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Chapter 18 : Immune Reconstitution Inflammatory Syndrome
Category: Clinical Microbiology
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The prognosis of patients with human immunodeficiency virus (HIV) infection has dramatically improved since the advent of potent antiretroviral therapy (ART), which has enabled sustained suppression of HIV replication, recovery of CD4 Tcell counts, and a substantial decrease in the frequency of opportunistic infections (OIs) and of mortality. In three large retrospective studies, up to 30% of ART responders developed one or more inflammatory syndromes consistent with immune reconstitution inflammatory syndrome (IRIS). One study reported 182 episodes of IRIS: the most frequently reported associated infections were localized varicella-zoster virus (22%), TB (20%), nontuberculous mycobacterial (NTM) infection (17%), cytomegalovirus (CMV; 12%), and cryptococcal infection (6%). In a study conducted on over 300 HIVinfected patients commencing ART in a country with a high prevalence of TB, a whole-blood IFN- γ release assay was used to demonstrate that T-cell IFN-γ responses to PPD increased in patients who developed paradoxical or ‘’unmasking’’ TB-IRIS. Narita et al. documented that paradoxical reactions were more common in HIV-infected patients after starting ART compared with HIV-infected patients not on ART and HIV-uninfected patients. In this study the timing of the paradoxical reaction was also more closely temporally related to ART initiation than TB treatment initiation. Focal or diffuse lymph node enlargement is the most commonly described feature in the literature. Eye disease is the most common presentation of CMV-IRIS. The existing data suggest that the majority of patients who develop IRIS have good long-term clinical outcomes, partially due to the good immunological and viral response to ART.
Paradoxical pulmonary TB-IRIS. In 2003, an 18-year-old Ghanaian woman was admitted because of cough for 3 months, persistent fever, and loss of more than 10% of body weight. A chest X-ray showed a right lobe pulmonary infiltrate (A). A bronchoalveolar lavage confirmed the diagnosis of M. tuberculosis infection. She was found to be HIV seropositive, and her CD4+ lymphocyte count was 19 cells/μl. After 2 days of antituberculosis treatment the fever disappeared. She was started on efavirenz, lamivudine, and zidovudine. One week later she again developed high fever, and the pulmonary infiltrate had markedly increased (B). Moreover, she developed signs of polyarthritis of the hands, elbows, and knees. A puncture of an inflamed joint did not reveal any pathogen. She recovered finally with corticosteroid treatment and the continuation of the antituberculosis and antiretroviral treatment.
Paradoxical type of TB-IRIS with abscess formation. In August 2004, a Ugandan women with HIV infection was diagnosed with pulmonary M. tuberculosis infection. Her CD4+ lymphocyte count was 9 cells/μl. Two weeks after the start of the antituberculosis treatment, antiretroviral treatment was started (zidovudine, lamivudine, and efavirenz). Four months later she presented with a swollen cervical lymph node, hilar lympadenopathy (A), and a thoracic wall tuberculous abscess (B). Aspiration of the lymph node showed the presence of acid-fast bacilli, but a culture was not performed.
Recurrent paradoxical TB-IRIS. In 2000, a 32-year-old Caucasian woman with a CD4+ lymphocyte count of 19 cells/μl was started on antituberculosis treatment because of disseminated tuberculosis. Her clinical condition initially improved, but 2 weeks after starting highly active ART she developed high fever, multiple inflammatory lymph nodes and abscesses (A), a pleural effusion, and ascites. Aspiration of an abscess revealed acid-fast bacilli and a positive M. tuberculosis culture. Over the next 9 months the abscesses and fever waxed and waned, usually responding temporarily to the administration of prednisone. They finally disappeared completely after 1 year of antituberculosis treatment ( 28 ). After 4 years on highly active ART she developed a cervical abscess (B) and a thoracic wall abscess (C) (the computed tomography scan shows a thoracic wall abscess similar to the abscess of the patient shown in Fig. 2 ). Her CD4+ lymphocyte count was then 300 cells/μl. On aspiration of an abscess, only one acid-fast bacillus was found, and cultures remained negative. The abscesses finally disappeared after antituberculosis treatment ( 117 ).
Unmasking Mycobacterium avium complex (MAC)-associated IRIS. In 1996, a 44-year-old Caucasian man, with a CD4+ lymphocyte count of 17 cells/μl, was started on lamivudine, stavudine, saquinavir, and ritonavir. Four months later he was admitted to the hospital because of 2 months of abdominal pain and episodes of fever. His CD4+ lymphocyte count was then 150 cells/μl. A computed tomography scan of the abdomen showed multiple intraabdominal hypodense multilocular structures (abscesses). During an exploratory laparotomy, biopsies and cultures were obtained. Cultures grew MAC. The patient recovered completely during highly active ART and MAC treatment.
Paradoxical cryptococcus-associated IRIS. In 2002, a 26-year-old Caucasian man was hospitalized because of worsening headache and vomiting over a period of a few weeks. He was diagnosed as being HIV seropositive, with a CD4+ lymphocyte count of 12 cells/μl and a viral load of >750,000 copies/ml. India ink staining of the CSF revealed C. neoformans. Visual acuity was normal. Treatment with amphotericin B and methylprednisolone (80 mg/day, intravenous) was started, together with lopinavir-ritonavir, lamivudine, and zidovudine. Initially his clinical condition improved, but after 2 weeks of amphotericin therapy the nausea and vomiting reappeared. The intracranial pressure was 45 mm Hg (normal is <21 mm Hg). Six weeks after admission he was discharged on oral fluconazole, lopinavir-ritonavir, lamivudine, zidovudine, methylprednisolone (16 mg daily), and acetazolamid. At that time, his CD4 lymphocyte count was 28 cells/μl and his HIV viral load was <400 copies/ml. Eight weeks later, he was readmitted with vomiting, anorexia, weight loss, and bilateral progressive visual loss. One week before readmission the methylprednisolone had been decreased to 8 mg daily. India ink examination of the CSF showed the presence of C. neoformans, but cultures remained negative. One week after the onset of his visual complaints, he experienced complete loss of vision. Fundoscopy showed bilateral papilledema. Magnetic resonance imaging of the brain revealed an effusion around the optic nerves. Surgical decompression of the right optic nerve was performed. Microscopic examination of the fluid obtained during surgery revealed C. neoformans, but a fungal culture of the fluid remained negative. Today he is in good general health, with a CD4+ lymphocyte count of >400 cells/μl and a viral load of <50 copies/ml, but the bilateral blindness remains ( 71 ).