2 Icahn School of Medicine at Mount Sinai, New York, NY, USA
Background
Definition of disease
Acquired immune deficiency syndrome (AIDS) is a potentially life‐threatening condition caused by human immunodeficiency virus (HIV) infection, in which depletion of CD4‐bearing helper T cells (to ≤20% of normal) renders the patient highly vulnerable to life‐threatening conditions.
Disease classification
HIV infection is divided into HIV‐1 and HIV‐2.
HIV‐1 infection is widespread worldwide and HIV‐2 infection is more common in western Africa.
Third and fourth generation HIV antibody tests detect both HIV‐1 and HIV‐2 infection.
CDC classification divides HIV infection into A, B, and C (Table 48.1).
Incidence/prevalence
The syndrome of immunosuppression was first described in the USA in 1981 when homosexual men were reported to have unusual infections like Pneumocystis jiroveci pneumonia (PCP) and a rare malignancy, Kaposi’s sarcoma. In 1986 it was officially named HIV.
Worldwide 37 million people live with HIV and a majority of them are in sub‐Saharan Africa.
The CDC estimated 1.2 million people in the USA were infected with HIV by the end of 2012.
About 50 000 people contract new HIV infection every year.
It is not unusual to make a new diagnosis of HIV infection in an ICU patient.
Hepatitis C coinfection is common in HIV patients admitted to the ICU (as high as 35–60%) and is associated with higher short‐term and long‐term mortality.
Etiology
HIV patients may be admitted to the ICU for various reasons depending on the organ system involvement.
PCP may be responsible for 50–60% of ICU admissions in newly diagnosed HIV infection.
The spectrum of disease causing ICU admission has changed with ART. The most recent observational studies continue to demonstrate respiratory failure as the most common ICU diagnosis.
Mechanical ventilation is required in 40–60% of patients.
Causes of ICU admission in HIV‐positive patients
Respiratory failure
40%
PCP
10–20%
Sepsis (including pneumonia)
10–20%
Neurologic
14%
Cardiac
10%
GI bleed
7%
Hematologic
6%
Metabolic
2%
Pathology/pathogenesis
HIV virus infects and replicates in lymphocytes leading to destruction and gradual decrease of CD4 cells making the patient susceptible to opportunistic infections.
CD4 count <200 cells/μL: PCP.
CD4 count <100 cells/μL: Toxoplasma, Aspergillus, and CMV.
CD4 count < 50/uL: Mycobacterium avium.
Malignancy and Mycobacterium tuberculosis can occur at any stage with any CD4 cell count.
Predictive/risk factors
Severity of illness on admission to the ICU rather than CD4 cell count is a more reliable predictor of mortality.
Risk factor
Odds ratio for in‐hospital mortality
Acute renal failure
4.2
Hepatic cirrhosis
3.8
Severe sepsis
3.7
Mechanical ventilation
3.5
ICU admission for coma
2.7
PCP
2.5
Prevention
ART is a combination of two or more classes of antiretroviral medications used to limit replication of the virus and progression to AIDS.
The success of ART in reducing progression of the disease has led to a reduction in ICU admissions for AIDS‐related opportunistic infections.
Screening
The CDC recommends screening all patients in all health care settings for HIV infection.
Consent is required for HIV testing. For patients who lack capacity to consent, most states permit consent by the person lawfully authorized to consent for the patient’s health care. For HIV testing for a patient without capacity, the CDC website includes individual state laws concerning HIV testing.
Secondary prevention
Initiate appropriate prophylaxis for opportunistic infection per guidelines.
Diagnosis
Differential diagnosis
Differential diagnosis on initial presentation is broad, based on organ system involvement. There are multiple potential causes of acute respiratory failure, alteration in mental status, sepsis, seizures, gastrointestinal hemorrhage, multiorgan failure, hematologic disorders, and electrolyte/metabolic disturbances.
Typical presentation
Typically, patients present with acute respiratory failure; the onset of respiratory symptoms may be acute, e.g. within days due to bacterial pneumonia, or slowly progressive dyspnea over weeks, e.g. in PCP.
Meningitis and meningoencephalitis: altered mental status, headache, confusion lethargy, personality changes, and seizures. Fevers, neck stiffness, and photophobia are less common.
History should include: recurrent infections, unexplained weight loss, fevers, night sweats, poly‐substance or intravenous drug abuse, unprotected sex, men having sex with men, previous opportunistic infections, viral load, CD4 count, adherence to ART, and reason for previous ICU admission.
Physical examination
In addition to a thorough general physical exam that is required for every patient admitted to ICU, focus on organ‐specific examination findings:
Respiratory: cough with or without purulent sputum, tachypnea, rhonchi, rales, bronchial breath sounds, and rarely hemoptysis.
Kaposi’s sarcoma: blue‐purple lesions on face, nose, legs, and gingival and buccal mucosa.
Non‐Hodgkin’s lymphoma: rubbery and enlarged cervical, supraclavicular, axillary, and inguinal lymph nodes and splenomegaly.
Metabolic: lipodystrophy, central obesity.
Laboratory diagnosis
List of diagnostic tests
Complete blood count:
Leukocytosis from bacterial infection such as pneumonia or urinary tract infection. Lack of leukocytosis in the setting of acute infection is not uncommon in advanced or newly diagnosed HIV with low CD4 counts.
Thrombocytopenia from HIV or autoimmune thrombocytopenia.
Anemia from gastrointestinal hemorrhage.
Metabolic panel: elevated creatinine from acute kidney injury in sepsis, or HIV‐associated nephropathy. Hyperkalemia and hyponatremia in patients with suspected adrenal insufficiency.
AST, ALT, and bilirubin: may be elevated due to viral hepatitis, ART, or chronic liver disease.
Lactate: elevated in severe sepsis or septic shock, hypoperfusion from cardiogenic shock, hepatic failure, and antiretroviral medications.
LDH: elevated in hemolytic anemia, malignancy such as Hodgkin’s or non‐Hodgkin’s lymphoma, and PCP.
Arterial blood gas analysis: hypoxemia with low PaO2/FiO2 ratio <300 consistent with acute respiratory distress syndrome (ARDS), metabolic acidosis, and hypercapnia (e.g. in COPD).
Blood and urine cultures: as indicated for infectious evaluation.
Sputum specimen: bacterial and acid‐fast bacilli cultures; PCR for influenza, parainfluenza, coronavirus, rhinovirus, and adenovirus are helpful in establishing etiology of respiratory infection.
Bronchoscopy with bronchoalveolar lavage (BAL) for PCP has a high sensitivity of 97% (Figure 48.1). BAL can also diagnose bacterial pneumonia or tuberculosis (acid‐fast bacilli) when sputum samples are inadequate. Bronchoscopic biopsy may be required for diagnosis of CMV pneumonia and also may increase the diagnostic yield for fungal or mycobacterial infections.
Urine Legionella and pneumococcal antigen testing have high sensitivity and specificity compared with sputum cultures and remains positive after initiation of antibiotics.
Lumbar puncture with cerebrospinal fluid (CSF) analysis: cell count with differential, gram stain, and cultures for bacterial meningitis, India ink stain for Cryptococcus, cryptococcal antigen, rapid plasma reagin test for syphilis, and HSV PCR and CMV PCR for meningoencephalitis. Increased opening pressure in crypotococcal meningitis indicates increased intracranial pressure.
Hematologic/oncologic testing: peripheral blood smear to confirm thrombocytopenia and look for schistocytes in DIC and thrombotic thrombocytopenic purpura; d‐dimer, fibrin split products, fibrinogen, PT, PTT, and INR in suspected DIC from severe sepsis/septic shock. Coombs test and haptoglobin for hemolytic anemia. Peripheral blood flow cytometry and bone marrow biopsy to investigate leukemia and lymphoma.
Hepatitis viral serologies: hepatitis A, B, or C virus infection.
Toxicology screen: based on clinical presentation.
List of imaging techniques
CXR posteroanterior and lateral views: may be normal in as many as 20–25% of patients with PCP. Dense or focal air space opacity in bacterial pneumonia, diffuse bilateral interstitial or alveolar opacities in PCP (Figure 48.2), and pneumothorax from pneumocystis or mechanical ventilation.
CT scan of chest: allows evaluation for pneumonia, pneumothorax, or lung mass in suspected lung cancer. PCP results in characteristic ‘ground glass’ reticulonodular infiltrates (Figure 48.3). CT also provides evaluation of mediastinal and hilar lymph nodes in suspected malignancy and fungal and mycobacterial infections.
CT scan head/MRI head: cerebral edema, meningeal enhancement in meningitis/encephalitis, intracranial hemorrhage, or stroke. Primary CNS lymphoma with surrounding edema and toxoplasmosis lesions are better demonstrated on MRI.
EEG: Evaluation of non‐convulsive status epilepticus in altered mental status or coma.
Ultrasound of liver: can diagnose cirrhosis and portal hypertension.
CT scan and whole body PET scan: diagnosis and staging of cancer.
Potential pitfalls/common errors made regarding diagnosis of disease
Coinfections are common in immunocompromised patients who are critically ill and should be suspected when patients do not respond to initial treatment (e.g. bacterial and pneumocystis pneumonia coinfection).
Two or more disease processes can occur simultaneously and a high degree of clinical suspicion is required for diagnosis (e.g. hepatic encephalopathy and cerebral ischemic infarcts from embolic infective endocarditis in a comatose patient).
HIV‐infected patients are at increased risk of accelerated atherosclerosis, poorly controlled diabetes mellitus, hyperlipidemia, acute kidney injury, renal failure, and coinfection with hepatitis B and hepatitis C. Therefore, patients may be admitted to the ICU with myocardial infarction, heart failure, DKA, renal failure and hepatic encephalopathy – in the absence of infection.
Treatment
Treatment rationale
Acute respiratory failure is the most common admitting diagnosis to ICU and up to 50% of all patients undergo invasive mechanical ventilation; 70–80% of these patients have ARDS.
Lung protective ventilation with low tidal volume has been shown in the ARDSNET trial to improve mortality and should be initiated early in all patients requiring mechanical ventilation.
Treatment of specific infections with effective antibiotics is the mainstay of treatment.
Antiretroviral therapy in the ICU
No prospective studies are available regarding timing of ART in the ICU. Current practice is guided by expert opinion.
Consultation with an HIV expert and clinical pharmacist is recommended for decisions about initiating, continuing and withholding ART in the ICU.
Continuing ART
For patients already receiving ART, we generally continue therapy, unless toxicity from the medications is a cause or contributing factor to ICU admission.
Concerns regarding continuation of ART in ICU involve unpredictable drug absorption from the GI tract due to altered splanchnic blood flow, use of H2‐blockers or proton pump inhibitors, nasogastric feeding, and gastric suctioning which can all lead to sub‐therapeutic levels.
There is a significant potential for adverse drug interactions.
Poor functional reserve in critically ill patients increases vulnerability to adverse effects of drug reaction and immune reconstitution inflammatory syndrome (IRIS).
Drug interactions
Antiretroviral agents are metabolized through cytochrome P450 and UGT1A1 enzymes that are responsible for numerous drug interactions.
Close monitoring for adverse reactions is warranted when ART is administered with the medications listed in Table 48.2.
Protease inhibitors interact with many classes of drugs and drug interaction should be checked before initiation of any new medication.
Initiation of ART
Treatment with ART may potentially outweigh risks by improving immune function, thus reducing risk of opportunistic infections and HIV‐associated malignancy.
Certain HIV‐associated conditions such as progressive multifocal leukoencephalopathy and HIV‐associated thrombotic thrombocytopenic purpura lack disease‐specific therapy, and treatment with ART is associated with improved outcomes.
Discontinuing ART
When treatment is withheld, development of viral resistance and impact on future antiretroviral treatment must be considered.
HIV resistance genotyping should be performed before restarting ART.
Table 48.2Medications with significant interactions with antiretroviral medications.
Long‐term effect of interrupting ART in the non‐critical care setting is associated with HIV‐ and non‐HIV‐specific disease progression and mortality.
Overall, the decision to start, continue, or stop ART is complex and involves consideration of a multitude of factors. Consultation with an expert in HIV/AIDS is recommended.
Lactic acidosis in critically ill HIV‐infected patients
Lactic acidosis in HIV‐infected patients usually results from hypoperfusion in the setting of critical illness such as sepsis and circulatory shock.
Lactic acidosis from antiretroviral agents such as didanosine and stavudine was more common in the past. The incidence has decreased with use of newer nucleoside/nucleotide reverse transcriptase inhibitors.
Lactic acidosis from ART is due to mitochondrial injury. Creatinine clearance of less than 70 mL/min and low CD4 count are risk factors.
ART should be stopped when lactate >5 mmol/L. An initial lactate level of >9 mmol/L is associated with increased mortality.
Treatment is supportive with bicarbonate infusion, renal replacement therapy, and mechanical ventilation. Case reports and case series have reported potential benefit of riboflavin, thiamine, and l‐carnitine.
Acute kidney injury in HIV
Acute kidney injury (AKI) is defined as a serum creatinine increase of 50% or 0.3 mg/dL above the baseline creatinine level.
AKI affects two‐thirds of patients admitted to ICU and 32% of these may need renal replacement therapy.
AKI is associated with increased length of ICU stay and increased mortality.
Risk factors for AKI include chronic kidney disease, hepatitis C infection, hypertension, and higher severity of illness on admission to ICU.
HIV‐induced nephropathy is characterized by significant proteinuria; renal biopsy may be required for diagnosis. ART may prevent progression to end‐stage renal disease (ESRD).
Nucleoside reverse transcriptase inhibitors (NRTIs) and non‐NRTIs require dose adjustment when creatinine clearance is <50 mL/min. Dose adjustment is not required for protease inhibitors.
Renal replacement therapy should be initiated when appropriate.
Pancreatitis in HIV
The incidence of acute pancreatitis is increased in HIV‐positive patients compared with the general population; incidence varies from 6.1 to 140 per 1000 person‐years.
Lower CD4 count and higher viral loads are associated with increased risk of pancreatitis.
Medication‐induced pancreatitis is still the most common cause of pancreatitis in HIV‐infected patients.
NRTIs associated with pancreatitis such as didanosine and stavudine are seldom used in ART therapy in the USA but their use is still prevalent in resource limited settings.
Hypertriglyceridemia from protease inhibitors can cause pancreatitis.
Pentamidine, corticosteroids, ketoconazole, sulfonamides, metronidazole, and isoniazid used in treatment and prophylaxis of opportunistic infections in HIV are associated with pancreatitis.
Table of treatment
Diagnosis
First line treatment
Alternative treatment
PCP
Trimethoprim‐sulfamethoxazole for 21 days
Prednisone for moderate to severe PCP
Days 1–5
40 mg PO twice daily
Days 5–10
40 mg PO daily
Days 11–21
20 mg PO daily
Pentamidine Or Primaquine + clindamycin
Bacterial pneumonia
Antipseudomonal penicillin cephalosporin (cefepime, ceftazidime) Or Antipseudomonal carbapenem (imipenem or meropenem) Or Lactam/lactamase inhibitor (piperacillin‐tazobactam) Plus MRSA: linezolid or vancomycin Suspected Legionella pneumonia: macrolide or fluoroquinolone
Bacterial meningitis
Vancomycin Plus Third generation cephalosporin Plus Ampicillin or penicillin G if Listeria infection is suspected
