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Influenza A/pandemic 2009/H1N1 in the setting of allogeneic hematopoietic cell transplantation: a potentially catastrophic problem in a vulnerable population

Influenza A/pandemic 2009/H1N1 in the setting of allogeneic hematopoietic cell transplantation: a potentially catastrophic problem in a vulnerable pop

Influenza A/pandemic 2009/H1N1 in the setting of allogeneic hematopoietic cell transplantation: a potentially catastrophic problem in a vulnerable population   (Citations: 12)
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We describe Influenza A/pandemic 2009/H1N1 in two allogeneic hematopoietic cell transplantation recipients. The main presentation in both cases consisted of flu-like symptoms manifesting as, fever, arthralgias and myalgias. The virus was isolated in one case from a throat swab and in another case following a bronchoalveolar lavage. Both patients received oseltamivir at a dose of 75 mg orally twice day. The dose of oseltamivir was increased to 150 mg twice per day due to the lack of improvement or progression of symptoms. In one case, clinical symptoms resolved without sequelae. In the second case, pulmonary symptomatology continued to deteriorate, despite aggressive polymicrobial treatment, requiring mechanical ventilation and ultimately the patient died from respiratory failure. These cases highlight the potentially serious effect of the ongoing Influenza A/pandemic 2009/H1N1 pandemic in this very vulnerable population and the urgent need to establish emergency preparedness strategies by oncology and bone marrow transplantation staff to face this serious healthcare challenge.
Journal: International Journal of Hematology - INT J HEMATOL , vol. 91, no. 1, pp. 124-127, 2010
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    • ...In view of 2009 pandemic influenza A (H1N1) and against the background of the preventive nationwide availability of the vaccine Pandemrix™ (GlaxoSmithKline) in Germany since October 2009, the question was raised if patients after allogeneic hematopoietic stem cell transplantation (HSCT) should be vaccinated or not [2]...

    Markus Ditschkowskiet al. H1N1 in allogeneic stem cell recipients: courses of infection and infl...

    • ...15 Our present knowledge about the 2009 H1N1 influenza among recipients of HSCT, however, is still limited; early reports have indicated a potential for increased morbidity and mortality among recipients of HSCT with the 2009 H1N1 influenza...

    R Rihaniet al. Infections with the 2009 H1N1 influenza virus among hematopoietic SCT ...

    • ...Intensive public health and health service planning for effective management of the pandemic was implemented in Italy. In particular, the Public Health Agency (Agenzia di Sanità Pubblica; ASP) of the Lazio region published operative indications for hospitals, emergency care units, and other public health services within the region (http://www.asplazio.it). As in most European countries, an intense wave of A (H1N1)v infections occurred in Italy during the period of October to December 2009 (http://www.iss.it/iflu/). Here we report the epidemiologic and clinical data derived from surveillance adopted at our center.Patients and MethodsClinical and Virologic Criteria of DiagnosisASP operative indications for the management of the 2009 A (H1N1)v influenza pandemic, updated in August 2009, were applied (http://www.asplazio.it/home/notizie/files/inf_suina/ aggiornamenti/Nota%20h1n1%20aggiornamento_Agosto_ 2009%20.pdf).A case of influenza A (H1N1)v infection was defined by clinical and microbiologic criteria. The clinical criteria were represented by an influenza-like illness with fever and signs of acute respiratory infection defined as at least 1 of the following symptoms: cough, nasal congestion, and sore throat. Detection of an A (H1N1)v influenza virus RNA-specific fragment by real-time reverse transcriptase polymerase chain reaction (RT-PCR) provided the microbiologic diagnostic criteria. Detections were performed on respiratory secretions collected by viral-specific nasopharyngeal swabs (Virocult; Medical Wire & Equipment, Corsham, UK) and resuspended in 4 ml of phosphate-buffered saline. A 400-µl aliquot of the specimen was used for automated RNA extraction with an EZ1 viral kit (QIAGEN, Hilden, Germany) for use in RT-PCR. The primers and probes for the H1 gene (swH1) and M gene (InfA) used in this work were recommended by the World Health Organization [WHO; protocol of real-time RT-PCR for influenza A (H1N1); http://www.who.int/csr/resources/publications/swineflu/CDCRealtimeRTPCR_Swine H1 Assay-2009, 20090430.pdf.] and synthesized by Applied Biosystems (Forest City, Calif., USA). RT-PCR was performed in a 25-µl reaction volume containing 5 µl of the extracted RNA, 12.5 µl 2× AgPath-ID™ One-Step RT-PCR buffer, 1 µl enzyme mix, and 0.5 µl primers and probes (assay mix) in a fluorometric PCR instrument (ABI 7300). Thermal cycling conditions were 30 min at 50°C followed by 10 min at 95°C and a subsequent 45-cycle amplification (95°C for 15 s and 55°C for 30 s; fluorescence was collected at 55°C).Design of the StudyStarting in October 2009, a wide information campaign addressed to patients and health care personnel was carried out at our hematologic Institute according to the above-mentioned ASP operative indications. Information regarded A/H1N1 vaccination and the epidemiologic control strategy (diagnosis, treatment, and management of suspected cases). Outpatients with HM or nonmalignant severe hematologic diseases or those who had been submitted to HSCT were instructed to refer to the dedicated Hematologic Emergency Unit (HEU) of the institute in the event of fever and respiratory symptoms. Careful surveillance of inpatients was also implemented in order to detect nosocomial cases of influenza infection early. Patients were evaluated by physical examination, laboratory exams, blood cultures, radiography or computed tomography of the chest, and other exams as indicated. Patients with signs and symptoms compatible with a definition of influenza-like illness were considered. Those in unstable clinical conditions and/or with progressive underlying hematologic disease were hospitalized in single-bed rooms and respiratory specimens were sent for RT-PCR to the regional reference Virology Laboratory (Policlinico Agostino Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy). Inpatients diagnosed with a hospital-acquired influenza-like illness underwent clinical evaluation and virologic tests and were transferred to a single-bed room. Antiviral therapy with oral oseltamivir (75 mg b.i.d. in adults and dosed according to body weight in children, for at least 5 days) was administered empirically early after patient presentation and regardless of the virologic test results. Systemic antibacterial agents were almost always empirically associated with the antiviral therapy. Targeted antimicrobial therapy was administered to patients with other documented infections. Patients in good clinical condition and with stable underlying hematologic disease were managed in an outpatient setting, and RT-PCR was not performed.The Review Board of our institute discussed and approved the adapted application protocol and operative indications of the ASP of Lazio. Each case of influenza-like illness, regardless of RT-PCR confirmation, was reported to the local Epidemiologic Infection Control Service and informed consent was obtained from all patients.Statistical AnalysisStudent’s t test and Fisher’s exact test were used for comparisons when appropriate. p < 0.05 was considered statistically significant. All probabilities were 2 tailed.ResultsForty-six outpatients presented at our HEU between October 9 and December 22, 2009, with signs and symptoms compatible with an influenza-like illness. The onset of symptoms had occurred an average of 1 day (range <1–4) before HEU presentation. Of these patients, 15 (32.6%) presented with mild symptoms and stable underlying disease; therefore, they were not hospitalized and the virologic test was not performed according to operative indications. These patients were excluded from further analysis. The remaining 31 outpatients who presented to the HEU with unstable clinical conditions or progressive underlying disease were hospitalized. Six further suspected cases were observed among patients already hospitalized in our department. Overall, RT-PCR for influenza A (H1N1)v was performed in the 31 outpatients who were newly admitted and in the 6 patients already hospitalized. The virologic exam was positive in 21 (56.8%) cases (18 outpatients and 3 inpatients).The frequency and time of documentation of the 21 A/H1N1v RT-PCR-positive cases and the 16 A/H1N1v RT-PCR-negative cases is shown in figure 1. The frequency of cases observed reached its peak between weeks 45 and 48. This epidemiologic pattern was in agreement with the official data of the epidemiologic surveillance program of influenza-like illness of the Italian National Institute of Health (fig. 2) (http://www.iss.it/binary/iflu/cont/ Grafici_Regioni2010_13.pdf).
      1Fig. 1. Frequency and time of observation of RT-PCR-positive and RT-PCR-negative influenza-like illness cases at a hematologic institute in Rome during the period of October to December 2009.F01
      2Fig. 2. Incidence of influenza in Lazio, Italy, during the season of 2009–2010 (http://www.iss.it/binary/iflu/cont/Grafici_ Regioni2010_13.pdf).F02
      The characteristics and the outcome of influenza A/H1N1v RT-PCR-positive and A/H1N1v RT-PCR-negative patients are detailed in table 1. Out of 21 patients with positive A/H1N1v RT-PCR, 23.8% were children (age <18 years), 9.5% were >65years, 47.4% had received intensive chemotherapy during the previous month, 19% had been submitted to an allogeneic HSCT, and 19% had a concomitant chronic pulmonary disease. Only 2 patients (9.5%) with positive A/H1N1v RT-PCR had been vaccinated with the pandemic vaccine (Focetria; Novartis Vaccines, Siena, Italy) during the 2 weeks before the onset of symptoms.1Table 1. Characteristics and outcome of 37 patients with influenza-like illness who required hospitalizationT01
      Each patient’s absolute lymphocyte count (ALC) and absolute neutrophil count (ANC) at influenza-like illness diagnosis were compared to their baseline values (most recent ALC and ANC that had been measured at least 1 week prior to the diagnosis of influenza-like illness). In A/H1N1v RT-PCR-positive patients, the mean baseline ALC was 1.261 ! 109/l cells (range 0.150–4.700) which declined to a mean of 1.089 ! 109/l cells (range 0.40–3.520) (p < 0.001), whereas the mean baseline ANC was 5.489 ! 109/l cells (range 0.830–15.900) which declined to a mean of 4.725 ! 109/l cells (range 0.040–22.670) (p = 0.31). In A/H1N1v RT-PCR-negative patients, the mean baseline ALC was 1.958 ! 109/l cells (range 0.220–9.700) which declined to a mean of 1.468 ! 109/l cells (range 0.070–3.500) (p = 0.38), whereas the mean baseline ANC was 4.656 ! 109/l cells (range 0.090–15.200) which declined to a mean of 4.186 ! 109/l cells (range 0.050–19.000) (p = 0.75).Fever, cough, and nasal congestion represented the clinical manifestations more frequently observed in both A/H1N1v RT-PCR-positive and A/H1N1v RT-PCR-negative cases. Ten out of 21 (47.6%) A/H1N1v RT-PCR-positive patients had a radiologically documented pulmonary infiltrate. The radiographic findings included alveolar, ground glass, and diffuse interstitial infiltrates in 4, 4, and 2 patients, respectively. Seven (70%) of these patients developed respiratory failure which required oxygen therapy in 6 cases. The factors potentially associated with the development of pneumonia in A/H1N1v RT-PCR-positive patients are detailed in table 2. Pulmonary involvement was observed more frequently in patients with a baseline comorbidity (mainly chronic respiratory disease) compared to those without a baseline comorbidity (p = 0.06). Despite the high incidence of pneumonia, no patient was transferred to the intensive care unit and in all cases respiratory impairment improved with supportive and antimicrobial therapy. A/H1N1v RT-PCR-positive patients required 7 median days (range 3–45) of hospitalization. There was no difference in days of hospitalization among patients with or without confirmation of A (H1N1)v infection. Regardless of RT-PCR confirmation of A/H1N1v infection, all patients received a course of oseltamivir therapy starting an average of 1 day (range <1–2) after the onset of symptoms. The duration of treatment with oseltamivir was 5 days for all patients, but 4 patients with a confirmed infection and respiratory failure received 10 days of antiviral treatment because of prolonged symptoms (1 of them had a persistent RT-PCR-positive test). Overall, 2 patients (9.5%) with an RT-PCR-confirmed A/H1N1v infection died during the same hospitalization. Death was due to the underlying hematologic disease, and the viral infection played no primary role in the outcome.2Table 2. Risk of pneumonia in 21 cases with RT-PCR-confirmed influenza A (H1N1)v infectionT02
      DiscussionSeasonal influenza infection has been reported as a severe complication in HM and HSCT patients, with a high frequency of pneumonia and a case fatality rate of up to 30% [,,,,,,,,,...

    Corrado Girmeniaet al. Management of the 2009 A/H1N1 Influenza Pandemic in Patients with Hema...

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