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Role of rhinovirus C in apparently life-threatening events in infants, Spain.

Human rhinovirus (HRV) is 1 of the most common agents associated with upper and lower respiratory tract infections in children and infants (1) and is a major trigger of asthma exacerbations (2). Recently, molecular methods have shown substantial phenotypic variation of HRV and identified a novel HRV genogroup provisionally named HRV-C (3). Severe asthma exacerbations in children have been associated with this new genogroup of rhinoviruses. Genogroup C could be resistant to a new candidate group of antipicornavirus drugs, including pleconaril (4).

Apparently life-threatening events (ALTEs) in infants are associated with bronchiolitis or infections in up to 6% of patients by diagnosis after hospital admission (5). We assessed the relation between ALTEs and respiratory virus infection in a secondary hospital in Spain.

The Study

Our study was part of a systematic prospective study to assess the epidemiology of respiratory virus infections in children admitted to the Severo Ochoa Hospital (Leganes, Madrid Province, Spain).We conducted a specific study to determine the incidence of respiratory virus infections in all infants admitted after ALTEs during November 2004-December 2008. An ALTE in a child <1 year of age was defined as an episode that is frightening to the observer and characterized by some combination of apnea, color change, marked change in muscle tone, choking, or gagging so the observer fears the infant has died (6).

Nasopharyngeal aspirate (NPA) specimens were acquired from each eligible patient at the time of hospital admission (on Monday-Friday). Samples were sent for virologic study to the Influenza and Respiratory Virus Laboratory (National Centre for Microbiology, Institute of Health Carlos III, Spain). Specimens were processed within 24 hours after collection.

Total nucleic acids were extracted from 200-[micro]L aliquots by using a QIAamp MinElute Virus Spin Kit in a QIAcube automated extractor (QIAGEN, Valencia, CA, USA). Simple or multiplex reverse transcription-nested PCR assays (RT-PCR) previously described (7-9) were used to assess the virus diagnosis, including 16 respiratory viruses or groups of viruses. Degenerated primers for HRV and enteroviruses were designed between the 3' end of the 5' noncoding region (NCR) and the viral protein (VP) 4/ VP2 polyprotein gene (TCIGGIARYTTCCASYACCAICC3' and CTGTGTTGAWACYTGAGCICCCA-3'). HRVs from positive samples were identified by sequencing and phylogenetic analysis of these sequences. Amplified products (about 500 bp, depending on HRV serotype) were purified and sequenced in both directions by using an automated ABI PRISM 377 model sequencer. Partial sequences of HRV have been submitted to GenBank (accession nos. FJ841954-FJ841957, FJ841959-FJ841961, EU697826, and EU697832). Appropriate precautions were implemented to avoid false-positive results by carryover contamination. Positive results were confirmed by testing a second aliquot of the sample stored at -70[degrees]C.

Sixteen infants (8 of each sex) were enrolled in the study. All patients were <5 months of age (range 7 days-5 months, mean age 7.6 weeks, median 4 weeks). Twelve infants had rhinorrea, cough, and distress signs (Table). A total of 11 (69%) NPA specimens were positive for at least 1 viral agent. For 9 of these patients, positive results for HRV were confirmed, and for the other 2 patients, respiratory syncytial virus was detected.

Phylogenetic analyses of 9 sequences obtained from patients showed distribution of HRV in 3 clusters. Three sequences were included in previously characterized clades, defined by HRV group A (HRV-A, SO4923-EU697826) and B (HRV-B, SO3970-FJ841954 and SO4998-EU697832). Sequence from patient SO4923 had a low sequence similarity with the other serotypes of HRV-A. In contrast, sequences from patients SO3970 and SO4998 were closely related to HRV-35 and HRV-79, respectively. Six sequences were included in the third group corresponding to the new HRV-C: SO5854, SO6666, SO5797, SO6819, SO5986, SO6813- FJ841955-57 and FJ841959-61) (3,10) (Figure). Different genotypes (collectively called HRV-Cs) were identified in 6 NPA specimens from children with ALTEs (67% of total HRV). Two received cardiopulmonary resuscitation at home; for these 2 patients, a respiratory syncytial virus and an HRV-C were identified. All 16 children survived.

Conclusions

The most common discharge diagnoses reported for ALTEs are gastroesophageal reflux disease (GERD), unknown causes, seizures, and lower respiratory tract infections (11). Our series suggests that ALTEs of previously unknown etiology could be related to HRV infections. Rhinovirus infections are known to be a major cause of illness and hospital admission for young children, particularly infants <2 years of age (12). Detection of viral genomes by nested RT-PCR in NPA specimens led us to analyze the effect of HRV infections in different clinical situations. Respiratory infections associated with HRV might play a major role in young infants, probably with few clinical signs, and might contribute to apnea as a first manifestation. GERD is the most frequent hospital discharge diagnosis in published series (5,11). For our patients, GERD also was the most frequent clinical diagnosis (9 patients), but for 7 of them, a respiratory virus was identified. We cannot conclude whether GERD is a risk factor for apnea or whether signs are so nonspecific that diagnoses could be confused.

Alternatively, the new HRV-C group could account for as many as a quarter or even half of HRV infections (4,13). In children, it has been associated with bronchiolitis, wheezing, and asthma exacerbations severe enough to require hospitalization; the percentage of these children with hypoxia was substantial (13). In a case-control study, Khetsuriani et al. (4) found HRV-C only in case-patients, supporting the pathogenic role of this genogroup. They considered that HRV-C infections could be associated with more severe clinical manifestations than infections with other HRV genogroups A and B. These data could also support the role of HRV-C in infants with ALTEs found in this work.

[FIGURE OMITTED]

Although we had no control group for our patients, we recently published a study of a cohort of 316 newborns up to 6 months of age tested weekly for respiratory diseases (mainly upper respiratory tract infections), coincident in age and time with our patients (14). HRV was present in 5 (3.6%) of 72 infants tested. Two viruses were genetically identified as HRV-C, demonstrating they form distinct genetic clusters, and no genetic similarity was obtained with the ALTE-related HRV-C viruses. In addition, a second group of asymptomatic children of different ages but in coincident epidemic seasons was studied. The group of children with HRV was substantially smaller than the group of children with respiratory disease (15).

Viral infections could play a major role in ALTEs. Rhinoviruses, especially HRV-C, could cause a respiratory infection with few symptoms in young infants and could trigger ALTEs in this age group. Therefore, HRVs and posterior genotyping should be included in studies of the etiology of ALTEs to help identify the true relevance of HRV-C infection to these episodes.

Acknowledgments

We thank Lola Lopez-Valero, Nieves Cruz, Monica Sanchez, and Ana Calderon for technical assistance.

This work was supported by grant PI060532 by Fondo de Investigaciones Sanitarias, Institute of Health Carlos III. Research on viral respiratory infections is carried out in collaboration with the Influenza and Respiratory Viruses Laboratory at the National Center of Microbiology (ISCIII) and supported by the Health Research Fund.

DOI: 10.3201/eid1509.090453

References

(1.) Kusel MMH, Klerk NH, Holt PG, Kebadze T, Johnston SL, Sly P. Role of respiratory viruses in upper and lower respiratory tract illness in the first year of life. A birth cohort study. Pediatr Infect Dis J. 2006;25:680-6. DOI: 10.1097/01.inf.0000226912.88900.a3

(2.) Lemanske RF Jr, Jackson DJ, Gangnon RE, Evans MD, Li Z, Shult PA, et al. Rhinovirus illnesses during infancy predict subsequent childhood wheezing. J Allergy Clin Immunol. 2005;116:571-7. DOI: 10.1016/j.jaci.2005.06.024

(3.) Lamson D, Renwick N, Kapoor V, Liu Z, Palacios G, Ju J, et al. MassTag polymerase-chain-reaction detection of respiratory pathogens, including a new rhinovirus genotype, that caused influenzalike illness in New York State during 2004-2005. J Infect Dis. 2006;194:1398-402. DOI: 10.1086/508551

(4.) Khetsuriani N, Lu X, Teague WG, Kazerouni N, Aderson LJ, Erdman DD. Novel human rhinoviruses and exacerbation of asthma in children. Emerg Infect Dis. 2008;14:1793-6. DOI: 10.3201/ eid1411.080386

(5.) Bonkowsky JL, Guenther E, Filloux FM, Srivastava R. Death, child abuse and adverse neurological outcome of infants after apparent life-threatening event. Pediatrics. 2008;122:125-31. DOI: 10.1542/ peds.2007-3376

(6.) National Institutes of Health Consensus Development Conference on Infantile Apnea and Home Monitoring, Sep 29 to Oct 1, 1986. Pediatrics. 1987;79:292-9.

(7.) Pozo F, Garcia-Garcia ML, Calvo C, Cuesta I, Perez-Brena P, Casas I. High incidence of human bocavirus infection in children in Spain. J Clin Virol. 2007;40:224-8. DOI: 10.1016/j.jcv.2007.08.010

(8.) Coiras MT, Aguilar JC, Garcia ML, Casas I, Perez-Brena P. Simultaneous detection of fourteen respiratory viruses in clinical specimens by two multiplex reverse transcription nested-PCR assays. J Med Virol. 2004;72:484-95.

(9.) Lopez-Huertas MR, Casas I, Acosta-Herrera B, Garcia ML, Coiras MT, Perez-Brena P. Two RT-PCR based assays to detect human metapneumovirus in nasopharyngeal aspirates. J Virol Methods. 2005;129:1-7. DOI: 10.1016/j.jviromet.2005.05.004

(10.) Briese T, Renwick N, van den Berg M, Jarman R, Ghosh D, Kondgen S, et al. Role of rhinovirus in hospitalized infants with respiratory tract infections in Spain. Emerg Infect Dis. 2008;14:944-7. DOI: 10.3201/eid1406.080271

(11.) McGovern MC, Smith MB. Causes of apparent life threatening events in infants: a systematic review. Arch Dis Child. 2004;89:1043-8. DOI: 10.1136/adc.2003.031740

(12.) Calvo C, Garcia-Garcia ML, Blanco C, Pozo F, Casas I, Perez-Brena P. Rhole of rhinovirus in hospitalized infants with respiratory tract disease in Spain. Pediatr Infect Dis J. 2007;26:904-8. DOI: 10.1097/ INF.0b013e31812e52e6

(13.) Miller EK, Edwards KM, Weinberg GA, Iwane MK, Griffin MR, Hall CB et al. A novel group of rhinoviruses is associated with asthma hospitalizations. J Allergy Clin Immunol. 2009;123:105-6.

(14.) Bueno Campana M, Calvo Rey C, Vazquez Alvarez MC, Parra Cuadrado E, Molina Amores A, Rodrigo Garcia G, et al. Infecciones virales de vias respiratorias en los primeros 6 meses de vida. An Pediatr (Barc). 2008;69:400-5. DOI: 10.1157/13127993

(15.) Garcia-Garcia ML, Calvo C, Pozo F, Perez-Brena P, Quevedo S, Bracamonte T, et al. Human bocavirus detection in nasopharyngeal aspirates of children without clinical symptoms of respiratory infection. Pediatr Infect Dis J. 2008;27:358-60. DOI: 10.1097/ INF.0b013e3181626d2a

Author affiliations: Hospital Severo Ochoa, Leganes, Madrid, Spain (C. Calvo, M.L. Garcia); and National Center for Microbiology, Institute of Health Carlos III, Madrid (F. Pozo, N. Reyes, P. Perez-Brena, I. Casas).

DOI: 10.3201/eid1509.090453

Address for correspondence: Cristina Calvo, Hospital Severo Ochoa, Avda. Orellana, s.n.; 28911 Leganes; Madrid; Spain; email: ccalvorey@ ono.com

Dr Calvo is chief clinician of pediatrics at Hospital Severo Ochoa, Leganes, Madrid, Spain. Her research interests include infectious diseases in children.
Table. Characteristics of infants with ALTEs, Spain, November
2004-December 2008 *

Laboratory Sex/ Admission
no. age, wk date Clinical signs

SO3970 M/4 2004 Nov Cough, rhinorrea, loss of
 consciousness, flaccidity
SO4891 M/4 2005 Oct Cyanosis, loss of consciousness,
 flaccidity
SO4923 M/15 2005 Nov Apnea, flushing
SO4998 F/8 2005 Nov Choking, flushing, distress
SO5260 F/9 2006 Apr Cough, choking
SO5355 M/6 2006 Jun Apnea, cyanosis
SO5529 F/4 2006 Nov Apnea, congestion, cyanosis
SO5749 M/24 2007 Mar Choking, cyanosis
SO5797 F/6 2007 Mar Apnea, flushing
SO5854 F/6 2007 Apr Cough, rhinorrea, apnea
SO5896 M/13 2007 Sep Apnea, rhinorrea
SO6012 F/7 2007 Oct Cough, distress, apnea
SO6666 M/4 2008 Oct Cyanosis, choking
SO6813 F/6 2008 Nov Apnea, flaccidity
SO6819 M/6 2008 Nov Cough, rhinorrea, flushing
SO6816 F/1 2009 Jan Choking, flushing

Laboratory
no. Discharge diagnosis Virus Prematurity

SO3970 Choking HRV-B No

SO4891 Cyanosis No Yes (35 wk)

SO4923 Cyanosis + URTI HRV-A Yes (36 wk)
SO4998 URTI + GERD HRV-B No
SO5260 GERD No No
SO5355 URTI + GERD No No
SO5529 Bronchiolitis + GERD RSV No
SO5749 Wheezing No No
SO5797 Choking + GERD HRV-C No
SO5854 URTI + GERD HRV-C No
SO5896 Bronchiolitis + GERD HRV-C No
SO6012 URTI RSV-A No
SO6666 Choking HRV-C No
SO6813 Apnea + GERD HRV-C No
SO6819 URTI + GERD HRV-C No
SO6816 Choking No No

* ALTEs, acute life-threatening events; URTI, upper respiratory tract
infection; RSV, respiratory syncytial virus; HRV, human rhinovirus;
EV, enterovirus; GERD, gastroesophageal reflux disease.
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Article Details
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Title Annotation:DISPATCHES
Author:Calvo, Cristina; Garcia, M. Luz; Pozo, Francisco; Reyes, Noelia; Perez-Brena, Pilar; Casas, Inmacula
Publication:Emerging Infectious Diseases
Geographic Code:4EUSP
Date:Sep 1, 2009
Words:2047
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