LETTER TO THE EDITOR Antiviral treatment of Influenza A (H1N1-09) guided by molecular resistance testing in aplasia after allo-SCT Bone Marrow Transplantation advance online publication, 17 January 2011; doi:10.1038/bmt.2010.331 Pulmonary injury is a major cause of morbidity and mortality in patients after SCT. Although bacterial and fungal infections account for most infections, a variety of viruses can be involved as well. In the SCT setting, parti- cularly during aplasia, early after transplantation, patients are most vulnerable and therefore urgently need effective anti-infection drugs. We report the clinical course and molecular data of a patient who acquired influenza A (H1N1-09) pneumonia in aplasia after SCT. We present the case of a 59-year-old woman with kappa light-chain myeloma, who was transplanted in second CR. Previous treatment comprised high-dose melphalan and autologous hematopoietic cell transplantation, and salvage therapy with bortezomib and dexamethasone. After conditioning with treosulfan, fludarabine and ATG, she received a graft from an unrelated donor with a single HLA-B-locus mismatch. The prophylactic anti- biotics administered were ciprofloxacin, fluconazole and acyclovir. On day þ 1, the patient developed fever of 38.5 1C and high C-reactive protein levels. Ciprofloxacin was changed empirically to piperacillin–tazobactam. The fever was persistent through the following 4 days, though antibiotics were switched empirically to meropenem and teicoplanin. Coughing and refractory fever prompted us to perform, on day þ 5, a computed tomography (CT) scan of the chest showing bilaterally unspecific patchy infiltrates (Figure 1a). Respiratory viruses are clearly recognized as an important cause of infection after SCT. The epidemiology varies each year and is dependent on the viruses present in the community. Hence, H1N1-09 involvement was first con- sidered. Subsequent RT-PCR of pharyngeal wash was positive for H1N1-09. Oseltamivir, 75 mg twice daily was started. 1 GVHD prophylaxis consisted of CYA starting day –1 and MTX on days þ 1 and þ 3. To shorten aplasia, MTX was not given on days þ 6 and þ 11, and G-CSF was started on day þ 8. Instead, prednisolone was administered according to the Stanford scheme and tapered by day þ 27. On day þ 20, the patient was still positive for pandemic H1N1, and a serum galactomannan assay for aspergillus demonstrated a positive result. Fluconazole was replaced by voriconazole, and substitution with i.v. Igs was initiated. A second chest CT scan showed streaky consolidation and fibrosis involving subpleural and peribronchial areas, but no typical signs of invasive pulmonary aspergillosis (Figure 1b). At that time, the patient developed severe respiratory distress and required supplemental oxygen. Intermittent non-invasive ventilation was initiated. A triple combination of oseltamivir 150 mg twice daily, amantadin 75 mg thrice daily and ribavirin 200 mg twice daily was started. Because of suspected oseltamivir resis- tance and prolonged viral shedding, viral resistance was tested by genotyping and IC50 phenotyping from nasal and pharyngeal areas, before triple therapy. Resistance testing revealed two virus subpopulations, one susceptible to oseltamivir, the other resistant to oseltamivir (Figure 2a). There was a resistance to oseltamivir based on a known mutation that results in a histidine-to-tyrosine substitution at position 274 (H274Y). Both the subpopulations were susceptible to zanamivir. In accordance with the data of the World Health Organization, up to February 2010, a total of 225 oseltamivir-resistant H1N1-09 cases had been reported worldwide. All these cases were based on the H274Y mutation, conferring resistance to oseltamivir but not to zanamivir. 2 Therefore, zanamivir represents the therapeutic option for patients infected with the H274Y mutation of H1N1-09 virus. After 2 weeks, the triple therapy was stopped, as the oseltamivir-resistant virus population increased (Figure 2b) and, finally, only oseltamivir-resistant virus was detectable (Figure 2c). The follow-up CT scan showed worsening fibrosis (Figure 1c). At that time, we initiated i.v. zanamivir, supplied within a GlaxoSmithKline compassio- nate use program, and topical zanamivir. Zanamivir was administered twice daily 600 mg i.v. and at the same time as an aerosilized formula twice daily 10 mg. Ten days later, virus RNA was no longer detectable. Virus clearance was confirmed in subsequent tests. The final chest CT scan revealed post-pneumonia fibrosis (Figure 1d). The final pulmonary function test showed a moderate restrictive ventilation disorder and a moderate diffusion disturbance. Several aspects of this case report deserve attention. First, despite accommodation in single rooms with HEPA- filtered air supply, the use of face masks and frequent hand disinfections, the patient acquired H1N1 infection during the pandemic peak in Germany. Despite investigative efforts, the route of infection could not be clarified. It cannot be excluded that the patient has been infected by a medical staff with asymptomatic disease. The most effective measure to protect patients from influenza during a pandemia is by active immunization of medical staff. Personal rights of the medical staff, however, preclude Bone Marrow Transplantation (2011), 1–3 & 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11 www.nature.com/bmt