Critical Care in Human

Immunodeficiency
Virus–Infected Patients
•The development of combination antiretroviral therapies (cARTs) providing sustained control of
HIV replication stands among the most spectacular medical advances in recent decades
•A growing population of HIV-positive patients in Europe and North America now receives the
benefits of lifelong cART, including a marked drop in the incidence of opportunistic infections
(OIs) and other AIDS-related events and remarkable improvements in both life expectancy and
quality of life compared with the early HIV era.
•Conversely, over time, residual HIV replication and/or long-term cART toxicities may result in
HIV-associated non-AIDS (HANA) conditions, of which the most common are atherosclerosis,
renal dysfunction, certain neoplasms, and liver diseases.
Continuum of HIV Infection
•Acute HIV infection is characterized by a rapid rise in plasma HIV-RNA levels and may be
associated with myriad nonspecific clinical signs such as fever, myalgia, disseminated
lymphadenopathy, and rash that mimic mononucleosis syndrome.
•severe forms with acute encephalitis or myocarditis have occasionally been reported.5-7 After 3
to 4 weeks, the viremia level plateaus due to the appearance of HIV-specific antibodies.
•The disease then becomes chronic, with a gradual decline in CD4þ T cells, resulting in the
occurrence of AIDS defining conditions within 2 to 20 years following seroconversion.
•Of note, both innate and humoral immune alterations occur upon early HIV infection, explaining
the high risk of bacterial infection and TB at this stage.
•Without cART, HIV infection nearly always progresses to end-stage AIDS with wasting, recurrent
OIs, and other ultimately fatal complications
•In patients with acute infection or established AIDS, cART is imperative.
•In patients with good treatment adherence, cART rapidly controls HIV replication, thereby
elevating the CD4þ T-cell count (ideally > 500/mL), although substantial interindividual variations
exist regarding the pace and magnitude of recovery.
•compared with age- and sex matched HIV-negative individuals, patients on cART are at higher
risk for several HANA conditions such as COPD, coronary artery disease, chronic kidney disease,
and solid malignancies (eg, lung cancer).
•Contributors to this risk increase may include smoking, cART-induced alterations in lipid
metabolism, and viral coinfections (eg, cytomegalovirus [CMV]).
•Overall, chronic HANA conditions now account for > 75% of deaths in HIV-positive patients living
in Western countries
Changes in Features, Care, and Survival of
Critically Ill, HIV-Positive Patients
•At the beginning of the HIV epidemic in the early 1980s, the vast majority of HIV-positive
patients admitted to the ICU were young adults with severe OIs, malnutrition, and other
complications of end-stage AIDS.
•Many were unaware of their HIV infection. In- ICU fatality rates were extremely high, reaching
70% to 90% in patients requiring invasive mechanical ventilation (IMV) due to Pneumocystis
jirovecii pneumonia (PCP).
•Concern emerged among intensivists regarding the usefulness of ICU admission given this
catastrophic prognosis and the lack of therapeutic options for controlling AIDS progression in
critical illness survivors.
•The introduction of PCP prophylaxis in the late 1980s induced a first change in the requirement
for ICU admission in HIV-infected patients.
•the benefit of adjunctive corticosteroid therapy in patients with moderate to severe PCP, with an
approximately 50% reduction in day 30 and day 90 mortality rates, prompting intensivists to
reconsider the potential benefits of life-sustaining interventions in this population
•Soon afterward, cART was introduced, offering hope for effective long-term control of HIV
infection and establishing ICU admission as an intercurrent rather than a terminal event.
Critically Ill, HIV-Positive Patients in the cART Era: Selected Cohort Studies Published After 2005
•Simultaneously, intensive care strategies changed substantially. HIV-positive patients with acute
respiratory failure (ARF) benefited from improvements in respiratory support, including
noninvasive ventilation, as well as protective ventilation when IMV was required to treat ARDS
•The role for high-flow oxygen therapy has not been specifically investigated in HIV-positive
patients; however, in other immunocompromised populations, high-flow oxygen decreased
neither IMV requirements nor day 28 mortality compared with standard oxygenation.
•Advances in the management of sepsis and septic shock have probably benefited these patients
at high risk for severe bacterial infection
predictors of in-hospital death
•most predictors of in-hospital death are not directly related to HIV infection.
These predictors include:
1. malignancies;
2. chronic liver disease and hepatitis C virus infection;
3. high critical illness severity indexes;
4. admission for medical rather than surgical reasons; and
5. a need for IMV, vasopressor infusion, and/or renal replacement therapy.
•HIV-related characteristics such as CD4þ T-cell count, viral load, and previous cART are not
independently associated with short-term survival, notably in patients admitted for ARF, coma, or
sepsis
DIAGNOSIS AND INTERPRETING
RESULTS OF HIV DIAGNOSIS
•Diagnosing HIV in the CCU is important, as HIV infection often alters the differential diagnosis
and may dictate additional diagnostic workup
•Standard testing is through use of a fourth-generation enzyme-linked immunosorbent assay test,
with confirmation by HIV-1 and HIV-2 antibodies, and nucleic acid if these are both negative.
• The window from acquisition to positivity with fourth-generation testing is 18–45 days
•If HIV is diagnosed, it is important to pursue further testing to characterize the stage of disease,
including checking a CD4 count and HIV viral load.
•However, clinicians should remember that CD4 counts obtained in the CCU setting can be
deceptive, as critical illness alone will lead to a decrease in circulating CD4-positive cells, as cells
are redistributed from the circulation to activated tissue.
•A clue to the presence of this phenomenon is a CD4 count/CD4 percentage discrepancy
•In steady state, a CD4 count of 200 is roughly equivalent to a CD4 percentage of 14%. Clinicians
should suspect a “falsely” low CD4 count in patients with a low CD4 count but higher-than-
expected percentage.
•Because a transient drop in CD4þ T cells is usual at the acute phase of sepsis, diagnostic
algorithms should be based on a recent steady-state count, when available, rather than on the
count measured at admission
•When patients with a known or new HIV diagnosis are admitted to the CCU, it is important to
remember issues of patient confidentiality with any visitors or family members.
Main Reasons for ICU Admission
•ARF (40%-60% of all admissions), sepsis (10%-20%), and altered consciousness (10%-20%)
common reasons for ICU admission at all stages of HIV infection, although new indications such
as acute kidney injury, complicated liver disease, and postoperative care are emerging.
•Overall, OI-related admissions are decreasing steadily, and>70% ofHIV-positive patients are now
admitted for bacterial sepsis or other conditions not directly due to AIDS
Admission for ARF
•The risk of CAP is markedly higher at all stages of HIV Infection but is greatest in patients with
profound CD4þ T-cell depletion and decreases with cART therapy
•Bacteremia is more common in HIV positive patients, probably due to impaired alveolar
macrophage and neutrophil functions
Pneumocystis Pneumonia
•PCP risk increases as CD4 T-cell counts decrease below 200 cells/μL. PCP can still develop in
patients on PCP prophylaxis.
•Admission to the ICU, per se; need for mechanical ventilation; and development of
pneumothorax, irrespective of mode of ventilatory support, are strongly associated with PCP-
related mortality
•Other risk factors for PCP-related mortality at disease presentation include older age, severity of
illness, injection drug use, serum albumin less than 3 g/dL, elevated lactate dehydrogenase,
alveolar-arterial gradient 50 mm Hg, and recurrent PCP
•Clinical presentation of HIV-infected patients with PCP is nonspecific. Patients may present with
subacute dyspnea, cough, fever, marked hypoxemia, and elevated alveolar-arterial oxygen
gradient. Serum lactate dehydrogenase and 1,3 beta-D-glucan levels
•The radiological presentation evolves from reticular infiltrates to diffuse or patchy bilateral
ground-glass opacities with alveolar consolidation
•According to CT imaging, parenchymal cysts and sparing of subpleural regions are usual at
advanced stages of the disease, whereas lymph node enlargement and pleural effusion are not
attributable to PCP and should trigger a search for a concurrent O.I.
•The diagnosis of AIDS-related PCP is far easier than in other immunocompromised patients and
relies on the visualization of P. jirovecii trophozoites or cysts in BAL
•Induced sputum is only 50% to 90% sensitive, may be challenging to perform in patients with
ARF, and does not allow an exhaustive search for the bacterial or opportunistic coinfections seen
in up to 20% of patients with pronounced immunosuppression.
•The qualitative polymerase chain reaction (PCR) assay is valuable for diagnosing non-AIDS-
related PCP notably in patients receiving prophylactic therapy, but lacks specificity in HIV-
positive patients due to their 14% to 69% prevalence of colonization
•Sulfamethoxazole plus trimethoprim remains the first-line treatment
•For patients with an arterial partial pressure of oxygen less than 70 mmHg or with an alveolar-
arterial gradient of 35 mmHg or more, adjuvant corticosteroids should be used
•Recommended dosing is 40 mg oral prednisone twice daily for 5 days followed by 40 mg once
daily for 5 days and then 20 mg daily for an additional 11 days. Total treatment duration is
recommended for 21 days
•Adjunctive corticosteroid therapy reduces the risk of IMV and in hospital death, and it should be
started within 72 h in all patients with suspected or definite severe PCP
Bacterial Pneumonia
•Risk for bacterial pneumonia increases as CD4 counts decrease, but can be seen with any CD4
count. Age, injection drug use, and cigarette smoking are also risk factors for bacterial
pneumonia
•Mortality for HIV-infected patients admitted to the ICU with bacterial pneumonia is estimated
between 17 and 24%.
•CD4 count <100 cells/mm3, shock, and radiographic progression of disease are independently
associated with pneumonia-related mortality.
•Mortality from bacterial pneumonia is increasingly associated with secondary organ dysfunction
such as kidney and liver disease rather than HIV biomarkers
Radiographic patterns of pathogens associated
with infectious pneumonia in HIV
Recommendations
Question: In adults with suspected CAP, should routine diagnostics include nucleic acid–based
testing of respiratory samples for viral pathogens other than influenza?
In hospitalized patients with suspected CAP, we suggest nucleic acid–based testing of respiratory
samples for viral pathogens other than influenza only in patients who meet one of the following
conditions (conditional recommendation, very-low-quality evidence):
Patients with severe CAP (i.e., patients with >1 major or >3 minor criteria )
And
Immunocompromised patients (including those with neutropenia, those undergoing active
cancer therapy, those with a history of solid-organ or blood-component transplantation, those
with advanced HIV disease, or those with a history of chronic use of immunosuppressive
medications
Admission for Neurological Disorders
In a single-ICU study, AIDS-related diseases accounted for only 42% of admissions for altered
consciousness, with the most common diagnoses being cerebral toxoplasmosis, tuberculous
meningitis, and cryptococcal meningitis
•AIDS-related cerebral toxoplasmosis is nearly always due to reactivation of latent
intraparenchymal Toxoplasma gondii cysts rather than to the primary infection.
•In a multi-ICU study, altered consciousness, focal deficits, and seizures were observed in 67%,
59%, and 22% of patients, respectively, whereas fever was absent in almost one-half of the cases
•Brain MRI shows multifocal, ring-enhanced, and sometimes hemorrhagic lesions in the cortex
and/or basal ganglia region with a mass effect from peripheral edema that may require
corticosteroid therapy.
• Solitary lesions and diffuse encephalitis are far less common. The PCR assay for T gondii in
cerebrospinal fluid (CSF) is highly specific (> 95%) but is no more than 50% sensitive after a few
days of therapy.
•The diagnosis must be confirmed by a clinical and radiological response to empirical toxoplasmosis
therapy within 10 to 14 days.
•A brain biopsy should be considered promptly in patients who fail to respond, have negative IgG
serology or PCR results, or have imaging study findings suggesting another etiology
•Tuberculous meningitis is present in up to 20% of HIV positive patients admitted to the ICU with
active TB.
•Most cases of cryptococcal meningitis and meningoencephalitis are due to the ubiquitous species C
neoformans, although Cryptococcus gattii infections also occur in subtropical regions.
•Patients present with fever, headaches, and impaired mental status due to intracranial hypertension.
• Moderate lymphocytic pleocytosis, mild protein elevation, low to normal glucose levels, and
encapsulated yeasts according to Gram or Indian ink staining are the most common CSF findings.
The diagnostic evaluation for neurological failure is similar in cART-treated patients with CD4þ T
cells > 200/mL and in HIV-negative patients
Cryptococcal antigen test results on CSF and serum are both sensitive and specific and allow
earlier confirmation of the diagnosis, including in cases of disseminated disease.
Admission for Sepsis
•Sepsis remains a major reason for ICU admission in HIV-positive patients:
•HIV-positive patients are also at increased risk of primary bloodstream infection due to non-
typhi Salmonella species, S aureus, and Escherichia coli, whose incidence correlates with the
depth of immunodeficiency
•Other severe bacterial infections such as endocarditis or urinary tract infection are also more
common in patients with advanced HIV Infection
•The management of sepsis in HIV-positive patients has no specific characteristics and should
follow general guidelines
•Septic shock and multiorgan failure occur occasionally during the course of disseminated OIs,
notably toxoplasmosis, TB, and histoplasmosis
•These infections commonly trigger hemophagocytic lymphohistiocytosis, which may
substantially worsen organ dysfunctions
•Lastly, Clostridioides difficile (formerly Clostridium difficile) infection is the leading cause of
bacterial diarrhea in HIV-positive patients
EVALUATION OF SEPSIS IN PLHIV
Despite advances in molecular diagnostic techniques, blood culture analysis remains the gold
standard for diagnosing sepsis for bacterial infections.
LIMITATIONS OF STANDARD DIAGNOSTIC BLOOD CULTURE METHODOLOGIES IN HIV:
•routine blood cultures can take 6 h to 5 days to grow an organism to detectable levels, with
additional time being required to identify (24 h) and test for (48 h) antibiotic susceptibility
•False-negative results can also occur due to the challenge of recovering infectious etiologies by
routine blood culture techniques after the initiation of antibiotic therapy.
•Inability to identify all opportunistic viral pathogens
•Cell culture isolation also has limited scope because some viruses cannot easily be grown in
culture
THE IDEAL SEPSIS DIAGNOSTIC
TEST
1. rapid detection (the pathogen needs to be identified in less than 3 h)
2. broad-based detection, including bacteria, viruses, and fungi
3. minimal invasiveness, utilizing clinical samples with low specimen volumes (1 ml blood for
pediatric patients, including neonates, and 5 to 10 ml blood for adults)
4. high sensitivity and specificity for the immediate initiation of targeted antibiotic use in the
presence of signs and symptoms of systemic inflammation
5. polymicrobial detection of pathogens in the presence of contaminants across a wide range of
pathogen loads (1 to 100,000 CFU/ml blood
6. detection of drug resistance
7. the ability to detect unknown and emerging pathogens
EMERGING TECHNOLOGIES FOR RAPID
DIAGNOSIS OF INFECTIONS WITHOUT CULTURE
nearly all U.S. Food and Drug Administration (FDA)- approved sepsis molecular diagnostic tests are
postculture technologies, meaning that a blood sample must be cultured to allow the number of
microbes to increase before the diagnostic test can be conducted.
LIMITATIONS:
•This initial growth-based amplification ensures sensitive detection but extends the diagnostic timeline
such that test results do not effectively impact patient management.
•It also restricts the breadth of organisms detected by relying on a single culture medium formulation,
which cannot support the growth of all organisms or may mask susceptibilities
•While molecular diagnostic tests are completed within 20 min to 2 h, the initial step of blood culture
takes several hours to days and may not be successful.
•determining the antibiotic susceptibility of the pathogen also depends first on additional culture
methods
Current technologies do not benefit antibiotic stewardship programs aimed at deescalating empirical
antibiotic therapy and encouraging timely targeted treatment
Advantages of molecular diagnosis directly from blood
•microorganism detection is independent of enrichment via BC.
•microorganism identification is culture independent, unlike most phenotypic methods.
•The low detection limit of specific PCRs can potentially make them more sensitive than BC.
•In addition, molecular methods are not very sensitive to antibiotic treatment, whereas BC requires
living organisms.  Thus, PCR is much less affected by previous empirical antibiotic treatment that is
generally provided to patients with symptomatic BSI.
•Quantitative real-time PCR may help interpreting positive results because contamination is generally
characterized by a very low amount of bacteria.
Quantification of the bacteria load can also provided some indirect information regarding
infection severity
Inconvenience of molecular diagnostic directly from blood
•Because of their high sensitivity, PCRs are exposed to contamination and may result in false-
positive results. Contamination can be brought by DNA from the environment or from PCR
reagents despite using nucleic acid–free compounds
•False-positive PCR findings can be due to circulating cell-free DNA from dead bacteria or fungal
DNA in the absence of infection—DNAemia rather than a true bacteremia or fungemia
Pros and cons of microbial diagnosis of bloodstream infection directly from blood samples
Main commercially available systems for identification of microbes directly from blood samples
Managing Antiretroviral Treatment
Decisions in the CCU
There are two distinct clinical scenarios to consider: Patients who are stably on ART and patients
who are not on therapy due to a new diagnosis, a decision not to start therapy, or poor
adherence.
Patients Stably on ART
•Perhaps the most common scenario in modern CCUs is that of HIV-infected patients who are
already stably on ART.
•There are a number of issues raised by an CCU admission that can involve complex decision
making around continuing antiretrovirals, including the following:
1. Drug-drug interactions between some antiretrovirals and commonly used CCU drugs,
particularly regimens containing the CYP3A4 antagonists ritonavir and cobicistat
2. Concerns about absorption, due to modification of gastric pH (which can be of concern with
integrase inhibitors, rilpivirine, and atazanavir), or impaired gut motility due to ileus
3. Administration concerns in the setting of lack of enteral access, gastric tubes, or ileus
4. Concern for precipitating IRIS
5. Renal insufficiency and the possibility of drug-induced renal insufficiency, as well as the need
for dose-adjustment in the setting of changes in renal function
6. Hepatic insufficiency and the fact that a number of antiretrovirals are contraindicated with
advanced liver disease
•There is no consensus statement on maintenance of ART in the CCU setting, because there
remains a lack of data specific to the CCU.
•However, data generally support continuation of a patient’s antiretroviral regimen, if feasible, as
higher mortality has been seen in patients with treatment interruption
•However, situations can occur in an CCU setting that necessitate stopping or holding ART for
patients, such as drug toxicity; intercurrent illnesses that preclude oral intake, such as
gastroenteritis or pancreatitis; surgical procedures; and interrupted access to drugs
•In these situations, stopping ART for a short time would be indicated. Considerations when
making this decision would include duration of the expected treatment interruption,
administration requirements of the antiretroviral medications
Patients Who Are Not on ART
•This includes individuals who present with a new diagnosis of HIV and individuals with known
HIV infection who are not taking medications, perhaps after being lost to care, due to struggling
with medication adherence, or through a decision by the patient and/or their providers.
•A number of non-randomized trials have attempted to address whether ART should be initiated
in the CCU; however, all studies to date have the limitation of being retrospective.
•DOI: 10.1371/journal.pone.0186968
Important Considerations for cART Management in ICU
Patients
Drug interactions between common ICU drugs and antiretroviral therapy
IMMUNE RECONSTITUTION
INFLAMMATORY SYNDROME
•The Immune Reconstitution Inflammatory Syndrome (IRIS) is a complication of initiation of ART
in a severely immunocompromised patient.
•IRIS can be defined as either a paradoxical worsening of treated OIs (“paradoxical IRIS”), or the
unmasking of previously subclinical, untreated infections (“unmasking IRIS”).
•IRIS is described as occurring any time between 4 weeks and one year after initiating ART,
though rare otherwise clinically compatible cases may present earlier or later than this.
• There is significant morbidity to IRIS, as up to 50% of IRIS cases require hospitalization, and
often require extensive testing and both diagnostic and therapeutic procedures
General IRIS case definition proposed by Robertson et al (2006)
Required criterion
• Worsening symptoms of inflammation/infection
• Temporal relationship with starting of antiretroviral treatment
• Symptoms not explained by newly acquired infection or disease or the usual course of a previously acquired
disease
• >1 log10 decrease in plasma HIV load
Supportive criterion
• Increase in CD4+ cell count of ≥25 cells/μl
• Biopsy demonstrating well-formed granulomatous inflammation or unusually exuberant inflammatory
response
In India, the agreed practical definition of IRIS would be the “occurrence or manifestations of new
OIs or existing OIs within six weeks to six months after initiating ART; with an increase in CD4
count”.
Risk factors for developing IRIS
•Male sex
•Younger age
•Lower CD4+ cell count at ART initiation
•Higher HIV RNA at ART initiation
•Lower CD4+ cell percentage at ART initiation
•Lower CD4+:CD8+ ratio at ART initiation
•Disseminated versus localized OI
•ART- naïve patient
•More rapid initial fall in HIV RNA on ART
•Shorter interval between OI therapy initiation and ART initiation
Pathogenesis
•The immunopathogenesis of the syndrome is unclear
•IRIS results from a dysregulated immune response to a variety of antigenic stimuli following
initiation of ART
paradoxical IRIS –
Paradoxical IRIS is diagnosed based on a clinical scenario of a known opportunistic infection
initially improving and then deteriorating, with clinical features suggestive of the same
opportunistic infection
unmasking associated IRIS –
a new presentation of O.I that is “unmasked” in the weeks following initiation of ART with an
exaggerated inflammatory clinical presentation or complicated by a paradoxical reaction
Biomarkers of IRIS
1. C-reactive protein (CRP)
2. Interferon (INF)-γ
3. Interleukin (IL)-2,6,7,12,13,17,18
4. Tumour necrosis factor (TNF)-α
5. INF- γ inducible protein-10 (IP-10)
6. D-dimer
 Suggestive features of IRIS:
Temporal association between the initiation of ART and the development of clinical phenomena
(mostly within 3 months).
1. Typically, IRIS occurs within 2–12 weeks of the initiation of ART, although it may present later
(usually between 6 weeks to 6 months)
2. The incidence of IRIS is estimated to be 10% among all patients in whom ART has been initiated; and
up to 25% among those who have started ART and who have a CD4 cell count of below 50 cells/mm3
Unusual clinical manifestations in patients responding to ART include:
•Unexpected localized disease, e.g. lymph nodes (appearance or enlargement and/or suppuration), or
involving liver or spleen
• Exaggerated inflammatory reaction, e.g. severe fever, with exclusion of other causes
• Painful lesions
•Atypical inflammatory response in affected tissues, e.g. granulomas, suppuration, necrosis
•Progression of organ dysfunction or enlargement of preexisting lesions
•Development or enlargement of cerebral space-occupying lesions after treatment for cerebral
cryptococcosis or toxoplasmosis
• Progressive pneumonitis or the development of organizing pneumonia after treatment
forpulmonary MTB or PCP
• Onset or worsening of uveitis/vitritis after the resolution of CMV retinitis
• Fever and cytopenia after treatment for disseminated MAC
treatment
•There are limited treatment options for IRIS. In all but life-threatening cases, ART should be continued,
as there is a clear mortality benefit associated with ART even in the setting of IRIS
•Examples of clinical situations in which stopping ART might be considered would be life-threatening
tuberculous meningitis
•NSAID use may be helpful in milder disease, but there are no clinical trial data on efficacy, and this
recommendation is based on data from case series and expert opinion
•There are a few case reports of success with other agents, including pentoxifylline, montelukast,
thalidomide, and hydroxychloroquine
•The only treatment for IRIS for which there are randomized clinical trial data is corticosteroids.
•However, in severe IRIS, a short course of oral prednisolone is required to alleviate the symptoms. The
dosage and duration of treatment required is variable and should be judged clinically. Severe disease
requires at least 1–2 mg of prednisolone per kg body weight.