Abacavir, a carbocyclic nucleoside analogue reverse transcriptase inhibitor, is used in combination with other antiretroviral agents for the treatment of HIV-1 infection. The major toxicity associated with therapy is a potentially life-threatening hypersensitivity reaction occurring in approximately 3–5% of patients, usually during the first 6 weeks of treatment, with a median time to onset of 8 days [1,2]. Clinical manifestations most frequently include fever, rash, fatigue, gastrointestinal symptoms such as nausea, vomiting, diarrhea and abdominal pain, and respiratory symptoms such as pharyngitis, dyspnea and cough. Although the described respiratory symptoms are usually mild, we report here the case of a man who developed acute, severe pneumonitis leading to acute respiratory distress syndrome after 11 days of therapy with abacavir. The patient was a 57-year-old man with HIV who came to medical attention in October 2002 as a result of 2 days of subjective fever, malaise and diarrhea. Approximately 6 days before the onset of symptoms he was seen in the infectious disease clinic, where his antiretroviral regimen was changed from sustiva and lamivudine–zidovudine to zidovudine, abacavir and lopinavir–ritonavir. The change was prompted by a drop in his CD4 cell count from 164 to 128 cells/ml over the previous 3 months. Six days after the initiation of this abacavir-containing regimen, he began to describe profound fatigue, loose stools, along with episodic sweats and chills, which worsened over the next 2 days, requiring hospitalization. He denied dyspnea or cough at that time and a chest X-ray was negative for acute disease (Fig. 1a).Fig. 1: Chest radiographs (anteroposterior views) of the patient. (a) On admission; (b) 11 days after the initiation of abacavir therapy; and (c) 3 days after abacavir discontinuation.Within 72 h of admission, his initial symptoms were followed by acute dyspnea, along with severe hypoxemia, hemoptysis and new diffuse bilateral pulmonary infiltrates on a chest X-ray (Fig. 1b). Abacavir was promptly discontinued because of the suspicion of a hypersensitivity drug reaction. The patient was then placed on mechanical ventilation, underwent diagnostic bronchoscopy, and was started on empiric antibiotic therapy for a possible infectious etiology of symptoms. Transthoracic echocardiography revealed normal left ventricular wall motion and a normal ejection fraction. After 3 days of abacavir discontinuation, the patient's pulmonary status improved dramatically, mechanical ventilation was terminated, and the patient's chest films showed almost complete resolution of the infiltrative disease (Fig. 1c). Electron microscopy of the bronchial washings revealed blood, mucus, benign respiratory epithelium, macrophages and neutrophils. No microorganisms or malignant cells were seen. Cultures (blood and bronchial lavage fluid) remained negative. The hypersensitivity reaction described here highlights the potential aggressive respiratory manifestations associated with the use of abacavir. Although the clinical presentation of our patient at first suggested an infection causing his symptoms, tests for infectious diseases were negative, and in particular we witnessed a dramatic improvement within 72 h after the withdrawal of abacavir. Approximately 30% of life-threatening hypersensitivity cases involve a respiratory symptom, the most frequently reported of which are dyspnea, cough or pharyngitis [3]. Our observation is remarkable because of the unusual presentation of acute respiratory distress syndrome as the manifestation of a hypersensitivity reaction to abacavir. Although the pathogenesis of abacavir hypersensitivity is not entirely clear, data suggest that in certain individuals, the creation of a chemically reactive metabolite leads to immune activation and, ultimately, cellular damage [1]. The reactive intermediate acts as a hapten that covalently binds to autologous proteins, creating an immunologically reactive metabolite–protein adduct. On interaction of the metabolite–protein adduct with cells of the immune system, the release of cytokines results in the development of symptoms. The exact metabolite responsible for hypersensitivity is unknown; however, the generation of a carboxylate derivative after oxidation may be implicated as the causative agent [4]. The key to appropriate clinical management is early and accurate recognition of abacavir hypersensitivity to avoid the symptoms described. The only established treatment is discontinuation of the drug. Rechallenge with abacavir after a hypersensitivity reaction typically results in the recurrence of symptoms within hours, with the potential to induce a more severe clinical syndrome with an increased risk of life-threatening hypotension and death [3]. Given the possibility of severe lung involvement, clinicians need to monitor their patients on abacavir closely and understand the need for the rapid discontinuation of the drug, as this is the only established treatment, if symptoms arise.
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Sep 11, 2008
Hua Li + 1
Open Access