A proportion of people who start an antiretroviral therapy regimen develop unusual manifestations of opportunistic infections during the first few months of treatment. Researchers believe that these reactions are often caused by excessive responses by the recovering immune system.

Immune recovery disease may in part explain the continuing high rates of opportunistic infections during the first three to six months of antiretroviral therapy (Furrer 2002). However, these immune recovery conditions only seem to affect a minority of people and usually occur within the first few weeks of starting antiretroviral therapy.

What is an immune recovery disease?

Conditions most associated with immune recovery include:

• Uveitis: inflammation of the pigmented layer of the eye.

• Vitritis: inflammation of the jelly-like substance behind the eye lens.

• Inflammation of the lymph nodes associated with Mycobacterium avium intracellulare (MAI) or tuberculosis (TB).

• Elevated liver enzymes due to hepatitis B or C.

Immune restoration conditions are often associated with the herpesvirus family (e.g. cytomegalovirus [CMV], herpes zoster, and herpes simplex) or other mycobacterial infections (French 2000). However, herpes zoster as an immune reconstitution illness is very difficult to distinguish from the condition developing co-incidentally after the start of antiretroviral therapy^[1].

For example, people with low CD4 cell counts may have an MAI infection that is not causing any symptoms. After starting antiretroviral therapy, they may develop swollen lymph nodes or, sometimes, skin abscesses within a few weeks, apparently caused by the immune system's reactions against the MAI organisms. A Canadian study found that swollen lymph nodes tended to develop within a median of two and half weeks of commencing therapy (Phillips 1999).

People with low CD4 cell counts are also at risk of CMV infection at the back of the eye. These lesions are thought to be caused by the immune system killing retinal cells that have been infected with CMV. With treatment and maintenance therapy with anti-CMV drugs, the lesions may become inactive. However, in some cases the lesions reactivate and begin to spread at their edges when people start antiretroviral therapy, presumably because the recovering immune system becomes more aggressive in killing CMV-infected retinal cells.

There have also been reports of new types of CMV-related eye problems, such as vitritis, among people who had previously been treated for CMV retinitis. One research group reported that 19 out of 30 patients with previous CMV developed vitritis within a year of starting antiretroviral therapy and experiencing a CD4 cell count increase of at least 60 cells/mm³. None of the 22 patients with CMV who did not respond to antiretroviral therapy developed vitritis. This condition, which can affect the sight, is thought to be caused by the immune system's reactions against inactive CMV in the eye, rather than by CMV itself. It may be possible to treat the vitritis with steroids, although there is a theoretical risk that these could encourage CMV itself to reactivate.

A third type of CMV-related immune reconstitution inflammatory disease is CMV uveitis which is a painless reaction at the back of the eye in people who have had previous CMV retinitis and can cause cataracts or macular edema. This can lead to permanent blindness. Unlike other types of immune reconstitution inflammatory disease this rare complication usually occurs a median of three years after starting antiretroviral therapy. There is no evidence that restarting anti-CMV therapy or injections of immunosuppressive steroids into the eye are have either a preventative effect or affect the outcome of uveitis-inflammatory disease (Nguyen 2000)

A worsening or flare-up of TB, hepatitis B or C, and herpes may also occur during the early days of antiretroviral therapy. These flare-ups are thought to reflect genuine improvements in the body's ability to control the infection, and antiretroviral therapy is generally continued. A report from India shows that immune reconstitution inflammatory syndrome associated with TB occurred in approximately 10% of patients beginning HIV treatment, after an average of two months. The syndrome was characterised by new lymph node enlargement, localised tenderness or fever (Kumarasamy 2003).

There have also been case reports of temporary worsening of Pneumocystis pneumonia (PCP; Dean 2002), progressive multifocal lymphadenopathy (PML; De Pasquier 2003; Safdar 2002), folliculitis, herpes, and varicella zoster virus (shingles; Handa 2002).

Three cases of immune reconstitution inflammatory syndrome initially diagnosed as non-Hodgkin lymphoma have also been reported (Powles 2003). Another unusual manifestation includes a case of neurological problems caused by an inflammatory reaction to JC virus (Moretti 2003).

A case note review of 350 patients starting antiretroviral therapy identified four cases of acute appendicitis within six months, leading the authors to speculate that appendicitis is also a potential inflammatory response to immune reconstitution (Aldeen 2000). However, a subsequent study found that whilst the rate of appendicitis amongst HIV patients had grown since the introduction of HAART, the interval between starting treatment and developing appendicitis averaged one year (Klein 2002).

Perhaps the most unusual reaction reported is a Spanish case, in which a severe skin rash developed in response to ten-year-old tattoos two months after starting HAART (Silvestre 2001).

A case definition published in 2004 indicates that the following conditions can be considered suggestive of immune reconstitution syndrome in patients with an immunologic response to HAART:

• Localised disease: an infection focused on the lymph nodes, liver or spleen.

• An exaggerated inflammatory reaction.

• Severe fever, with exclusion of other causes.

• Painful lesions

• An unusual inflammatory response in affected tissues, e.g. granulomas (tumours with rough grainy texture), suppuration (the formation of pus-feld abscesses), necrosis (tissue death) or microscopic evidence of inflammatory cells invading the tissue

• Progression of conditions that were successfully treated prior to antiretroviral therapy with organ dysfunction or enlargement of pre-existing lesions and exclusion of treatment toxicity and new diagnoses. Examples include the development or enlargement of cerebral space-occupying lesions after treatment for cerebral cryptococcosis or toxoplasmosis, progressive or new pneumonia after successful treatment for pulmonary TB or PCP, new onset or worsening of uveitis or vitritis after the resolution of CMV retinitis, fever and cytopenia (cell death) after treatment for disseminated MAC and enlargement of Kaposis sarcoma lesions and subsequent resolution or partial regression without commencement of radiotherapy, systemic chemotherapy or intralesional therapy.

• Decrease in plasma HIV viral load more than 1 log₁₀.

Minor criteria for immune reconstitution syndrome include:

• Increased CD4 cell count after antiretroviral therapy.

• Increase in an immune response specific to the relevant pathogen, e.g. lymphocyte proliferative response or a delayed-type hypersensitivity response to mycobacterial antigens.

• Spontaneous resolution of disease without specific antimicrobial therapy or tumour chemotherapy with continuation of antiretroviral therapy.

The best approach to management of immune recobsitution syndrome is unclear. Although treatment will differ depending on the causal infection, this does not always lead to clinical improvement. Reports of successful treatment are anecdotal. Since many cases resolve on their own it is impossible to say what works without conducting prospective clinical studies.

In all but the most serious cases, antiretroviral therapy should be continued, although there may be extreme cases where it should be stopped temporarily until the patient's condition has stabilised.

Anti-inflammatory medications may help decrease symptoms during the intense inflammatory phase but routine use of corticosteroid therapy is not yet defined. Other anti-inflammatory medications that target specific inflammatory cytokines, such as pentoxifylline (Trental) and thalidomide, may also have a role, particularly for treating mycobacteria-related immune reconsitution syndrome (French 2004).

Who gets immune restoration illnesses?

People who have CD4 cell counts below 100 cells/mm³ before starting an effective antiretroviral regimen are most at risk of immune restoration disease. However, innate differences also appear to play a role. Minor variations in the genes of cytokines influence a person's risk of immune restoration disease. Researchers have recently identified particular genetic variations linked to herpesvirus and mycobacterial infections following immune restoration (Price 2002).

A case note review of 199 HIV-positive individuals who commenced antiretroviral therapy between January 2000 and August 2002 at a London hospital found that a lower CD4 cell count after twelve weeks on treatment, suggesting a partial or deferred rise in CD4 cell counts, was found to be a predictor of immune restoration illness. Twenty-two per cent of the patients experienced immune restoration illnesses a median of twelve weeks after starting treatment.

The majority (78%) of events were due to dermatological problems, with genital herpes simplex making up 50% of the cases. Genital warts caused by human papilloma virus (HPV) made up 24% of cases, molluscum contagiosum 10% and varicella zoster virus 10%. Non-dermatological manifestations of immune restoration illness were much less common: 2% had TB symptoms, 2% had new liver problems related to hepatitis B, and there was one case each of Kaposi's sarcoma and PCP symptoms (Thevarajan 2003).

In contrast, another study of patients starting antiretroviral therapy between 1997 and 2000 in Texas found that the CD4 cell count and viral load at the start of treatment were not related to the development of immune restoration illness (Shelburne 2005). In this study 180 patients were identified who had received a previous diagnosis of tuberculosis, MAI or Cryptococcus neoformans, which had been treated before antiretroviral therapy had started. Immune restoration illness developed in 57 (32%) of the patients but no association was found between any of the specific infections and risk of developing it. The patients most likely to develop immune restoration illness were those who started antiretroviral therapy closest to the time their infection was first treated: patients starting HIV treatment within 30 days of initiating treatment for one of the opportunistic infections were twice as likely as those who started more than 30 days later to develop immune restoration illness.

The most important risk factor for developing immune restoration illness in this study was the scale of the reduction in viral load, although CD4 cell count rises were also greater in patients who developed immune restoration illness compared to those who did not. There was no significant difference in mortality between patients who developed immune restoration illness and those who did not.

In another study of 389 patients in Serbia, the risk factors for immune restoration illness were assessed 35 months after the start of antiretroviral therapy (Jevtovic 2005). Sixty-five patients (17%) experienced at least one episode of immune restoration illness, including TB, CMV, cryptococcosis and toxoplasmosis. There were no significant differences in median CD4 cell count gain or reduction in viral load between patients who developed immune restoration illness and those who did not, although a baseline CD4 cell count below 100 cells/mm³ was the only significant risk factor.

Recently, a set of criteria for diagnosing immune reconstitution illness were developed by experts from the AIDS Clinical Trials Group, and subsequently validated by a team of doctors from the University of Cincinnati. These are:

• New or worsening symptoms of an infection or inflammation after starting antiretroviral therapy.
• Symptoms not explained by a new infection or the expected course of an infection that was diagnosed previously.
• A decrease in viral load of at least 1 log₁₀.

The doctors also developed a set of questions for predicting which patients are at risk of developing immune reconstiution syndrome after starting antiretroviral therapy, based on the number of prior opportunistic infections, haemoglobin levels and CD8 cell counts. This 'decision tree' can help doctors decide which patients may benefit from treatment with anti-inflammatory drugs^[2].

References

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