Rhinovirus – New Insights Into a Complex Epidemiology

Rhinovirus – New Insights Into a Complex Epidemiology rhinovirus, daycare, pediatric, transmission, epidemiology, wheezing, genotype, sequencing, PCR, respiratory Many of us recall the excitement early in this century when advances in molecular diagnostics led clinicians to detect surprisingly high rates of rhinovirus from patients with serious respiratory disease. One of the first of these studies was reported by Miller et al, in this journal in 2007, where human rhinovirus (HRV) was identified by culture and polymerase chain reaction (PCR) of respiratory specimens in 26% of children under the age of 5 years hospitalized with acute respiratory infection (ARI) or fever [1]. The authors also suggested an important association of serious illness with HRV in patients with a history of wheezing or asthma. The ability of HRV to alter innate immune responses may contribute to more-severe disease in asthmatics, and play a role in the development of subsequent wheezing, particularly in those genetically predisposed to allergic phenotypes [2, 3]. An accompanying editorial suggested that rhinovirus should now be recognized as “more than just a common cold virus,” because of similar observations replicated globally in several studies [4]. However, attempts to link HRV with clinical disease are challenged by the high rates of recovery of HRV from asymptomatic individuals, a problem not addressed in studies that only sample symptomatic individuals without a similar asymptomatic comparison group [5]. Subsequent studies sought to better describe the role of the 3 major species of HRV (A, B, C) in hospitalized children and adults, comparing recovery rates to similar asymptomatic control groups, while looking for differences in severity of clinical disease among the species. A large multicenter study of 1947 hospitalizations in children for ARI found nearly 4-fold higher rates of HRV-A detection in ill 24 to 59 month olds, and 2-fold higher rates of HRV-C in ill 6 to 59-month-old children, compared to 784 children sampled at well-child visits [6]. These findings supported a role for HRV in clinical disease and again noted an association with asthma or wheezing, although clinical presentations were similar across all 3 species. A Spanish study reported that the A and C species of rhinovirus were associated more specifically with wheezing and asthma, while B was more associated with pneumonia [7]. The association of disease severity and wheezing with HRV species and genotype has relied primarily upon sequencing of VP1, a capsid gene, which has a very high rate of mutation, rather than the entire genome. This limits comparison between studies and results in very divergent genotype associations. Expanding use of multiplex diagnostic platforms has enabled further insight into the association of disease with rhinovirus, as epidemiologic studies now routinely identify additional “copathogens,” especially from younger children, with ARI. A European study of children (under 14 years of age) with radiologically confirmed community-acquired pneumonia (CAP) reported 29% with HRV, 40% of whom yielded concurrent recovery of 2 or more viruses [8]. Concurrent viral infection was most common in infants under a year of age, although clinical severity was not increased in those subjects. HRV was the most commonly identified pathogen in the Etiology of Pneumonia in the Community Study (EPIC), supported by the Centers for Disease Control, where it was recovered in 9% of hospitalized adults with CAP, yet was rarely identified in an asymptomatic control group [9]. In contrast, similar rates of HRV were identified in children <18 years of age admitted for radiographically proven CAP (22%), compared to asymptomatic controls (17%), adjusted for age and enrolled at the same study sites [10]. A nested EPIC study analyzed the 13 most common respiratory viruses, and noted a 24.4% isolation rate for 1 or more viruses from asymptomatic children [11]. Additionally, a recent single-site study documented a 10.7% recovery rate of HRV in children with CAP, which was lower than the 22.4% in controls [12]. The authors of that study, as well as others, have suggested that the initial excitement over the contribution of HRV to respiratory disease might be overestimated. The range of these studies, and their mixed findings, underscore the need to develop a better understanding of the basic epidemiology of rhinoviruses in children and adults. This cannot be accomplished by sampling symptomatic individuals alone, or by identifying the relative distribution of the 3 species in unrelated populations. In this issue of The Journal of Infectious Diseases, Martin et al bring much more clarity into the epidemiology of baseline rhinovirus shedding, and recovery during clinical disease, through their longitudinal study of children enrolled in a set of daycare center classrooms [13]. This population (5 weeks to 30 months of age) was sampled at enrollment, establishing a relevant comparison group from the population being studied, in addition to obtaining weekly longitudinal sampling information from symptomatic children with ARI, until illness resolution or negative PCRs. Furthermore, the authors were able to determine genotypes for nearly half of the human rhinoviruses identified through full-length sequencing rather than single or paired gene analysis. From this information they generated assessments regarding circulation in the small classrooms environment of the childcare center. A previous publication about this cohort reported that rhinovirus was the most frequent virus isolated, but commonly in conjunction with another virus (66% as coinfections), similar to other studies of infants [14]. HRV was identified by PCR in 49% of 455 ARIs. Recurrent infection was common, occurring in nearly half of those with HRV infection. HRV was found in 41% of the initial swabs in asymptomatic enrollees, and in 30% of those with mild ARI symptoms on enrollment. Species A, B, and C were mixed among the asymptomatic enrollees, while A and C predominated in symptomatic children. Overall, no significant differences in severity of illness, or even wheezing, were noted between A, B, or C species; though children with C infection were observed to be less active, this did not result in a difference in school days missed. The study noted that full sequence data were obtained from too few numbers of symptomatic children to assess the association of genotype and sequence variation with severity of disease. The most interesting information gained was from the molecular epidemiologic results. Samples obtained were a heterologous mix of 41 different predominantly A and C genotypes. Eleven different clusters of like genotypes occurred, in patterns suggesting easy person-to-person spread within and between classrooms. However, the mixture in the smallest classroom, as well as among the entire population, changed dynamically every week, with cocirculation of multiple genotypes. The lack of evidence for any protection against serial and subsequent infection was dramatic. Children rarely shed the same genotype for more than 2 weeks, yet in at least 7 longer sequential illnesses, the recovered genotypes changed over time from the same individual. In summary, the chaotic and unpredictable spread of such a heterotypic mix of viruses sheds considerable light on the very fluid diversity of this virus in a situation with “family-like” groupings of individuals. In 2 recent studies, including 1 of the larger studies of hospitalized children discussed above [6], and an emergency room sampling from children with ARI [15], results of genetic sequencing of hundreds of the samples recovered from unrelated individuals did not permit many conclusions to be drawn regarding patterns of circulation or transmission of HRV. A study of hospitalized HRV-positive children, however, found 2-fold higher rates of HRV recovery from siblings and parents (with half symptomatic), and frequently isolated the same genotype, suggesting efficient intrafamily transmission [16]. Yet even within these immediate contacts, a variety of unrelated rhinoviruses were also isolated, again demonstrating the extreme heterogeneity of HRV. Further transmission studies will be challenging, as the continued circulation of heterotypic viruses is, as suggested by Martin et al, very robust, and viral diversity will continue to make identification of patterns of spread difficult, even with powerful sequencing tools. This new work by Martin et al, coupled with previous studies, identify challenges that will require careful study design and considerable resources for future studies of the epidemiology, transmission, clinical disease, and the role of coinfection in respiratory disease associated with HRV [13]. Future studies must identify rates of recovery from a comparison group from the same population, when making conclusions about any subset of symptomatic individuals. Additionally, complete viral genome sequencing will be necessary to make meaningful observations regarding patterns of transmission and clustering of infections. Determining when the presence of HRV indicates asymptomatic shedding as opposed to symptomatic disease may be clarified by analysis of the host response, requiring increased biological sample acquisition and detailed analysis of immune responsiveness. A recent study reported that whole-blood RNA transcriptomes revealed a relative increased innate immune “signature” in infants and children with symptomatic HRV infections compared to asymptomatic individuals [17]. Finally, elucidation of the role of copathogens will require both longitudinal observation and sampling, along with delineation of immune responses to distinct pathogens. As with many advances in our clinical knowledge through the application of new and advanced methodologies, more questions and challenges are raised with each new level of understanding!Notes Notes Disclaimer. The opinions contained herein are those of the authors and do not necessarily reflect those of the Uniformed Services University or the Department of Defense Potential conflicts of interest. Both authors: No reported conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Miller EK, Lu X, Erdman DD, et al.   Rhinovirus-associated hospitaliza tions in young children. J Infect Dis   2007; 195: 773– 81. Google Scholar CrossRef Search ADS PubMed  2. Durrani SR, Montville DJ, Pratt AS, et al.   Innate immune responses to rhinovirus are reduced by the high-affinity IgE receptor in allergic asthmatic children. J Allergy Clin Immunol   2012; 130: 489– 95. Google Scholar CrossRef Search ADS PubMed  3. Turunen R, Jartti T, Bochkov YA, Gern JE, Vuorinen T. Rhinovirus species and clinical characteristics in the first wheezing episode in children. J Med Virol   2016; 88: 2059– 68. Google Scholar CrossRef Search ADS PubMed  4. Turner RB. Rhinovirus: more than just a common cold virus. J Infect Dis   2007; 195: 765– 6. Google Scholar CrossRef Search ADS PubMed  5. Hasegawa K, Linnemann RW, Avadhanula V, et al.   Detection of respiratory syncytial virus and rhinovirus in healthy infants. BMC Res Notes   2015; 8: 718. Google Scholar CrossRef Search ADS PubMed  6. Iwane MK, Prill MM, Lu X, et al.   Human rhinovirus species associated with hospitalizations for acute respiratory illness in young US children. J Infect Dis   2011; 204: 1702– 10. Google Scholar CrossRef Search ADS PubMed  7. Calvo C, Casas I, García-García ML, et al.   Role of rhinovirus C respiratory infections in sick and healthy children in Spain. Pediatr Infect Dis J   2010; 29: 717– 20. Google Scholar CrossRef Search ADS PubMed  8. Esposito S, Daleno C, Tagliabue C, et al.   Impact of rhinoviruses on pediatric community-acquired pneumonia. Eur J Clin Microbiol Infect Dis   2012; 31: 1637– 45. Google Scholar CrossRef Search ADS PubMed  9. Jain S, Self WH, Wunderink RG, et al.  ; CDC EPIC Study Team. Community-acquired pneumonia requiring hospitalization among U.S. adults. N Engl J Med   2015; 373: 415– 27. Google Scholar CrossRef Search ADS PubMed  10. Jain S, Williams DJ, Arnold SR, et al.  ; CDC EPIC Study Team. Community-acquired pneumonia requiring hospitalization among U.S. children. N Engl J Med   2015; 372: 835– 45. Google Scholar CrossRef Search ADS PubMed  11. Self WH, Williams DJ, Zhu Y, et al.   Respiratory viral detection in children and adults: comparing asymptomatic controls and patients with community-acquired pneumonia. J Infect Dis   2016; 213: 584– 91. Google Scholar CrossRef Search ADS PubMed  12. Spichak TV, Yatsyshina SB, Кatosova LК, Kim SS, Korppi MO. Is the role of rhinoviruses as causative agents of pediatric community-acquired pneumonia over-estimated? Eur J Pediatr   2016; 175: 1951– 8. Google Scholar CrossRef Search ADS PubMed  13. Martin ET, Kuypers J, Chu HY, et al.   Heterotypic infection and spread of rhinovirus A, B, and C among childcare attendees. J Infect Dis   2018. 14. Martin ET, Fairchok MP, Stednick ZJ, Kuypers J, Englund JA. Epidemiology of multiple respiratory viruses in childcare attendees. J Infect Dis   2013; 207: 982– 9. Google Scholar CrossRef Search ADS PubMed  15. Martin EK, Kuypers J, Chu HY, et al.   Molecular epidemiology of human rhinovirus infections in the pediatric emergency department. J Clin Virol   2015; 62: 25– 31. Google Scholar CrossRef Search ADS PubMed  16. Peltola V, Waris M, Osterback R, Susi P, Ruuskanen O, Hyypiä T. Rhinovirus transmission within families with children: incidence of symptomatic and asymptomatic infections. J Infect Dis   2008; 197: 382– 9. Google Scholar CrossRef Search ADS PubMed  17. Heinonen S, Jartti T, Garcia C, et al.   Rhinovirus detection in symptomatic and asymptomatic children: value of host transcriptome analysis. Am J Respir Crit Care Med   2016; 193: 772– 82. Google Scholar CrossRef Search ADS PubMed  Published by Oxford University Press for the Infectious Diseases Society of America 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US. This work is written by (a) US Government employee(s) and is in the public domain in the US. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Infectious Diseases Oxford University Press

Rhinovirus – New Insights Into a Complex Epidemiology

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Abstract

rhinovirus, daycare, pediatric, transmission, epidemiology, wheezing, genotype, sequencing, PCR, respiratory Many of us recall the excitement early in this century when advances in molecular diagnostics led clinicians to detect surprisingly high rates of rhinovirus from patients with serious respiratory disease. One of the first of these studies was reported by Miller et al, in this journal in 2007, where human rhinovirus (HRV) was identified by culture and polymerase chain reaction (PCR) of respiratory specimens in 26% of children under the age of 5 years hospitalized with acute respiratory infection (ARI) or fever [1]. The authors also suggested an important association of serious illness with HRV in patients with a history of wheezing or asthma. The ability of HRV to alter innate immune responses may contribute to more-severe disease in asthmatics, and play a role in the development of subsequent wheezing, particularly in those genetically predisposed to allergic phenotypes [2, 3]. An accompanying editorial suggested that rhinovirus should now be recognized as “more than just a common cold virus,” because of similar observations replicated globally in several studies [4]. However, attempts to link HRV with clinical disease are challenged by the high rates of recovery of HRV from asymptomatic individuals, a problem not addressed in studies that only sample symptomatic individuals without a similar asymptomatic comparison group [5]. Subsequent studies sought to better describe the role of the 3 major species of HRV (A, B, C) in hospitalized children and adults, comparing recovery rates to similar asymptomatic control groups, while looking for differences in severity of clinical disease among the species. A large multicenter study of 1947 hospitalizations in children for ARI found nearly 4-fold higher rates of HRV-A detection in ill 24 to 59 month olds, and 2-fold higher rates of HRV-C in ill 6 to 59-month-old children, compared to 784 children sampled at well-child visits [6]. These findings supported a role for HRV in clinical disease and again noted an association with asthma or wheezing, although clinical presentations were similar across all 3 species. A Spanish study reported that the A and C species of rhinovirus were associated more specifically with wheezing and asthma, while B was more associated with pneumonia [7]. The association of disease severity and wheezing with HRV species and genotype has relied primarily upon sequencing of VP1, a capsid gene, which has a very high rate of mutation, rather than the entire genome. This limits comparison between studies and results in very divergent genotype associations. Expanding use of multiplex diagnostic platforms has enabled further insight into the association of disease with rhinovirus, as epidemiologic studies now routinely identify additional “copathogens,” especially from younger children, with ARI. A European study of children (under 14 years of age) with radiologically confirmed community-acquired pneumonia (CAP) reported 29% with HRV, 40% of whom yielded concurrent recovery of 2 or more viruses [8]. Concurrent viral infection was most common in infants under a year of age, although clinical severity was not increased in those subjects. HRV was the most commonly identified pathogen in the Etiology of Pneumonia in the Community Study (EPIC), supported by the Centers for Disease Control, where it was recovered in 9% of hospitalized adults with CAP, yet was rarely identified in an asymptomatic control group [9]. In contrast, similar rates of HRV were identified in children <18 years of age admitted for radiographically proven CAP (22%), compared to asymptomatic controls (17%), adjusted for age and enrolled at the same study sites [10]. A nested EPIC study analyzed the 13 most common respiratory viruses, and noted a 24.4% isolation rate for 1 or more viruses from asymptomatic children [11]. Additionally, a recent single-site study documented a 10.7% recovery rate of HRV in children with CAP, which was lower than the 22.4% in controls [12]. The authors of that study, as well as others, have suggested that the initial excitement over the contribution of HRV to respiratory disease might be overestimated. The range of these studies, and their mixed findings, underscore the need to develop a better understanding of the basic epidemiology of rhinoviruses in children and adults. This cannot be accomplished by sampling symptomatic individuals alone, or by identifying the relative distribution of the 3 species in unrelated populations. In this issue of The Journal of Infectious Diseases, Martin et al bring much more clarity into the epidemiology of baseline rhinovirus shedding, and recovery during clinical disease, through their longitudinal study of children enrolled in a set of daycare center classrooms [13]. This population (5 weeks to 30 months of age) was sampled at enrollment, establishing a relevant comparison group from the population being studied, in addition to obtaining weekly longitudinal sampling information from symptomatic children with ARI, until illness resolution or negative PCRs. Furthermore, the authors were able to determine genotypes for nearly half of the human rhinoviruses identified through full-length sequencing rather than single or paired gene analysis. From this information they generated assessments regarding circulation in the small classrooms environment of the childcare center. A previous publication about this cohort reported that rhinovirus was the most frequent virus isolated, but commonly in conjunction with another virus (66% as coinfections), similar to other studies of infants [14]. HRV was identified by PCR in 49% of 455 ARIs. Recurrent infection was common, occurring in nearly half of those with HRV infection. HRV was found in 41% of the initial swabs in asymptomatic enrollees, and in 30% of those with mild ARI symptoms on enrollment. Species A, B, and C were mixed among the asymptomatic enrollees, while A and C predominated in symptomatic children. Overall, no significant differences in severity of illness, or even wheezing, were noted between A, B, or C species; though children with C infection were observed to be less active, this did not result in a difference in school days missed. The study noted that full sequence data were obtained from too few numbers of symptomatic children to assess the association of genotype and sequence variation with severity of disease. The most interesting information gained was from the molecular epidemiologic results. Samples obtained were a heterologous mix of 41 different predominantly A and C genotypes. Eleven different clusters of like genotypes occurred, in patterns suggesting easy person-to-person spread within and between classrooms. However, the mixture in the smallest classroom, as well as among the entire population, changed dynamically every week, with cocirculation of multiple genotypes. The lack of evidence for any protection against serial and subsequent infection was dramatic. Children rarely shed the same genotype for more than 2 weeks, yet in at least 7 longer sequential illnesses, the recovered genotypes changed over time from the same individual. In summary, the chaotic and unpredictable spread of such a heterotypic mix of viruses sheds considerable light on the very fluid diversity of this virus in a situation with “family-like” groupings of individuals. In 2 recent studies, including 1 of the larger studies of hospitalized children discussed above [6], and an emergency room sampling from children with ARI [15], results of genetic sequencing of hundreds of the samples recovered from unrelated individuals did not permit many conclusions to be drawn regarding patterns of circulation or transmission of HRV. A study of hospitalized HRV-positive children, however, found 2-fold higher rates of HRV recovery from siblings and parents (with half symptomatic), and frequently isolated the same genotype, suggesting efficient intrafamily transmission [16]. Yet even within these immediate contacts, a variety of unrelated rhinoviruses were also isolated, again demonstrating the extreme heterogeneity of HRV. Further transmission studies will be challenging, as the continued circulation of heterotypic viruses is, as suggested by Martin et al, very robust, and viral diversity will continue to make identification of patterns of spread difficult, even with powerful sequencing tools. This new work by Martin et al, coupled with previous studies, identify challenges that will require careful study design and considerable resources for future studies of the epidemiology, transmission, clinical disease, and the role of coinfection in respiratory disease associated with HRV [13]. Future studies must identify rates of recovery from a comparison group from the same population, when making conclusions about any subset of symptomatic individuals. Additionally, complete viral genome sequencing will be necessary to make meaningful observations regarding patterns of transmission and clustering of infections. Determining when the presence of HRV indicates asymptomatic shedding as opposed to symptomatic disease may be clarified by analysis of the host response, requiring increased biological sample acquisition and detailed analysis of immune responsiveness. A recent study reported that whole-blood RNA transcriptomes revealed a relative increased innate immune “signature” in infants and children with symptomatic HRV infections compared to asymptomatic individuals [17]. Finally, elucidation of the role of copathogens will require both longitudinal observation and sampling, along with delineation of immune responses to distinct pathogens. As with many advances in our clinical knowledge through the application of new and advanced methodologies, more questions and challenges are raised with each new level of understanding!Notes Notes Disclaimer. The opinions contained herein are those of the authors and do not necessarily reflect those of the Uniformed Services University or the Department of Defense Potential conflicts of interest. Both authors: No reported conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Miller EK, Lu X, Erdman DD, et al.   Rhinovirus-associated hospitaliza tions in young children. J Infect Dis   2007; 195: 773– 81. Google Scholar CrossRef Search ADS PubMed  2. Durrani SR, Montville DJ, Pratt AS, et al.   Innate immune responses to rhinovirus are reduced by the high-affinity IgE receptor in allergic asthmatic children. J Allergy Clin Immunol   2012; 130: 489– 95. Google Scholar CrossRef Search ADS PubMed  3. Turunen R, Jartti T, Bochkov YA, Gern JE, Vuorinen T. Rhinovirus species and clinical characteristics in the first wheezing episode in children. J Med Virol   2016; 88: 2059– 68. Google Scholar CrossRef Search ADS PubMed  4. Turner RB. Rhinovirus: more than just a common cold virus. J Infect Dis   2007; 195: 765– 6. Google Scholar CrossRef Search ADS PubMed  5. Hasegawa K, Linnemann RW, Avadhanula V, et al.   Detection of respiratory syncytial virus and rhinovirus in healthy infants. BMC Res Notes   2015; 8: 718. Google Scholar CrossRef Search ADS PubMed  6. Iwane MK, Prill MM, Lu X, et al.   Human rhinovirus species associated with hospitalizations for acute respiratory illness in young US children. J Infect Dis   2011; 204: 1702– 10. Google Scholar CrossRef Search ADS PubMed  7. Calvo C, Casas I, García-García ML, et al.   Role of rhinovirus C respiratory infections in sick and healthy children in Spain. Pediatr Infect Dis J   2010; 29: 717– 20. Google Scholar CrossRef Search ADS PubMed  8. Esposito S, Daleno C, Tagliabue C, et al.   Impact of rhinoviruses on pediatric community-acquired pneumonia. Eur J Clin Microbiol Infect Dis   2012; 31: 1637– 45. Google Scholar CrossRef Search ADS PubMed  9. Jain S, Self WH, Wunderink RG, et al.  ; CDC EPIC Study Team. Community-acquired pneumonia requiring hospitalization among U.S. adults. N Engl J Med   2015; 373: 415– 27. Google Scholar CrossRef Search ADS PubMed  10. Jain S, Williams DJ, Arnold SR, et al.  ; CDC EPIC Study Team. Community-acquired pneumonia requiring hospitalization among U.S. children. N Engl J Med   2015; 372: 835– 45. Google Scholar CrossRef Search ADS PubMed  11. Self WH, Williams DJ, Zhu Y, et al.   Respiratory viral detection in children and adults: comparing asymptomatic controls and patients with community-acquired pneumonia. J Infect Dis   2016; 213: 584– 91. Google Scholar CrossRef Search ADS PubMed  12. Spichak TV, Yatsyshina SB, Кatosova LК, Kim SS, Korppi MO. Is the role of rhinoviruses as causative agents of pediatric community-acquired pneumonia over-estimated? Eur J Pediatr   2016; 175: 1951– 8. Google Scholar CrossRef Search ADS PubMed  13. Martin ET, Kuypers J, Chu HY, et al.   Heterotypic infection and spread of rhinovirus A, B, and C among childcare attendees. J Infect Dis   2018. 14. Martin ET, Fairchok MP, Stednick ZJ, Kuypers J, Englund JA. Epidemiology of multiple respiratory viruses in childcare attendees. J Infect Dis   2013; 207: 982– 9. Google Scholar CrossRef Search ADS PubMed  15. Martin EK, Kuypers J, Chu HY, et al.   Molecular epidemiology of human rhinovirus infections in the pediatric emergency department. J Clin Virol   2015; 62: 25– 31. Google Scholar CrossRef Search ADS PubMed  16. Peltola V, Waris M, Osterback R, Susi P, Ruuskanen O, Hyypiä T. Rhinovirus transmission within families with children: incidence of symptomatic and asymptomatic infections. J Infect Dis   2008; 197: 382– 9. Google Scholar CrossRef Search ADS PubMed  17. Heinonen S, Jartti T, Garcia C, et al.   Rhinovirus detection in symptomatic and asymptomatic children: value of host transcriptome analysis. Am J Respir Crit Care Med   2016; 193: 772– 82. Google Scholar CrossRef Search ADS PubMed  Published by Oxford University Press for the Infectious Diseases Society of America 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Journal

The Journal of Infectious DiseasesOxford University Press

Published: Apr 19, 2018

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