Author’s Accepted Manuscript

Immune Reconstitution Inflammatory Syndrome

(IRIS): What pathologists should know

Ann Marie Nelson, Yukari C. Manabe, Sebastian B

Lucas

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PII: S0740-2570(17)30055-2
DOI: http://dx.doi.org/10.1053/j.semdp.2017.04.010
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To appear in: Seminars in Diagnostic Pathology
Cite this article as: Ann Marie Nelson, Yukari C. Manabe and Sebastian B Lucas,
Immune Reconstitution Inflammatory Syndrome (IRIS): What pathologists
should know, Seminars in Diagnostic Pathology,
http://dx.doi.org/10.1053/j.semdp.2017.04.010
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Immune Reconstitution Inflammatory Syndrome (IRIS): What pathologists should know

Ann Marie Nelson, MD1*; Yukari C. Manabe, MD2; Sebastian B Lucas, MD3

1
InPaLa Consulting, Washington, DC, USA
2
Johns Hopkins School of Medicine, Baltimore, MD, USA
3
Guy's & St Thomas' Hospitals, London, UK. (Emeritus Professor).

*
Corresponding author. Ann Marie Nelson, M.D. InPaLa Consulting 1330 Floral St. Washington, DC,
USA amnpath62@gmail.com

Summary:
Antiretroviral therapy has significantly improved the quality and length of life for those patients able to
access effective and sustained treatment. The resulting restoration of the immune response is associated
with a change in the clinical presentation of opportunistic infections, and the histologic reaction to
pathogens. A complex combination of alterations in host response across the stages of HIV infection has
been documented over the past 3 decades. The defects are seen in both acute and chronic phases of
inflammation and involve innate and adaptive immunity. In advanced stages of HIV infection, the marked
disruption of lymphoid tissue and loss of follicular dendritic cells limits the host’s ability to process antigen
and mount specific responses to pathogens. There are qualitative and quantitative defects in CD4 T cells
due to HIV infection. The resulting indirect effects include loss of cytokine production, dysregulation of B-
cell function, loss of cellular mediated immunity and “holes” in the immunologic repertoire that may not be
restored with the use of antiretroviral therapy. Immune reconstitution allows the host to respond to and
control infection, but a significant number of patients will have atypical inflammatory syndromes during the
recovery period. We briefly discuss the impact of HIV infection on the immune system and give an
overview of the spectrum of conditions attributed to the Immune Reconstitution Inflammatory syndrome
(IRIS).

Introduction
Medicine and diagnostic pathology were presented with unexpected challenges from the late 1970s on,
when increasing numbers of people presented to hospitals with signs of advanced immunodeficiency, of
unknown cause, and died. They had opportunistic infections (OI) that hitherto were uncommon (e.g.
pneumocystosis and mycobacteriosis avium) and unusual tumors such as Kaposi sarcoma and primary
cerebral lymphoma. All had profound cell-mediated immune deficiency with reduced CD4+ T-cell
numbers, as measured in tissues and (more conveniently) in peripheral blood counts. Within a few years
of the first publications announcing this ‘new’ disease (1,2), the viral cause had been identified: initially
1
named HTLV-3, it was renamed human immunodeficiency virus (HIV), and the commoner species
renamed HIV-1 after the less common and less virulent HIV-2 had been identified in west Africa (3).
Initially, the only treatments available were directed against the OI and tumors, but these did not greatly
slow down the inexorable course of the disease. Prophylaxis against certain infections such as
tuberculosis, pneumocystosis and toxoplasmosis did prolong life to an extent. The breakthrough came
with the development of anti-HIV therapies; when used in combination to reduce the likelihood of drug
resistance, these could clear the body of measurable HIV viruses (though not sterilize the infection or
effect a cure) (4,5). Combination anti-retroviral therapy (cART) has been increasingly given to HIV-
infected persons across the globe, with dramatic reduction in mortality from advanced disease (acquired
immune deficiency syndrome --AIDS), such that life-expectancy in properly treated individuals
approaches that of non-HIV-infected persons(6-9). Furthermore, such treated people are unlikely to
develop the classical OI originally associated with HIV/AIDS (10,11).
However, all potent medicines have potential serious side effects, and as well as the multiple direct drug
toxicities due to the cART drugs, a new class of side effects quickly became evident – IRIS, or immune
reconstitution inflammatory syndrome, the subject of this review. As the blood CD4+ T-cell count rises
on treatment (immune reconstitution) and the blood HIV viral load falls towards undetectable levels,
around a quarter of treated patients suffer a deterioration in their clinical status, or even develop a new
syndrome having been without apparent disease. These IRIS phenomena were not completely
unprecedented. Before HIV, patients treated for tuberculosis often suffered a worsening of signs and
symptoms as the lesions expanded in size due to increasing inflammation – so-called ‘paradoxical
tuberculosis’ (26). And patients with multibacillary leprosy frequently suffer enlargement of skin lesions
and development of new neuritis – so-called type 1 lepra reactions. These have a similar immunological
basis to what is happening in IRIS, in that the balance between pathogenic antigens and host immune
response is being rapidly altered.

HIV and the Immune System

The normal host has several mechanisms to prevent and control infection. Non-specific barriers are the
primary line of defense, if these fail, the body has an incremental defense system which evolves from a
general, nonspecific “innate” reaction to a highly specific “adaptive” response. Inflammation is a host
response to the cellular injury these agents cause; it aids in the elimination of the offending agent and in
subsequent healing and repair.

The hallmark of the innate response is acute inflammation; the intensity and duration of the reaction is
determined by the virulence of the microorganism and the competence of the host. This response is
mediated by cytokines, prostaglandins, the alternate (primitive) complement pathway, and phagocytic
and endothelial cells. Neutrophils and macrophages (phagocytes) kill many types of organisms and also
process and present antigen for the induction of the adaptive immune system. The adaptive immune
system has humoral and cellular arms. The humoral immune system is primarily a B-cell response
characterized by antibody (immunoglobulin) formation and activation of the classic complement
pathway. Antibodies provide protective immunity and are important in opsonization to facilitate
phagocytosis of encapsulated organisms. The cellular immune system modulates all aspects of immunity

2
including control of intracellular pathogens, tumor surveillance, healing and repair. Failure of the innate
and adaptive immune systems to eliminate intracellular microorganisms may incite a granulomatous
response to entrap the organism or other material.

A variety of altered host responses occur during the various stages of HIV infection. The defects are
seen in both the acute and chronic phases of inflammation. Leukopenias are common, occurring in 10%
of patients in early stages of HIV disease to 60% of those in late stage of AIDS. There are multiple
causes of this and other cytopenias - including immune dysfunction, cytotoxic drugs, concomitant
infection or malignancies, and direct infection by HIV of hematopoietic cells (12). Defects in humoral
immunity in HIV-infection are related to chronic non-specific B-cell stimulation. Clinically these
patients have generalized lymphadenopathy and hypergammaglobulinemia. Hyperstimulated B cells are
unable to respond to new antigens or to mount adequate immune responses. Susceptibility to infections
by encapsulated organisms such as Streptococcus pneumoniae, Hemophilus influenza, and Klesbsiella sp
is increased (13,14).

T-cell defects are one of the most important consequences of HIV infection and the basis for much of
the immune dysfunction. Absolute CD4+ lymphocyte counts of <200 are diagnostic of AIDS. In
addition to quantitative defects, CD4+ lymphocyte helper and inducer functions are also abnormal with
loss of the ability to respond to soluble antigens. Lymphokine-dependent monocyte/macrophage system
functions of chemotaxis, phagocytosis, intracellular killing and antigen presentation are abnormal.
Macrophage activation and intracellular killing are defective and the host is unable to mount an adequate
response (10,14). A key feature of severe immunosuppression is the loss of granuloma formation (15).

The overall dysfunction of the cellular immune response, results in increased frequency of OI.
Surveillance for tumorogenic viruses is altered, resulting in a higher incidence of EBV related
lymphomas, HPV associated squamous neoplasms, and Kaposi sarcoma. Chronic immune
dysregulation, even in treated HIV disease, manifests as early aging and non-AIDS defining morbidities
16,17).

The Impact of Combination Antiretroviral Therapy (cART)

By the mid-90s, the availability of several medications from four major classes of antiretroviral drugs
allowed for various combinations of drugs to boost activity and prevent resistance. Early studies that
looked at the incidence of infections in patients on highly active antiretroviral therapy (HAART) showed
a decrease in the number and severity of infections in patients with improved CD4+ T-cell lymphocyte
counts (18-21). They also noted that a subgroup of patients developed exaggerated local and systemic
inflammatory reactions (22,23). Various terms were applied: immune recovery syndrome, immune
restitution disease, immune restitution vitritis (ocular cases), paradoxical immune activation, paradoxical
inflammatory flares, partial immune restoration and pathogen associated inflammatory disease (24,25).
The currently accepted term, immune restoration inflammatory syndrome (IRIS), was proposed by
Shelburne et al in 2002 (26) as “a paradoxical deterioration in clinical status attributable to the recovery
of the immune system during HAART”. The case definition criteria were: A diagnosis of AIDS;
HAART treatment resulting in an increase in CD4 counts and a decrease in HIV viral load; symptoms

3
consistent with an infectious/inflammatory (autoimmune) condition appeared while on therapy; and
these symptoms could not be explained by a newly acquired infection, by the expected clinical course of
a previously recognized infectious agent, or by side effects of therapy (26). Another definition required
2 major and at least one minor criteria that emphasized viral load over CD4 count (27). The International
Network for the Study of HIV-associated IRIS developed a case definition for use in resource limited
settings (28,29). Most definitions describe two distinct presentations:
1) Paradoxical worsening of a pre-existing partially treated condition (tuberculosis, Mycobacterium
avium complex, cryptococcosis, and Kaposi sarcoma being the most frequent.) This has led to a
policy of treating the known infection prior to initiation of cART.
2) Unmasking of previously undiagnosed/latent infection such as leprosy, hepatitis B and C,
tuberculosis (30-32) and a few autoimmune diseases (33).
An incomplete, aberrant immune response develops as viral load drops and CD4+ and CD8+ T-
lymphocyte counts increase. The lower the nadir CD4 counts (<100 cells/ml), the greater the risk of
IRIS (23,34-36). The reaction can occur from weeks to several months after effective therapy begins.
Since many patients in resource limited settings have higher rates of co-infection and often start ARV
therapy with lower CD4 counts, the incidence of IRIS is higher there, as are the rates of mortality.
We have compiled more than 100 conditions from reviews and case reports. Table 1 lists the most
common infections seen in IRIS and other, less common presentations of IRIS in response to those
pathogens. These are detailed by etiology, presentation, geographic distribution and frequency. Table 2
lists other reported infections and Table 3 lists non-infections conditions related to IRIS (13, 17, 23-57).
The most common OI in any given population will be the most frequently seen in IRIS. Pulmonary and
extrapulmonary mycobacterial infections remain the leading cause of mortality and morbidity in
untreated HIV infection and the most common co-infection in IRIS (28,31-33,36). Following
mycobacterial infections, cryptococcal meningitis, Kaposi sarcoma, JC virus encephalitis and
pneumocystis pneumonia comprise the largest number of reported cases. Table 1 lists the incidence of
IRIS in response to a given pathogen. Studies vary in the proportion of cases classified as paradoxical
versus unmasking (37).
Mucocutaneous lesions account for more than half of the reported cases of IRIS (49): Kaposi sarcoma
and herpes virus infections being the most common, followed by leishmaniasis, leprosy, cryptococcosis,
histoplasmosis, and several dermatophytes. Less common but increasing in frequency are the immune
mediated conditions listed in Table 3.

Risk Factors
Timing of ART – longer duration of specific treatment for the OI prior to initiation of ART decreases
the risk of IRIS as is likely related to the amount of residual antigen present and is related, in turn, to the
duration of effective therapy. In clinical trials of ART initiation in tuberculosis-HIV co-infected patients,
initiation of ART 2-8 weeks after initiation of tuberculosis therapy resulted in decreased mortality, but
increased risk for IRIS (58,59). For cryptococcal immune reconstitution disease, data are conflicting
regarding whether earlier ART initiation increases the risk for IRIS (60-63). The increased mortality
with earlier ART initiation may be related to IRIS, though deterioration due to cryptococcal meningitis

4
is clinically indistinguishable (64,65). Extent of disease particularly in patients with disseminated or
extensive disease increases risk for IRIS. This is likely due to antigen burden at the time of immune
reconstitution as shown in the rabbit model of tuberculosis using dexamethasone immunosuppression
(66).
Nadir CD4 T cell counts <100 cells/ul are independently predictive of IRIS (23, 26, 60,67,68) as well as
the increase in CD4 after the initiation of ART (68,69). Viral load decline has also been associated with
IRIS (35,67,70-73). Interestingly, given the rate of viral load suppression with integrase inhibitors like
dolutegravir, introduction of these agents into tuberculosis endemic or countries with high human herpes
virus 8 (HHV-8) or cryptococcal antigenemia prevalence may increase the risk of IRIS due to these OIs.

Prevention:
1) ART should be started early in all HIV infected patients before CD4 T cell counts fall to levels
where they were at increased risk for IRIS. This is because late presentation with advanced
immunodeficiency and high risk for OI places patients at increased risk for IRIS. Currently, ART
is increasingly viewed as prevention and it is now recommended that all HIV infected patients
regardless of CD4 be initiated on ART.
2) In those patients with a nadir CD4 low enough to be at risk for OI, starting ART after specific
treatment for the OI has been instituted leads to decrease in pathogen load as well as decreasing
the risk for IRIS. However, this must be balanced against the benefit of immune reconstitution
since patients with low CD4s are also at risk for other OIs. In general, the length of time between
specific therapy for the OI and ART should be longer for patients with intracranial infections
such as tuberculosis (73) or cryptococcosis (74).

Diagnosis
Clinical and Laboratory (27-29,67)
In an HIV-infected patient
• Major Criteria
– Atypical presentation of OI or tumor after antiretroviral therapy (example, atypical
inflammatory response in affected tissues, localized disease including exaggerated
inflammatory reaction, progressive organ dysfunction or enlargement of pre-existing
lesions after definite clinical improvement) after improvement with pathogen specific
therapy before the initiation of ART and exclusion of treatment toxicity, drug resistance
and/or new alternative diagnoses
– Decrease in plasma HIV RNA>1 log copies/ml
• Minor Criteria
– Increase in blood CD4 T cell count after ART
– Increase in immune response specific to relevant pathogen (example, delayed-type
hypersensitivity skin response to mycobacterial antigens)
– Spontaneous resolution of disease without specific antimicrobial therapy or tumor
chemotherapy with continuation of ART

5
Histopathology
Host reaction in IRIS is variable and depends on the baseline immune status and types of coinfection at
the time therapy is initiated. The type of host response to a specific pathogen or to a range of different
pathogens is neither uniform nor predictable and IRIS cannot be diagnosed by histology alone. The
recovery of both innate and adaptive immune functions vary in sequence and intensity. An atypical or
exaggerated response to a pathogen or an unusual presentation of a non-infectious condition in a patient
known to be on ART should alert the pathologist to get more detailed clinical information (14).
Histologic findings are usually similar to those seen in non-IRIS cases but the level of response may
exceed what is expected for the number of organisms. In mycobacterial, fungal and some parasitic
infections there is often a necrotizing, granulomatous reaction, often with few or no organisms. It is not
uncommon to have negative cultures, although the patients have fever and evidence of significant
inflammation.

Figures 1-6 present several examples that span the spectrum of IRIS pathology.

Mycobacterial Infections
Mycobacteria species are the leading cause of IRIS. The clinical and histologic presentations vary
between and within species; and can present early and late following initiation of cART as either
paradoxical or unmasking events. A cellular immune response with macrophages, lymphocytes and
granuloma formation is common but the underlying immune deficits and dysregulation often result in
atypical presentations.

Mycobacteriosis avium complex (MAC) was one of the first and most common manifestations of IRIS
in the US (26,38). In severely immunosuppressed patients, the infection is usually disseminated with
mycobacteremia, but MAC-IRIS tends to be a localized reaction. Massive mesenteric, retroperitoneal or
intrathoracic adenopathy can cause life-threatening complications; cervical node involvement frequently
presents as scrofula. Liver, lung, and gastrointestinal involvement is reported. In those who received
prophylactic therapy, cultures can be negative (26,33).
Biopsies of affected tissues show granulomatous inflammation, with or without necrosis. Figure 1,
demonstrates the good cellular response with CD4+ T-lymphocytes in the granuloma. Many of the
lymphocytes in the surrounding lymphoid tissue mark with CD8 (cytotoxic T-cell) antibodies. As seen
in Figure 1B, fragments of mycobacteria in macrophages indicate treatment effect. Cultures in this case
were negative.

Tuberculosis is a pathogen in the normal host with a classic pattern of caseating granulomas. Early,
progressive primary disease occurs when the host response does not halt the proliferation and spread of
the mycobacteria. Pleural effusions and seeding of extrapulmonary sites occurs more frequently in
patients with an underlying immune defect - HIV being the most common predisposing condition.
Paradoxical deterioration in tuberculosis-IRIS can be transient worsening of pulmonary symptoms,

6
prolonged high fever, pleural effusions, and extrapulmonary sites of inflammation similar to primary
tuberculosis. Severe meningitis requires steroid therapy as a life-saving measure (26,31-33).
The more common histopathology is granulomatous inflammation with extensive necrosis and few acid
fast bacilli. However, IRIS may present as acute inflammation and necrosis in patients with high
bacillary counts and no prior therapy. Figure 2, case 1 illustrates an atypical presentation of an
endobronchial lesion while case 2 is a presentation of disseminated of tuberculosis in the central nervous
system and a lymph node.

Leprosy. When HIV disease was described in leprosy-endemic zones, particularly in Africa, it was
feared that there would be a resurgent co-epidemic of HIV and Mycobacterium leprae disease, much as
there evidently was for tuberculosis. Multibacillary (lepromatous) leprosy would worsen as the bacilli
multiplied without any immune control, drug treatment would be less effective, and transmission of
infection would increase – so reversing all the progress made in global leprosy control.

In fact, none of that occurred. The main features of HIV-M. leprae co-infection have continued to
present as tuberculoid, pauci-bacillary disease rather than lepromatous, an increased rate of leprosy
reactions (mainly type 1, reversal or upgrading, delayed hypersensitivity reactions), and IRIS reactions
(75,76).

The leprosy-IRIS reactions include infrequent cases of erythema nodosum leprosum in known
lepromatous patients, and – more strikingly – examples of unmasking leprosy (Figure 3). Here, the
newly diagnosed HIV positive person is started on cART, and within a few weeks or months, presents
with skin and or nerve leprosy lesions, having previously been asymptomatic. The pathology of these
lesions is generally tuberculoid, with granulomas and edema and rare leprosy bacilli are seen on biopsy.
The augmented immune response after cART presumably recognizes the leprosy antigens and induces a
reaction, having previously been just sufficient to control the latent infection without causing any
pathology.

Fungal Infections
Pneumocystosis was one of the initial infections reported in AIDS patients (1,2). In US and Europe, it is
still a common presenting infection in undiagnosed and non-compliant HIV-infected patients (77). IRIS
in cases of Pneumocystis jiroveci pneumonia occurs within a few weeks and presents with fever and
worsening of respiratory symptoms and chest radiographs (78). Histology can range from mixed
inflammatory changes with alveolar damage to granulomas surrounding clusters of cysts in the foamy
alveolar exudate as demonstrated in Figure 4, Case 1.

Cryptococcal infection of the brain – meningoencephalitis – in advanced HIV disease is generally a

non-inflammatory process. The proliferating fungi progressively accumulate in the subarachnoid space
and around the Virchow-Robin spaces in the brain, exciting minimal macrophage response. Clinical
disease comes from obstruction to cerebrospinal fluid flow and multiple space-occupying lesions in the
brain parenchyma. Once on anti-fungal therapy, the infection is inactivated and the host cellular

7
response removes it. IRIS is a common occurrence in cART-treated patients. Following a period of
recovery, they become obtunded again, with recurrent headache and often seizures.

The pathology of cryptococcal-IRIS has been observed at autopsy. The brain surface has a miliary
nodular meningitis (in contrast to the usual smooth granular appearance pre-treatment), and resembles
tuberculous meningitis. The histology consists of a non-necrotizing granulomatous inflammation,
around fragmented and intact cryptococci (Figure 4, Case 2). Patients with central nervous system
cryptococcosis on cART may also develop intracerebral expansile cryptococcomas.

Such paradoxical reactions are relatively common in central nervous system tuberculosis and
cryptococcosis – and were already documented in treated tuberculosis before the recognition of HIV
disease.

Viral Infections
Herpes virus infections, simplex (HSV) and zoster (VZV), occur in HIV-infected patients with or
without antiretroviral therapy. VZV-IRIS manifests as dermatomal lesions that may involve the eyes.
The lesions are usually limited to a single dermatome. Histology is similar to that seen in other
scenarios. Genital HSV-IRIS lesions are exuberant, presenting as pseudotumors that respond poorly to
therapy (46). The histology is striking with dermal or mucosal mixed inflammation comprised of
lymphocytes, plasma cells and eosinophils. Figure 5, Case 1.

Kaposi Sarcoma/ Human Herpes Virus 8 (HHV8) is the most frequent malignancy associated with
HIV-infection and was also one of the first reported conditions (2). Kaposi sarcoma IRIS presents
several weeks after the initiation of antiretroviral therapy as local inflammation of an existing lesion or
as an eruptive process that involves skin, mucosae and internal organs. Figure 5, Case 2 shows the
extensive lesions in the oropharynx. The nodular, spindle cell proliferation is typical of Kaposi sarcoma.
There may be some increase in host inflammatory response. The HHV8 LANA-1 staining shows a
strong nuclear staining. Other conditions associated with HHV8-coinfection are listed in Table 1.

JC virus. One of the OI with the worst prognosis in HIV disease is JC virus. The syndrome is termed
JCV encephalitis (JCVE), previously progressive multifocal leukoencephalopathy (PML). Most people
are infected with JC virus latently in the brain from an early age. The virus is found using
immunohistochemistry in oligodendrocytes and to a lesser extent in astrocytes. The virus can lead to
myelin destruction when it replicates. The histology of JCVE in those not on cART is variable: in
addition to myelin destruction, there is microgliosis, and astrocytosis with characteristic enlarged bizarre
nuclei. Eosinophilic viral inclusion bodies are visible in oligodendrocytes. Some cases also manifest an
eosinophil leukocyte infiltration. The amount of virus present is variable, from little to vast amounts, and
the intensity of the T-cell reactive infiltrate varies from minimal to moderate (79).

JCVE-IRIS is more aggressive clinically and pathologically, and presents with one or more cerebral
lesions. It may be either unmasking or reactivation IRIS. There is more severe T-cell inflammation than
in untreated patients, corresponding to the augmented cytotoxic T-cell response as the CD4 counts rise
8
and HIV viral loads fall as well as less JCV than that seen in cART-untreated disease. Figure 6 Case 1
shows the lesions from a patient where JC virus is visible as eosinophilic nuclear inclusions on
hematoxylin and eosin and by using immunohistochemistry with an anti JCV antibody.

It should also be noted that a comparable JCVE occurs in HIV-uninfected persons given some
monoclonal immunosuppressive therapies such as rituximab; this exemplifies the parallels that IRIS
shares with many non-HIV-related paradoxical reactions in the treatment of infectious diseases when
patients are immunosuppressed (80).

CD8 encephalitis (CD8E). Prior to effective anti-retroviral therapy, the major HIV-associated diseases
of the brain and spinal cord were many OI, primary cerebral lymphoma, HIV encephalitis with
multinucleate giant cells and detectable HIV virus in microglial cells, cerebral atrophy, and vacuolar
myelopathy of the cord. With cART, OI and HIV encephalitis became less common. However, small
numbers of patients who had been long-term virologically well-controlled (high CD4 count,
undetectable blood viral load) have been observed, mainly in France and UK, with acute and sub-acute
presentations of headache, confusion, dementia, seizure and collapse, and many of them died. They had
no systemic symptoms or signs. Notably, the great majority of patients were black Africans, infected
with HIV heterosexually.

At presentation, cerebral imaging showed diffuse bilateral cerebral swelling and high signal intensities
in white and grey matter. Autopsy – and biopsies in life - showed a diffuse severe encephalitis
comprising perivascular and parenchymal infiltration of CD8+ T-cells, few or no CD4+ T-cells or B-
cells, and microgliosis but uncommonly astrocytosis. Neuronophagia was not a feature. An example of
CD8E is presented in Figure 6 case 2. Immunostains for HIV virus were negative and there were no
multinucleated giant cells (thus this is not HIV encephalitis). All investigations for other infections were
negative, but some had HIV detectable in cerebrospinal fluid. Those patients treated promptly with high
dose steroids (which suppress T-cells) survived and recovered.

This clinical pathology has become known as the CD8 encephalitis (CD8E) syndrome. In the absence of
any identifiable triggers, it is likely that a delayed IRIS reaction to sub-detectable quantities of HIV in
the brain is a cause of CD8E, perhaps associated with a slowly developing abnormal immune response
between different subsets of T-cells. A similar syndrome also appears to arise from a novel HIV
presentation in the brain, triggered by interruption of cART, virological escape (ie drug resistance) or a
concomitant minor infection (such as a lung infection).

The practical importance of this obscure phenomenon concerns its prompt recognition and diagnosis
when treated HIV patients suffer unexplained cerebral malfunction, usually without focal neurological
symptoms (81,82).

Parasitic Infections
Toxoplasmosis

9
Encephalitis, one of the initial 12 indicator conditions for AIDS (10), remains the most common
parasitic infection and an important cause of life-threating central nervous system infections in HIV
patients. Toxoplasmosis-IRIS in the central nervous system has the highest rate of mortality of all
presentations, but is also under estimated and difficult to diagnose (83). Most reported cases occur as
paradoxical worsening of known infection. Findings in brain biopsies are similar to those reported in
non-IRIS cases. There is vasculitis and necrosis and variable numbers of organisms.

Non-infectious
Sarcoidosis and Graves Disease were included in the early papers on IRIS. Sarcoid progression was
slowed in patients with severe immune suppression, but returned with recovery of the cellular immune
response (26,33). Graves disease and other autoimmune conditions are thought to be related to the
development of autoantibodies (84).

Management
The management of tuberculosis-IRIS is largely symptomatic with either non-steroidal anti-
inflammatory drugs or steroids particularly if organ function is impaired or threatened. A randomized
clinical trial of 4 weeks of prednisone showed that the combined clinical outcome of days of
hospitalization and occurrence of outpatient therapeutic procedures was significantly reduced in patients
getting prednisone. Consideration for the discontinuation of cART should be given if no specific therapy
for the underlying infection exists or if ART toxicity is in the differential.
As sensitive diagnostic testing for OIs has become more available (cryptococcal lateral flow test (85)
Xpert MTB/RIF molecular testing for tuberculosis)(86), screening prior to ART initiation and specific
therapy can decrease the incidence of IRIS. In a randomized placebo controlled trial of tuberculosis
patients with CD4 T cells counts <100 cells/µL, prednisone for 4 weeks initiated with ART decreased
the incidence of IRIS by 30% and decreased the need for steroids by 53% (87). Starting patients at
higher CD4 T cell counts and avoiding late presentation through improved test and treat programs will
also be a key component of IRIS prevention.

Conclusions
Although IRIS cannot be diagnoses by histopathology alone, the role of pathology in describing the
spectrum of morphologic changes in altered immunity remains a key factor in understanding
complications of HIV-infection. Histology and the use of special stains and immunohistochemistry are
necessary to detect infectious agents in atypical lesions and in lesions with low numbers of organisms or
those in which the organisms are non-viable or cannot be cultured. Erosive HSV and CD8 encephalitis
required pathology to determine the cell types involved these intense inflammatory host responses.
Pathologists need to be aware of IRIS in order to consider it in their differential diagnosis and to
determine the appropriate work-up. Clinical correlation regarding HIV status (or other
immunosuppressive conditions), previous diagnoses, and anti-retroviral therapy should be obtained.

10
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Fig 1 Mycobacteriosis. Mesenteric lymph node from a patient with diarrhea and abdominal pain, on
cART for 10 months and a history of treated Mycobacterium avium intracellulare infection. Delayed
paradoxical IRIS. Hematoxylin and eosin showing non-caseating granulomas Ziehl Neelsen acid-fast
stain reveals fragmented mycobacteria in macrophages (treatment effect) CD4 immunostain highlights
scattered T-helper cells in and around the granuloma CD8 immunostain highlights diffuse infiltrate of
cytotoxic T-cells.
Fig 2 Tuberculosis. Case 1: Endobronchial lesion from a patient with acute onset wheezing who has
been on cART for 4 months, no history of tuberculosis. Unmasking tuberculosis-IRIS. a. Hematoxylin
and eosin showing a polypoid lesion in the submucosa with extensive necrosis b. Ziehl Neelsen acid-fast
stain reveals rare mycobacteria. Case 2 Patient on cART with mental status changes, multiple swellings
in the neck and chest and a liver abscess. Diagnosis of disseminated tuberculosis. c. Central nervous
system expanding lesion, with formed tuberculoid granuloma. Scant acid fast bacilli were visible on the
Ziehl Neelsen stain. d. Lymph node with amorphous necrosis.
Fig 3. Leprosy. HIV-infected patient with no previous skin or nerve lesions, commenced on cART. Two
months later, this leprosy lesion erupted on his face. Histology showed edematous tuberculoid
inflammation. (not shown).
Fig 4 Fungal Infections Case 1. Pneumocystosis, paradoxical IRIS: lung from a patient with history of
treated Pneumocystis jiroveci who has been on cART for 5 months (viral load decreased from 334,000
to 25,000). Presented with cough and a right lung mass. Hematoxylin and eosin shows a spindle cell
lesion with an entrapped exudate. Methenamine silver stain highlights rare cysts. Case 2. Cryptococcal
meningitis in a patient on cART c. Magnetic resonance reveals diffuse inflammation on the meningeal
surfaces d. Hematoxylin and eosin showing marked thickening of the meninges e. Higher power with

16
granulomatous inflammation f. Methenamine silver highlights the narrow-necked budding of
Cryptococcus
Fig 5 Viral infections Case 1. Herpes simplex erosive paradoxical IRIS, penile lesion in a patient with a
history of successful treatment of HSV ulcer 1 year prior. Diagnosed with HIV and started on cART 8
months prior to onset of current presentation. The patient did not respond to anti-HSV therapy. Clinical
photograph of penile and groin ulcerated expansible lesions Hematoxylin and eosin of glands ulcerated
nodular lesion. Higher power showing the classic mixed cellular inflammatory infiltrate with
lymphocytes, plasma cells and eosinophils. Immunostain identifying viral inclusions, difficult to
visualize on Hematoxylin and eosin stains. Case 2. Human herpes virus 8, Kaposi sarcoma, paradoxical,
eruptive IRIS. Patient with cutaneous Kaposi sarcoma on cART for 6 weeks presented with shortness of
breath, kidney failure. He died 2 days after admission. Autopsy revealed disseminated Kaposi sarcoma
with hundreds of nodules extending from the oropharynx to entire gastrointestinal tract and in the
trachea and bronchi. e. Gross photograph of the oropharynx showing multiple erythematous nodules f.
Hematoxylin and eosin, low power magnification of nodular tonsil lesion g. Hematoxylin and eosin,
higher power shows spindle cell proliferation typical of Kaposi sarcoma h. LANA 1 immunostaining
highlights latent antinuclear HHV8.
Fig 6 Central nervous system viruses Case 1 JC Virus Encephalitis Medium power hematoxylin and
eosin, showing florid lymphocytic encephalitis High power, with nuclear inclusions in some
oligodendrocytes Anti-JC immunostain confirming the infection. Case 2 CD8 Encephalitis. The patient
died two days after presenting with confusion. She had been on cART for several years, apparently well
controlled. c. Grossly swollen brain.d. CD8 immunostain highlights large numbers of CD8+ cells around
vessels and throughout the neuropil.

Figure 1

A B

17
C D

18
Figure 2
Case 1

A B

Case 2

C D

19
Figure 3

20
Figure 4
Case 1

A B
Case 2

C D

E F

21
Figure 5
Case 1

A B

C D

Case 2

E F

G H

22
Figure 6
Case 1

A B

Case 2

D E

Table 1 Common IRIS-Associated Infections

Infectio Presentation Median Time after Distribution Frequency
n Antiretroviral
Treatment
CD8 Altered mental status, sudden death Months to years Global Common
encepha

23
 litis
Cryptoc Meningitis, high mortality 1 week to 6 months Global Very
occosis common
Encephalitis Uncommon
Pneumonia - cavitary, acute Uncommon
respiratory distress syndrome +/-
hypercalcemia
Lymphadenitis Uncommon
Cytome Immune recovery uveitis, retinitis 10 months (1 to 48) Global Common
galoviru
s
Organ specific (skin, bone, lung, 4-5 weeks Global Common
gastrointestinal)
Hepatiti Flare: elevated liver function tests, 2-8 weeks Global Common
s B, C fever
HHV8 Kaposi sarcoma, eruptive 7-16 weeks Africa, Americas, Very
cutaneous, visceral low in Asia common
Pleuropulomary Kaposi
Multicentric Castleman Disease
Herpes Genital Ulcers 2-4 weeks Global Common
Simplex
Nodular proliferations, genital
Herpes Shingles, single or multiple 1-4 month Global Common
zoster dermatomes
Central nervous system vasculitis Rare
JC JC viral encephalitis, PML 3-6 weeks Global Common
Virus
Mycoba
cteriose
s
Leprosy Tuberculoid, unmasking Africa, Asia, Brazil Frequent
Erythema nodosum leprosum
Nerve abscess
MAI Lymphadenitis (thoracic and 2-8 weeks North America, Common
abdominal) Europe but
decreasing
Organ specific (skin, bone, lung,
gastrointestinal)
TB Pulmonary 2-4 weeks Higher Sub Saharan Very
Africa, Southeast common
Asia
Meningitis, high mortality 2-4 weeks Very
common
Pulmonary fibrosis
Lymphadentis (some scrofula)
Hepatosplenic 1-4 months
Interstitial nephritis
Orchitis
BCG Vaccine reaction, mycobacteremia Global, where used Reported
Pneumo Pneumonia 2-3 weeks Temperate zones Common

24
 cystosis
Granuloma
Toxopla Space occupying lesions, brain 2-10 weeks Global Frequent
smosis
Shaded conditions are the most common. Spectrum of less frequently reported complications also listed. Abbreviations:
MAI= Mycobacterium avium intracellulare; TB= tuberculosis; BCG= Bacille Calmette Guerin.

25
Table 2 Other Infections Reported as IRIS-associated

Infection Presentation Distribution

Aspergillosis Sinusitis, pneumonia Global
Bacillary
angiomatosis/Bartonella Lympadenitis, splenitis, vascular tumors Global
Blastomycosis Cutaneous and systemic US
Candidiasis Esophagitis Global
Southwest US, Latin
Coccidioidomycosis Pneumonia America
Cryptosporidiosis Diarrhea, pneumonia Global
Disseminated or multifocal, inflammatory skin
Dermatophytosis, severe lesions Global
Epidermodysplasia
verruciformis Skin plaques and elevated eruptions Sporadic or familial
Burkitt lymphoma, EBV+ B-cell and Hodgkin
Epstein Barr Virus (EBV) lymphomas Most in Africa
Fusariosis Cutaneous and systemic Global
Histoplasmosis Cutaneous and systemic Global
Human immunodeficiency Gastrointestinal adenopathy and ulceration,
virus encephalitis Global
Leishmaniasis Visceral, cutaneous, dermal post KalaAzar Endemic areas
Molloscum contangiosum,
giant Cutaneous Global
Paracoccidioidomycosis Cutaneous and systemic South America
Parvovirus B19 Red cell hypo or aplasia, encephalitis Global
Penicilliosis Skin, blood and bone marrow Southeast Asia
Schistosomiasis Colonic polyposis Endemic areas
Disseminated or multifocal, inflammatory skin
Sporotrichosis lesions Global
Strongyloidiasis Hyperinfection Global
Syphilis Secondary cutaneous, uveitis, encephalitis Global
Whipple Severe diarrhea, neuropathies menigoencephalitis Sporadic

26
Table 3 Non-Infectious Conditions Attributed to Restoration of the Immune System

Autoimmune bullous dermatitis

Autoimmune endotheliopathy (Susac syndrome)
Autoimmune hepatitis
Autoimmune inflammatory syndrome adjuvant (AISA)
Autoimmune vasculitis (?cardiac, cerebral)
Diffuse infiltrative lymphocytosis syndrome (DILS)
Eosinophilic folliculitis
Epidermodysplasia verruciformis
Erythema elevatum diutinum
Graves disease
Guillan-Barre Syndrome
Hemolytic anemia
Hemophagocytic syndrome
HIV-associated neurologic disease (HAND)
Idiosyncratic drug eruptions
Opsoclonus-myoclonus-ataxia syndrome
Porphyria
Pruritic eruption
Psoriasis
Pyoderma gangrenosum
Reiters Syndrome
Sarcoidosis
Sweet syndrome
Thyroid dysfunction
Urticaria
Uveitis, noninfectious

27