From October 2004 through October 2006 a study was performed to evaluate the prevalence of human Metapneumovirus (hMPV) infection in adult hematopoietic stem cell transplant (HSCT) recipients. Sequential nasopharyngeal aspirates (NPA) were collected independently from respiratory symptoms and evaluated for hMPV-RNA by polymerase chain reaction (PCR) and sequence analysis. Results indicate epidemiological and molecular differences between the 2004-2005 and 2005-2006 periods and that hMPV seems not to symptomatically affect HSCT patients or cause late respiratory sequelae. In addition, data collected suggest a hospital origin of hMPV infection in most HSCT patients during the 2004-2005 period

ALESSANDRINO PAOLO EMILIO

BIANCHI EMANUELA

CALDERA DANIELA

CANDUCCI FILIPPO

CLEMENTI MASSIMO

COLOMBO ANNA AMELIA

DEBIAGGI MAURIZIA

MARINOZZI MARIA CHIARA

MIGLIAVACCA ROBERTA

ROMERO EGIDIO

SAMPAOLO MICHELA

TERULLA CRISTINA

ZENONE BRAGOTTI LETIZIA

DEBIAGGI, MAURIZIA

Canducci F

TERULLA, CRISTINA

Sampaolo M

Marinozzi MC

Alessandrino PE

Colombo AA

Caldera D

Bragotti LZ

MIGLIAVACCA, ROBERTA

Bianchi E

ROMERO, EGIDIO

Clementi M.

Archivio Istituzionale della Ricerca - Università degli Studi di Pavia

NEW MICROBIOLOGICA, 30, 255-258, 2007Long-term study on symptomless humanmetapneumovirus infection in hematopoieticstem cell transplant recipientsMaurizia Debiaggi1, Filippo Canducci2,3, Cristina Terulla4, Michela Sampaolo2,3,Maria Chiara Marinozzi2,3, Paolo Emilio Alessandrino5, Anna Amelia Colombo5, Daniela Caldera5,Letizia Zenone Bragotti5, Roberta Migliavacca1, Emanuela Bianchi6, Egidio Romero1,4,Massimo Clementi2,31Dipartimento Scienze Morfologiche Eidologiche e Cliniche, Sezione Microbiologia, Università di Pavia, Italy;4Servizio Analisi Microbiologiche;5Centro Trapianti Midollo Osseo, IRCCS San Matteo, Pavia, Italy2Lab Microbiologia e Virologia, IRCCS;3Università Vita-Salute San Raffaele, Milano, Italy;6Azienda Ospedaliera Melegnano, Presidio Vizzolo PredabissiFrom October 2004 through October 2006 a study was performed to evaluate the prevalence of humanMetapneumovirus (hMPV) infection in adult hematopoietic stem cell transplant (HSCT) recipients. Sequential nasopha-ryngeal aspirates (NPA) were collected independently from respiratory symptoms and evaluated for hMPV-RNA bypolymerase chain reaction (PCR) and sequence analysis. Results indicate epidemiological and molecular differ-ences between the 2004-2005 and 2005-2006 periods and that hMPV seems not to symptomatically affect HSCTpatients or cause late respiratory sequelae. In addition, data collected suggest a hospital origin of hMPV infectionin most HSCT patients during the 2004-2005 period.KEY WORDS: Human metapneumovirus, Hematopoietic stem cell transplantation, Acute respiratory diseaseSUMMARYHuman Metapneumovirus (hMPV) is an impor-tant cause of acute respiratory tract disease innormal infants and children worldwide, and alsoplays a role in adults, particularly the elderly andthose with comorbid conditions such as chron-ic obstructive pulmonary disease, asthma andcancer (van den Hoogen et al., 2002; Williams etal., 2004; Hamelin et al., 2005; Williams, 2005;Martinello et al., 2006). In adult patients withhaematological malignancies and symptomaticrespiratory tract infection, hMPV was recoveredwith a positivity rate of 3-9% (Williams et al.,2005; Englund et al., 2006). Clustered cases sug-gesting the possibility of nosocomial epidemicsin hospitalized patients were also reported(Larcher et al., 2005; Honda et al., 2006). We recently described a high rate of asympto-matic and persistent hMPV infection in immuno-compromised patients undergoing hematopoieticstem cell transplantation (HSCT) (Debiaggi et al.,2006). From October 2004 through October 2005,we recovered positive samples from 18 out of 21patients without differences in seasonal distri-bution. In addition, sequence analysis docu-mented infection by hMPV genotype A only andwere identical in the amplified region.This previous observation led us to perform along-term survey to evaluate the real prevalenceof asymptomatic hMPV infection, and the pos-sible appearance of late respiratory sequelae inCorresponding authorMaurizia DebiaggiUniversità di PaviaDipartimento di Scienze morfologiche Eidologiche e ClinicheSezione di MicrobiologiaVia Brambilla 74, 27100 Pavia, ItalyE-mail: mdeb@unipv.itHSCT positive recipients by collecting additionalepidemiological and molecular data through twoconsecutive epidemic periods. In this study we evaluated patients admitted fromOctober 2005 through October 2006 at theDivision of Hematology, IRCCS San MatteoHospital for allogenic or autologous stem celltransplantation. At the same time, patients whoexperienced transplantation during the 2004-2005period, most of whom were described in our pre-vious survey, were included in this study for long-term monitoring. All patients were enrolled irre-spective of respiratory symptomsIn the same two-year period, NPA samples fromchildren <2 years recruited at Melegnano Hospitalwith acute respiratory diseases (ARDs) were eval-uated as controls of hMPV seasonal prevalence.In HSCT patients, NPA samples were collectedat different times points (from before HSCT to180 days after HSCT) as described (Debiaggi etal., 2006). In patients recruited from the 2004-2005 period the presence of hMPV RNA in NPAsamples was evaluated from 180 days up to 14months after transplant.In all patients clinical data were collected andexamined for sign or symptoms of respiratorytract infection or late respiratory sequelae. Detection of hMPV RNA in NPA samples was per-formed by reverse transcription (RT)-poly-merase chain reaction (PCR) as described(Debiaggi et al., 2006). Briefly, viral RNA wasextracted from samples using a Qiagen RNAminikit (Qiagen), reverse transcribed by use ofrandom hexamers and amplified by use of aprimer mix including 1 forward and 2 reverseprimers to amplify a 150-bp region of the N geneof all known or possible hMPV subtypes.Amplified PCR products were separated byagarose gel electrophoresis and sequenceddirectly by use of BigDye Terminator v3.1 anda ABI 3100 sequencer (Applied Biosystems).Alignments of sequences and phylogenetic rela-tionships were evaluated as previously reportedin detail (Debiaggi et al., 2006). From October 2004 through October 2006, 53adult HSCT patients (23 in 2004-2005 and 30 in2005-2006 period ) recruited at the Division ofHematology, IRCCS san Matteo Hospital wereevaluated. In the first year, twenty-one out of the23 were allogenic HSCT patients and belongedto the group of patients included in our previ-ous study, and the remaining two were autolo-gous HSCT. From patients recruited in 2004 and 2005, a totalof 168 NPA samples (125 obtained in the 2004-2005 and 43 in the 2005-2006 two years follow-up) were examined. The presence of hMPV RNAsequences was detected in 58 (34.5%) out of 168NPA samples collected from 19 out of 23enrolled patients (82.6%, 18 allogenic and 1 autol-ogous). Fifty-five (94.8%) out of the 58 positivesamples were collected in the 2004-2005 period. From the 30 patients enrolled in the 2005-2006period (10 allogenic and 20 autologous HSCT)133 NPA samples were obtained and evaluatedfor presence of hMPV RNA. Viral RNA sequenceswere detected in 3 (2.2%) out of 133 samples from2 (6.6%, one allogenic and one autologous) outof 30 patients.In children with ARDs, hMPV RNA was detect-ed in 37 out of 244 (15.1%) in the 2004-2005 andin 30 out of 132 (23%) in the 2005-2005 period. Month1y distribution of positive samples fromOctober 2004 to October 2006 in both HSCT andpediatric patients is reported in Figure 1. In chil-dren a similar prevalence was observed through-out the two seasonal periods. Positive sampleswere detected mainly in winter and spring withincidence peaking in January-February in 2004-2005 and in March-April in 2005-2006 (Figure la).A different pattern in hMPV distribution andprevalence of positive samples was observed inHSCT patients between the two years with highprevalence isolation throughout the entire 2004-2005 seasonal period and very low prevalence onlyin February-March throughout the following year.Sequencing studies revealed hMPV genotype Ain all specimens from HSCT patients, neverthe-less nucleotide comparison of amplified sequencefrom samples collected in the 2004-2005 periodshowed a 100% similarity. Three specific muta-tions (2.5% difference) were instead observed inisolates amplified in the 2005-2006 season.No specific respiratory symptoms were docu-mented in HSCT patients at the time of hMPVdetection in NPA samples and only mild upperrespiratory tract symptoms (rhinorrea or drycough) were present in 9 out of 19 positivepatients in the first period and in one out of twopositive patients in the following season. In addi-tion, long-term monitoring of patients recruit-ed in 2004-2005 period, when most of them were256 M. Debiaggi, et al.persistently infected, showed no late respirato-ry sequelae.In this long-term prospective study we docu-mented epidemiologic and molecular differencesin hMPV infection both in two groups ofpatients (HSCT and pediatric) and during twoepidemic periods in transplanted patients. Weevaluated 23 HSCT patients, including 21 whohad an allogenic and two who underwent anautologous transplantation in the 2004-2005 peri-od and 30 patients including 10 allogenic and 20autologous in the 2005-2006 period. Though wecompared groups having a different distributionbetween autologous and allogenic transplantsduring the two epidemic periods, our resultsabout the observed difference in prevalencewould not change even considering only the allo-genic HSCT. These patients are comparable innumber during the two periods and are the mostnumerous in the study.The hMPV seasonal distribution as well as theprevalence in the two consecutive periods, whenreferred to the pediatric patients, is similar to thatobtained in several studies and reflects the effec-tive yearly virus circulation (Maggi et al., 2003,Kahn, 2006). In HSCT patients we observed a high-er prevalence and a lack of seasonal peaks dur-ing the 2004-2005 period compared to the fol-lowing period in the same patient group and inpediatric patients. These results are consistent withan intrahospital viral spread in a large proportionof these transplanted patients. The molecularresults obtained in this study support such viruscirculation, since possibly the same viral strain wasdetected during the 2004-2005 period, and two dis-tinct viral strains were identified in the 2005-2006period. On the other hand, viral spread in hospi-talized patients has also been reported in recentpapers (Larcher et al., 2005, Honda et al., 2006).This survey revealed that hMPV infection in HSCTpatients observed in this study is always asymp-tomatic and patients suffer no late respiratorysequelae. Nevertheless other studies addressingsymptomatic patients found hMPV infection inabout 9% of adults with hematologic malignan-cies (Williams et al., 2005, Englund et al., 2006),so that symptomatic infection cannot be exclud-ed and the pathogenic (or co-pathogenic) role ofthe virus in these patients remains unclear.In conclusion our data indicate that hMPV maybe transmitted among hospitalized immuno-compromised patients. Furthermore in HSCTpatients hMPV infection is frequently asympto-matic suggesting that further research is need-ed to evaluate the virus-host interactions and therole of the immune system both on protectionand eventually in the pathogenic mechanism ofthe disease caused by hMPV.ACNOWLEDGMENTSThis research was founded by the IRCCSPoliclinico San Matteo (grant 08058605) andUniversità di Pavia, Fondo Ateneo di Ricerca 2006.Symptomless Metapneumovirus infection 257FIGURE 1 - Human metapneumovirus (hMPV) infection in pediatric patients with acute respiratory diseases(1a) and in HSCT recipients (1b) from October 2004 to October 2006. hMPV positive samples (striped bars) andtotal number of tested samples (black bars) per month are shown.A BREFERENCESDEBIAGGI, M., CANDUCCI, F., SAMPAOLO, M., MARINOZZI,M.C., PAREA, M., TERULLA, C., COLOMBO, A.A.,ALESSANDRINO, P.E., ZENONE BRAGOTTI, L.,ARGHITTU, M., GOGLIO, A., MIGLIAVACCA, R.,ROMERO, E., AND CLEMENTI, M. (2006). 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Long-term study on symptomless human metapneumovirus infection in hematopoietic stem cell transplant recipients.

Long-term study on symptomless human metapneumovirus infection in hematopoietic stem cell transplant recipients

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Long-term study on symptomless human metapneumovirus infection in hematopoietic stem cell transplant recipients

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Archivio Istituzionale della Ricerca - Università degli Studi di Pavia

Archivio Istituzionale della Ricerca - Università degli Studi di Pavia