Abstract
We report a case of a 45-year-old patient with a history of cryptococcal meningitis who was started on antiretroviral therapy. The patient presented four months later with complaints of fever and memory loss. Lumbar puncture revealed positive cryptococcal antigen and therefore the patient was treated for recurrent cryptococcal meningitis. Unfortunately, the patient did not improve even after two weeks. The diagnosis of immune reconstitution was made at this time and steroids were started. The patient showed remarkable improvement.
INTRODUCTION
Immune reconstitution inflammatory syndrome (IRIS) is a condition seen in some cases of AIDS, in which the immune system responds to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse. Rarely patients with a history of cryptococcal meningitis (CM) can develop IRIS when started on antiretroviral therapy (ART). IRIS can be confused with CM as both can present with similar clinical features. The indifferentiation is very important as the management for both is completely different. Physicians treating HIV with ART should be aware of this as a delay in diagnosis can be fatal.
CASE REPORT
A 45-year-old patient had an episode of cryptococcal meningitis and was treated with antifungal agents. At the same time he was diagnosed with AIDS with a CD4 count of 57 cells/ mm3. He was discharged on highly active antiretroviral therapy (HAART), oral fluconazole, trimethoprim/sulphamethoxazole and azithromycin. He presented four months later with chronic headaches, low-grade fevers and memory loss for one month. On examination, the patient was alert but confused with short-term memory loss with no other focal neurological deficits. Lumbar puncture revealed increased opening pressure. Cerebrospinal fluid (CSF) examination revealed 20 white blood cells (WBCs) (lymphocytes), normal glucose and protein and it was positive for Cryptococcus antigen and India ink stain. The patient was started on intravenous amphotericin B and flucytosine for the treatment of recurrent CM and had serial lumbar taps. His symptom continued to progress. Magnetic resonance imaging with contrast was suggestive of old meningeal inflammation with no masses. The patient showed no improvement in clinical status even after two weeks of intravenous antifungal therapy. All cultures remained negative, including CSF cultures for cryptococcus. On day 14 after further consultation, the patient was started on dexamethasone 4 mg every six hours for presumptive diagnosis of IRIS along with antifungal and HAART therapy. The patient showed significant improvement within two days and was switched to only posaconazole for antifungal therapy. He was discharged later on HAART, slow steroid taper and oral posaconazole and asked to follow up with Infectious Diseases department as an outpatient.
DISCUSSION
CM has been the AIDS-defining illness for 60% of HIV-infected patients in whom it is diagnosed. It rarely occurs in patients with CD4 T-lymphocyte counts greater than 100/µL. The definitive diagnosis of CM is made by culture along with positive CSF India ink for capsulated bodies and positive CSF for cryptococcal antigen. However, titres in CSF and serum are not helpful in the management of acute disease in HIV-infected patients since changes in titre do not accurately correlate with clinical response. 1 CSF staining can also be positive in patients previously treated for CM due to the presence of dead capsules in the CSF as seen in our patient.
IRIS is a condition seen in some cases of AIDS or immunosuppression, in which the immune system begins to recover, but then responds to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse. 2 There is paradoxical worsening of pre-existing infectious processes following the initiation of HAART in HIV-infected individuals. 2–5 It is a rare and often missed diagnosis and can be fatal.
The likelihood and severity of IRIS correlate with inter-related factors: (1) the extent of CD4+ T-cell immune suppression prior to the initiation of HAART, (2) the degree of viral suppression and immune recovery following the initiation of HAART and (3) the likelihood of a pre-existing opportunistic infection. IRIS developed within the first two to three months of HAART commencement in two-thirds of patients in three retrospective case series. 3,5 The most frequently reported associated infections were localized herpes zoster (22%), Mycobacterium tuberculosis (20%), M. avium complex (17%), cytomegalovirus (12%) and Cryptococcus (6%). 4,6,7
The clinical features of IRIS are strongly related to the type and location of pre-existing opportunistic infection. HIV-infected patients with pre-existing CM may develop fever, increased headache, nausea, eye pain, photophobia and nuchal rigidity following the initiation of HAART. 8 Due to the similar presentation of infection and IRIS, it is often confused with the relapse of CM as in our patient. One retrospective study found that compared with classical forms of AIDS-related CM, patients with IRIS-related CM had significantly higher opening pressures, CSF WBCs counts (56 versus 12 cells/µL) and CD4 cell counts, and lower HIV viral loads. 9,10 However, cultures usually remain sterile. Serum cryptococcal antigen is not helpful in management because changes in titre do not correlate with clinical improvement. 6 Appropriate treatment for IRIS with cryptococcal infection is the continuation of antifungal and HAART therapy along with steroids.
IRIS is often a diagnosis of exclusion and must have a temporal association with initiation of HAART therapy. Treatment for IRIS depends on the underlying infection. HAART therapy can be continued except in conditions with life-threatening IRIS.
IRIS can be prevented by starting HAART therapy after 1–2 months of treating infections, although it has been seen even after 1–2 years of starting HAART. 3–5