CHAPTER 367
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Immune Reconstitution Inflammatory Syndrome in HIV/AIDS
TABLE 367-1 EXAMPLES OF IMMUNE RECONSTITUTION
INFLAMMATORY SYNDROME
PATHOGEN
367
IMMUNE RECONSTITUTION
INFLAMMATORY SYNDROME
IN HIV/AIDS
MARTYN A. FRENCH AND GRAEME MEINTJES
DEFINITION
Treatment of human immunodeficiency virus (HIV) infection with combination antiretroviral therapy (ART) results in the restoration of protective
pathogen-specific immune responses and the regression or prevention of
opportunistic infections and cancers in most individuals (Chapter 365).
However, restoration of an immune response against a pathogen may also
result in immunopathology at body sites infected by the pathogen. This
has been referred to as immune restoration disease to differentiate it from
immunodeficiency disease, but it is now commonly known as immune reconstitution inflammatory syndrome (IRIS) because an inflammatory illness is
the most common clinical feature.1,2
Essentially any pathogen that causes an infection as a result of HIV-induced
cellular immunodeficiency may be associated with IRIS after ART is commenced.3 However, the clinical characteristics and severity of IRIS associated
with each type of pathogen vary greatly (Table 367-1). For example, IRIS associated with Mycobacterium tuberculosis, cryptococcal, or JC polyomavirus infection is manifested differently from an opportunistic infection caused by these
pathogens, and the resulting illness is often severe and may result in death
(Chapter 346). In contrast, herpes zoster after ART is usually indistinguishable
from that occurring before ART, and it is only the timing of onset and its increased
frequency during early ART that suggest that it results from IRIS.
IRIS develops mainly during the first 3 months of ART but occasionally
later. Two patterns are recognized. Paradoxical IRIS refers to the worsening
or atypical manifestation (or both) of an established opportunistic infection after
ART is commenced. In most cases the infection had been treated before ART was
initiated, and the immune response appears to be against residual antigens of the
pathogen or the dying organism. Unmasking IRIS refers to disease that occurs
for the first time after ART is commenced and appears to result from an immune
response against a subclinical infection by an opportunistic pathogen or a missed
diagnosis of an opportunistic infection. Typically, unmasking IRIS manifests with
accelerated or exaggerated inflammatory presentations of the infection.
EPIDEMIOLOGY
The reported incidence of IRIS has varied from 8% to over 40% in different
studies. To some extent, the large variation reflects the lack of universally
accepted diagnostic criteria. It also probably reflects differences in risk factors
in the populations of patients studied. The most important risk factors for IRIS
are a low CD4+ T-cell count when ART is initiated and, in patients in whom
paradoxical IRIS develops, disseminated infection and a short time interval
between treatment of the infection and commencement of ART.
PATHOGENESIS
Information about the pathogenesis of IRIS has been obtained mostly by
studying patients who experience disease associated with a mycobacterial
infection.4 Both clinicopathologic and immunologic studies have shown an
association with a TH1 cellular immune response against mycobacterial antigens, which has been demonstrated by measuring delayed-type hypersensitivity skin test responses or the frequency of circulating antigen-specific T cells
that produce interferon (IFN)-γ. However, there is increasing evidence that
innate immune responses by myeloid cells (monocytes, macrophages, and
neutrophils) and their mediators also contribute to the immunopathology,
particularly in paradoxical tuberculosis-associated IRIS. Patients who develop
IRIS tend to have severe immunosuppression with high levels of C-reactive
protein prior to starting anti-retroviral therapy.4b The immunopathogenesis
NOMENCLATURE
TYPICAL
CHARACTERISTICS
OF THE DISEASE
Mycobacterium
tuberculosis
TB-IRIS
Paradoxical exacerbation
of TB
Nontuberculous
mycobacteria (NTM)
NTM-IRIS
Mainly lymphadenitis,
also pulmonary and
abdominal disease
Bacille Calmette-Guérin
(BCG)
BCG-IRIS
Necrotizing regional
lymphadenitis
Mycobacterium leprae
Leprosy-associated IRIS
Borderline and type 1
reactional state
Cryptococcus neoformans
C-IRIS
Mainly meningitis, also
lymphadenitis
Pneumocystis jiroveci
Pneumocystosis-associated
IRIS
Paradoxical exacerbation
of pneumonitis
Cytomegalovirus (CMV)
CMV retinitis after ART
or immune recovery
uveitis
Acute retinitis after
commencing ART or
uveitis
JC polyomavirus
PML-IRIS
Multifocal
leukoencephalopathy
with inflammatory
features
Human herpesvirus 8
KS-IRIS
Rapid progression of
existing and/or new
KS lesions
Hepatitis B or C virus
Hepatitis B or C
virus-associated IRIS
(that may mimic DILI)
Hepatitis flare and/or
liver enzyme elevation
Varicella-zoster virus
Dermatomal or
multidermatomal
zoster and rarely
myelitis after ART
Herpes simplex virus
Herpes lesions with
exaggerated
inflammation and
rarely myelitis or
encephalitis after ART
Molluscum contagiosum
virus
Inflammatory molluscum
contagiosum
Inflamed molluscum
lesions
Malassezia spp.
Inflammatory seborrheic
dermatitis
Abnormally inflamed
seborrheic dermatitis
ART = antiretroviral therapy; DILI = drug-induced liver injury; C = cryptococcosis; IRIS = immune
reconstitution inflammatory syndrome; KS = Kaposi sarcoma; PML = progressive multifocal
leukoencephalopathy; TB = tuberculosis.
of IRIS associated with other pathogens is less well understood and appears
to vary depending on the provoking pathogen.5 For example, IRIS associated
with JC polyomavirus infection (progressive multifocal leukoencephalopathy
IRIS) is characterized by an inflammatory cell infiltrate dominated by CD8+ T
cells in affected areas of the brain. Other forms of IRIS associated with virus
infections also appear to be CD8+ T-cell mediated.
CLINICAL MANIFESTATIONS
The clinical manifestations of IRIS are different for each associated pathogen
and will therefore be described for individual pathogens. Only disease that
presents a significant patient management problem will be discussed.
Tuberculosis-associated IRIS
M. tuberculosis is the most common pathogen involved in IRIS, with estimates of paradoxical tuberculosis-associated IRIS incidence ranging from
4 to 54% of patients with HIV infection and treated tuberculosis. Most
tuberculosis-associated IRIS develops within the first 3 months after the initiation of ART. Patients in whom paradoxical tuberculosis-associated IRIS
develops typically give a history of having severe immunosuppresion5b and
improving with the treatment of tuberculosis before initiation of ART. After
starting ART, recurrent, worsening, or new clinical or radiologic manifestations of tuberculosis develop. Common manifestations include fever, enlargement of lymph nodes, and worsening radiographic pulmonary infiltrates.
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2292.e4
ABSTRACT
CHAPTER 367
Immune Reconstitution Inflammatory Syndrome in HIV/AIDS
HIV patients commencing antiretroviral therapy (ART) with very low CD4+
T cell counts are at risk of developing an immune reconstitution inflammatory
syndrome (IRIS) resulting from the restoration of immune responses against
pathogens that cause exaggerated and often atypical inflammation. The inflammation appears to be a paradoxical worsening of the infection (paradoxical
IRIS) or was subclinical and unmasked by the immune response (unmasking
IRIS). Most cases of IRIS are associated with an infection by Mycobacterium
tuberculosis or Mycobacterium avium complex, but IRIS may also be associated
with infections by fungi and viruses. Almost all cases of IRIS occur during
the first 3 months of ART and often during the first 2 weeks. Prevention of an
IRIS is achievable by commencing ART before CD4+ T cell counts become
low (<350/mL) and by optimally treating opportunistic infections before
commencing ART. Deferment of ART until an opportunistic infection is
optimally treated is particularly important when the infection affects the central
nervous system. Management of an IRIS generally includes continuing ART
and the use of anti-inflammatory therapy, which may include corticosteroids
in tuberculosis-associated IRIS. ART should only be stopped in exceptional
circumstances.
KEYWORDS
HIV
antiretroviral therapy
immune reconstitution
IRIS
paradoxical IRIS
unmasking IRIS
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CHAPTER 367
Immune Reconstitution Inflammatory Syndrome in HIV/AIDS
Tracheal compression by intrathoracic lymph nodes or massive pleural effusions can cause life-threatening dyspnea. Respiratory failure as a result of
worsening pulmonary infiltrates and acute respiratory distress syndrome have
occasionally been reported. In a prospective case series from South Africa, neurologic tuberculosis-associated IRIS accounted for 12% of cases of paradoxical
tuberculosis-associated IRIS. Meningitis, tuberculoma, or both were the most
common manifestations. Tuberculosis-associated IRIS may cause granulomatous hepatitis, typically with tender hepatomegaly and cholestatic liver function derangement. Peritonitis due to IRIS-mediated peritoneal inflammation
and peritonitis secondary to bowel perforation or splenic rupture are other
unusual presentations. Although usually negative, mycobacterial cultures may
be positive, particularly if IRIS occurs early during anti-tubercular therapy
and in patients with multidrug-resistant tuberculosis. Histologic examination
often reveals necrotizing granulomas.
High rates of tuberculosis have been reported during ART, especially in the
initial months of treatment in ART programs in resource-limited settings. This type
of tuberculosis has been referred to as ART-associated tuberculosis because the
mechanisms underlying the manifestations of tuberculosis after initiating ART
are likely to be heterogeneous. Diagnoses of active tuberculosis before initiation
of ART may be missed because of the inherent insensitivity of tuberculosis
diagnostics in this patient group and only later be diagnosed during ART.
Because ART-induced immune recovery is a time-dependent process and
some patients fail to respond immunologically, a proportion of cases may
develop as a result of persisting immunodeficiency. Other patients may have
active subclinical disease at the time of ART initiation or a missed diagnosis of
tuberculosis, and progression to symptomatic disease may be accelerated with
exaggerated inflammatory features by ART-induced restoration of a cellular
immune response against M. tuberculosis antigens. Of patients in this latter
group, some have exuberant inflammatory clinical features that are consistent
with a diagnosis of unmasking tuberculosis-associated IRIS.
Nontuberculous Mycobacterial IRIS
Atypical manifestations of Mycobacterium avium complex (MAC) disease in
patients who had commenced zidovudine monotherapy were the first indication that IRIS may be a complication of ART. MAC and other nontuberculous
mycobacteria have been associated with IRIS in up to 4% of patients who
commence combination ART with a CD4+ T-cell count lower than 100/µL.
Disease is usually localized, as opposed to the disseminated nontuberculous
mycobacterial disease of patients with acquired immunodeficiency syndrome
(AIDS) not on ART, and is most commonly manifested as fever, night sweats,
and lymphadenitis. Unmasking disease is most common. Peripheral lymphadenitis may suppurate and sometimes cause chronically discharging fistulas to
the skin. Abdominal disease frequently causes pain, which is usually associated with lymphadenitis and occasionally with omental masses, hepatitis, and
inflammation of the spleen (Fig. 367-1). Pulmonary and thoracic disease
2293
usually causes cough that is sometimes associated with chest pain. Microscopic
examination of biopsy material or aspirates from affected tissues often reveals
mycobacteria, but these may not be cultured.
In HIV-seropositive children vaccinated with bacille Calmette-Guérin (BCG),
a BCG-associated lymphadenitis with or without abscess formation may
develop after starting ART (Fig. 367-2).
Leprosy-associated IRIS is usually manifested as unmasking of previous
subclinical Mycobacterium leprae infection, with a borderline and type I reactional state (Chapter 310).
Cryptococcosis-IRIS
The proportion of patients with HIV infection and treated cryptococcosis in
whom cryptococcosis-IRIS develops ranges from 8 to 49%. Themajority represent
a recurrence of previously treated cryptococcal meningitis.Unmasking inflammatory reactions to unrecognized meningeal infection during the first few weeks of
ART have also been reported.6 The time of onset of cryptococcosis-IRIS varies
from 4 days to around 3 years after initiation of ART. In addition to recurrent
meningitis, the central nervous system (CNS) features of cryptococcosis-IRIS
include intracranial cryptococcoma or abscesses, spinal cord abscesses, recalcitrant
raised intracranial pressure, optic disc swelling, cranial nerve lesions, dysarthria,
hemiparesis, and paraparesis. Extracranial manifestations of cryptococcosis-IRIS
include lymphadenitis, eye disease, suppurating soft tissue lesions, and pulmonary
disease that may include cavitating or nodular lesions.
At the diagnosis of cryptococcal meningitis, cerebrospinal fluid (CSF) white
blood cell counts of 25 cells/µL or less and protein levels of 50 mg/dL or less
are associated with the development of cryptococcosis-IRIS. On the other
hand, CSF profiles at the moment of paradoxical cryptococcosis-IRIS may
show an increased white blood cell count and an increased opening pressure of greater than 25 cm H2O, but these features overlap significantly with
those observed in patients with non–IRIS-related relapses of cryptococcal
meningitis. A positive CSF cryptococcal culture prior to commencing ART
is a predictor for paradoxical cryptococcosis-IRIS. Cultures of CSF or tissue
samples obtained at the time of paradoxical cryptococcosis-IRIS are usually
negative even when cryptococci can beseen on microscopy.
The importance of cryptococcosis-IRIS is emphasized by the finding that
earlier (1 to 2 weeks) ART initiation in cryptococcal meningitis results in
higher mortality compared with deferred (5 weeks) ART initiation likely due
to enhanced immune cell recruitment and activation when ART is started very
early in thecontext of a partially treated CNS infection.7,8
Histoplasmosis-IRIS
Histoplasmosis-IRIS is uncommon but reported in areas in which the fungal
agent is endemic (Chapter 316), including the Ohio River Valley of the U.S.
and French Guiana. Histoplasmosis-IRIS can generate significant morbidity,
so screening for latent or subclinical histoplasmosis should be considered
before initiating antiretroviral therapy in endemic areas.8b
Pneumocystosis-IRIS
Patients who have been treated for P. jiroveci pneumonitis may experience
pulmonary inflammation after ART is commenced. It is usually characterized by fever, cough, dyspnea, chest discomfort, and patchy alveolar infiltrates
on the chest radiograph (Fig. 367-3). In some patients, organizing pneumonia
develops. This condition is relatively rare, occurring in less than 5% of patients
treated for P. jiroveci pneumonitis prior to ART.
FIGURE 367-2. Bacille Calmette-Guérin (BCG)–associated immune reconstitution
FIGURE 367-1. Mycobacterium avium complex–associated immune reconstitution
inflammatory syndrome manifested as necrotizing inflammation in the spleen and
abdominal lymph nodes.
inflammatory syndrome after starting antiretroviral therapy for human immunodeficiency virus infection in a child who received BCG vaccination shortly after birth.
A biopsy specimen from the larger lesion demonstrated necrotizing granulomatous
inflammation.
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2294
CHAPTER 367
Immune Reconstitution Inflammatory Syndrome in HIV/AIDS
Liver Disease after ART Associated with Hepatitis B and C
Virus Infection
FIGURE 367-3. Pneumocystosis-associated immune reconstitution inflammatory
syndrome. Left, Before treatment of the P. jiroveci infection. Right, After treatment of the
P. jiroveci infection and commencing antiretroviral therapy.
Progressive Multifocal Leukoencephalopathy IRIS
Progressive multifocal leukoencephalopathy of the brain occurs when cellular
immune responses fail to control JC polyomavirus infection of oligodendrocytes and astrocytes. It is characterized by a paucity of inflammatory cells in
brain lesions (Chapter 346). ART is effective in some patients, presumably
because it enhances cellular immune responses against JC polyomavirus antigens. However, ART may also result in a paradoxical worsening of established
progressive multifocal leukoencephalopathy or in unmasking of subclinical
JC polyomavirus infection and appearance of progressive multifocal leukoencephalopathy for the first time. These manifestations of progressive multifocal
leukoencephalopathy on ART are often atypical in that imaging studies of the
brain demonstrate changes associated with inflammation, and brain biopsy
specimens demonstrate inflammatory cell infiltrates with a prominence of
CD8+ T cells. Between 19 and 23% of cases of progressive multifocal leukoencephalopathy in HIV-infected patients are due to paradoxical or unmasking progressive multifocal leukoencephalopathy IRIS. The median time at
onset is 7 weeks on ART, and most cases occur within the first 3 months but
very occasionally as late as 26 months after commencing ART. Predictors of
progressive multifocal leukoencephalopathy IRIS have not been identified.
Other CNS manifestations of IRIS, which vary greatly in incidence following
ART, may include cryptococcal meningitis and meningoencephalitis,
cerebral toxoplasmosis, primary CNS lymphoma, and HIV encephalitis,9 as
well as stroke.10
KS-IRIS
A prospective study of Kaposi sarcoma (KS) in patients from Mozambique
commencing ART found that paradoxical KS-IRIS developed in 31% of patients
with pre-ART KS, and that unmasking KS-IRIS developed in 7% of patients
without pre-ART KS. Clinical manifestations included an increased number
of preexisting skin lesions that sometimes exhibited increased nodularity and
ulceration, new skin or mucosal lesions, and lymphedema. Independent risk
factors for the development of KS-IRIS were KS before ART, human herpesvirus 8 DNA detectable in plasma, a hematocrit of less than 30%, and a plasma
HIV RNA level greater than 5 log10 copies/mL. This form of IRIS may be
life-threatening when there is worsening of pulmonary KS or airway obstruction due to enlarging KS lesions.
Some cases of KS-IRIS will resolve without treatment, but chemotherapy
is usually necessary.
Cytomegalovirus-associated IRIS
Eye disease is the most common manifestation of IRIS associated with
cytomegalovirus infection. Retinitis usually develops during the first few
weeks of ART as a “paradoxical” worsening of treated retinitis or as a new
manifestation of cytomegalovirus retinitis. Previously treated cytomegalovirus infection is the most common cause of immune recovery uveitis,
which presumably results from the restoration of an immune response
against residual cytomegalovirus antigens in the eye. The risk for development of cytomegalovirus-associated immune recovery uveitis is greatest in
patients who had a large proportion of the retina affected by cytomegalovirus infection. It may develop up to 21 months after ART is commenced, and the clinical
manifestations vary in severity from a transient vitreitis to persistent uveitis,
papillitis, cystoid macular edema, and detachment of epiretinal membranes.
Elevations of serum liver enzyme levels occur in up to 18% of patients after ART
is initiated. Several causes have been defined, but the most important risk factor
is concomitant infection with hepatitis B virus or hepatitis C virus. Prospective
studies of patients with HIV infection who are coinfected with hepatitis B virus,
hepatitis C virus, or both, who commenced ART demonstrated that 22 to 24%
of patients with hepatitis B coinfection, 13.5% of patients with hepatitis C
coinfection, and 50% of patients with both hepatitis B and C coinfection experienced a “flare” of hepatitis. Flares of hepatitis B were associated with increased
plasma levels of several immune mediators, suggesting that at least some
of these cases were due to IRIS related to hepatitis B in the liver. Patients who
experienced flares of hepatitis B had higher plasma hepatitis B virus DNA levels
and serum alanine transaminase levels before ART was commenced. Severe
hepatitis after ART in patients with HIV infection and coinfection with hepatitis
B or hepatitis C is uncommon but can occasionally result in liver decompensation and death. It is difficult to determine with certainty in an individual case
whether this phenomenon is due to direct drug hepatoxicity or IRIS associated with hepatitis viruses.
Herpes Simplex Virus and Varicella Zoster Virus Disease
after ART
Recurrence or exacerbation of mucocutaneous herpes simplex virus disease
may occur after ART is initiated. Sometimes lesions become hemorrhagic and
exhibit significant tissue necrosis. Rarely herpes simplex virus infection of the
brain or spinal cord may be unmasked by commencing ART and be manifested
as encephalitis or myelitis. Dermatomal or multidermatomal zoster lesions
may also develop after commencing ART and are usually indistinguishable
from zoster that occurs in patients not receiving ART. Rarely, myelitis may
be associated with varicella-zoster virus infection.
DIAGNOSIS
Immunologic tests for diagnosing IRIS are currently not available for routine
use. In the absence of diagnostic tests, IRIS may be established with diagnostic
criteria that take into consideration the timing, clinical characteristics, and
pathology of the disease, as well as the virologic response to the ART as measured by HIV viral load.
TREATMENT
The general approach to the treatment of IRIS is to continue ART and provide
appropriate antimicrobial therapy for the provoking infection. Cessation of ART
should be considered only in patients with life-threatening disease when all
other measures have failed. Anti-inflammatory therapy should not be given
routinely but be reserved for patients with severe inflammation, particularly
when it is life-threatening, or significant symptoms. Corticosteroid therapy is
used most often, but its effectiveness may vary from one type of IRIS to another.
Thus, a randomized controlled trial in South Africa demonstrated that corticosteroids (prednisone 1.5 mg/kg/day for 2 weeks, then 0.75 mg/kg/day for 2 weeks)
are a safe and effective treatment option for paradoxical tuberculosis-associated IRIS.A1 In contrast, in an analysis of data from previously reported
cases of progressive multifocal leukoencephalopathy IRIS, it was suggested that corticosteroid therapy is not effective, although it was indicated
that it may be effective if used early in the course. There is anecdotal evidence
suggesting that corticosteroid therapy can be effective in other types of IRIS,
but there are potential risks to using corticosteroid therapy in HIV patients who
are already very immunodeficient, and it should be started only after weighing
all considerations. Corticosteroid therapy for IRIS affecting the eye should be
supervised by an ophthalmologist. Corticosteroid therapy may cause worsening
of KS.
PREVENTION
Given that a low CD4+ T-cell count is a major risk factor for the development
of IRIS, commencing ART at a CD4+ T-cell count higher than 350/µL, as
recommended by treatment guidelines, will prevent most cases. However,
this is not possible in patients who are seen for the first time with an opportunistic infection or low CD4+ T cell count. Other strategies to prevent paradoxical IRIS are therefore under investigation. A randomized controlled trial
demonstrated that the risk of paradoxical tuberculosis-associated IRIS could be
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CHAPTER 367
Immune Reconstitution Inflammatory Syndrome in HIV/AIDS
reduced by 30% in high-risk patients (CD4+ T-cell count ≤100 cells/µL) with
HIV-associated tuberculosis starting ART by prescribing prednisone for the
first 4 weeks of ART (40 mg daily for 2 weeks then 20 mg daily for 2 weeks).A2
Several observations indicate that a high pathogen load is an important risk
factor for IRIS, including the association with disseminated tuberculosis, a
shorter duration of treatment of tuberculosis or cryptococcal meningitis, and
positive CSF cultures for cryptococcal or Mycobacterium tuberculosis infections
prior to commencing ART. Therefore, delaying the introduction of ART so that
the opportunistic infection can be fully treated might be beneficial. However,
doing so may increase the risk for development of other opportunistic infections
or cancers and of mortality. The results of an AIDS Clinical Trial Group study
provided evidence supporting the introduction of ART within 1 to 2 weeks
of starting antimicrobial therapy, particularly in patients with P. jiroveci pneumonitis. In addition, randomized controlled trials demonstrated that for
patients with HIV-associated tuberculosis and CD4+ T-cell count less than 50
cells/µL, the survival benefit of starting ART within the first 2 weeks of
tuberculosis therapy outweighs the risk for IRIS and other adverse events.A3-A6
Nevertheless, a more recent clinical trial of the effect of timing of ART initiation on outcomes of tuberculosis treatment for HIV-positive patients
with CD4+ T-cell counts of 220 cells/µL or more showed that ART can be
delayed until after completion of 6 months of tuberculosis treatment in this
population.A7 In contrast, commencing ART at the same time as treatment of
cryptococcal meningitis has been shown to increase mortality when compared
with delaying ART until 5 to 6 weeks after starting antifungal treatment.A8 It
seems probable that IRIS affecting the CNS is more likely than other types
of IRIS to result in morbidity and mortality. Therefore, a single approach to
this issue may not be possible, and a strategy for commencing antimicrobial therapy and ART may have to be determined for each pathogen or for
infections of the CNS.
PROGNOSIS
The prognosis for patients in whom IRIS develops is highly variable because
of differences in the extent of the infection by the provoking pathogen, the
characteristics of the immunopathology caused by the restored immune
response, and the body site affected. Most cases of IRIS are self-limited,
and outcomes are usually good. However, mortality rates of up to 66% have
been reported for cryptococcosis-IRIS. The mortality rate for tuberculosis-associated IRIS is much lower, but hospital admissions are common. Mortality and
hospitalization rates are particularly high when tuberculosis-associated IRIS
or cryptococcosis-IRIS affects the CNS. Indeed, involvement of the CNS by
2295
any type of IRIS may result in death or permanent neurologic disability. For
example, mortality rates of 53% have been reported for paradoxical progressive
multifocal leukoencephalopathy IRIS and 31% for unmasking progressive multifocal leukoencephalopathy IRIS. Furthermore, patients who survive progressive multifocal leukoencephalopathy IRIS may have neurologic sequelae such as
hemiparesis or seizures. Patients with lymphadenitis resulting from tuberculosisassociated IRIS11 or nontuberculous mycobacterial IRIS and those with meningitis or cerebral lesions resulting from cryptococcosis-IRIS may experience
recurrent relapses.
Autoimmune Disease and Sarcoidosis
Patients with HIV infection who are receiving ART have an increased susceptibility to some autoimmune diseases, mainly Graves disease, and sarcoidosis.
Although sometimes referred to as types of IRIS, they appear to have a different immunopathogenesis.
Grade A References
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for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS.
2010;24:2381-2390.
A2.Meintjes G, Stek C, Blumenthal L, et al. PredART Trial Team. Prednisone for the prevention of
paradoxical tuberculosis-associated IRIS. N Engl J Med. 2018;379:1915-1925.
A3.Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during
tuberculosis therapy. N Engl J Med. 2010;362:697-706.
A4.Blanc FX, Sok T, Laureillard D, et al. CAMELIA (ANRS 1295–CIPRA KH001) Study Team. Earlier
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A5.Havlir DV, Kendall MA, Ive P, et al. AIDS Clinical Trials Group Study A5221. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011;365:1482-1491.
A6.Uthman OA, Okwundu C, Gbenga K, et al. Optimal timing of antiretroviral therapy initiation for
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GENERAL REFERENCES
For the General References and other additional features, please visit Expert Consult
at https://expertconsult.inkling.com.
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CHAPTER 367
Immune Reconstitution Inflammatory Syndrome in HIV/AIDS
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10.Benjamin LA, Allain TJ, Mzinganjira H, et al. The role of human immunodeficiency virus-associated
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2295.e2
CHAPTER 367
Immune Reconstitution Inflammatory Syndrome in HIV/AIDS
REVIEW QUESTIONS
1.A major risk factor for developing paradoxical tuberculosis immune reconstitution inflammatory syndrome (tuberculosis-associated IRIS) is:
A.Starting antiretroviral therapy (ART) in a patient with a low CD4+
T-cell count
B.Starting ART in a patient with a high CD4+ T-cell count
C.Starting ART in a patient with pulmonary tuberculosis
D.Starting a protease inhibitor–containing regimen
E.Starting ART in a patient with rifampin-resistant tuberculosis
Answer: A Tuberculosis-associated IRIS has been associated with a low CD4+
T-cell count (usually <50/µL) in several studies, probably because it is a marker
of a high pathogen load and an increased susceptibility to restoration of a pathogen-specific immune response that causes immunopathology. All ART regimens may cause tuberculosis-associated IRIS, and tuberculosis-associated IRIS
may develop in patients with all types of tuberculosis, including patients with
multidrug-resistant tuberculosis.
2.Which of the following statements is correct?
A.In an HIV-infected patient with cryptococcal meningitis, ART should
be started within 2 weeks after the start of the cryptococcal treatment.
B.In an HIV-infected patient with cryptococcal meningitis, ART should
be started at least 4 weeks after the start of the cryptococcal treatment.
C.In an HIV-infected patient with cryptococcal meningitis and a CD4+
T-cell count below 50 cells/µL, ART should be started within 2 weeks
after the start of the cryptococcal treatment.
D.In an HIV-infected patient with cryptococcal meningitis and very few
leucocytes in the cerebrospinal fluid (CSF), ART can be started together
with the start of the cryptococcal treatment.
Answer: B Commencing ART within the first 2 weeks after starting cryptococcal meningitis treatment is associated with increased mortality compared
with starting ART at least 4 weeks after the start of the cryptococcal treatment.
The presence of very few leukocytes in the CSF is a further risk factor for
developing cryptococcal IRIS.
3.Which of the following statements is correct?
A.All patients with IRIS should be treated with prednisone.
B.Patients with IRIS should never be treated with prednisone.
C.In patients with IRIS, ART should be stopped.
D.In patients with tuberculosis-associated IRIS, prednisone may be
beneficial.
Answer: D The effectiveness of prednisone as treatment for IRIS varies from
one type of IRIS to another. A randomized controlled trial in South Africa demonstrated that prednisone therapy is a safe and effective treatment option for
paradoxical tuberculosis-associated IRIS. For progressive multifocal leukoencephalopathy IRIS, only early use of corticosteroid therapy may be effective. For
Kaposi sarcoma (KS)-IRIS, corticosteroids are likely to be harmful. Potential
risks of using corticosteroid therapy in patients with HIV infection who are very
immunodeficient should always be considered.
4.IRIS can be prevented by which one of the following?
A.Early ART at a high CD4+ T-cell count
B.Prophylaxis for opportunistic infections
C.Early diagnosis and treatment of opportunistic infections
D.All of the above
Answer: D Commencing ART at a high CD4+ T-cell count, as well as
prophylaxis for opportunistic infections, will prevent the occurrence of
opportunistic infections and therefore IRIS. Earlier diagnosis and treatment of
opportunistic infections will reduce the pathogen load and therefore the risk
of developing IRIS.
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