Human Metapneumovirus and Lower Respiratory Tract Disease in Otherwise Healthy Infants and Children
John V. Williams, M.D., Paul A. Harris, Ph.D., Sharon J. Tollefson, B.A., Lisa L. Halburnt-Rush, M.Ed., Joyce M. Pingsterhaus, B.A., Kathryn M. Edwards, M.D., Peter F. Wright, M.D., and James E. Crowe, Jr., M.D.
Background We sought to determine the role of human metapneumovirusin lower respiratory tract illness in previously healthy infantsand children.
Methods We tested nasal-wash specimens, obtained over a 25-yearperiod from otherwise healthy children presenting with acuterespiratory tract illness, for human metapneumovirus.
Results A viral cause other than human metapneumovirus was determinedfor 279 of 687 visits for acute lower respiratory tract illness(41 percent) by 463 children in a population of 2009 infantsand children prospectively seen from 1976 to 2001. There were408 visits for lower respiratory tract illness by 321 childrenfor which no cause was identified. Of these 321 children, specimensfrom 248 were available. Forty-nine of these 248 specimens (20percent) contained human metapneumovirus RNA or viable virus.Thus, 20 percent of all previously virus-negative lower respiratorytract illnesses were attributable to human metapneumovirus,which means that 12 percent of all lower respiratory tract illnessesin this cohort were most likely due to this virus. The meanage of human metapneumovirus–infected children was 11.6months, the male:female ratio was 1.8:1, 78 percent of illnessesoccurred between December and April, and the hospitalizationrate was 2 percent. The virus was associated with bronchiolitisin 59 percent of cases, pneumonia in 8 percent, croup in 18percent, and an exacerbation of asthma in 14 percent. We alsodetected human metapneumovirus in 15 percent of samples from261 patients with upper respiratory tract infection but in only1 of 86 samples from asymptomatic children.
Conclusions Human metapneumovirus infection is a leading causeof respiratory tract infection in the first years of life, witha spectrum of disease similar to that of respiratory syncytialvirus.
Source Information
From the Division of Infectious Diseases, Departments of Pediatrics (J.V.W., S.J.T., L.L.H.-R., J.M.P., K.M.E., P.F.W., J.E.C.), Biomedical Engineering (P.A.H.), and Microbiology and Immunology (P.F.W., J.E.C.), Vanderbilt University Medical Center, Nashville.
Address reprint requests to Dr. Crowe at Vanderbilt University Medical Center, D-7235 Medical Center N., 1161 21st Ave. S., Nashville, TN 37232-2581, or at james.crowe{at}vanderbilt.edu.
Porotto, M., Yokoyama, C. C., Orefice, G., Kim, H.-S., Aljofan, M., Mungall, B. A., Moscona, A.
(2009). Kinetic Dependence of Paramyxovirus Entry Inhibition. J. Virol.
83: 6947-6951
[Abstract][Full Text]
Newcomb, D. C., Peebles, R. S. Jr.
(2009). Bugs and Asthma: A Different Disease?. Proc Am Thorac Soc
6: 266-271
[Abstract][Full Text]
Guerrero-Plata, A., Kolli, D., Hong, C., Casola, A., Garofalo, R. P.
(2009). Subversion of Pulmonary Dendritic Cell Function by Paramyxovirus Infections. J. Immunol.
182: 3072-3083
[Abstract][Full Text]
Cseke, G., Maginnis, M. S., Cox, R. G., Tollefson, S. J., Podsiad, A. B., Wright, D. W., Dermody, T. S., Williams, J. V.
(2009). Integrin {alpha}v{beta}1 promotes infection by human metapneumovirus. Proc. Natl. Acad. Sci. USA
106: 1566-1571
[Abstract][Full Text]
Kukavica-Ibrulj, I., Hamelin, M.-E., Prince, G. A., Gagnon, C., Bergeron, Y., Bergeron, M. G., Boivin, G.
(2009). Infection with Human Metapneumovirus Predisposes Mice to Severe Pneumococcal Pneumonia. J. Virol.
83: 1341-1349
[Abstract][Full Text]
Schowalter, R. M., Chang, A., Robach, J. G., Buchholz, U. J., Dutch, R. E.
(2009). Low-pH Triggering of Human Metapneumovirus Fusion: Essential Residues and Importance in Entry. J. Virol.
83: 1511-1522
[Abstract][Full Text]
Walsh, E. E., Peterson, D. R., Falsey, A. R.
(2008). Human Metapneumovirus Infections in Adults: Another Piece of the Puzzle. Arch Intern Med
168: 2489-2496
[Abstract][Full Text]
de Graaf, M., Osterhaus, A. D. M. E., Fouchier, R. A. M., Holmes, E. C.
(2008). Evolutionary dynamics of human and avian metapneumoviruses. J. Gen. Virol.
89: 2933-2942
[Abstract][Full Text]
Mok, H., Tollefson, S. J., Podsiad, A. B., Shepherd, B. E., Polosukhin, V. V., Johnston, R. E., Williams, J. V., Crowe, J. E. Jr
(2008). An Alphavirus Replicon-Based Human Metapneumovirus Vaccine Is Immunogenic and Protective in Mice and Cotton Rats. J. Virol.
82: 11410-11418
[Abstract][Full Text]
Derdowski, A., Peters, T. R., Glover, N., Qian, R., Utley, T. J., Burnett, A., Williams, J. V., Spearman, P., Crowe, J. E. Jr
(2008). Human metapneumovirus nucleoprotein and phosphoprotein interact and provide the minimal requirements for inclusion body formation. J. Gen. Virol.
89: 2698-2708
[Abstract][Full Text]
Mahony, J. B.
(2008). Detection of Respiratory Viruses by Molecular Methods. Clin. Microbiol. Rev.
21: 716-747
[Abstract][Full Text]
Shirogane, Y., Takeda, M., Iwasaki, M., Ishiguro, N., Takeuchi, H., Nakatsu, Y., Tahara, M., Kikuta, H., Yanagi, Y.
(2008). Efficient Multiplication of Human Metapneumovirus in Vero Cells Expressing the Transmembrane Serine Protease TMPRSS2. J. Virol.
82: 8942-8946
[Abstract][Full Text]
Kolli, D., Bataki, E. L., Spetch, L., Guerrero-Plata, A., Jewell, A. M., Piedra, P. A., Milligan, G. N., Garofalo, R. P., Casola, A.
(2008). T Lymphocytes Contribute to Antiviral Immunity and Pathogenesis in Experimental Human Metapneumovirus Infection. J. Virol.
82: 8560-8569
[Abstract][Full Text]
Yanney, M, Vyas, H
(2008). The treatment of bronchiolitis. Arch. Dis. Child.
93: 793-798
[Abstract][Full Text]
Liao, S., Bao, X., Liu, T., Lai, S., Li, K., Garofalo, R. P., Casola, A.
(2008). Role of retinoic acid inducible gene-I in human metapneumovirus-induced cellular signalling. J. Gen. Virol.
89: 1978-1986
[Abstract][Full Text]
Carroll, K. N., Gebretsadik, T., Griffin, M. R., Wu, P., Dupont, W. D., Mitchel, E. F., Enriquez, R., Hartert, T. V.
(2008). Increasing Burden and Risk Factors for Bronchiolitis-Related Medical Visits in Infants Enrolled in a State Health Care Insurance Plan. Pediatrics
122: 58-64
[Abstract][Full Text]
Aslanzadeh, J., Zheng, X., Li, H., Tetreault, J., Ratkiewicz, I., Meng, S., Hamilton, P., Tang, Y.-W.
(2008). Prospective Evaluation of Rapid Antigen Tests for Diagnosis of Respiratory Syncytial Virus and Human Metapneumovirus Infections. J. Clin. Microbiol.
46: 1682-1685
[Abstract][Full Text]
Nichols, W. G., Peck Campbell, A. J., Boeckh, M.
(2008). Respiratory Viruses Other than Influenza Virus: Impact and Therapeutic Advances. Clin. Microbiol. Rev.
21: 274-290
[Abstract][Full Text]
Schildgen, O., Muller, A., Allander, T., Mackay, I. M., Volz, S., Kupfer, B., Simon, A.
(2008). Human Bocavirus: Passenger or Pathogen in Acute Respiratory Tract Infections?. Clin. Microbiol. Rev.
21: 291-304
[Abstract][Full Text]
Arnold, J. C., Singh, K. K., Spector, S. A., Sawyer, M. H.
(2008). Undiagnosed Respiratory Viruses in Children. Pediatrics
121: e631-e637
[Abstract][Full Text]
Hamelin, M.-E., Couture, C., Sackett, M. K., Boivin, G.
(2007). Enhanced lung disease and Th2 response following human metapneumovirus infection in mice immunized with the inactivated virus. J. Gen. Virol.
88: 3391-3400
[Abstract][Full Text]
Melendi, G. A., Zavala, F., Buchholz, U. J., Boivin, G., Collins, P. L., Kleeberger, S. R., Polack, F. P.
(2007). Mapping and Characterization of the Primary and Anamnestic H-2d-Restricted Cytotoxic T-Lymphocyte Response in Mice against Human Metapneumovirus. J. Virol.
81: 11461-11467
[Abstract][Full Text]
Williams, J. V., Chen, Z., Cseke, G., Wright, D. W., Keefer, C. J., Tollefson, S. J., Hessell, A., Podsiad, A., Shepherd, B. E., Sanna, P. P., Burton, D. R., Crowe, J. E. Jr., Williamson, R. A.
(2007). A Recombinant Human Monoclonal Antibody to Human Metapneumovirus Fusion Protein That Neutralizes Virus In Vitro and Is Effective Therapeutically In Vivo. J. Virol.
81: 8315-8324
[Abstract][Full Text]
Panitch, H. B.
(2007). The Relationship Between Early Respiratory Viral Infections and Subsequent Wheezing and Asthma. CLIN PEDIATR
46: 392-400
Abiko, C., Mizuta, K., Itagaki, T., Katsushima, N., Ito, S., Matsuzaki, Y., Okamoto, M., Nishimura, H., Aoki, Y., Murata, T., Hoshina, H., Hongo, S., Ootani, K.
(2007). Outbreak of Human Metapneumovirus Detected by Use of the Vero E6 Cell Line in Isolates Collected in Yamagata, Japan, in 2004 and 2005. J. Clin. Microbiol.
45: 1912-1919
[Abstract][Full Text]
Biacchesi, S., Murphy, B. R., Collins, P. L., Buchholz, U. J.
(2007). Frequent Frameshift and Point Mutations in the SH Gene of Human Metapneumovirus Passaged In Vitro. J. Virol.
81: 6057-6067
[Abstract][Full Text]
Estrada, B., Carter, M., Barik, S., Vidal, R., Herbert, D., Ramsey, K. M.
(2007). Severe Human Metapneumovirus Infection in Hospitalized Children. CLIN PEDIATR
46: 258-262
[Abstract]
Dare, R., Sanghavi, S., Bullotta, A., Keightley, M.-C., George, K. St., Wadowsky, R. M., Paterson, D. L., McCurry, K. R., Reinhart, T. A., Husain, S., Rinaldo, C. R.
(2007). Diagnosis of Human Metapneumovirus Infection in Immunosuppressed Lung Transplant Recipients and Children Evaluated for Pertussis. J. Clin. Microbiol.
45: 548-552
[Abstract][Full Text]
Cseke, G., Wright, D. W., Tollefson, S. J., Johnson, J. E., Crowe, J. E. Jr., Williams, J. V.
(2007). Human Metapneumovirus Fusion Protein Vaccines That Are Immunogenic and Protective in Cotton Rats. J. Virol.
81: 698-707
[Abstract][Full Text]
Rathore, M. H.
(2007). Bocavirus: Yet Another New Pediatric Respiratory Virus. AAP Grand Rounds
17: 6-7
[Full Text]
Miller, S. A., Tollefson, S., Crowe, J. E. Jr., Williams, J. V., Wright, D. W.
(2007). Examination of a Fusogenic Hexameric Core from Human Metapneumovirus and Identification of a Potent Synthetic Peptide Inhibitor from the Heptad Repeat 1 Region. J. Virol.
81: 141-149
[Abstract][Full Text]
Schowalter, R. M., Smith, S. E., Dutch, R. E.
(2006). Characterization of Human Metapneumovirus F Protein-Promoted Membrane Fusion: Critical Roles for Proteolytic Processing and Low pH. J. Virol.
80: 10931-10941
[Abstract][Full Text]
Proud, D., Chow, C.-W.
(2006). Role of Viral Infections in Asthma and Chronic Obstructive Pulmonary Disease. Am. J. Respir. Cell Mol. Bio.
35: 513-518
[Abstract][Full Text]
Gillim-Ross, L., Subbarao, K.
(2006). Emerging Respiratory Viruses: Challenges and Vaccine Strategies. Clin. Microbiol. Rev.
19: 614-636
[Abstract][Full Text]
Singh, A M, Busse, W W
(2006). Asthma exacerbations {middle dot} 2: Aetiology. Thorax
61: 809-816
[Abstract][Full Text]
Ordas, J., Boga, J. A., Alvarez-Arguelles, M., Villa, L., Rodriguez-Dehli, C., de Ona, M., Rodriguez, J., Melon, S.
(2006). Role of metapneumovirus in viral respiratory infections in young children.. J. Clin. Microbiol.
44: 2739-2742
[Abstract][Full Text]
Ulbrandt, N. D., Ji, H., Patel, N. K., Riggs, J. M., Brewah, Y. A., Ready, S., Donacki, N. E., Folliot, K., Barnes, A. S., Senthil, K., Wilson, S., Chen, M., Clarke, L., MacPhail, M., Li, J., Woods, R. M., Coelingh, K., Reed, J. L., McCarthy, M. P., Pfarr, D. S., Osterhaus, A. D. M. E., Fouchier, R. A. M., Kiener, P. A., Suzich, J. A.
(2006). Isolation and characterization of monoclonal antibodies which neutralize human metapneumovirus in vitro and in vivo.. J. Virol.
80: 7799-7806
[Abstract][Full Text]
Kahn, J. S.
(2006). Epidemiology of Human Metapneumovirus. Clin. Microbiol. Rev.
19: 546-557
[Abstract][Full Text]
Douville, R. N., Bastien, N., Li, Y., Pochard, P., Simons, F. E. R., HayGlass, K. T.
(2006). Human Metapneumovirus Elicits Weak IFN-{gamma} Memory Responses Compared with Respiratory Syncytial Virus. J. Immunol.
176: 5848-5855
[Abstract][Full Text]
Rathore, M. H.
(2006). Role of Metapneumovirus in URI. AAP Grand Rounds
15: 58-58
[Full Text]
Regev, L., Hindiyeh, M., Shulman, L. M., Barak, A., Levy, V., Azar, R., Shalev, Y., Grossman, Z., Mendelson, E.
(2006). Characterization of Human Metapneumovirus Infections in Israel. J. Clin. Microbiol.
44: 1484-1489
[Abstract][Full Text]
Garcia-Garcia, M L, Calvo, C, Martin, F, Perez-Brena, P, Acosta, B, Casas, I
(2006). Human metapneumovirus infections in hospitalised infants in Spain. Arch. Dis. Child.
91: 290-295
[Abstract][Full Text]
Englund, J. A., Boeckh, M., Kuypers, J., Nichols, W. G., Hackman, R. C., Morrow, R. A., Fredricks, D. N., Corey, L.
(2006). Brief communication: fatal human metapneumovirus infection in stem-cell transplant recipients.. ANN INTERN MED
144: 344-349
[Abstract][Full Text]
van Burik, J.-A. H.
(2006). Human metapneumovirus: important but not currently diagnosable.. ANN INTERN MED
144: 374-375
[Full Text]
Guerrero-Plata, A., Casola, A., Suarez, G., Yu, X., Spetch, L., Peeples, M. E., Garofalo, R. P.
(2006). Differential Response of Dendritic Cells to Human Metapneumovirus and Respiratory Syncytial Virus. Am. J. Respir. Cell Mol. Bio.
34: 320-329
[Abstract][Full Text]
Espy, M. J., Uhl, J. R., Sloan, L. M., Buckwalter, S. P., Jones, M. F., Vetter, E. A., Yao, J. D. C., Wengenack, N. L., Rosenblatt, J. E., Cockerill, F. R. III, Smith, T. F.
(2006). Real-Time PCR in Clinical Microbiology: Applications for Routine Laboratory Testing. Clin. Microbiol. Rev.
19: 165-256
[Abstract][Full Text]
Wade, J. C.
(2006). Viral Infections in Patients with Hematological Malignancies. ASH Education Book
2006: 368-374
[Abstract][Full Text]
Pham, Q. N., Biacchesi, S., Skiadopoulos, M. H., Murphy, B. R., Collins, P. L., Buchholz, U. J.
(2005). Chimeric Recombinant Human Metapneumoviruses with the Nucleoprotein or Phosphoprotein Open Reading Frame Replaced by That of Avian Metapneumovirus Exhibit Improved Growth In Vitro and Attenuation In Vivo. J. Virol.
79: 15114-15122
[Abstract][Full Text]
Guerrero-Plata, A., Casola, A., Garofalo, R. P.
(2005). Human Metapneumovirus Induces a Profile of Lung Cytokines Distinct from That of Respiratory Syncytial Virus. J. Virol.
79: 14992-14997
[Abstract][Full Text]
Meates-Dennis, M.
(2005). BRONCHIOLITIS. EDUCATION AND PRACTICE
90: ep81-ep86
[Full Text]
Chano, F., Rousseau, C., Laferriere, C., Couillard, M., Charest, H.
(2005). Epidemiological Survey of Human Metapneumovirus Infection in a Large Pediatric Tertiary Care Center. J. Clin. Microbiol.
43: 5520-5525
[Abstract][Full Text]
Biacchesi, S., Pham, Q. N., Skiadopoulos, M. H., Murphy, B. R., Collins, P. L., Buchholz, U. J.
(2005). Infection of Nonhuman Primates with Recombinant Human Metapneumovirus Lacking the SH, G, or M2-2 Protein Categorizes Each as a Nonessential Accessory Protein and Identifies Vaccine Candidates. J. Virol.
79: 12608-12613
[Abstract][Full Text]
Noyola, D. E, Alpuche-Solis, A. G, Herrera-Diaz, A., Soria-Guerra, R. E, Sanchez-Alvarado, J., Lopez-Revilla, R.
(2005). Human metapneumovirus infections in Mexico: epidemiological and clinical characteristics. J Med Microbiol
54: 969-974
[Abstract][Full Text]
Williams, J. V., Tollefson, S. J., Johnson, J. E., Crowe, J. E. Jr.
(2005). The Cotton Rat (Sigmodon hispidus) Is a Permissive Small Animal Model of Human Metapneumovirus Infection, Pathogenesis, and Protective Immunity. J. Virol.
79: 10944-10951
[Abstract][Full Text]
Schickli, J. H., Kaur, J., Ulbrandt, N., Spaete, R. R., Tang, R. S.
(2005). An S101P Substitution in the Putative Cleavage Motif of the Human Metapneumovirus Fusion Protein Is a Major Determinant for Trypsin-Independent Growth in Vero Cells and Does Not Alter Tissue Tropism in Hamsters. J. Virol.
79: 10678-10689
[Abstract][Full Text]
Martinez, F. D.
(2005). Heterogeneity of the Association between Lower Respiratory Illness in Infancy and Subsequent Asthma. Proc Am Thorac Soc
2: 157-161
[Abstract][Full Text]
Percivalle, E., Sarasini, A., Visai, L., Revello, M. G., Gerna, G.
(2005). Rapid Detection of Human Metapneumovirus Strains in Nasopharyngeal Aspirates and Shell Vial Cultures by Monoclonal Antibodies. J. Clin. Microbiol.
43: 3443-3446
[Abstract][Full Text]
Fleming, D. M, Pannell, R. S, Cross, K. W
(2005). Mortality in children from influenza and respiratory syncytial virus. J. Epidemiol. Community Health
59: 586-590
[Abstract][Full Text]
Buchholz, U. J., Biacchesi, S., Pham, Q. N., Tran, K. C., Yang, L., Luongo, C. L., Skiadopoulos, M. H., Murphy, B. R., Collins, P. L.
(2005). Deletion of M2 Gene Open Reading Frames 1 and 2 of Human Metapneumovirus: Effects on RNA Synthesis, Attenuation, and Immunogenicity. J. Virol.
79: 6588-6597
[Abstract][Full Text]
Falsey, A. R., Hennessey, P. A., Formica, M. A., Cox, C., Walsh, E. E.
(2005). Respiratory Syncytial Virus Infection in Elderly and High-Risk Adults. NEJM
352: 1749-1759
[Abstract][Full Text]
Ebihara, T., Endo, R., Ma, X., Ishiguro, N., Kikuta, H.
(2005). Detection of Human Metapneumovirus Antigens in Nasopharyngeal Secretions by an Immunofluorescent-Antibody Test. J. Clin. Microbiol.
43: 1138-1141
[Abstract][Full Text]
Leung, J., Esper, F., Weibel, C., Kahn, J. S.
(2005). Seroepidemiology of Human Metapneumovirus (hMPV) on the Basis of a Novel Enzyme-Linked Immunosorbent Assay Utilizing hMPV Fusion Protein Expressed in Recombinant Vesicular Stomatitis Virus. J. Clin. Microbiol.
43: 1213-1219
[Abstract][Full Text]
Bisgaard, H., Zielen, S., Garcia-Garcia, M. L., Johnston, S. L., Gilles, L., Menten, J., Tozzi, C. A., Polos, P.
(2005). Montelukast Reduces Asthma Exacerbations in 2- to 5-Year-Old Children with Intermittent Asthma. Am. J. Respir. Crit. Care Med.
171: 315-322
[Abstract][Full Text]
Ebihara, T., Endo, R., Ishiguro, N., Nakayama, T., Sawada, H., Kikuta, H.
(2004). Early Reinfection with Human Metapneumovirus in an Infant. J. Clin. Microbiol.
42: 5944-5946
[Abstract][Full Text]
Garbino, J., Gerbase, M. W., Wunderli, W., Deffernez, C., Thomas, Y., Rochat, T., Ninet, B., Schrenzel, J., Yerly, S., Perrin, L., Soccal, P. M., Nicod, L., Kaiser, L.
(2004). Lower Respiratory Viral Illnesses: Improved Diagnosis by Molecular Methods and Clinical Impact. Am. J. Respir. Crit. Care Med.
170: 1197-1203
[Abstract][Full Text]
Alto, W. A.
(2004). Human Metapneumovirus: A Newly Described Respiratory Tract Pathogen. J Am Board Fam Med
17: 466-469
[Abstract][Full Text]
Lakhanpaul, M., Atkinson, M., Stephenson, T.
(2004). Community acquired pneumonia in children: a clinical update. EDUCATION AND PRACTICE
89: ep29-ep34
[Full Text]
Ulloa-Gutierrez, R., Skippen, P., Synnes, A., Seear, M., Bastien, N., Li, Y., Forbes, J. C
(2004). Life-Threatening Human Metapneumovirus Pneumonia Requiring Extracorporeal Membrane Oxygenation in a Preterm Infant. Pediatrics
114: e517-e519
[Abstract][Full Text]
(2004). The human metapneumovirus and respiratory tract infection. Arch. Dis. Child.
89: 696-696
[Full Text]
MacPhail, M., Schickli, J. H., Tang, R. S., Kaur, J., Robinson, C., Fouchier, R. A. M., Osterhaus, A. D. M. E., Spaete, R. R., Haller, A. A.
(2004). Identification of small-animal and primate models for evaluation of vaccine candidates for human metapneumovirus (hMPV) and implications for hMPV vaccine design. J. Gen. Virol.
85: 1655-1663
[Abstract][Full Text]
Meissner, H. C., Rennels, M. B.
(2004). Unpredictable Patterns of Viral Respiratory Disease in Children. Pediatrics
113: 1814-1816
[Full Text]
Ho, H.-K., Principi, N., Esposito, S., Bosis, S., Williams, J. V., Crowe, J. E. Jr.
(2004). Human Metapneumovirus and Lower Respiratory Tract Disease in Children. NEJM
350: 1788-1790
[Full Text]
Fowler, S J
(2004). Human metapneumovirus: a new cause of respiratory tract infections in children?. Thorax
59: 359-359
[Full Text]
(2004). Human Metapneumovirus: A New Respiratory Pathogen. JWatch Pediatrics
2004: 2-2
[Full Text]
(2004). Metapneumovirus Often Is Associated with Childhood Respiratory Infections. JWatch General
2004: 4-4
[Full Text]
Gottlieb, S.
(2004). Metapneumovirus is a leading cause of respiratory tract infection in infants. BMJ
328: 246-
[Full Text]
Previous
