Chapter 41: HIV Infection in Critically Ill Patients

Human immunodeficiency virus (HIV) is a sexually transmitted retrovirus composed of RNA (ribonucleic acid) genome and enzymes such as protease, reverse transcriptase and integrase; enveloped within an outer shell that has binding sites for two cell receptors, CCR5 and CXCR4. CXCR4 is a coreceptor found on CD4+ T cells and CCR5 is found on CD4+ T helper cells, macrophages, and dendritic cells. In the first 2 to 3 weeks of acute infection, macrophages and CD4+ T cells are depleted rapidly as the virus replicates within these cells. Clinically, this period manifests as a febrile viral syndrome commonly with symptoms of atypical rash and lymphadenopathy. Seroconversion eventually follows 2 to 4 weeks after primary HIV infection as humoral immunity develops. As the immune system recognizes and destroys systemic viral particles and infected cells, the body enters a long phase of clinical latency and asymptomatic disease. Using the enzyme reverse transcriptase the viral RNA genome is used as a template to make DNA replica which is integrated into human DNA genome by the enzyme integrase leading to chronic viral replication. Over time, the body loses the ability to replenish infected cell pools especially helper T cells resulting in immune deficiency known as acquired immunodeficiency syndrome (AIDS). Table 41–1 lists common infections that are seen in HIV-infected persons.

AIDS is defined clinically as depletion of CD4 cells less than 200 cells/mm³ (normal > 800) or development of AIDS-qualifying opportunistic infection. Without antiretroviral treatment, progression to AIDS occurs within an average of 8 to 10 years. The availability of effective antiretroviral therapy and chemoprophylaxis for opportunistic infections has increased the latency phase of HIV infection prolonging asymptomatic disease to several decades. Nonetheless, it is estimated that 1 in 6 newly HIV-infected persons are unaware of their infection status and will present with AIDS associated complications at the time of initial diagnosis.

Current armamentarium of antiretroviral drugs successfully suppress viral replication hence delaying loss of CD4 cells and progression to AIDS. But some anatomical sites are poorly penetrated by drugs and act as viral reservoirs (such as latent CD4 cells, central nervous system [CNS] tissue, and lymphoid tissues in the GI and genital tracts). Within these sites, ongoing viral spread and replication can occur via cell-to-cell transmission and syncytium formation, leading to a chronic proinflammatory state, which in turn has been linked to increased risk of malignancy, autoimmune, and early cardiovascular disease in HIV patients.

Antiretroviral therapy has dramatically changed the spectrum of illness seen in HIV-infected patients. Studies have shown that hospital and ICU admission rates remain unchanged in HIV-infected persons, although their admitting diagnoses appears to have shifted from infectious to noninfectious illnesses. Following is a summary of frequently encountered ICU diagnoses in HIV-infected patients in the current highly active antiretroviral treatment (HAART) era.

Pulmonary complication in the form of infectious and noninfectious disease remains the leading cause of morbidity and mortality in HIV-infected individuals. The spectrum of infectious complications appears to have changed since the introduction of combination antiretroviral drugs in the mid-1990s. In the early AIDS epidemic, respiratory failure due to Pneumocystis jiroveci pneumonia (PCP) was the leading cause of death. Although respiratory failure remains the most common indication for ICU admission, the rates of PCP have decline. Bacterial pathogens such as streptococcus pneumoniae, stapylococcus aureus and tuberculosis are common causes of respiratory failure. In fact, TB is responsible for 1 of 10 HIV/AIDS-related deaths worldwide. As HIV infection is becoming a chronic medical condition with a long-life expectancy, its association with noninfectious respiratory complications is also becoming widely recognized. Reactive airway disease, lung cancer (irrespective of smoking history) and pulmonary arterial hypertension (PAH) are increasingly becoming common indications for ICU admission in HIV-infected patients. Table 41–2 lists the pulmonary complications frequently encountered in critically ill HIV-infected patients.

Pneumonia

Alterations in host defense mechanisms, such as B lymphocyte dysfunction, abnormal secretion of immunoglobulin and mucociliary dysfunction, and other risk behaviors, such as tobacco use appear to increase the risk of pneumonia in HIV-infected patients irrespective of CD4 counts or antiretroviral use. Streptococcus pneumoniae and Mycobacterium tuberculosis are the leading cause of pneumonia but other bacterial, viral, and fungal (especially endemic fungi) pathogens are also prevalent.

Acute respiratory failure is commonly seen with viral and bacterial pneumonias, whereas tuberculosis, PCP, and other fungal infections have more of a subacute presentation. Chemoprophylaxis, vaccination history (pneumococcal and influenza), travel, and endemic exposures are clues when developing a differential diagnosis. Cough, fever, and dyspnea are the most common presenting symptoms.

Basic laboratory workup including lactate dehydrogenase (LDH) and sputum Gram stain and cultures (bacterial, mycobacterial, and fungal) should be obtained. Chest radiography (CXR) showing lobar pneumonia is suggestive of common community-acquired bacterial pathogens including Streptococcus pneumoniae, Hemophilus influenzae, and Staphylococcus aureus. Bronchoscopy is of limited value in establishing the diagnosis of bacterial pneumonia in HIV-infected patients with the exception of cases where there is high suspicion for mycobacterial disease or fungal process. Ancillary testing with urine antigen detection for Pneumococcus and Legionella have high specificity, but low sensitivity. For the endemic fungi, Histoplasma, Coccidioidomycosis, and Cryptococcus urine or serum antigen detection tests are available but have better yield in the setting of disseminated disease.

Community-acquired pneumonia coverage with third- or fourth-generation cephalosporin plus a respiratory fluoroquinolone (eg, levofloxacin or moxifloxacin) or macrolide (eg, azithromycin) should be initiated in patients presenting with suspected bacterial pneumonia. In severe respiratory failure requiring ICU admission, initial empiric coverage for gram-negative organisms (eg, Pseudomonas spp.) and resistant pathogens such as methicillin-resistant Staphylococcus aureus should be considered until culture data is available to guide therapy.

Pneumocystis Jiroveci Pneumonia

Since the widespread use of HAART and prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX), the prevalence of PCP-associated respiratory failure has decreased. Commonly presenting symptoms are nonproductive cough, fever, and anorexia evolving over 2 to 4 weeks in an AIDS patient (CD4 < 200). Hypoxia is the most common symptomatic and laboratory finding. Elevated LDH along with an alveolar-arterial (A-a) gradient more than 35 mm Hg is suggestive of PCP pneumonia. CXR commonly shows interstitial infiltrates with classic “butterfly” pattern or an atypical presentation with nodular, cavitary, or cystic lesions. In 20% of the cases, the CXR may be normal. Spontaneous pneumothorax in a patient with HIV should raise the suspicion for PCP.

Special stains of induced sputum for cysts or trophozoites are sensitive in less than 60% of cases; thus negative results warrant further investigation with bronchoscopy and bronchoalveolar lavage. Standard stains and techniques used for PCP diagnosis include Giemsa or modified Wright–Giemsa (also known as Diff–Quik), Gomori-methanamine silver, and immunofluorescent staining (direct fluorescent antibody). Recently, polymerase chain reaction (PCR) detection and measurement of 1-3 β-d-glucan levels are gaining wide acceptance in the diagnosis of PCP associated with AIDS although the utility in non-HIV patients is not yet well defined.

TMP-SMX remains the first-line therapeutic agent for PCP pneumonia. Adjunctive corticosteroid therapy is recommended to prevent lung injury in severe cases, clinically defined as PaO₂ of less than 70 mm Hg or A-a oxygen gradient of more than 35 mm Hg on room air. For those patients who are intolerant to sulfa drugs, IV pentamidine is an alternate choice, but serious side effects including pancreatitis, renal failure, and hypoglycemia limit its use. Other alternative agents include the combination of clindamycin and primaquine, dapsone, and TMX or atovaquone. These regimens may not be ideal in critically ill patients, as primaquine, dapsone, and atovaquone are only available orally. Duration of therapy for PCP pneumonia is 21 days and clinical response is expected within 3 to 5 days. Treatment failure should be suspected if response lags more than 8 days. TMP-SMX is commonly associated with atypical adverse reactions such as fever, hepatitis, and leukopenia, which can be mistaken for treatment failure. The most common side effect reported with TMX-SMX is a rash.

Viral Pneumonitis

HIV-infected individuals are at increased risk of developing serious complications from respiratory viruses especially with the influenza virus. During influenza season, HIV-infected patients are hospitalized at increased rates with influenza-related complications so aggressive preventive care with vaccination should be sought. Unlike the influenza virus, the significance of other viral pathogens such as herpes simplex virus (HSV), cytomegalovirus (CMV), and adenovirus when isolated from respiratory secretions is difficult to interpret and may represent viral shedding. For most patients, this may represent severe immunosuppression and is a sign of poor prognosis. The role of antiviral therapy has been debated and does not seem to show survival improvement.

HIV-Related Pulmonary Arterial Hypertension

The increased prevalence of PAH in HIV-infected patients has been recognized since the 1980s and seems to occur independent of the severity of immune deficiency or antiretroviral use. These patients usually present with clinical symptoms of chronic dyspnea and lower extremity edema. Doppler echocardiography shows elevated right ventricular and pulmonary pressures but confirmation of the diagnosis of PAH requires right heart catheterization showing mean pulmonary artery pressure more than 25 mm Hg at rest and normal pulmonary capillary wedge pressure less than 15 mm Hg. Conventional treatment with calcium channel blockers is not effective in HIV-PAH and antiretroviral therapy also does not seem to alter the disease course. Standard treatment agents available for PAH seem to have similar efficacy in HIV-infected patients but drug–drug interactions with antiretroviral agents (especially protease inhibitors, PIs) must be considered.

Most gastrointestinal (GI) manifestations associated with HIV infection do not warrant ICU level of care. Infections that have predilection for the GI tract, such as Candida, CMV, HSV, and Mycobacterium avium intracellulare (MAI) cause mucosal disease and commonly manifest with symptoms of odynophagia, dysphagia, and anorexia. Catastrophic complications rarely can develop, such as bowel perforation, obstruction, and life-threatening hemorrhage. In addition, compromise of the mucosal integrity of the GI tract allows gut translocation of bacteria leading to sepsis and septic shock. Pancreatitis and complications of liver disease are also frequent and common indications for ICU admission.

Pancreatitis

A higher incidence of pancreatitis has been reported in HIV patients related to multiple factors. Medications especially older nucleoside reverse transcriptase agents, such as didanosine/stavudine are common culprits. As a class, PIs are known to cause dyslipidemia including hypertriglyceridemia, which may increase the risk of hyperlipidemic injury to the pancreas. Drugs used to treat opportunistic infections, such as pentamidine, sulfa drugs, and isoniazid also cause pancreatitis. Certain pathogens associated with HIV/AIDS, such as CMV and Cryptosporidium have a predilection for the pancreas.

A common presenting complaint is abdominal pain with laboratory data showing elevated amylase or lipase levels. Imaging with CT shows inflammation of the pancreas. Further workup with fine needle aspiration may be helpful in ruling out infectious causes of pancreatitis but is seldom performed. Treatment in most cases is supportive.

Liver Disease

Due to shared risk factors, coinfection with hepatitis B and C is common in HIV patients. HIV virus is known to accelerate liver disease in coinfected patients leading to chronic infection, high levels of viremia and early progression to end-stage liver disease. Hepatic steatosis in association with and without alcohol and medications is also common in HIV patients. Liver disease accounts for 20% of non-AIDS-related mortality in HIV patients. Complications associated with end-stage liver disease, such as hepatic encephalopathy, variceal bleeding, and other organ failures are common indications for ICU admission. Management does not differ from the general population and focuses on preventing further liver damage, slowing the progression of liver disease, and management of cirrhotic complications.

Hepatitis B and HIV Coinfection

Initiation and discontinuation of antiviral therapy in HIV-HBV coinfected patients should be cautiously performed. The choice of antiretroviral agent must also consider treatment of both infections and must avoid monotherapy of hepatitis B virus due to the increased rates of acquiring drug resistance. Table 41–3 lists the medications that are effective against both HIV and HBV. Ideally, two of the combination antiretroviral HIV medications should be active against HBV. Treatment discontinuation should be avoided if possible, as severe a flare of HBV has been reported with withdrawal. Immune reconstitution syndrome, which commonly presents within 2 months of antiretroviral initiation can also present with hepatitis flare.

Hepatitis C and HIV Coinfection

Hepatitis C infection does not appear to affect the course of HIV disease, but as in the case of HBV infection, liver disease is accelerated with HIV-HCV coinfection. Drug-induced liver injury is also common in coinfected patients. The mainstay of HCV therapy is PEG interferon and ribavirin, but a newer class of agents has recently been introduced for specific genotypes of HCV. These agents are PIs that are metabolized by the liver cytochrome P450 system and may interact with many drugs including antiretroviral agents. Complications from cirrhosis and end-stage liver disease are also of concern in the ICU setting. Many studies have shown acceleration to liver failure, noncirrhotic portal hypertension, and hepatocellular carcinoma with HIV-HCV coinfection. Early consideration for liver transplantation is warranted in these settings. Management of these complications is identical as in non-HIV-infected patients.

Neuro-AIDS is a terminology used to describe the neurological complications in HIV and AIDS patients. These complications range from neurocognitive disorders, such as HIV dementia to opportunistic infections that cause life-threatening acute illnesses that most commonly present with change in mental status, seizures, or weakness. Evaluation of these symptoms frequently mandates hospitalization and with severe symptoms, ICU admission is indicated.

Neurological manifestations of HIV have changed since the widespread availability of HAART. Neurocognitive disorders and neuropathies are becoming more prevalent as opportunistic infections and malignancies of the CNS remain fatal, but less frequently encountered in the Western world. Cerebral toxoplasmosis, primary CNS lymphoma (PCNSL), and Cryptococcal meningitis are frequently encountered in HIV/AIDS patients in the ICU setting as severe symptoms, such as acute encephalopathy, seizures, cerebral edema, or increased intracranial pressure are associated with these diagnosis. Nonetheless, HIV-infected patients are also at risk for community-acquired meningitis/encephalitis and vascular disorders, such as strokes. The primary goal in management is securing the airway and symptomatic treatment, such as seizure control while undergoing the appropriate workup.

Cerebral Toxoplasmosis

Toxoplasma gondii is an obligate intracellular protozoa acquired via consumption of undercooked meats (commonly beef or pork) or via exposure to cat feces (usual carriers of oocytes). Primary infection usually presents with a mononucleosis-like illness and is usually subclinical and self-limiting. Prior exposure to toxoplasmosis is diagnosed by antibody detection (IgG for T. gondii). Seroprevalence is variable throughout the world. In the United States, 15% of the population has prior exposure. In France and developing countries, higher seroprevalence rates (> 50%) have been reported. Latent cysts can reactivate in the setting of severe immune suppression and cause devastating illness, such as encephalitis, chorioretinitis, myocarditis, and pneumonitis.

Toxoplasma encephalitis (TE) is the most common manifestation in AIDS patients (CD4 counts < 50). It usually presents with fever, headache, and change in mental status. Imaging with contrast MRI or CT shows single or multiple ring-enhancing lesions. Unfortunately, these radiographic findings are nonspecific and may be seen with other CNS infections and malignancies, such as PCNSL. TE is usually a clinical diagnosis in AIDS patients. The presence of multiple lesions or a single ring-enhancing lesion (especially basal ganglia lesions) in a Toxoplasma IgG seropositive patient warrants presumptive treatment. The preferred treatment regimen is sulfadiazine/pyrimethamine with leucovorin (to prevent bone marrow suppression commonly seen with prolonged pyrimethamine use). Treatment duration is 6 weeks with follow-up imaging after 2 weeks to document radiographic improvement. If clinical improvement is not seen at this point, further diagnostic workup, usually a brain biopsy is warranted to rule out PCNSL. In the pre-HAART era, life-long suppressive therapy was mandatory following diagnosis of TE, but with effective antiretroviral therapy, it is now generally continued until immune reconstitution (CD4 rise > 200). It is also worth noting that rates of TE have decreased with widespread use of chemoprophylaxis with sulfa-based drugs for PCP, which is also effecting in preventing toxoplasmosis.

Primary CNS Lymphoma

Primary CNS lymphoma (PCNSL) is an AIDS-defining illness with a prevalence of approximately 5% pre-HAART, but a significant reduction has been seen in recent years. PCNSL is a non-Hodgkin's B-cell lymphoma that is thought to result from malignant transformation of chronically activated EBV infected B cells. Clinical presentation and radiographic findings are similar between TE and PCNSL. Patients present with headache, change in mental status, and visual disturbances, and CT/MRI usually shows a contrast-enhancing lesion. CSF fluid with EBV PCR presence or cytology showing malignant cells is also supportive of diagnosis, but has low yield. Some studies have supported the use of functional imaging studies such as single photon emission computed tomography or positron emission tomography scan to differentiate between TE and PCNSL (especially when a single CNS mass lesion is present). Increased tracer uptake with these studies is suggestive of PCNSL, but should not be used as a definitive diagnosis. In clinical practice, AIDS patients presenting with a contrast enhancing lesion are treated with a trial of toxoplasma therapy with close clinical and imaging follow up, and brain biopsy is pursued if clinical improvement is not attained after 2 weeks.

Treatment for PCNSL is whole brain radiation and chemotherapy, which includes high dose corticosteroids, which are effective as antitumor agents but also treat tumor-associated edema.

Cryptococcal Meningitis

Cryptococcus neoformans is a saprophytic fungus abundant in the environment. Disease results from inhalation of spores, which usually causes self-limited acute respiratory infection. In immunocompromised hosts, disseminated disease to multiple sites including skin, prostate, bone marrow, and CNS can develop. In HIV/AIDS patients, cryptococcal meningitis is the most common presentation and is thought to arise from hematogenous spread following cryptoccocemia in acute infection or from reactivation of latent disease (especially in those with CD4 counts < 100). Patients commonly present with indolent symptoms, such as headache, malaise, and fevers, but in delayed diagnosis obtundation and seizures may warrant ICU level of care. Imaging with CT or MRI of the brain should be performed first to rule out intracranial lesions, but rarely hydrocephalus or infectious granulomas (cryptococcoma), which present as noncontrast enhancing well-circumscribed lesions may be present. CSF analysis should be performed when Cryptococcus is suspected along with measurement of opening pressure. Lumbar puncture may show CSF pleocytosis with low glucose and elevated opening pressure (> 20 cm H₂O). Cryptococcal antigen from both serum and CSF are highly sensitive and specific tests. Cryptococcal CSF antigen is nearly 100% sensitive as compared to India ink stains (75% sensitivity) in the case of meningitis, and serum is approximately 95% sensitive and useful when lumbar puncture cannot be performed. Treatment of cryptococcal meningitis includes antifungal therapy and management of intracranial pressure. Treatment duration is for 10 weeks starting with liposomal preparation of amphotericin plus flucytosine induction for the first 2 weeks followed by consolidation therapy with fluconazole for the next 8 weeks. Maintenance with lower dose fluconazole should be continued until sustained immune reconstitution is attained (CD4 > 200). In those patients with opening pressure more than 25 cm H₂O, daily lumbar puncture needs to be performed to reduce pressure (< 20 cm H₂0 or by 50%); lumbar drain or ventriculoperitoneal shunt may be warranted for persistently elevated ICP.

Cytopenias are the most common complication of HIV disease and develop as a result dysregulated of cytokine release encountered in HIV infection, bone marrow suppression due to medication and infiltration of bone marrow by opportunistic infections that is, CMV, Cryptococcus, Histoplasma, Mycobacteria (MTB, MAI), or malignancy (ie, lymphoma and Kaposi sarcoma).

Anemia

Anemia of chronic disease is the most common cytopenia encountered, and is frequently associated with use of drugs such as Zidovudine (AZT). Discontinuation of medication and supportive care is the standard of care. Rarely severe anemia may mandate ICU admission as in the case of parvovirus B19 infection or drug-induced hemolytic anemia (eg, use of dapsone in G6PD-deficient patients, primaquine, and ribavirin). Although parvovirus B19 infection causes a self-limited disease in immunocompetent hosts, AIDS patients (especially with CD4 count < 100) are unable to eradicate the infection and may develop pure red cell aplasia. Management includes transfusions, supportive care, and a 5-day course of IV immune globulin.

Hemolytic anemia is rare in HIV disease, but can be seen in association with medication use as in the case of G6PD deficiency and in the setting of thrombotic thrombocytopenic purpura (TTP). Because G6PD deficiency is the most common enzymatic disorder worldwide (especially in African and Mediterranean descendants), preemptive evaluation of patients for G6PD deficiency prior to initiation of drugs known to cause hemolysis is the best management approach. Once complications develop, treatment is usually supportive.

Neutropenia

Prolonged neutropenia is common especially in end-stage HIV disease. HIV associated neutropenia is highly responsive to colony stimulating factors. Neutropenic sepsis is a rare complication, as HIV patients develop gradual neutrophil depletion and mucosal integrity is usually preserved unlike the neutropenia that occurs in cancer patients.

Thrombocytopenia

Thrombocytopenia can develop as a result of idiopathic (immune) thrombocytopenic purpura (ITP) and TTP. The pathogenesis of ITP is related to autoantibodies generated during HIV infection. For most patients, it may be the initial manifestation of HIV disease. Management is with pulse dose corticosteroids and if unresponsive to corticosteroid therapy, splenectomy may be warranted.

HIV is also known to be one of the triggers for TTP. TTP is a rare but life-threatening hemolytic process characterized by pentad of fever, neurologic changes (altered mental status and seizures), renal failure, microangiopathic hemolytic anemia, and thrombocytopenia. Standard diagnostic tests to evaluate for hemolysis and renal failure should be obtained. Since disease may progress to fatal outcomes, prompt recognition and initiation of treatment with plasmapheresis and possibly corticosteroids is essential.

Insulin resistance, dyslipidemia, and abnormal fat distribution are common metabolic changes encountered in HIV-infected individuals that are not only directly related to the pathogenesis of HIV infection, but also medications used to treat HIV disease. Several studies have shown an increased rate of early cardiovascular disease associated with prolonged exposure to certain classes of antiretroviral agents (PIs and nucleoside reverse transcriptase agents), but also with their discontinuation. The pathogenesis of heart disease in HIV patients is multifactorial and likely related to the proinflammatory state caused by HIV infection along with the metabolic changes and accelerated rate of atherosclerotic disease. Cardiac events are the leading cause of morbidity and mortality in HIV patients in the post-HAART era. Traditional risk factors along with the socioeconomic status of the HIV population also heighten this risk. Therapeutic measures do not differ in HIV patients with the exception of the need for increased awareness of drug–drug interactions when initiating medical management.

Initiation of antiretroviral therapy usually is reserved for the outpatient setting, as genotypic and resistance testing must be performed even in treatment-naïve patients. A common concern encountered in the ICU setting is the question of continuing HIV therapy in the critically ill patient. Critical care providers should be aware of the numerous drug interactions associated with antiretroviral agents. In addition, the erratic drug absorption from the GI tract in the critically ill, need for dose adjustment in the setting of renal and hepatic dysfunction, risk for Immune Reconstitution Inflammatory Syndrome (IRIS) should be considered. It is usually safer to withhold HIV medications in the critically ill patient, but in the rare instances where continuing or initiation of antiretroviral agents is warranted, it should be done in consultation with an infectious disease specialist.

IRIS is a rare atypical inflammatory disorder usually associated with immune recovery. Patients may present with paradoxical worsening or development of an opportunistic infection, or a new autoimmune process. The pathogenesis is thought to be recovery of cellular and humoral immunity with improvement in CD4 cell counts. It is commonly seen 4 to 6 weeks after initiation of HAART in treatment-naïve patients who are severely immunosuppressed (CD4 < 50-100) and have an opportunistic infection at the time of HIV diagnosis. Common disease processes presenting in the setting of IRIS are mycobacterial diseases (MTB, MAI), Cryptococcus, and CMV. Treatment requires close observation, while continuing HAART and treating the opportunistic infection. The role of corticosteroids and nonsteroidal anti-inflammatory drugs is unclear, but commonly utilized in an attempt to subdue the inflammatory reaction.