July 26, 2005
William Powderly, from University College in Dublin, Ireland, presented an excellent review of the current state of knowledge regarding the relatively uncommon condition called immune reconstitution syndrome (IRS), which is a syndrome known by many other names including immune reconstitution inflammatory syndrome, immune restoration/restitution/recovery disease, immune rebound illness, etc.
Ironically, immune reconstitution syndrome is a syndrome that exists because of the progress we've made in treating HIV, Powderly noted. Ten years ago, before the widespread use of highly active antiretroviral therapy (HAART), immune restoration was not an issue because HIV-related immunosuppression was much too relentless and progressive. The advent of HAART has restored the ability of an HIV-infected person's immune system to mount a strong immune response to an infectious agent or self-antigen.
The current case definition of immune reconstitution syndrome is: A paradoxical deterioration in clinical status after starting HAART -- a deterioration that is attributable to the recovery or reactivation of someone's immune response to a latent or sub-clinical process. This process may be infectious or autoimmune, with HAART causing a flare-up or an unmasking of symptoms. HAART decreases the amount of circulating HIV virus, thus decreasing immune activation. This leads to qualitative/functional improvements in immune function by decreasing anergy and improving lymphocyte proliferative capacity. Quantitative improvements result from decreasing death, increased production and redistribution of CD4+ cells. The final result is improved pathogen specific immunity -- both to HIV and other pathogens. While improved immunity to HIV is a good thing, improved immunity to other opportunistic pathogens or development of autoimmunity can be quite problematic and result in immune reconstitution syndrome. The incidence of immune reconstitution syndrome in cohort studies ranges from 3% to 25%. While most common at CD4+ cell counts below 50, it may occur at any CD4+ cell count.
Although there are still few ideas regarding how to prevent or manage immune reconstitution syndrome, we know that there are several potential situations in which immune reconstitution syndrome may occur. One such case is an HIV-infected patient who has a very low CD4+ cell count and an undiagnosed opportunistic infection (OI). Initiation of HAART may unmask the infection, causing symptoms consistent with immune reconstitution syndrome.
Another case is an HIV-infected patient who has a known OI. When this patient begins HAART, 1 of 3 things may occur:
Although Powderly did not discuss autoimmune disease and immune reconstitution syndrome, HAART has been reported to flare known autoimmune diseases as well as trigger new autoimmune disease such as systemic lupus erythematosus and Graves' Disease.
As providers, it is often quite difficult to discern the underlying etiology of the problem in each of these cases. This syndrome is a diagnosis of exclusion, so active OIs always need to be ruled out.
HAART improves both the qualitative and quantitative immune defects that lead to impairment of pathogen-specific immunity, a phenomenon of which we currently have limited understanding. OIs are basically random events occurring primarily in patients with advanced HIV with CD4+ cell counts below 200. The patient may have been exposed to many different pathogens, but usually only manifests active infection with one at a time -- although later on, he or she may develop another active infection in quite a random order. The potential for variability in one patient is wide and may be influenced by genetics.
The question is: At what point does a patient's improved immunity interact with pathogens, and what is the final result? Do patients develop a normal immune response or an enhanced one that results in immune reconstitution disease?
Manifestations of Immune Reconstitution Syndrome
All HIV-related opportunistic pathogens may be associated with immune reconstitution syndrome: bartonella, cryptococcosis, cytomegalovirus, hepatitis B and C, herpes simplex virus, histoplasmosis, Kaposi's sarcoma, mycobacterium avium complex, pneumocystis jiroveci, tuberculosis, varicella zoster virus, etc. In his talk, Powderly briefly reviewed information about the following infections:
Mycobacterium avium complex. In the context of immune reconstitution syndrome, this illness usually presents as lymphadenopathy with large, painful lymph nodes -- with few organisms and negative blood cultures. The course may be protracted. Other manifestations may occur, such as pulmonary infiltrates, mediastinitis, liver granulomas and cerebritis.
Tuberculosis. "Paradoxical reactions" to tuberculosis were first recognized in the 1950s, with 12% to 25% of patients developing lymphadenitis at the start of therapy. In a manner similar to immune reconstitution syndrome, these patients have worsening of their symptoms with the initiation of anti-tuberculosis therapy. In HIV-infected patients, the rate of paradoxical reactions is usually 25% to 30%, with a mean onset of symptoms at 2 weeks and a mean duration of symptoms of 3 weeks. Other common symptoms include fever and cervical and intrathoracic lymphadenopathy. Restoration of a skin test response may occur. Cerebritis with morbidity and mortality has been reported. Risk factors include greater post-HAART viral load reduction and extra-pulmonary tuberculosis at presentation.
Cryptococcus. In the context of immune reconstitution syndrome, this is usually associated with central nervous system disease. In a French study of 120 patients, there was a 10% incidence,1 and in a U.S. study of 60 patients, there was a 30% incidence.2 Cranial nerve palsies, hearing loss, mediastinitis, lymphadenitis and subcutaneous abscesses have all been reported, and are often quite severe.
Pneumocystis jiroveci pneumonia (PCP). This complication often worsens after HAART initiation. While it's difficult to do a holistic interpretation of all of the data currently available from case series, the one recurring theme is a worsening of symptoms as the usual steroid course given for PCP is tapered.
Kaposi's sarcoma (KS). At this conference, Mark Bower et al from Chelsea & Westminster Hospital in London presented a poster on KS in the context of immune reconstitution syndrome. Ten of the 150 treatment-naive patients who were starting HAART developed new KS lesions and progression of established lesions. The rate of KS accelerated as compared to their pre-HAART period. While there was no difference in KS stage, visceral involvement, or HIV viral load between the 10 who developed immune reconstitution syndrome and the 140 who did not, the 10 developing the syndrome did have a higher CD4+ cell count at the start of HAART (325 cells/mm3 versus 121 cells/mm3).3
Immune Reconstitution Syndrome Surveillance
There have also been reports of autoimmune-like syndromes occurring with HIV, such as Guillain-Barré and Graves' Disease. One such report was presented at this conference by Maria Jesus Perez-Elias and colleagues from Hospital Ramón y Cajal and Hospital Reina Sofía in Spain. Her poster examined Graves' Disease among a large cohort of Spanish patients in the pre- and post-HAART eras. The researchers saw no cases of Graves' Disease from 1990 to 1996. However, in the post-HAART era (from 1997 to 2003), they saw 6 cases. The gender distribution of the cases was 5 female to 1 male, which is the opposite distribution of the general HIV-infected population. While the nadir CD4+ cell count among the 6 patients was 37 cells/mm3, the mean CD4+ cell count was 682 cells/mm3 at the time of diagnosis. In the long term, drug therapy did not control the Graves' Disease.4
Another researcher, Sergio Lupo, M.D., of the Instituto CAICI and Universidad Abierta Interamericana in Rosario, Argentina, presented a poster that described the long-term follow-up of 21 patients who were diagnosed with immune reconstitution syndrome. Sixteen had infectious pathogens identified, 3 neoplasias and 2 hyperthyroidism. At HAART initiation, the median CD4+ cell count was 51 cells/mm3, with an HIV viral load of 5.9 logs. All patients had experienced a rapid and effective response to HAART. Two deaths occurred -- one from non-Hodgkin's lymphoma and one from tuberculosis -- and 9 patients had long-term sequellae causing illness.5
Looking at the TREAT Asia HIV Observational Database, Jialun Zhou from the National Centre in HIV Epidemiology and Clinical Research at The University of New South Wales in Sydney noted that new AIDS-defining illnesses were found to be more common after HAART initiation. Seven percent (108) of 1,489 people who started antiretroviral treatment with 2 or more drugs and had at least one follow-up recorded developed AIDS-defining illness at a median of 23 days after HAART initiation. Tuberculosis (26%) was the most common new AIDS-defining illness, followed by PCP (19%) and non-tuberculosis mycobacterial diseases (12%).
Patients who developed AIDS-defining illnesses had a median CD4+ cell count of 34 cells/mm3 (61% had a CD4+ cell count below 50 cells/µl) and 90% had an HIV viral load over 10,000 copies/mL. Fifty-three percent also had experienced a prior AIDS-defining illness. While the authors note that it is difficult to be sure that these events were indeed immune reconstitution syndrome, it is likely that many were. They thus point out that this syndrome will probably become increasingly problematic as developing countries gain access to HAART.6
Risk Factors for Immune Reconstitution Syndrome
So the big question is: What are the risk factors for immune reconstitution syndrome? Powderly noted they include microbial antigens, susceptibility of individual patients, and advanced immunosuppression with a CD4+ cell count usually below 50. But, in addition to the advanced immunosuppression, there needs to be an antigen to which the immune response will react. The greater the pathogen burden, the greater the response. Individual patient susceptibility is also involved with some patients being genetically predisposed to develop certain infections and/or have a hyperimmune response to a particular pathogen. Martin French from western Australia did a study7 that showed that patients with a vigorous type II immune response were actually at increased risk for immune reconstitution syndrome.
Factors associated with immune reconstitution syndrome in case series have been:
Management of Immune Reconstitution Syndrome
A number of dilemmas surround the management of immune reconstitution syndrome. Are a patient's symptoms the result of immune reconstitution syndrome, a relapse of a past OI, drug toxicity or a new disease process? From a therapeutic standpoint, do we stop or continue HAART, stop or change the OI treatment or add immunosuppressives? There is still a lack of good clinical data in all of these areas.
Powderly noted that in terms of therapeutic interventions, if there is any evidence of an active OI, it's best to use the appropriate anti-infective therapy. Depending on the severity of the immune reconstitution syndrome and the validity of the need for HAART, temporary stoppage of HAART, with restart when the immune reconstitution syndrome has abated, may be an option. If the immune reconstitution syndrome symptoms are severe, anti-inflammatory agents such as NSAIDS, steroids, thalidomide, or cytokine inhibitors may be employed, though no good data on the use of these agents in immune reconstitution syndrome exists. Powderly declined to answer specific questions about recommended steroid doses as he feels existing data are inadequate. He recommended continuing HAART if at all possible and considering immunosuppressives as the better option for severe immune reconstitution syndrome.
One important study, which is currently still enrolling in North America, is the U.S. AIDS Clinical Trials Group (ACTG) Study 5164. This study will evaluate the effect of starting anti-HIV drugs in HIV-infected patients who are being treated for OIs. All patients will receive immediate treatment for their OI or bacterial infection, but will be randomized to 1 of 2 arms -- immediate HAART versus delayed HAART that is begun 8 weeks after study entry.
Powderly concluded his presentation by noting that with immune reconstitution syndrome, there still remains many more questions than answers. While overall prevalence is low, it may climb in the future as HAART becomes available to more and more advanced patients in the developing world. In the majority of HIV-infected patients, the benefits of HAART outweigh the risks and thus it should not be withheld from patients with advanced HIV/AIDS. As providers, we need to be aware of the many faces of immune reconstitution syndrome and know when to treat opportunistic pathogens, when to hold HAART, and when to use anti-inflammatory and immunosuppressive agents. Hopefully much more will be known as results of trials such as ACTG 5164 become available.