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PEDIATRICS Vol. 111 No. 6 June 2003, pp. 1407-1410

Human Metapneumovirus Infection in the United States: Clinical Manifestations Associated With a Newly Emerging Respiratory Infection in Children

Frank Esper, MD*, Derek Boucher, BS{ddagger}, Carla Weibel, BS*, Richard A. Martinello, MD§ and Jeffrey S. Kahn, MD, PhD*,{ddagger}

* Department of Pediatrics, Division of Infectious Diseases, Yale University School of Medicine, New Haven, Connecticut
{ddagger} Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut
§ Department of Internal Medicine, Division of Infectious Diseases, Yale University School of Medicine, New Haven, Connecticut


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Objective. Respiratory tract infections are a leading cause of morbidity and mortality worldwide. Recently, a newly identified human respiratory virus, human metapneumovirus (hMPV), was reported by investigators in the Netherlands. We sought to determine whether hMPV was circulating in our community and to determine the clinical features associated with hMPV infection.

Methods. Respiratory specimens from children who were younger than 5 years and had a negative result for respiratory syncytial virus, influenza A and B, parainfluenza viruses 1 to 3, and adenovirus by direct fluorescent antibody test were screened for hMPV by reverse transcriptase–polymerase chain reaction. Samples were collected from October 30, 2001, to February 28, 2002.

Results. Of the 296 patients screened, 19 (6.4%) had evidence of hMPV infection. hMPV was identified in patients with either upper or lower respiratory tract infection or both. Clinical manifestations included wheezing, hypoxia, and abnormal findings on chest radiographs (eg, focal infiltrates, peribronchial cuffing). Nosocomial infection occurred in at least 1 patient.

Conclusions. hMPV is circulating in the United States and is associated with respiratory tract disease in patients with respiratory illnesses not caused by respiratory syncytial virus, influenza, parainfluenza viruses, and adenovirus. Additional studies are required to define the epidemiology and the extent of disease in the general population caused by hMPV.

Key Words: human metapneumovirus • clinical features

Abbreviations: RSV, respiratory syncytial virus • hMPV, human metapneumovirus • DFA, direct fluorescent antibody • RT-PCR, reverse transcriptase–polymerase chain reaction


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Respiratory tract infections are a major cause of morbidity and mortality. The World Health Organization ranks respiratory diseases as the second-leading cause of death worldwide in children younger than 5 years.1 Influenza, influenza-like illnesses, and pneumonia are the sixth-leading cause of death in the United States.2 However, the cause of nearly half of the cases of community-acquired pneumonia remains undetermined.3 In the pediatric population, respiratory syncytial virus (RSV), parainfluenza viruses, and influenza account for a majority of the cases of bronchiolitis and pneumonia, although the cause of 15% to 34% of these illnesses cannot be determined.4,5 This evidence suggests the presence of unidentified pathogens. Recently, van den Hoogen et al6 characterized a previously unknown viral pathogen from children in the Netherlands. During a 20-year period, this pathogen was isolated from 28 infants and children with respiratory tract disease. Biochemical and genetic evidence suggested that this new agent is the first human pathogen in the Metapneumovirus genus. This new human pathogen was named human metapneumovirus (hMPV).

Recently, hMPV was detected in Australia, Canada, and the United Kingdom. The 3 children reported from Australia presented with respiratory tract disease.7 In Canada, hMPV was identified retrospectively in children and adults with clinical evidence of respiratory tract infection.8,9 In these studies, an unidentified agent that induced cytopathic effects on rhesus monkey kidney (LLC-MK-2) cells was subsequently identified as hMPV by reverse transcriptase–polymerase chain reaction (RT-PCR). In the United Kingdom, hMPV was associated with an influenza-like illness in 9 individuals.10 Although hMPV is associated with respiratory tract illness, the clinical manifestations of hMPV infection in children are poorly characterized.

The prevalence of hMPV is unknown. Infected patients were identified either retrospectively6,8–10 or by random screening of respiratory specimens.7 The reports of hMPV in 3 continents suggest worldwide distribution; however, the epidemiology of hMPV remains to be defined. Because the presence of hMPV in the United States is unknown, we sought to determine whether hMPV was circulating in New Haven, Connecticut, during the 2001–2002 fall/winter season. We also sought to define the clinical manifestations of hMPV infection in infants and children.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The Clinical Virology Laboratory at Yale-New Haven Hospital routinely screens respiratory specimens by direct fluorescent antibody (DFA) test for the presence of RSV, parainfluenza, influenza, and adenovirus antigens. We attempted to obtain all specimens collected from children who were younger than 5 years and negative by DFA. Previous data from the Netherlands suggested that by the age of 5 years, nearly all individuals have been infected with hMPV.6 Respiratory specimens (nasopharyngeal swabs, washes, and bronchoalveolar lavage fluid) were submitted at the discretion of the medical team and were screened for the presence of hMPV by RT-PCR. RNA extraction (QIAmp Viral RNA Mini Kit; Qiagen, Valencia, CA), RT Moloney murine leukemia virus reverse transcriptase (New England Biolabs, Beverly, MA), and PCR HotStar Taq DNA polymerase (Qiagen) were performed according to the manufacturer’s specification. Primers used in the initial screening were based on GenBank data of the Netherlands strains and targeted the hMPV F gene (GenBank accession number AF371367). Nested PCR primers were designed after sequencing of the first New Haven isolate. These primers (forward primer, 5'-CTGGATAGTAAAAGCAGCCCC-3'; reverse primer, 5'-ATCATGCTGGAGCCAAGGACAGC-3') corresponded to regions of the hMPV F gene conserved between the Netherlands and New Haven strains. The hMPV F gene was chosen for sequence and phylogenetic analysis because of the availability of F gene sequences from hMPV strains identified in the Netherlands over a period of years. In addition, other studies have used the F gene to determine the phylogenetic relationship between strains of hMPV.6,8,9,11 PCR amplification cycles were as follows: 95°C for 15 minutes followed by 35 cycles of 94°C for 1 minute, 45° to 60°C for 1 minute, 72°C for 1 minute, and completed with a 10-minute 72° cycle. Each set of reactions contained negative controls for the RT and PCR steps. Sequencing was performed on Applied Biosystems 377 DNA automated sequencers at the W.M. Keck Biotechnology Resource Lab, Yale University School of Medicine.

Sequence alignment and phylogenetic analysis were performed with DNASTAR (DNASTAR, Inc, Madison, WI) and PILEUP (Genetics Computer Group, Madison, WI) software. Maximum likelihood phylogenetic trees were constructed using the PHYLIP program DNAML with the default transition to transversion ratio of 2.0. Five hundred bootstrap data sets were created using the PHYLIP program SEQBOOT.

Clinical data from children who had hMPV infection was obtained by chart review. The Yale University Human Investigation Committee approved collection of clinical data.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
From October 30, 2001, to February 28, 2002, 357 respiratory specimens from 296 individuals in which a viral pathogen could not be identified by DFA were obtained from the Clinical Virology Laboratory at Yale-New Haven Hospital. A total of 20 hMPV RT-PCR–positive samples from 19 individuals were identified. Our laboratory did not have access to materials from the Netherlands, Australia, Canada, or the United Kingdom; therefore, the results cannot represent laboratory contamination from material obtained elsewhere. Children who had hMPV infection had clinical evidence of either upper or lower respiratory tract infection or both (Table 1). Of the children who were not infected with other recognized pathogens, the most common clinical findings of hMPV infection were cough (11 of 16 [69%]), rhinorrhea (11 of 16 [69%]), fever (10 of 16 [63%]), and wheezing (8 of 16 [50%]). Five of these patients (31%) developed hypoxia (oxygen saturation of ≤90%). Chest radiographs were obtained for 14 patients. Abnormal findings such as peribronchial cuffing, prominent hilum, and focal infiltrates were noted. All hMPV infections occurred during a 6-week span in January and February 2002, although only 59% of the specimens were from this period. No hMPV-positive isolates were noted in November or December 2001.


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  		TABLE 1. Clinical Manifestations of HPMV Infection

 
Nosocomial hMPV infection was discovered in at least 1 patient. This infant (patient 7) never left the hospital after birth and became symptomatic during the 25th week of life. A second patient (patient 10) was initially admitted with fever and hyponatremia. Influenza A antigen was detected in a respiratory specimen by DFA test. On the 12th day of hospitalization, patient 10 developed respiratory symptoms, and a nasopharyngeal swab was subsequently found to contain hMPV. This specimen was negative for influenza A by both DFA test and culture. The initial specimen that contained influenza A antigen was not tested for hMPV. Because the incubation period of hMPV is unknown, it is unclear when patient 10 became infected. Patient 7 and patient 10 had no known contact with each other or with any of the other known hMPV-infected patients.

Co-infection with other respiratory pathogens was observed. One patient (patient 5) was found to be co-infected with RSV on subsequent screening. The interval between the samplings was 2 days; therefore, the illness may have been attributed to both pathogens. Patient 3 was subsequently found to be co-infected with both influenza A and cytomegalovirus by culture.

The PCR amplicon from each positive specimen was sequenced and was consistent with hMPV. Rare polymorphisms were noted in the hMPV sequences (data not shown), suggesting that a single strain was circulating in the community during the study period. Phylogenetic analysis indicated that the New Haven strain was most closely related to the 93-3 Netherlands strain, although distinct from other Netherlands strains (Fig 1).


Figure 1
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  		Fig 1. Phylogenetic analysis of the New Haven and Netherlands strains. Alignments were based on the hMPV F gene (nucleotide sequence 1168–1307). Strain numbers are indicated for the Netherlands strains (GenBank accession numbers AF371339-AF371345, AF371367). Bootstrap values are as indicated at the respective branch points.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
We report here the first identification of hMPV in the United States as well as the largest single-season case series of hMPV to date. hMPV circulated in New Haven, Connecticut, in the 2001–2002 fall/winter seasons. hMPV was detected in 6.4% of children who had a respiratory specimen collected and who had no other respiratory pathogen identified by DFA testing. This is similar to the findings in the Netherlands. Seven (10.3%) of 68 samples from a single winter season were positive for hMPV.6 Patients from whom hMPV was identified had clinical features of either upper or lower respiratory infection or both. Hypoxia was observed in >30% of patients who had hMPV infection.

Bronchiolitis was the most common diagnosis in children identified with hMPV infection. Each year in the United States, >150 000 infants and children younger than 5 years are hospitalized with bronchiolitis, and these rates have increased during the past 2 decades.12 Our findings suggest that hMPV may be responsible for a significant portion of these hospitalizations. Preterm infants may be particularly prone to hMPV infection and disease similar to that observed with RSV.13

hMPV shares epidemiologic features with RSV. Phylogenetic analysis revealed that the 2001–2002 New Haven hMPV strain was closely related to the 93-3 Netherlands strain but distinct from other strains collected in that area in different years. Nearly identical strains of RSV circulate within different geographical locations in different years.14 RSV has a seasonal distribution,15 and data from the Netherlands support a winter circulation of hMPV.6 Although we studied only a 4-month period, the presence of hMPV during a 6-week span indicates a seasonal distribution.

Our study was limited to screening respiratory samples collected at the discretion of the medical team, although the data suggest that hMPV infection is not rare in our population. Active surveillance is required to determine the full spectrum of disease caused by this pathogen. Likewise, asymptomatic infants and children were not studied, so the frequency of hMPV infection could not be ascertained. Furthermore, we limited our study to children younger than 5 years. The clinical manifestations and prevalence of hMPV in older individuals remains to be determined. Although identification of viral nucleic acid in respiratory specimens does not prove that hMPV was responsible for the patients’ symptoms, the association between respiratory tract illness and presence of the virus suggests a causative role. Other investigation including immunologic assays and case-control studies would be required to confirm the role of hMPV in respiratory tract infections.

Co-infection was noted in 2 patients, indicating that infection with hMPV and other respiratory pathogens occurs and may contribute to the severity of illness. Because we screened only respiratory specimens that tested negative by DFA test, the extent and significance of co-infection with hMPV and other respiratory pathogens requires additional studies. Nosocomial infection, noted in at least 1 patient, is concerning. This finding suggests that the patient-isolation and cohorting criteria in many health care facilities may have to be reevaluated.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
We demonstrated that hMPV is circulating in the United States and may be a major cause of respiratory tract infection in infants and children. Future development and application of diagnostic tools will determine the burden of disease caused by this newly discovered pathogen.


   ACKNOWLEDGMENTS
 
This work was supported in part by the Yale Children’s Clinical Research Center grant M01-RR06022, General Clinical Research Centers Program, National Center for Research Resources, and by grants from the National Institutes of Health (T32 AI07517-05 and T32 AI07210-20).

We are indebted to Marie Landry, MD; David Ferguson; and the staff of the Clinical Virology Laboratory at Yale-New Haven Hospital for assistance in collection of clinical specimens and to George Miller, MD; Michael Cappello, MD; and Eugene D. Shapiro, MD, for thoughtful and critical review of the manuscript.


   FOOTNOTES
 
Received for publication Sep 12, 2002; Accepted Nov 20, 2002.

Reprint requests to (J.S.K.) Department of Pediatrics, Division of Infectious Diseases, Yale University School of Medicine, PO Box 208064, New Haven, CT 06520-8064. E-mail: jeffrey.kahn{at}yale.edu


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 CONCLUSIONS
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  1. Murray CJL, Lopez AD, Mathers CD, Stein C. The Global Burden of Disease 2000 project: aims, methods and data sources. Global Programme on Evidence for Health Policy. Geneva, Switzerland: World Health Organization; 2001
  2. Pinner RW, Teutsch SM, Simonsen L, et al. Trends in infectious diseases mortality in the United States. JAMA.1996; 275 :189 –193[Abstract]
  3. Ruiz M, Ewig S, Marcos MA, et al. Etiology of community-acquired pneumonia: impact of age, comorbidity, and severity. Am J Respir Crit Care Med.1999; 160 :397 –405[Abstract/Free Full Text]
  4. Wright AL, Taussig LM, Ray CG, Harrison HR, Holberg CJ. The Tucson Children’s Respiratory Study: II. Lower respiratory tract illness in the first year of life. Am J Epidemiol.1989; 129 :1232 –1246[Abstract/Free Full Text]
  5. Davies HD, Matlow A, Petric M, Glazier R, Wang EE. Prospective comparative study of viral, bacterial and atypical organisms identified in pneumonia and bronchiolitis in hospitalized Canadian infants. Pediatr Infect Dis J.1996; 15 :371 –375[CrossRef][ISI][Medline]
  6. van den Hoogen BG, de Jong JC, Groen J, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med.2001; 7 :719 –724[CrossRef][ISI][Medline]
  7. Nissen MD, Siebert DJ, Mackay IM, Sloots TP, Withers SJ. Evidence of human metapneumovirus in Australian children. Med J Aust.2002; 176 :188
  8. Peret TCT, Boivin G, Li Y, et al. Characterization of human metapneumovirus isolated from patients in North America. J Infect Dis.2002; 185 :1660 –1663[CrossRef][ISI][Medline]
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  12. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-associated hospitalizations among US children, 1980–1996. JAMA.1999; 282 :1440 –1446[Abstract/Free Full Text]
  13. Groothuis JR, Gutierrez KM, Lauer BA. Respiratory syncytial virus infection in children with bronchopulmonary dysplasia. Pediatrics.1988; 82 :199 –203[Abstract/Free Full Text]
  14. Anderson LJ, Hendry RM, Pierik LT, Tsou C, McIntosh K. Multicenter study of strains of respiratory syncytial virus. J Infect Dis.1991; 163 :687 –692[ISI][Medline]
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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics



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