Age: 11.0
Sex: F
Vaccine: FLU(H1N1)
Symptoms: T-lymphocyte count decreased, Viral test negative, White blood cell count decreased
Clinical narrative: Case number PHHY2012US061251 is an initial literature report received on 07 Jul 2012: In this article the authors reported a case of an immunosuppressed pediatric renal transplant patient with mild pneumonia caused by oseltamivir-resistant 2009 H1N1 influenza and successfully treated with zanamivir. This report refers to an 11-year-old female patient. Her medical history included renal transplant (Aug 2004) for solitary dysplastic kidney. She had been managed with sirolimus 1 mg twice a day, azathioprine 50 mg daily, and prednisone 6 mg every other day until August 2009 when nephrotic-range proteinuria was noted. Sirolimus was discontinued, and tacrollmus 2 mg twice daily was started. Two months later, her proteinuria persisted, and her renal function deteriorated with a creatinine up to 2.0 mg/dL. Renal allograft biopsy showed acute cellular and humoral rejection. Donor-specific antibodies were positive to both HLA class I and class II antigens. She was treated with pulse methylprednisolone and five days of plasmapheresis, followed by intravenous immunoglobulin G (IgG) GAMUNEX and two doses of rituximab IV 600 mg/m2 dose two week apart. Her baseline immunosuppression was intensified with tacrolimus levels of 8-10 ng/mL and initiation of mycophenolate mofetil. Trimethoprim/sulfamethoxazole and valganciclovir prophylaxis was started. Subsequent flow cytometry revealed significantly low numbers of T cells (533 cells/mm cube) with no immunophenotypic abnormalities, three NK cells per mm cube, and no B cells. Within 10 days of her hospitalization for allograft rejection, she was exposed to an asymptomatic cousin who was later diagnosed with confirmed 2009 H1N1. She was asymptomatic and received an empiric 10-day course of oseltamivir prophylaxis (60 mg PO daily) as an outpatient within 48 hours of post-exposure. She was vaccinated with S-OIV FLUVIRIN (batch number: unknown) on 05 Nov 2009, eight days after her last rituximab infusion. She had previously received a seasonal influenza vaccine. One month later, she was admitted in a hospital due to increased fatigue in the preceding day, fever to 104 degree Fahrenheit, and a history of exposure to classmates with presumed viral infections. Had no upper or lower respiratory symptoms or signs and had normal oxygen saturation on room air. In the emergency department, a chest roentgenogram revealed poorly defined left lower lobe opacity and she was reported to have mild pneumonia. A nasopharyngeal swab specimen was positive for influenza A virus by direct fluorescent antibody (DFA). A separate nasopharyngeal swab specimen tested positive for 2009 H1N1 influenza A virus by real time polymerase chain reaction (RT-PCR). Blood and urine cultures were sterile. She was started on oseltamivir 60 mg orally twice daily and ceftriaxone 50 mg/kg intravenous daily. She defervesced promptly and had no other symptoms. She was hospitalized for three days and completed a 10-day course of oseltamivir and amoxicillin/clavulanate. Seven days after cessation of antimicrobials, the girl developed fatigue and a fever to 103.3 degree Fahrenheit. Evaluation in the emergency department revealed crackles in the left lower zone on chest auscultation but no respiratory distress, oxygen saturations of 98% on room air, white blood cell count 3300/mL with 54% neutrophils and 31% lymphocytes, blood urea nitrogen 26 mg/dL and creatinine 1.7 mg/dL, and an increased opacification in the left lower lobe with new patchy consolidation in the left upper lobe on chest roentgenogram. A DFA test and RT-PCR assay performed on nasopharyngeal swabs were positive for 2009 H1N1 influenza. Resistance testing for the H1N1 influenza virus was initiated given her history of recent confirmed H1N1 infection with oseltamivir treatment, as well as prior oseltamivir prophylaxis. Tests for Epstein Barr virus (EBV, blood PCR), Chimpanzee cytomegalovirus (CMV, blood antigenemia), influenza B virus, parainfluenza virus, adenovirus, human metapneumovirus and respiratory syncytial virus, and Legionella pneumophilia (urine antigen) as well as blood and urine cultures were negative. Subsequently, influenza A virus was isolated by viral shell culture using R-mix, a combination of mink lung and A549 cells and rhesus monkey kidney cells (RMK) cells. She required no supplemental oxygen and was treated with inhaled zanamivir 10 mg twice daily, vancomycin 15 mg/kg IV every eight hours, and levofloxacin 10 mg/kg orally daily for presumed oseltamivir-resistant 2009 H1N1 and possible bacterial coinfection. Blood and urine cultures were sterile, and she defervesced within 24 hours. She was discharged on the third hospital day and completed a 10-day course of zanamivir, trimethoprim/sulfamethoxazole 160 mg orally twice daily, and cefdinir 250 mg orally twice daily and a five-day course of azithromycin 200 mg orally daily as an outpatient. The nasopharyngeal sample from the second admission to this institution was confirmed to be positive for 2009 H1N1 in real-time RT-PCR assay at the Centers for Disease Control and Prevention (CDC) followed by sequencing the hemagglutinin (HA), neuraminidase (NA), and matrix (M) genes from the respiratory sample. The H275Y mutation in the NA was detected. This mutation conferred virus resistance to oseltamivir while retaining susceptibility to zanamivir. There were no individual changes in the M gene, while a number of mutations were found in the Ha gene (V19I, E112K, S203T, H273Y, E374K). Two weeks after initiating zanamivir, a repeat nasopharyngeal swab was positive for influenza A in a DFA assay but it was negative by viral culture. She also experienced fever and cough in Dec 2009. One month after the patient's clinical recovery, repeat flow cytometry demonstrated persistently low numbers of peripheral blood lymphocytes: 363 T cells per mm cube, 4 NK cells per mm cube, and no B cells. The CDC performed micro neutralization and hemagglutination inhibition assays for specific antibodies to 2009 H1N1 influenza in sera obtained six week after the patient's second hospitalization. No antibodies were detected, indicating a lack of an influenza-specific adaptive immune response that was likely due to her recent rituximab infusions. She remained asymptomatic despite persistently positive influenza A DFA tests for at least six week after initiating zanamivir, repeat viral cultures were sterile. She had no further complications during the following six months of close monitoring, including no recurrence of allograft rejection.