Immune reconstitution syndrome

Immune Reconstitution Inflammatory Syndrome (IRIS) also known as Immune Reconstitution Syndrome or Immune Restoration Disease in HIV infection, is an exaggerated inflammatory reaction to a disease-causing microorganism that sometimes occurs when the immune system begins to recover following treatment with antiretroviral drugs ¹, despite effective therapy and microbiologic cure and cannot be explained by a persistent primary infection, new secondary infection, or adverse drug events ². IRIS can be mild or life-threatening.

Immune reconstitution inflammatory syndrome (IRIS) occurs in two forms:

1. “Unmasking” IRIS refers to the flare-up of an underlying, previously undiagnosed infection soon after antiretroviral therapy is started;
2. “Paradoxical” IRIS refers to the worsening of a previously treated infection after antiretroviral therapy is started.

IRIS has been classified as either “paradoxical,” in which a previously known opportunistic infection seems to worsen after initiation of antiretroviral therapy (ART) or “unmasking,” which is an inflammatory response to an opportunistic infection that was previously unrecognized. IRIS of either type usually occurs at the time of rapid viral load decrease or an increase in CD4 cell count. Most cases occur within the first 4 to 8 weeks after ART initiation in patients with initially low CD4 counts, but IRIS can occur at any CD4 count and many weeks to months after a patient starts or restarts ART ³.

The immunopathogenesis of the immune reconstitution syndrome is unclear and appears to be result of unbalanced reconstitution of effector and regulatory T-cells, leading to exuberant inflammatory response in patients receiving antiretroviral therapy (ART) ⁴. Biomarkers, including interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and interleukin (IL)-2, 6 and 7, are subject of intense investigation at present ⁴.

Potential mechanisms for immune reconstitution syndrome include a partial recovery of the immune system or exuberant host immunological responses to antigenic stimuli. The overall incidence of IRIS is unknown, but is dependent on the population studied and its underlying opportunistic infectious burden ⁵. IRIS has been reported in 10 to 32 per cent of patients starting ART ⁶. The variation in reported frequency reflect differences in case definitions, and more importantly, differences in study populations with differing risk profiles and underlying burden of opportunistic infections.

Most of the literature on epidemiology comes from the developed countries. In a series from southern India tuberculosis-associated IRIS (TB-IRIS) was reported in 7.6 per cent of patients ⁷. Sharma et al. ⁸ have reported incidence rates of 7.5 per cent for paradoxical TB-IRIS and 3 per cent for ART-associated TB in a retrospective study using consensus case-definitions. In a prospective study, using stringent case-definitions criteria ⁹, paradoxical TB-IRIS was seen in 4 per cent of patients and ART-associated TB in 7.5 per cent of patients. No cases of ART-associated TB fulfilling the criteria of unmasking TB-IRIS were identified in either of the studies. The higher incidence of TB-IRIS reported, particularly in the western literature, may be explained by leniency of clinical diagnostic criteria.

The infectious pathogens most frequently implicated in the immune reconstitution inflammatory syndrome are mycobacterial infections, fungi, varicella zoster, herpesviruses, and cytomegalovirus (CMV). Majority of patients with IRIS have a self-limiting disease course. No single treatment option exists and depends on the underlying infectious agent and its clinical presentation. Antiretroviral therapy (ART) is usually continued and treatment for the associated condition optimized. The overall mortality associated with IRIS is low; however, patients with central nervous system involvement with raised intracranial pressures in cryptococcal and tubercular meningitis, and respiratory failure due to acute respiratory distress syndrome (ARDS) have poor prognosis and require aggressive management including corticosteroids ⁴. Paradigm shifts in management of HIV with earlier initiation of ART is expected to decrease the burden of IRIS in developed countries; however, with enhanced rollout of ART in recent years and the enormous burden of opportunistic infections in developing countries like India, IRIS is likely to remain an area of major concern.

Immune reconstitution inflammatory syndrome causes

Despite numerous descriptions of the manifestations of IRIS, its pathogenesis remains largely speculative. Current theories concerning the pathogenesis of the syndrome involve a combination of underlying antigenic burden, the degree of immune restoration following highly active antiretroviral therapy (HAART), and host genetic susceptibility. These pathogenic mechanisms may interact and likely depend on the underlying burden of infectious or noninfectious agent.

Whether elicited by an infectious or noninfectious agent, the presence of an antigenic stimulus for development of the syndrome appears necessary. This antigenic stimulus can be intact, “clinically silent” organisms or dead or dying organisms and their residual antigens. IRIS that occurs as a result of “unmasking” of clinically silent infection is characterized by atypical exuberant inflammation and/or an accelerated clinical presentation suggesting a restoration of antigen-specific immunity. These characteristics differentiate IRIS from incident opportunistic infections that occur on ART as a result of delayed adequate immunity.

Table 1. Infectious and noninfectious causes of IRIS in HIV-infected patients

Infectious causes	Noninfectious causes
Mycobacteria	Rheumatologic/Autoimmune
Mycobacterium tuberculosis 10	Rheumatoid arthritis 11, Systemic lupus erythematosus (SLE) 12
	Graves disease 13, Autoimmune thyroid disease 14
Mycobacterium avium complex 15	Sarcoidosis & granulomatous reactions 16
Other mycobacteria 17	Tattoo ink 18
Cytomegalovirus 19	AIDS-related lymphoma 20
Herpes viruses	Guillain-Barre’ syndrome 21
Herpes zoster virus 22	Interstitial lymphoid pneumonitis 23
Herpes simplex virus 24
Herpes virus-associated Kaposi’s sarcoma 24
Cryptococcus neoformans 15
Pneumocystis jirovecii pneumonia (PCP) 24
Histoplasmosis capsulatum 25
Toxoplasmosis 19
Hepatitis B virus 24
Hepatitis C virus 19
Progressive multifocal leukoencephalitis 26
Parvovirus B19 27
Strongyloides stercoralis infection 28 and other parasitic infections 29
Molluscum contagiosum & genital warts 24
Sinusitis 30
Folliculitis 31

[Source ⁵ ]

Examples of IRIS in response to intact organisms include, but are not limited to, the unmasking of latent cryptococcal infection ³² and infection with Mycobacterium avium complex (MAC) ³³. The most frequently reported IRIS symptoms in response to previously treated or partially treated infections include reports of clinical worsening and recurrence of clinical manifestations of Mycobacterium tuberculosis (TB) and cryptococcal meningitis following initiation of ART ³⁴. In noninfectious causes of IRIS, autoimmunity to innate antigens plays a likely role in the syndrome. Examples include exacerbation of rheumatoid arthritis and other autoimmune diseases ¹¹. Given the role of this antigenic stimulus, the frequency and manifestations of IRIS in a given population may be determined by the prevalence of opportunistic and non-opportunistic infections to initiation of ART.

The mechanism receiving the most attention involves the theory that the immune reconstitution inflammatory syndrome is precipitated by the degree of immune restoration following ART. In assessing this theory, investigators have examined the association between CD4 cell counts and viral loads and the risk of IRIS. Some studies suggest differences in the baseline CD4 profiles or quantitative viral load at ART initiation or their rate of change during HAART between IRIS and non-IRIS patients ³⁵, while other studies demonstrate only trends or no significant difference between IRIS and non-IRIS patients ³⁶. These immunological differences between groups have been difficult to verify due to small numbers of IRIS cases and lack of control groups. An alternative immunological mechanism may involve qualitative changes in lymphocyte function or lymphocyte phenotypic expression. For instance, following ART an increase in memory CD4 cell types is observed ³⁷ possibly as a result of redistribution from peripheral lymphoid tissue ³⁸. This CD4 phenotype is primed to recognize previous antigenic stimuli, and thus may be responsible for manifestations of IRIS seen soon after ART initiation. After this redistribution, naïve T cells increase and are thought to be responsible for the later quantitative increase in CD4 cell counts ³⁹. These data suggest IRIS may be due to a combination of both quantitative restoration of immunity as well as qualitative function and phenotypic expression observed soon after the initiation of ART.

The third purported pathogenic mechanism for IRIS involves host genetic susceptibility to an exuberant immune response to the infectious or noninfectious antigenic stimulus upon immune restoration. Although evidence is limited, carriage of specific HLA alleles suggest associations with the development of IRIS and specific pathogens ⁴⁰. Increased levels of interleukin-6 (IL-6) in IRIS patients may explain the exuberant Th1 response to mycobacterial antigens in subjects with clinical IRIS ⁴¹. Such genetic predispositions may partially explain why manifestations of IRIS differ in patients with similar antigenic burden and immunological responses to ART.

Risk factors for the development of IRIS

Risk factors identified for the development of IRIS in one cohort included male sex, a shorter interval between initiating treatment for opportunistic infections and starting ART, a rapid fall in HIV-1 RNA after ART, and being ART-naïve at the time of opportunistic infections diagnosis ¹⁵. Other significant predictors have also included younger age, a lower baseline CD4 cell percentage, a lower CD4 cell count at ART initiation, and a lower CD4 to CD8 cell ratio at baseline ²⁴. It should be noted cohorts differ substantially in study populations and the type of IRIS (i.e. TB-IRIS only) examined, making conclusions regarding risk factors for IRIS difficult. Clinical factors associated with the development of IRIS are presented in Table 2.

Table 2. Clinical factors associated with the development of IRIS

Risk factor	Reference
Male sex	[31]
Younger age	[32]
Lower CD4 cell count at ART initiation	[4]
Higher HIV RNA at ART initiation	[4]
Lower CD4 cell percentage at ART initiation	[32]
Lower CD4:CD8 ratio at ART initiation	[32]
More rapid initial fall in HIV RNA on ART	[31]
Antiretroviral naïve at time of OI diagnosis	[31]
Shorter interval between OI therapy initiation and ART initiation	[31]

Footnote: Derived from cohorts where IRIS due to multiple pathogens were reported (i.e. cohorts which examined only TB-IRIS were excluded)

Immune reconstitution inflammatory syndrome symptoms

Presentations of IRIS may differ according to the triggering opportunistic infection. TB IRIS can present with worsening of the pulmonary or extrapulmonary symptoms of TB or with hepatotoxicity ⁴². Mycobacterium avium complex (MAC) IRIS may result in pulmonary or systemic inflammation that is indistinguishable from the original infection or with lymphadenitis, mass lesions, or osteomyelitis ⁴³. Cryptococcal meningitis may worsen, resulting in rapid development of hearing or vision loss, ataxia, and elevated intracranial pressures, all of which have been reported ⁴⁴. CMV retinitis IRIS can result in rapid and permanent vision loss with retinitis, vitritis, or uveitis ⁴⁵. IRIS with hepatitis B or C can cause hepatitis flares and may be confused with medication toxicity ⁴⁶. Brain lesions from progressive multifocal leukoencephalopathy may worsen or become unmasked with IRIS, as can Kaposi’s sarcoma, which can sometimes be fatal ⁴⁷. Cerebral toxoplasmosis IRIS can present as cerebral abscess, encephalitis, or chorioretinitis ⁴⁸. Exacerbation of autoimmune diseases such as sarcoid or Grave’s disease have been reported ⁴⁹ and reactivations of herpes simplex virus (HSV), varicella zoster virus (VZV), folliculitis, or oral or genital warts can occur.

Mycobacterium tuberculosis IRIS

The commonest clinical manifestations of TB-IRIS are fever, lymphadenopathy and worsening respiratory symptoms ⁵⁰. Pulmonary disorders, such as new pulmonary infiltrates, mediastinal lymphadenopathy, and pleural effusions are also common ⁵¹. Extrapulmonary presentations are also possible, including disseminated tuberculosis with associated acute renal failure ³⁴, systemic inflammatory responses ⁵², and intracranial tuberculomas ⁵³. Pulmonary TB-IRIS can be diagnosed by transient worsening of chest radiographs, especially if old radiographs are available for comparison. Other symptoms are nonspecific, and include persistent fever, weight loss, and worsening respiratory symptoms. Abdominal TB-IRIS can present with nonspecific abdominal pain and obstructive jaundice.

In most studies, TB-IRIS occurs within two months of ART initiation ³⁴. Among 43 cases of Mycobacterium tuberculosis-associated IRIS, the median onset of IRIS was 12–15 days (range 2–114 days), with only four of these cases occurring more than four weeks after the initiation of antiretroviral therapy ³⁵. These studies suggest the onset of mycobacterial-associated IRIS is relatively soon after initiation of ART, and clinicians should maintain a high level of vigilance during this period.

Paradoxical central nervous system TB reactions are well described in HIV-negative patients, and include expanding intracranial tuberculomas, tuberculous meningitis, and spinal cord lesions ⁵⁴. TB-associated central nervous system IRIS has also been reported in HIV-positive patients ⁵⁵. Compared to non-central nervous system TB-IRIS, symptoms tend to occur later, usually 5–10 months after ART initiation ⁵⁴. Crump et al ⁵⁶ described an HIV-seropositive patient in who developed cervical lymphadenopathy after five weeks of ART. Five months later, central nervous system symptoms associated with an expanding intracranial tuberculoma appeared after initiation of antituberculous therapy. The significant morbidity in this case illustrates the importance of maintaining a high clinical suspicion for the disease, particularly in endemic areas.

Treatment of tuberculosis-associated IRIS (TB-IRIS)

Treatment for mycobacterial-associated IRIS depends on the presentation and disease severity. Most patients present with non-life threatening presentations which respond to the institution of appropriate antituberculous therapy. However a range of life threatening presentations, such as acute renal failure ³⁴ and acute respiratory distress syndrome (ARDS) ⁵⁷, are described and have significant morbidity and mortality. Morbidity and mortality might also be greater in resource-limited settings where limited management options exist. Since the pathogenesis of the syndrome is an inflammatory one, systemic corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDS) may alleviate symptoms. In studies where therapy for IRIS was mentioned, the use of corticosteroids was variable ⁵¹ and anecdotally effective. Therapies ranged from intravenous methylprednisolone 40 mg every 12 hours to prednisone 20–70 mg/day for 5–12 weeks. These practices reflect the lack of evidence from controlled trials for the use of anti-inflammatory agents in IRIS. A randomized, placebo controlled trial examining doses of prednisone 1.5 mg/kg/day for two weeks followed by 0.75 mg/kg/day for two weeks in mild to moderate TB-IRIS is currently underway in South Africa. Until data become available, it is reasonable to administer corticosteroids for severe cases of IRIS such as tracheal compression due to lymphadenopathy, refractory or debilitating lymphadenitis, or severe respiratory symptoms, such as stridor and ARDS. Interruption of ART is rarely necessary but could be considered in life-threatening situations.

In HIV-negative patients, adjuvant corticosteroid use in tuberculous meningitis provides evidence of improved survival and decreased neurologic sequelae over standard therapy alone ⁵⁸. Once other infectious etiologies, have been excluded, standard antituberculous therapy should be initiated or continued as the clinical situation dictates, and a course of corticosteroid therapy should be considered for central nervous system TB-IRIS. Continuation of ART is desirable, although its discontinuation may be necessary in unresponsive cases or in those presenting with advanced neurological symptoms.

Atypical mycobacterial IRIS

In general, Mycobacterium avium complex-associated IRIS typically presents with lymphadenitis, with or without abscess formation and suppuration ⁵⁹. Other less common presentations include respiratory failure secondary to acute respiratory distress syndrome (ARDS) ¹⁷, leprosy ⁶⁰, pyomyositis with cutaneous abscesses ³³, intra-abdominal disease ⁶¹, and involvement of joints, skin, soft tissues, and spine ⁶¹.

Several studies have characterized the time of onset of Mycobacterium-associated IRIS. In one study of Mycobacterium avium complex lymphadenitis, the onset of a febrile illness was the first sign of IRIS and occurred between 6 and 20 days after initiation of antiretroviral therapy ⁵⁹. In another study, the median time interval from the start of antiretroviral therapy to the development of mycobacterial lymphadenitis was 17 days (range 7–85 days) ⁶².

Treatment atypical mycobacterial IRIS

As with TB-IRIS, evidence for treatment of IRIS due to atypical mycobacteria are scarce. Occasionally, surgical excision of profoundly enlarged nodes or debridement of necrotic areas is anecdotally reported ³³. However, healing is often poor leaving large, persistent sinuses. Needle aspiration is another option for enlarged, fluctuant and symptomatic nodes. Otherwise, treatment is similar to Mycobacterium tuberculosis IRIS (TB-IRIS).

Cytomegalovirus infection

In the pre-ART era, CMV retinitis, a vision-threatening disease, carried a high annual incidence and was one of the most significant AIDS-associated morbidities ⁶³. After the introduction of HAART, Jacobson et al described five patients diagnosed with CMV retinitis 4–7 weeks after ART initiation. They speculated that an HAART-induced inflammatory response may be responsible for unmasking a subclinical infection ⁶⁴. In addition to classical CMV retinitis, ART led to new clinical manifestations of the infection, termed immune recovery vitritis (IRV) or immune recovery uveitis (IRU), in patients previously diagnosed with inactive AIDS-related CMV retinitis ⁶⁵. Distinct from the minimal intraocular inflammation of classic CMV retinitis, these manifestations exhibit significant posterior segment ocular inflammation thought to be due to the presence of residual CMV antigens or proteins which serve as the antigenic stimulus for the syndrome ⁶⁶. Clinical manifestations include vision impairment and floaters.

In a retrospective cohort, CMV-related IRIS was common (6/33 of IRIS cases, or 18%) ¹⁰. In prospective cohorts, symptomatic vitritis occurred in 63% (incidence rate 83 per 100 p-yr) of ART responders who carried a previous diagnosis of CMV retinitis but had inactive disease at the onset of antiretroviral therapy. The median time from ART initiation to immune recovery vitritis was (43 weeks) ⁶⁷. Another large prospective surveillance study ⁶⁸ identified 374 patients with a history of CMV retinitis involving 539 eyes. Thirty-one of 176 ART responders (17.6%) were diagnosed with immune recovery uveitis. Male gender, use of ART, higher CD4 cell counts, and involvement of the posterior retinal pole as factors associated with a reduced risk of developing immune recovery uveitis, whereas prior use of intravitreous injections of cidofovir, large retinal lesions, and adequate immune recovery on ART were associated with increased risk.

The diagnosis of ocular manifestations of IRIS requires a high level of suspicion. In addition to signs of retinitis, inflammatory symptoms include vitritis, papillitis, and macular edema, resulting in symptoms of loss of visual acuity and floaters in affected eyes.

Treatment of IRIS associated CMV retinitis

Treatment of IRIS associated CMV retinitis and immune recovery vitritis may involve anti-CMV therapy with gancyclovir or valgancyclovir ⁶⁹. However, the occurrence of immune recovery uveitis in patients receiving anti-CMV therapy draws its use into question [64,66,67]. The use of systemic corticosteroids has been successful, and immune recovery vitritis may require periocular corticosteroid injections ⁷⁰. Due to its significant morbidity and varying temporal presentations, clinicians should maintain a high level of vigilance for ocular manifestations of CMV-associated IRIS.

Varicella zoster virus infection

Although complications such as encephalitis, myelitis, cranial and peripheral nerve palsies, and acute retinal necrosis can occur in immunocompromised HIV patients, the vast majority of patients exhibit typical or atypical dermatomal involvement without dissemination or systemic symptoms ⁷¹.

A randomized, controlled trial demonstrated oral acyclovir to be effective for dermatomal zoster in HIV-infected patients, facilitating healing and shortening the time of zoster-associated pain ⁷². Its use in cases of varicella zoster IRIS appears to be of clinical benefit ⁷³. The benefit of corticosteroids in combination with acyclovir in acute varicella zoster has been demonstrated in two large randomized, controlled trials. The combination of corticosteroids and acyclovir decreased healing times, improved acute pain, and quality of life, but did not affect the incidence or duration of postherpetic neuralgia ⁷⁴. The incidence of postherpetic neuralgia in immunocompetent individuals does not differ significantly from HIV-infected patients, but increases with increasing patient age ⁷⁵. Successful symptomatic management involving opioids, tricyclic antidepressants, gabapentin, and topical lidocaine patches individually or in combination has been shown to be beneficial ⁷⁶ and should be attempted in HIV patients with postherpetic neuralgia as a complication of herpes zoster IRIS.

Cryptococcus neoformans infection

Cryptococcus neoformans-induced IRIS meningitis symptoms range in onset from seven days to ten months after initiation of ART, with 20 (49%) occurring within four weeks of therapy ⁷⁷. In one study ⁷⁸, patients with Cryptococcus neoformans-related IRIS meningitis were compared to typical AIDS-related Cryptococcus neoformans meningitis. Patients with Cryptococcus neoformans-related IRIS meningitis exhibited no difference in clinical presentation. However, Cryptococcus neoformans-related IRIS patients exhibited had higher baseline plasma HIV RNA levels and higher CSF cryptococcal antigen titers, opening pressures, WBC counts, and glucose levels. Additionally, IRIS patients were more likely to have ART initiated within 30 days of previously diagnosed Cryptococcus neoformans meningitis. Most documented cases of Cryptococcus neoformans-induced IRIS meningitis have occurred in patients with CD4 counts <100 cells/mm³ ⁷⁹.

Cryptococcus neoformans infection treatment

A recent study ⁸⁰ evaluated antifungal combination therapies in the treatment of Cryptococcus neoformans meningitis in HIV patients. Although significant log reductions in colony forming units were observed with all combinations, substantial numbers of patients remained culture positive 2 weeks after therapy. It may be important to delay ART until CSF sterility can be achieved with effective antifungal combinations such as amphotericin B and flucytosine. However, the exact timing of ART and whether attaining CSF culture sterility is important in avoiding IRIS is unknown. This is illustrated by cases of reactivation cryptococcal meningitis described in four patients who had received at least four weeks of antifungal therapy prior to ART ⁷⁷. It is reasonable to administer systemic corticosteroids to alleviate unresponsive inflammatory effects, as anecdotal benefits have been observed in these patients ⁸¹. Furthermore, serial lumbar punctures may be required to manage persistent CSF pressure elevations in these patients ⁷⁸. Although continuation of ART has been performed safely ⁸¹, interruption of antiviral therapy may be necessary in severe or unresponsive cases.

Immune reconstitution inflammatory syndrome management

To date, no prospective therapeutic trials concerning the management of IRIS have been conducted ⁵. All evidence regarding the management of IRIS in the literature relates to case reports and small case series reporting on management practice. This does not provide reliable evidence regarding either the safety or efficacy of these approaches, but merely guidance regarding the practice of others in managing this difficult condition.

The infectious pathogens most frequently implicated in the immune reconstitution inflammatory syndrome are mycobacterial infections, fungi, varicella zoster, herpesviruses, and cytomegalovirus (CMV). Majority of patients with IRIS have a self-limiting disease course. No single treatment option exists and depends on the underlying infectious agent and its clinical presentation.

In most cases, ART should not be interrupted. The Committee recommends symptomatic treatment of mild IRIS with nonsteroidal anti-inflammatory drugs (NSAIDs), drainage of abscesses, excision of inflamed or painful lymph nodes, and inhaled steroids for bronchospasm of cough ⁸².

In severe or life-threatening cases, the decision to interrupt ART is based on many factors individualized to the patient; consultation with experienced HIV care providers is recommended.

In cases of severe IRIS not caused by Kaposi’s sarcoma or Cryptococcus, corticosteroids are usually the treatment of choice. The recommended dose has not been standardized; this Committee recommends 1 to 2 mg/kg daily of prednisone or the equivalent for 1 to 2 weeks, followed by a taper. Corticosteroids can increase a patient’s risk of contracting other OIs and can also cause hyperglycemia, hypertension, mental status changes, or avascular necrosis, so careful monitoring is warranted.

One strategy to minimize the effect of IRIS is to coordinate initiation of antiretroviral therapy (ART) with the treatment of known opportunistic infections ⁸². In most cases, it is recommended that ART be started as soon as possible after HIV infection is diagnosed and within 2 weeks of initiating most opportunistic infection treatment ⁸³. Exceptions to this include opportunistic infections that are known to carry a higher risk for severe or life-threatening IRIS when ART is initiated too soon, including tuberculous (TB) meningitis or other extrapulmonary TB ⁸⁴, cytomegalovirus (CMV) retinitis ⁸⁵ or Cryptococcus infections ⁸⁶. Expert clinicians should be consulted in these situations.

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