Objectives: The epidemiology of respiratory co-infection pairings is poorly understood. Here we assess the dynamics of respiratory viral co-infections in children and adults and determine predisposition for or against specific viral pairings. Methods: Over five respiratory seasons from 30 November 2013 through 6 June 2018, the mono-infection and co-infection prevalence of 13 viral pathogens was tabulated at The Cleveland Clinic. Employing a model to proportionally distribute viral pairs using individual virus co-infection rate with prevalence patterns of concurrent co-circulating viruses, we compared predicted occurrence with observed occurrence of 132 viral pairing permutations using binomial analysis. Results: Of 30 535 respiratory samples, 9843 (32.2%) were positive for at least one virus and 1018 (10.8%) of these were co-infected. Co-infected samples predominantly originated from children. Co-infection rate in paediatric population was 35.0% (2068/5906), compared with only 5.8% (270/4591) in adults. Adenovirus C (ADVC) had the highest co-infection rate (426/623, 68.3%) while influenza virus B had the lowest (55/546, 10.0%). ADVC-rhinovirus (HRV), respiratory syncytial virus A (RSVA)-HRV and RSVB -HRV pairings occurred at significantly higher frequencies than predicted by the proportional distribution model (p <0.05). Additionally, several viral pairings had fewer co-infections than predicted by our model: notably metapneumovirus (hMPV)-parainfluenza virus 3, hMPV-RSVA and RSVA-RSVB. Conclusions: This is one of the largest studies on respiratory viral co-infections in children and adults. Coinfections are substantially more common in children, especially under 5 years of age, and the most frequent pairings occurred at a higher frequency than would be expected by random. Specific pairings occur at altered rates compared with those predicted by proportional distribution, suggesting either direct or indirect interactions result between specific viral pathogens. (C) 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

In 2005, a new human coronavirus, HCoV-HKU1, was identified in Hong Kong. We screened respiratory specimens collected from December 16, 2001, to December 15, 2002, from children < 5 years of age who tested negative for respiratory syncytial virus, parainfluenza viruses, influenza virus, and adenovirus for HCoV-HKU1 by reverse transcription-polymerase chain reaction. Overall, 1,048 respiratory specimens from 851 children were tested, and 9 HCoV-HKU1-positive children (1%) were identified, 2 of whom had 2 positive specimens. Children who had HCoV-HKU1 infection had evidence of either upper or lower respiratory tract infection or both. Two patients had disease beyond the respiratory tract. HCoV-HKU1 was identified from December 2001 to February 2002. Sequence analyses suggest that a single strain was circulating. HCoV-HKU1 is therefore likely circulating in the United States and is associated with upper and lower respiratory tract disease.

ABSTRACT Human metapneumovirus (hMPV) is a newly identified human respiratory virus now recognized as a major respiratory pathogen of infants and children. To define the seroepidemiology of hMPV, we developed a novel enzyme-linked immunosorbent assay (ELISA) based on expression of the fusion protein of hMPV (hMPV F) in recombinant vesicular stomatitis virus (VSV). Western blot analysis using an hMPV F-specific antiserum confirmed the expression of hMPV in recombinant VSV. The ELISA is specific for hMPV F; antibody specific for the most closely related human paramyxovirus, respiratory syncytial virus, does not bind to hMPV F. Overall, 216 serum specimens were tested. The percentages of seropositive individuals were 89.1% in children ≤5 months old, 55.0% in children 6 to 11 months old, 36.0% in children 12 to 23 months old, 45.0% in children 24 to 47 months old, 77.3% in children 48 to 59 months old, 91.3% in children 5 to 10 years old, and 95.5% for individuals 11 to 20 years old. This is the first seroepidemiological survey of hMPV in the United States and the first analysis to determine the prevalence of antibody to a specific hMPV protein. The data suggest that exposure to hMPV is common in childhood and that hMPV F is an antigenic determinant of hMPV.

BACKGROUND:The etiological agents responsible for a substantial proportion of respiratory tract diseases have not been identified. We sought to determine whether novel human coronaviruses (HCoVs) are circulating in New Haven, Connecticut, and, if so, whether they are associated with respiratory tract disease in infants and young children.METHODS:We developed a polymerase chain reaction (PCR)-based approach for screening specimens from the respiratory tracts of symptomatic children. PCR probes that target regions of the replicase 1a gene that are conserved among genetically diverse animal CoVs and HCoVs were designed. Using these probes, we identified genomic sequences of a novel HCoV, designated "New Haven coronavirus" (HCoV-NH). Thereafter, we designed specific probes to screen respiratory specimens from children <5 years old for this novel HCoV. Clinical features associated with HCoV-NH infection were identified.RESULTS:Seventy-nine (8.8%) of 895 children tested positive for HCoV-NH. Cough, rhinorrhea, tachypnea, fever, abnormal breath sounds, and hypoxia were the most common findings associated with HCoV-NH infection. Sequence analysis revealed that HCoV-NH is closely related to a novel HCoV recently reported in The Netherlands.CONCLUSIONS:The novel HCoVs identified in New Haven and The Netherlands are similar and likely represent the same species. This newly discovered virus may have worldwide distribution and may account for a significant proportion of respiratory tract disease in infants and young children.

Kawasaki disease is a systemic vasculitis of childhood; its etiology is unknown. We identified evidence of a novel human coronavirus, designated "New Haven coronavirus" (HCoV-NH), in respiratory secretions from a 6-month-old infant with classic Kawasaki disease. To further investigate the possible association between HCoV-NH infection and Kawasaki disease, we conducted a case-control study. Specimens of respiratory secretions from 8 (72.7%) of 11 children with Kawasaki disease and from 1 (4.5%) of 22 control subjects ( children without Kawasaki disease matched by age and the time the specimens were obtained) tested positive for HCoV-NH by reverse-transcriptase polymerase chain reaction (Mantel-Haenszel matched odds ratio, 16.0 [95% confidence interval, 3.4-74.4];) P = .0015). These data suggest that HCoV-NH infection is associated with Kawasaki disease.

Human metapneumovirus (hMPV) is a recently discovered respiratory pathogen. We tested respiratory specimens for the presence of hMPV by reverse-transcription polymerase chain reaction. These specimens were obtained over a 1-year period from children aged <5 years and had negative results by the direct fluorescent antibody test for respiratory syncytial virus, influenza A and B, parainfluenza viruses 1 - 3, and adenovirus. Overall, 54 (8.1%) of 668 individuals tested positive for hMPV. During March and April of the study period, hMPV was detected in 17.6% and 25.0% of specimens tested, respectively. At least 2 distinct genotypes of hMPV circulated during the study period. Fever, tachypnea, cough, rhinorrhea, retractions of the chest wall, and wheezing were common findings. Of hMPV-positive children, 60.4% were aged <12 months. hMPV accounted for a small but significant proportion of respiratory-tract disease in infants and children.

CLINICAL SUMMARY A 3-year-old African-American boy presented with limping due to a thigh mass of recent appearance. The lesion was initially painless and nonmobile, without erythema or swelling. There was no fever or other constitutional symptom. Four days before admission, a second tumor appeared on the left parietal region. The leg mass became erythematous and painful, and fever of 39.4°C ensued. The relevant past medical history includes three soft tissue nodules removed from the buttock on the 3rd day of life, one of which is shown on Figure 1 (the patient’s father had an identical soft tissue lesion surgically removed as a newborn). In addition, there were frequent and recurrent infections including meningitis and pneumonias, and failure to thrive. At 2 years of age, the patient developed an intraabdominal lymphangioma which showed histological evidence of infection with multiple granulomata. At the time of admission, the patient was at the 5th percentile for height and below the 3rd percentile for weight. A computerized tomography (CT) scan revealed a large soft tissue lesion in the scalp, eroding the parietal bone, and several small lesions involving the brain parenchyma (Fig. 2). In addition, a large mass was found involving the posterior aspect of the right thorax. These findings were interpreted as suggestive of metastatic disease, possibly Ewing sarcoma or neuroblastoma. Pertinent lab results include normal levels of immunoglobulins and negative human immunodeficiency virus testing. The leg and parietal lesions were surgically removed and drained.

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.