune reconstitution, there is no CD4 count that by itself would be considered justification for exclusion of the patient from admission to the ICU. It also should be noted that the initiation of HAART may be associated with clinical improvement in patients with opportunistic diseases for which there is no proven specific effective therapy (e.g., microsporidiosis, cryptosporidiosis, PML, and macrolide-resistant disseminated MAC infection).

This work was supported in part by the National Health and Research Development Programme, Health and Welfare, Ottawa, Canada, and the National Institutes of Health. We thank Kelly Hsu for assistance in preparation of the manuscript.