A team of doctors from the University of Cincinnati have proven that a standard definition proposed by the AIDS Clinical Trials Group can be used to diagnose immune reconstitution syndrome in patients starting HIV treatment. The results of the study were published in the 1st June edition of Clinical Infectious Diseases.
The study’s investigators also developed a tool for predicting which patients are at risk of immune reconstitution syndrome, based on the number of prior opportunistic infections, CD8 cell count and haemoglobin levels.
Immune reconstitution syndrome is the development of symptoms of an opportunistic infection after a patient has started taking HIV treatment. It affects around 10% of patients with HIV, and as many as a quarter of those starting treatment with a CD4 cell count below 50 cells/mm3, with severe cases sometimes being fatal. It is caused by the recovering immune system becoming able to recognise and attack disease-causing organisms that were lying dormant in the body, causing the development of inflammation.
As there are many different targets that the immune system can recognise, the symptoms of immune reconstitution syndrome can vary widely. Consequently, there is no consensus on the definition of the syndrome, making diagnosis difficult and complicating studies of the syndrome.
Recently, a working group in the AIDS Clinical Trials Group proposed a set of criteria that could be useful in diagnosing immune reconstitution syndrome. 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.
To confirm the utility of these criteria, the doctors used them to identify 20 possible cases of immune reconstitution syndrome from their clinic between 1996 and 2002, and provided their case notes to two expert doctors who have been treating HIV and AIDS for over 15 years. They also gave the two experts four ‘mock’ cases that represented classic symptoms of opportunistic infections that were not due to immune reconstitution
The doctors agreed on the diagnosis of 22 (92%) of the 24 cases, confirming that most were due to immune reconstitution. However, both experts decided to exclude all six cases of herpes zoster, as it is not possible to distinguish new infections with this virus to an immune reconstitution phenomenon.
“We were successful in validating a proposed definition of immune reconstitution syndrome, because it was confirmed by a blinded panel of reviewers,” the investigators write. “The one exception was dermatomal herpes zoster, presumed to be a manifestation of immune reconstitution syndrome.
“Reviewers rejected zoster as a manifestation of immune reconstitution syndrome, because herpes zoster may manifest [itself] irrespective of the host’s ability to generate an inflammatory response, and there is no established way to clinically distinguish cases occurring as a result of immune reconstitution from cases occurring co-incidentally following the administration of antiretroviral therapy,” they explain.
The investigators went on to compare the 14 confirmed cases to a set of 40 control patients who had similar CD4 cell counts before starting anti-HIV treatment, but who did not experience immune reconstitution syndrome.
In a multivariate analysis, they discovered that the risk of developing immune reconstitution syndrome was significantly greater in patients who had had more opportunistic infections before starting HIV treatment (p = 0.007) and those with lower levels of haemoglobin in the blood (p = 0.003). Sex, age, race and symptoms before starting anti-HIV treatment were not associated with this risk.
They used this finding to develop a set of questions to help doctors identify patients at risk of developing the syndrome, who may benefit from preventive treatment with anti-inflammatory drugs. By answering questions on the number of prior opportunistic infections and haemoglobin levels in each patient, along with the CD8 cell count, doctors can predict the risk of the syndrome on a scale of zero to four.
The investigators calculated that using a threshold of four points led to the correct diagnosis of patients with immune reconstitution syndrome in 93% of cases, and 80% of those without the syndrome: these values are referred to as ‘sensitivity’ and ‘specificity’. Using a value of two as a cut-off, these values were 79 and 88%, respectively.
“It is possible to develop a clinical model predictive for developing immune reconstitution syndrome,” they conclude. “However, it would be useful to develop more refined models with greater sensitivity and specificity.”
The definition validated in this study does not include CD4 cell count or changes in the number of CD4 T-cells in the blood, since these values do not always reflect the level of activity of the immune system.
“This definition serves as a framework for considering the diagnosis of immune reconstitution syndrome, but it is limited by the absence of criteria for establishing that a restored immune response has occurred,” the researchers write. “An increase in CD4 cell count is not an adequate marker of restored immune function, because pathogen-specific responses may remain deficient despite an increase in CD4 cell count or may recover before a measurable increase in CD4 cell count.”
Robertson J et al. Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy. Clin Infect Dis 42: 1639-1646, 2006.