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628 PART 5: Infectious Disorders

NNRTI class are known to have longer pharmacologic half-life, lead- 17 patients with PJP immune reconstitution syndrome, the clinical
ing to essential monotherapy if the ART regimen is stopped abruptly. worsening was observed 3 to 17 days after starting the antiretroviral
This period of monotherapy is associated with the development of regimen. Flow cytometry of BAL specimens in such patients may show
drug resistance and therefore, replacement with a protease inhibitor is a higher CD4/CD8 ratio than usually observed in PJP owing to an
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recommended. If a regimen is to be discontinued due to toxicity, then influx of CD4 cells during immune reconstitution. Transbronchial lung
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the offending agent should be substituted with another agent if possible. biopsy may reveal a prominent alveolar infiltrate consisting of lympho-
If the entire NNRTI regimen is to be discontinued, a staggered stop cytes, macrophages, and neutrophils with few or no demonstrable PJP
in which the nucleoside backbone is continued for an additional 7 to organisms. The diagnosis is established by bronchoscopy and trans-
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10 days can be considered. 24 bronchial biopsy in order to demonstrate the above-mentioned findings
and exclude other possible opportunistic diseases.
Drug-Drug Interactions: Both the NNRTI and PI classes are active at the IRIS has been described in patients with cryptococcosis who sub-
level of the cytochrome P450 isoenzyme system, with the potential to sequently receive ART. Presentations may include pulmonary or soft
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act as either potent inducers or inhibitors of metabolism of many other tissue lesions that often are culture negative but demonstrate organisms
medications. Conversely levels of NNRTI and PI may be altered by the consistent with cryptococcus on smear or histology. Others may experi-
cytochrome P450 isoenzyme system action of other medications used ence an exacerbation of cryptococcal meningitis associat
https://kat.cr/user/tahir99/ed with a nega-
in the ICU setting. Accordingly, specific antiarrythmics, antihistamines, tive CSF culture and a higher than usual CSF pleocytosis. The optimal
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and some benzodiazepines may be contraindicated. Antiseizure medi- timing for initiation of ART in the setting of cryptococcal meningitis is
cations pose particular concern, as do rifampin, statins (simvastatin unclear because of concerns of risk of potentially life-threatening IRIS.
and lovastatin are contraindicated), and even inhaled corticosteroids. A randomized trial in Africa showed that concurrent initiation of both
Inhaled corticosteroids may induce steroid excess or adrenal suppres- antifungal therapy and ART (within 72 hours) increased mortality.
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sion. 43,44 Use of acid-lowering therapies may alter absorption of the PI Current guidelines suggest a minimum 2-week course of antifungal
atazanavir and the NNRTI agent rilpivirine. therapy; however, a longer duration (4-6 weeks) may be necessary.
Immune Reconstitution Inflammatory Syndrome: Suppression of HIV Clinical trials are ongoing to address this issue.
replication through the use of ART, and the associated CD4 cell count Clinical management of IRIS usually includes nonsteroidal
increase, occasionally causes exaggerated inflammatory responses anti-inflammatory agents or corticosteroids. A randomized clinical trial
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to newly recognized antigens. This phenomenon has been named supports the role of corticosteroids in the management of MTb-IRIS.
immune reconstitution inflammatory syndrome (IRIS). The current Timing of initiation of antiretroviral therapy in the context of IRIS is
understanding of the pathophysiology of IRIS includes interactions discussed above. If antiretroviral therapy has already been initiated, it
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between immune recovery, previously unrecognized (subclinical should be continued unless life-threatening features are present.
or residual) antigenic burden, and possible host genetic variation.
45
Among HIV-negative patients, this phenomenon occurs occasionally CHANGING SPECTRUM OF ICU PRESENTATIONS
during the course of chronic hepatitis B and during treatment for AMONG HIV-INFECTED PATIENTS IN THE ART ERA
borderline lepromatous leprosy (reversal reaction, Lepra type I) or
tuberculosis (eg, central nervous system tuberculomas) and is due to In retrospective series, approximately 5% to 12% of hospitalized HIV-
improvement in cell-mediated immunity. IRIS has been described infected patients require ICU support. Admissions in the pre-ART
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as both an unmasking of subclinical latent infection or a worsen- era were driven predominantly by opportunistic infections, notably
ing of already documented preexisting disease. IRIS has been well Pneumocystis jirovecii pneumonia. Causes of admissions in the ART era
described in the context of CMV retinitis, tuberculosis (MTb), MAC, are generally unrelated to HIV infection and are now very similar to the
Pneumocystis jirovecii pneumonia (PJP), cryptococcosis, progressive general non-HIV ICU population of comparable age and risk groups.
multifocal leukoencephalopathy, and herpes zoster infection. 45,47 Patients with these conditions usually respond to standard management,
Proposed criteria for diagnosis include documented viral load and their prognosis appears to be similar to that of non-HIV-infected
decreases and new or worsening symptoms of an infectious or inflam- patients who have the same condition unless there is concomitant severe
matory condition after initiation of ART. The differential diagnosis immunodeficiency, in which case the prognosis tends to be determined
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may include adverse drug effects and coexisting unrecognized infections by the severity of the immunodeficiency. Overall, survival of HIV-
(nosocomial or community acquired). Some opportunistic infections infected patients in the ICU has also improved, with over 70% surviving
show atypical features in the context of IRIS, particularly MAC, CMV to hospital discharge. 60
retinitis, and cryptococcal meningitis. 49,50 For preexisting opportunistic Acute respiratory failure (ARF) remains the most common reason for
infections, the diagnosis of IRIS should be consistent with published admission. Community-acquired bacterial pneumonia and complica-
case definitions, but to some extent is one of exclusion, including con- tions of chronic obstructive lung disease are common reasons for ICU
sideration of coexisting opportunistic infections and also drug-resistant admission of HIV-infected patients, while PJP accounts for 3% to 12%
opportunistic infections. MAC IRIS is usually an unmasking of subclini- of cases. Sepsis due to bacteria and other bacterial infections such as
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cal infection in the setting of a virologic response to ART, and when the endocarditis remain important etiologies of ICU admission and morbid-
organism is recovered from a normally sterile body site, the diagnosis is ity among HIV-infected individuals, particularly those with comorbid
established. IRIS is important to consider in the differential diagnosis of injection drug use. The mean age of HIV-infected individuals has
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any HIV-infected patient who appears to worsen during the course of increased because of better chronic HIV management. Comorbidities
therapy for tuberculosis or PJP after initiation of antiretroviral therapy. related to the aging of the HIV-infected population such as cardiovas-
M tuberculosis immune reconstitution syndrome (MTb-IRIS) is a para- cular disease or end-stage liver disease (due to hepatitis C coinfection)
doxical worsening of the signs and symptoms of tuberculosis during the are also common reasons for need for ICU support. Other conditions,
course of antituberculous therapy. MTb-IRIS has been reported to occur such as cerebral toxoplasmosis, gastrointestinal bleeding, Kaposi sar-
in up to 36% of HIV-infected patients who initiate ART. The manifes- coma, lymphoma, and other malignancies account for the remaining
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tations of MTb-IRIS may include fever, worsening pulmonary infiltrates, HIV-related ICU admissions. The broad differential diagnosis of oppor-
lymphadenopathy, and CNS granulomas. Case definitions for MTb-IRIS tunistic infections and diseases should be kept in mind to avoid delays
have been developed and help appropriately classify cases. 52 in diagnosis or misdiagnosis.
Initiation of combination antiretrovirals during therapy for PJP Less frequently, patients with AIDS may be admitted to the ICU
has been associated with a paradoxical worsening of the pulmonary without prior knowledge of their HIV status. Certainly, the presence or
infiltrates and lung function in up to 5% to 18% of patients. Among history of minor or major opportunistic infections, wasting, otherwise
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