A man in his early 50’s with a history of an unrelated donor allogeneic stem cell transplant for acute myelogenous leukemia in September 2007 presented in October 2009 with history of subjective fever, nausea, vomiting and new upper respiratory tract symptoms. The patient’s post-transplant course had been complicated by chronic graft-versus-host-disease involving the skin, liver, and gut that required ongoing treatment with immunosuppressive drugs (mycophenolate mofetil, prednisone, and tacrolimus). At presentation, vital signs were significant for a blood pressure of 180/98, and a temperature of 36.6°C. Initial laboratory investigation disclosed a leukocyte count of 5.3 × 103/µL, with significant lymphopenia (0.11 × 103/µL) and thrombocytopenia (127 × 103/µL); his creatinine was also elevated at 1.9 mg/dL (baseline 1.3 mg/dL). Blood cultures and a nasopharyngeal (NP) wash for influenza were performed, and admission chest radiograph showed left lower lobe consolidation and patchy opacities in the right middle lobe. He was started on empiric IV levofloxacin. Before admission, the patient was not receiving oseltamivir prophylaxis.
The following morning, he developed a fever to 38.4°C, increased shortness of breath, tachypnea, and progressive oxygen requirements. Repeat chest radiographs demonstrated new bibasilar opacities but, because of his elevated creatinine, a chest computed tomography was deferred. The patient was found to have a peroneal vein thrombosis, but a ventilation perfusion scan indicated low probability for an acute pulmonary embolus. IV vancomycin and imipenem were added.
Owing to a high clinical suspicion for influenza, empiric high-dose oseltamivir (150 mg orally twice daily) was added the morning of day 3. Later that evening, his admission NP wash was reported to be positive by polymerase chain reaction (PCR) for pH1N1 with a viral load of 7.3 log copies/reaction (c/rxn). His respiratory status continued to decline, and despite maximal oxygen therapy he required intubation. He underwent diagnostic bronchoscopy the following day, which showed clinical evidence of alveolar hemorrhage, and bronchoalveolar lavage (BAL) fluid was positive for pH1N1 by PCR with a viral load of 7.3 log c/rxn.
On day 7, the patient was switched to IV peramivir (600 mg loading dose and then dose adjusted for renal function 150–100 mg daily) because of the concern for poor oral absorption of oseltamivir and severity of disease; he was also given a dose of IV immunoglobulin on day 8. He tolerated peramivir well, although on day 14 developed hallucinations and, out of concerns that peramivir could be contributing, 1 dose was held. Repeat NP swab from day 14 detected pH1N1 with a viral load of 6.8 log c/rxn. Peramivir was restarted on day 16 and the patient required re-intubation secondary to respiratory distress. Because of viral persistence and continued clinical decline, there were concerns the virus had developed resistance. Peramivir was discontinued on day 17 and testing for the H275Y resistance mutation was ordered. Although it was presumed that the virus was resistant to oseltamivir and adamantanes, combination therapy with oseltamivir (150 mg twice daily), oral ribavirin (600 mg once, then 200 mg daily) and rimantidine (100 mg daily) were started pending emergency approval of IV zanamivir.
The patient underwent repeat bronchoscopy on day 18 and, although the PCR did not detect influenza on the BAL specimen, an NP swab from the same day had a viral load of 3.4 log c/rxn. On day 19, combination therapy was discontinued and IV zanamivir was started per an emergency new drug application from the FDA. The patient developed oliguric renal failure requiring daily dialysis by day 20. On day 22, a repeat PCR done on NP swab remained positive for pH1N1 with a viral load of 3.4 log c/rxn.
His respiratory status continued to worsen, and he eventually required inhaled nitrous oxide for ongoing hypoxemia despite maximum ventilator support. By day 24, his pH1N1 viral load on NP swab had declined to 2.5 log c/rxn. He eventually developed an ileus, began to experience cardiac dysrythmias, and was eventually transitioned to comfort measures. He died on day 28 of his hospital stay.
Prior to diagnosis and throughout his hospitalization the patient’s lymphocyte count remained persistently <250 cells/µL. An autopsy demonstrated bilateral pulmonary consolidation, hemorrhage with diffuse alveolar damage and patchy fibrosis, diffuse necrotizing pancreatitis, and marantic endocarditis with vegetation of aortic valve.