Download Immune Reconstitution Inflammatory Syndrome (IRIS) Demetre C

IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS)
Demetre C. Daskalakis, M.D.
October 29, 2002
Introduction
The advent of highly active antiretroviral therapy (HAART) has significantly decreased AIDS associated
morbidity and mortality. The basis for this improvement is the suppression of HIV replication leading to a
partial recovery of infected patient’s immune systems. It is this reconstitution of immune function that may
lead to a phenomenon called Immune Reconstitution Syndrome or Immune Reconstitution Inflammatory
Syndrome (IRIS). Though mainly discussed in HIV disease, removal of immunosuppression and
treatment of innate defects in immunity may lead to similar clinical manifestations. A general definition of
IRIS is clinical deterioration due to restoration of immune capacity soon after initiation of HAART
secondary to an apparent inflammatory response. In a recent descriptive study
of such events in a cohort of patients, the following inclusion criteria were used to select charts for
review:
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Patient with diagnosis of AIDS
Treatment with anti-HIV medicines (usually, but not necessarily including a protease inhibitor) has led to an
increase in CD4 T lymphocytes and a decrease in HIV-1 viral load.
Symptoms consistent with infectious/inflammatory (autoimmune) condition appeared while on HAART
Symptoms could not be explained by a newly acquired infection, the expected clinical course of a previously
recognized infectious agent, or by side effects of therapy.
Immune Reconstitution with HAART
Immune reconstitution is not a bad thing. It is the goal of HAART and other treatments for HIV. The
desired HAART induced reconstitution is both general and pathogen specific. To review:
 HAART usually causes a 90% drop in HIV RNA within 1-2 weeks
 As this happens a coincident increase in immune effector cells occurs. The first expansion is
made up of CD45RO+ cells (Memory CD4+ cells that have previously been activated by antigen
exposure) within 1-2 weeks after initiation of therapy. The increase in this cell population is
thought to be secondary to redistribution from nodes to blood rather than de novo cell proliferation
because of change in adhesion proteins on these cells or decrease in apoptosis.
 4-6 weeks after initiation of therapy, a second population of cells appears to increase. These
cells are naïve CD4+ cells (CD45RA+, CD62L+). This increase is noted in blood and lymph
nodes, supporting the hypothesis that the increase is secondary to proliferation rather than
redistribution. This population accounts for the long-term gains in CD4+ counts appreciated in
successfully treated patients. Though previously felt to be a vestigial organ in adults, it appears
as if some thymic tissue is active and accounts for the production of truly naïve CD4+ cells that
can respond to novel antigens rather than just memory antigens. It appears that thymic size may
correlate with the level of CD4 repletion in HAART treated patients; control of viremia also seems
to remove HIV’s inhibitory effect over the thymus.
 CD8+ cells follow a similar pattern with memory CD8 cells dominating early in HAART and then
naïve CD8+ cells becoming more prominent weeks into therapy. CD8+ count remains steady
during therapy leading to increase in CD4/CD8+ ratio.
 Functional improvement in the immunity occurs as well as increased in counts.
o Delayed-type hypersensitivity response increase.
o Pathogen specific responses appear to better in HAART treated patients.
This desired response, however, can lead to clinical symptoms due to enhanced cellular immunity.
Inflammation appears against infectious or self-antigens because of a recrudescence of the immune
response. Most description of reconstitution immune response are categorized by the antigen being
recognized by the returning immune system.
Antigen Specific IRIS
 Mycobacterium avium complex (MAC): One of the first agents associated with IRIS. MAC
infection often lies unappreciated in the immunocompromised host and can become apparent
after regained cellular immunity allows for an immunologic response. A reported scenario is a
patient treated for MAC who cleared their infection clinically or microbiologically and then begins
HAART. A few weeks into therapy, they present with fevers, lymphadenopathy, or MAC lesions
in unusual locations (skin, small bowel, osteo, bursitis, Addison’s, etc.). The CD4 memory
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response to MAC is likely rekindled leading to recognition of MAC antigens and exuberant
response. Reports of MAC-related IRIS have been observed 1-25 months after initiation of
HAART. Lymphocyte proliferation studies revealed similar responses in non-HIV and HAART
treated patients, while non-HAART patients had significantly lower response. LN often had
negative stains but were often culture positive in reported cases. Treatment is corticosteroids,
anti-MAC therapy, local drainage.
Mycobacteria tuberculosis: Even without HIV, treatment of MTB can lead to paradoxical clinical
worsening because of restored response to TB antigens as treatment continues and PPD
response is regained. The intrinsic immunosupression caused by MTB and the reconstitution on
immunity observed with treatment may be extended to the HIV population. After response to
MTB therapy, introduction of HAART can lead to apparent clinical worsening with fever,
pulmonary infiltrates, LAD, and tuberculomas. The time of onset ranged from 10 days to 9
months after initiation of HAART. Anti-inflammatory agents and Anti-TB meds are the
cornerstone of treating this reconstituted response to MTB.
CMV: Ocular and extraocular (viremia, colitis, pneumonitis ) CMV disease presenting after
HAART are reported. “Immune recovery vitritis” in patients with previous active or inactive CMV
retinitis has also been described after initiation of HAART. Incidence estimated at .1-.8/ personyear. In one cohort of 30 patients with CMVB retinitis, 19 (63%) developed this vitritis after a
median of 43 weeks on HAART. They presented with “floaters” and most had decreased visual
acuity. This post-HAART phenomenon may be vision threatening because of proliferative
vitreoretinopathy and posterior subcapsular cataracts. Treatment includes topical and ocular
steroids and anti-CMV meds as well as continuation of HAART.
Cryptococcus: Patients with CNS infection with advanced HIV often cannot mount a good
response against this organism. With HAART and immune recovery, the response can become
brisk as cellular immunity regains ability to activate PMN through increased IL-12 allowing for
oxidative bursts to fight cryptococcal infection. Interestingly, anti-fungal therapy may clear
organisms in CSF, but enough antigen may persist to cause an inflammatory response with
HAART-induced immune reconstitution. Cervical and mediastinal lymphadenopathy and
cutaneous lesions are alternate ways patients may present. Generalizations are difficult to make
since experience with post-HAART cryptococcal IRIS is very limited. Antifungals are the
mainstay of therapy. Anti-inflammatory medicines used in more severe cases.
Herpes Zoster: Most cases occur 4-16 weeks after initiation of HAART. These cases tended to
be mild. CD8%.> than 66% and a greater than 5% increase in CD8% post HAART were the only
risk factors identified in the 14/193 patients followed post HAART who developed zoster. Some
sources quote a five-fold increase in zoster in HAART-treated patients compared to their nonHAART treated HIV+ counterparts. Therapy is anti-HSVtherapy and continuation of HAART.
Progressive Multifocal Leukoencephalopathy: HAART significantly increases survival of patients
with PML because of increased immune response to JC virus in the CNS (JC Viral loads go
down while JCV antibodies go up). The age of HAART has heralded a new ring-enhancing,
inflammatory form of PML that is associated with demyelination and mononuclear infiltration.
These patients usually get better with continuing HAART.
OtherManifestations
o Acute Hepatitis in patients with previous Hepatitis B or C
o Granulomatous and other responses to Pneumocystis
o Recrudescence of sarcoidosis
o Worsening Kaposi’s Sarcoma (thought secondary to response to HHV-8)
o Graves Disease
Conclusion
So there isn’t one. The theme in IRIS is to treat the underlying OI while continuing HAART. If
inflammation becomes ‘”life or structure threatening,” sources recommend the use of anti-inflammatory
agents like steroids. Clear treatment recommendations are currently unavailable.
Bibliography
DeSimone, JA; Pomerantz, RJ; et al. Inflammaotory Reactions in HIV-1 Infected Persons after Initiation
of HAART. ANN Int Med.2000; 133: 447-454
Shelburne, SA. Et al. Immune Reconstitution Inflammatory Syndrome. Medicine. 2002; 81: 213-27.
Beth Israel Deaconess Medical Center Residents’ Report
MYCOBACTERIUM AVIUM COMPLEX AND HIV
Demetre C. Daskalakis, M.D.
October 29, 2002
Introduction
Mycobacterium avium complex refers two the two non-tubeculous mycobacteria M. intracellulare and M.
avium. MAC disease occurs in HIV negative patients, but epidemiologically, it is more of a concern in the
HIV infected population. Patients with CD4 counts less than 50cell/mm 3 are at increased risk for
disseminated disease. 15-40% of patients with advanced HIV are thought to harbor MAC infection.
Pathogenesis
 Bacterial factors: These are not well defined, since MAC tends not to be considered a particularly
virulent organism. Mycobacteria with plasmids or transparent colony morphology are associated
with increased virulence. One study also demonstrated increased replication of isolates from HIV
patients when compared to environmental isolates. It is unclear why this is.
 Route of Acquisition: Not person to person. Felt to be environmental. The majority of patients
get MAC through ingestion; pulmonary acquisition is also possible. It is unproven if MAC
infection can reactivate like TB. It is felt that most cases of disseminated MAC represent new
infections from the following lines of evidence:
o Rate of disseminated MAC infection in HIV greater than one would expect based on
prevalence of MAC + DTH reactions in the general population
o Disease can be detected locally in most cases prior to dissemination
o MAC antibodies absent in AIDS patients with disseminated disease
 Adherence and Invasion: Mycobacteria through unknown adherence receptors attach to the
intestinal epithelium and penetrate the mucosa though unclear mechanisms of invasion. These
organisms then undergo phagocytosis by macrophages. The macrophages of HIV infected
patients are unable to mediate intracellular killing, and the macrophages become MAC factories.
This defect is felt to be secondary to cytokine defects since these MAC-laden macrophages can
be activated with cytokines in vitro. The macrophages rupture releasing MAC bacilli leading to
local foci of sheets of MAC-laden macrophages most commonly in the duodenum but visible as 24 mm punctate lesions through out the gut. Infection spreads to lymphatics, reticuloendothelial
organs, the bone marrow and to the blood.
 Other: The macrophages infected with MAC also become HIV factories, producing more virus.
This complex interaction is felt to explain why patients with MAC seem more
immunocompromised than similar patients without MAC and are prone to other OI’s leading to
increased mortality rates.
Clinical Manifestations
 Disseminated Disease: Non-specific. These include fever, abdominal pain, night sweats,
diarrhea, and weight loss. Anemia is common and may be caused by bone marrow infiltration or
other “unclear” mechanisms that resemble anemia of chronic disease. Elevated alkaline
phosphotase of hepatic origin and LDH are also frequently seen. Diagnosis is by isolation of
MAC.
 Localized Disease: These focal findings were rarely encountered in the HIV population until the
dawn of HAART. Now focal lymphadenitis (cervical, abdominal, mediastinal) is reported after the
initiation of HAART and is thought to be a part of the spectrum of Immune Reconstitution
Inflammatory Syndrome (IRIS).
Diagnosis
 Blood cultures
 Bone marrow culture and AFB stain
Therapy
 Clarithromycin (500 PO BID)or azithromycin in combination with ethambutol or rifabutin
 In one study, clarithromycin + ethambutol was superior to azithromycin + ethambutol.
 Clarithromycin increases levels of rifabutin and rifabutin decreased levels of clarithromycin while
increasing levels of its metabolites. This combination also had a higher rate of rifabutin uveitis.
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A later study revealed that clarithromycin+ethambutol+rifabutin increased survival compared to
clarithroycin and either ethambutol or rifabutin. Three drug regimens are favored, but rifabutin
should be used cautiously in patients on protease inhibitors.
G-CSF is being studied as adjuvant therapy that may improve macrocyte killing of MAC.
Discontinuation of therapy after immune reconstitution is being studied. For now, therapy is life
long.
Prophylaxis
 All patients with CD4 counts less than 50 cells/mm 3 should be prophlaxed
 Preferred regimens are clarithromycin 500 mg PO BID or azithromycin 1200 mg q week
 Rifabutin is an inferior choice to the macrolides
 If immune reconstitution occurs (CD4 > 100 cells/mm 3 for 3-6 months), MAC prophlyaxis may
safely be discontinued.
Bibilography
Horsburgh, CR. The Pathophysiology of disseminated Mycobacterium avium complex disease in AIDS.
JID. 1999; 179 (Suppl3): S461-5.
Tantisiriwat. W. Prophylaxis of opportunistic infections. Infectious Disease Clinic of North America. 2000:
Vol 14. Number 4.
Beth Israel Deaconess Medical Center Residents’ Report