Next Article in Journal
Glycine Cleavage System and cAMP Receptor Protein Co-Regulate CRISPR/cas3 Expression to Resist Bacteriophage
Next Article in Special Issue
Risk Mapping of Influenza D Virus Occurrence in Ruminants and Swine in Togo Using a Spatial Multicriteria Decision Analysis Approach
Previous Article in Journal
Detection of a Reassortant H9N2 Avian Influenza Virus with Intercontinental Gene Segments in a Resident Australian Chestnut Teal
Previous Article in Special Issue
Influenza D Virus: Serological Evidence in the Italian Population from 2005 to 2017

Viruses 2020, 12(1), 89; https://doi.org/10.3390/v12010089

Review
Epidemiology and Clinical Characteristics of Influenza C Virus
1
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
2
Institute for Infection, Inflammation, and Immunity in Children (i4Kids), University of Pittsburgh, Pittsburgh, PA 15224, USA
*
Author to whom correspondence should be addressed.
Received: 30 December 2019 / Accepted: 7 January 2020 / Published: 13 January 2020

Abstract

:
Influenza C virus (ICV) is a common yet under-recognized cause of acute respiratory illness. ICV seropositivity has been found to be as high as 90% by 7–10 years of age, suggesting that most people are exposed to ICV at least once during childhood. Due to difficulty detecting ICV by cell culture, epidemiologic studies of ICV likely have underestimated the burden of ICV infection and disease. Recent development of highly sensitive RT-PCR has facilitated epidemiologic studies that provide further insights into the prevalence, seasonality, and course of ICV infection. In this review, we summarize the epidemiology and clinical characteristics of ICV.
Keywords:
orthomyxoviruses; influenza C; epidemiology

1. Introduction

Influenza C virus (ICV) is lesser known type of influenza virus that commonly causes cold-like symptoms and sometimes causes lower respiratory infection, especially in children <2 years of age [1]. ICV is mainly a human pathogen; however, the virus has been detected in pigs, dogs, and cattle, and rare swine–human transmission has been reported [2,3,4,5,6]. ICV seropositivity has been found to be as high as 90% by 7–10 years of age, suggesting that most people are exposed to influenza C virus at least once during childhood [7,8]. Although ICV was discovered in 1947, disease burden has been poorly described until recently due to difficulty isolating the virus in cell culture [9,10,11,12,13]. Human challenge studies confirmed that ICV caused upper respiratory disease and immune responses [14]. The recent development of RT-PCR for ICV detection has resulted in expanded understanding of ICV clinical characteristics, seasonality, and molecular epidemiology. A related novel influenza D virus (IDV), was discovered in swine in Oklahoma in 2011 and has been detected in other mammals [15,16,17,18,19]; however, while cattle workers exhibit seropositivity, no definitive evidence of productive human infection with IDV has been reported [20,21]. In this review, we discuss the epidemiology and clinical characteristics of ICV.

Virus Structure

ICV is an enveloped, negative-sense RNA virus that belongs to the Orthomyxoviridae family. It has a 7-segmented genome that encodes 9 viral proteins [22,23,24], distinguishing it from influenza A and B viruses that have 8-segment genomes encoding 10 major viral proteins [25]. Some IAV strains express other proteins PB1-F2 or PA-X from alternate reading frames [26,27]. The presence of a single surface glycoprotein that combines the function of two surface proteins found on influenza A and B viruses is another key feature that distinguishes ICV from influenza A and B viruses [28,29,30]. Influenza A and B surface proteins include hemagglutinin (HA) and neuraminidase (NA), which mediate attachment, entry, and escape [25,31]. In contrast to influenza A and B, ICV hemagglutinin-esterase-fusion (HEF) glycoprotein, encoded on segment 4, efficiently fulfills the roles of both HA and NA by facilitating host receptor binding, cleaving sialic acid, and membrane fusion [32,33,34,35]. However, ICV HEF binds to N-acetyl-9-O-acetylneuraminic acid rather than to N-acetyl-neuraminic acid for influenza A and B viruses [36]. HEF is the major target for host neutralizing antibodies, which appear to bind to epitopes near the receptor-binding site and the esterase site [37,38,39,40,41,42]. Human CD8+ T cells recognize epitopes of ICV internal proteins, some of which are conserved in IAV and IBV [43].
M1, encoded from segment 6, is the major structural protein of ICV that lies under the lipid bilayer [44,45]. The internal structure of ICV is dominated by ribonucleoproteins (RNPs) that are composed of ribonucleic acid and four structural proteins. Genome segment 5 codes for nucleoprotein (NP) and segments 1–3 code for the polymerase (P) subunits basic (PB)2, PB1, and P3, respectively [44,45,46]. Segment 6 also encodes CM2 protein, a minor envelope glycoprotein ion channel [47]. Segment 7 encodes Non-structural protein 1 (NS1), which inhibits host immune responses and Nuclear Export Protein (NEP), which mediates nuclear export of viral RNP [48,49,50,51,52,53]. Like other influenza viruses, ICV viruses have a segmented genome capable of reassortment; reassortment has been documented in vitro as well as in vivo among circulating strains [54,55,56,57,58].

2. Epidemiology and Clinical Characteristics

2.1. Methods of Detection

Seropositivity studies have provided key insights into the epidemiology of ICV but have several limitations including limited ability to determine time of infection. This makes it difficult to identify active infection, describe symptoms, isolate virus for molecular epidemiology, or determine seasonality. Recent epidemiologic studies have taken advantage of improved cell culture techniques and RT-PCR as a means of detecting ICV and have provided further insight into the characteristics of active ICV infection. Until recently, cell culture has been used as the primary method of detecting ICV cases and outbreaks, including many studies in Japan [1,58,59,60,61]. However, the weak cytopathic effect of ICV makes it difficult to detect, resulting in underestimation of burden [10,11,12,13,62]. Seroepidemiology studies of ICV infection measuring hemagglutinin inhibition (HAI) antibody titers have been key in demonstrating the widespread nature of ICV circulation and infection. Within the last decade, highly sensitive nucleic acid detection (RT-PCR) methods have been developed for the detection of ICV [63,64]. In a study comparing RT-PCR to cell culture detection of ICV, RT-PCR detection rate was nearly twice that of cell culture and samples with lower viral load were more likely to be detected with sensitive nucleic acid methods [64]. Several RT-PCR assays have been reported, with significantly increased sensitivity compared to culture [63,64,65,66,67,68,69,70]. These molecular assays have facilitated epidemiologic investigations of ICV.

2.2. Seroepidemiology

In the decade following initial recognition of ICV, studies reporting ICV outbreaks and seroprevalence suggested that ICV infection was widespread among children in the US and England [71,72,73]. Seropositivity studies have demonstrated that ICV has an extensive global distribution and is acquired during childhood, although the age of primary infection may vary [73]. A Japanese study including 434 individuals showed seropositivity of 100% among infants <6 months old, presumably maternally derived, dropping to a nadir by 6 months. Increases in ICV seroprevalence began to rise notably by one year of age and by age 7–10 years, 80–90% of children were seropositive [8]. A California group reported an ICV outbreak that was first detected among healthcare workers and tested 334 serum samples from participants <1 to 25 years of age. Seropositivity increased with age, with 64% seropositivity in children 0–5, 96% in children 6–10, and 98% in adults 16–25 years. Stability of HAI titer across age groups suggested periodic reinfection that maintained antibody titers [74].
Similar findings were reported in another US study that included sera from 237 subjects in 4 age groups: 1 to 2 years (36%), 2 to 5 years (47.2%), 20 to 30 years (96%), and 65 to 85 years (66.7). The highest level of seropositivity was found among young adults (20–30 years), while low ICV HAI titers and decreased seropositivity in those 65–85 years of age may suggest waning ICV immunity in the elderly [7]. These findings were supported by a French study of 301 subjects. HAI antibodies were detected in 61% of samples overall with the highest rate of seropositivity found among those 16–30 years of age (76%), while young children (<15 years) and older adults (51–88 years) had lower rates of seropositivity (46% and 44% respectively) [75]. A Spanish study including 191 subjects 1 to 80 years of age living showed seroprevalence of 68% [76].
Studies conducted in India, Jamaica, Japan, the Philippines, and other countries corroborate the widespread nature of ICV and general age distribution already described [77,78,79,80,81,82,83]. Collectively, these data indicate that ICV infection is widespread globally with most infections occurring in young children. ICV is uncommon in hospitalized adults but has caused outbreaks in military recruits [84,85,86,87,88]. ICV has been reported among travelers on the Hajj pilgrimage [89].

2.3. ICV in Children

A number of studies have focused on pediatric populations. As noted above, seroepidemiology shows that the majority of primary ICV infection occurs during early childhood. An early study from Japan noted most patients were around one year old [12], while reports from the UK detected ICV almost exclusively in children [11,90]. A Japanese longitudinal study of 190 ICV isolates collected over seven years found that nearly all were <6 years old, with the highest rates of infection in children 1–2 years old [60]. Rates of detection of ICV in outpatient or hospitalized children with acute respiratory illness have ranged from 0.7–10% in studies from Australia, Canada, Cuba, India, Italy, Japan, Nigeria, Peru, Scotland, and Spain [1,12,20,61,63,68,70,91,92,93,94,95,96,97,98,99,100,101,102]. Most of these studies found higher rates of ICV infection in younger children. Several studies have reported ICV as a cause of radiographic pneumonia in children, in some series as frequently as IBV [92,95,102]. These widely varied rates are likely due to varying circulation of ICV in different years; several studies have reported large outbreaks in a single year [61,94,98,99]. Outbreaks have been reported in long-term pediatric residential facilities and schools [68,91].

2.4. Seasonality

Seasonality of ICV is poorly understood, although outbreaks and cases of familial transmission have been described [74,101]. Matsuzaki et al. found in a multi-year Japanese study that the peak of ICV was in May during biennial epidemics in even-numbered years [60]. Gouarin et al. reported a peak of disease in France in winter-spring of 2005 while little ICV was detected in the two following seasons [101]. Fritsch et al. noted a similar seasonal pattern in Germany, with a peak of ICV detection in fall–winter–spring of 2012–2013, with minimal detection in the seasons preceding and following [99]. Thielen et al. describe a winter-spring outbreak of 51 cases in the US during 2013–2015 while in the seasons before and after only 2 and 8 cases were reported, respectively [103]. A single-year study performed by Pabbaraju et al. also identified a winter-spring seasonality in ICV detection [70]. In most studies, winter–spring seasonality remained consistent, though Anton et al. report year-round detection of ICV in Spain with highest numbers observed in the summer [104].
Population immunity may contribute to the variability of ICV. Substantial antigenic and genetic diversity exists among ICV isolates; there are six genetic lineages representing six antigenic groups of HEF, with two major genetic lineages of the internal genes [56,57,58,59,60,87,105,106,107,108,109,110,111]. Elegant longitudinal studies in Japan that compared the antigenic and genetic character of circulating isolates with concurrent serology showed periodic epidemics of ICV every few years. While multiple strains co-circulated, there was a dominant antigenic group that was replaced every few years, driven by herd immunity [56,60]. However, there was very little antigenic drift over time [56].

2.5. Clinical Characteristics

ICV is usually associated with mild respiratory disease. The most common symptoms associated with ICV infection are fever, rhinorrhea, and cough; however, the virus has been associated with pneumonia, bronchiolitis, and bronchitis [1,12,63,77,92,94,95,101,102,103,104]. Symptoms of gastroenteritis in patients infected with ICV are frequently reported (Table 1).
ICV infection is more commonly associated with hospitalization and lower respiratory disease in young children (Table 1). ICV-associated hospitalization occurs most often among children <3 years of age and cases of Intensive Care Unit admission among infants with prematurity and congenital heart disease have been described, as well as otherwise healthy young children [1,100,103]. Among children hospitalized for ICV infection, co-morbidity is reported in 58–80% of cases [1,103]. Prematurity is the most common comorbidity present in ICV-associated hospitalization; however, asthma, IgG deficiency, acute lymphoblastic leukemia, cystic fibrosis, and congenital heart disease have also been described [1,103].
Co-infection with other microbes is a common finding among patients with ICV infection, especially among those <2 years (Table 2). Rates of co-infection with at least 1 additional pathogen are reported in 8–50% [1,103]. Co-infection may be associated with increased severity of disease. Thielen et al. reported 3 of 5 ICV-positive patients admitted to the ICU with co-infections [103].
Respiratory viruses can interact with each other or bacteria affecting predisposition to severe respiratory disease, particularly in patients with underlying immunodeficiency or chronic respiratory disease such as chronic obstructive pulmonary disease or cystic fibrosis [112,113]. The presence of influenza or other community-acquired viruses can compromise physical and immunologic barriers and increase the likelihood of secondary bacterial infection [112]. The possible role of ICV in bacterial–viral or viral–viral respiratory co-infection is of interest but is not well understood. In a study of 706 infants <2 years old hospitalized with respiratory illness, 6 patients had influenza C virus infection, and 3 were co-infected with RSV or adenovirus [92]. While the low number of patients hospitalized with ICV and co-infection with another respiratory pathogen may minimize the role of ICV in respiratory infection leading to hospitalization, few studies have been performed and uncertainty remains.

3. Conclusions

ICV is an important respiratory pathogen of childhood, though there are wide variations in prevalence from year to year and in different regions. While the most common manifestation of ICV infection is upper respiratory infection, severe lower respiratory infection does occur. Co-infection with other viral and bacterial pathogens is frequent, making the causal role of ICV in these cases uncertainty. Larger scale studies describing year-to-year prevalence, clinical characteristics, and strain type are needed. ICV exhibits minimal antigenic drift over time, suggesting that a monovalent vaccine could be effective against childhood infection.

Author Contributions

B.K.S. and J.V.W. wrote the article. All authors have read and agreed to the published version of the manuscript.

Funding

B.K.S. was supported by a Grants for Emerging Researchers/Clinicians Mentorship (G.E.R.M.) award from the Infectious Diseases Society of America Foundation. J.V.W. was supported by CDC U01 IP001051 and the Henry L. Hillman Chair in Pediatric Immunology.

Conflicts of Interest

J.V.W. serves on a Scientific Advisory Board for Quidel and an Independent Data Monitoring Committee for GlaxoSmithKline, neither of which is related to the current work.

References

  1. Matsuzaki, Y.; Katsushima, N.; Nagai, Y.; Shoji, M.; Itagaki, T.; Sakamoto, M.; Kitaoka, S.; Mizuta, K.; Nishimura, H. Clinical features of influenza C virus infection in children. J. Infect. Dis. 2006, 193, 1229–1235. [Google Scholar] [CrossRef]
  2. Kimura, H.; Abiko, C.; Peng, G.; Muraki, Y.; Sugawara, K.; Hongo, S.; Kitame, F.; Mizuta, K.; Numazaki, Y.; Suzuki, H.; et al. Interspecies transmission of influenza C virus between humans and pigs. Virus Res. 1997, 48, 71–79. [Google Scholar] [CrossRef]
  3. Guo, Y.J.; Jin, F.G.; Wang, P.; Wang, M.; Zhu, J.M. Isolation of influenza C virus from pigs and experimental infection of pigs with influenza C virus. J. Gen. Virol. 1983, 64, 177–182. [Google Scholar] [CrossRef] [PubMed]
  4. Yamaoka, M.; Hotta, H.; Itoh, M.; Homma, M. Prevalence of antibody to influenza C virus among pigs in Hyogo Prefecture, Japan. J. Gen. Virol. 1991, 72, 711–714. [Google Scholar] [CrossRef] [PubMed]
  5. Manuguerra, J.C.; Hannoun, C. Natural infection of dogs by influenza C virus. Res. Virol. 1992, 143, 199–204. [Google Scholar] [CrossRef]
  6. Zhang, H.; Porter, E.; Lohman, M.; Lu, N.; Peddireddi, L.; Hanzlicek, G.; Marthaler, D.; Liu, X.; Bai, J. Influenza C Virus in Cattle with Respiratory Disease, United States, 2016–2018. Emerg. Infect. Dis. 2018, 24, 1926–1929. [Google Scholar] [CrossRef]
  7. O’Callaghan, R.J.; Gohd, R.S.; Labat, D.D. Human antibody to influenza C virus: Its age-related distribution and distinction from receptor analogs. Infect. Immun. 1980, 30, 500–505. [Google Scholar]
  8. Homma, M.; Ohyama, S.; Katagiri, S. Age distribution of the antibody to type C influenza virus. Microbiol. Immunol. 1982, 26, 639–642. [Google Scholar] [CrossRef]
  9. Taylor, R. Studies on survival of influenza virus between epidemics and antigenic variants of the virus. Am. J. Public Health Nations Health 1949, 39, 171–178. [Google Scholar] [CrossRef]
  10. Takao, S.; Matsuzaki, Y.; Shimazu, Y.; Fukuda, S.; Noda, M.; Tokumoto, S. Isolation of influenza C virus during the 1999/2000-influenza season in Hiroshima Prefecture, Japan. Jpn. J. Infect. Dis. 2000, 53, 173–174. [Google Scholar]
  11. Chakraverty, P.; Matthews, R.S. Detection of influenza C virus in the United Kingdom. Eur. J. Clin. Microbiol. Infect. Dis. 1994, 13, 622–624. [Google Scholar] [CrossRef] [PubMed]
  12. Moriuchi, H.; Katsushima, N.; Nishimura, H.; Nakamura, K.; Numazaki, Y. Community-acquired influenza C virus infection in children. J. Pediatr. 1991, 118, 235–238. [Google Scholar] [CrossRef]
  13. Chakraverty, P. The detection and multiplication of influenza C virus in tissue culture. J. Gen. Virol. 1974, 25, 421–425. [Google Scholar] [CrossRef] [PubMed]
  14. Joosting, A.C.; Head, B.; Bynoe, M.L.; Tyrrell, D.A. Production of common colds in human volunteers by influenza C virus. Br. Med. J. 1968, 4, 153–154. [Google Scholar] [CrossRef] [PubMed]
  15. Hause, B.M.; Ducatez, M.; Collin, E.A.; Ran, Z.; Liu, R.; Sheng, Z.; Armien, A.; Kaplan, B.; Chakravarty, S.; Hoppe, A.D.; et al. Isolation of a novel swine influenza virus from Oklahoma in 2011 which is distantly related to human influenza C viruses. PLoS Pathog 2013, 9, e1003176. [Google Scholar] [CrossRef]
  16. Salem, E.; Cook, E.A.J.; Lbacha, H.A.; Oliva, J.; Awoume, F.; Aplogan, G.L.; Hymann, E.C.; Muloi, D.; Deem, S.L.; Alali, S.; et al. Serologic Evidence for Influenza C and D Virus among Ruminants and Camelids, Africa, 1991–2015. Emerg. Infect. Dis. 2017, 23, 1556–1559. [Google Scholar] [CrossRef]
  17. Chiapponi, C.; Faccini, S.; Fusaro, A.; Moreno, A.; Prosperi, A.; Merenda, M.; Baioni, L.; Gabbi, V.; Rosignoli, C.; Alborali, G.L.; et al. Detection of a New Genetic Cluster of Influenza D Virus in Italian Cattle. Viruses 2019, 11, 1110. [Google Scholar] [CrossRef]
  18. Gorin, S.; Fablet, C.; Queguiner, S.; Barbier, N.; Paboeuf, F.; Herve, S.; Rose, N.; Simon, G. Assessment of Influenza D Virus in Domestic Pigs and Wild Boars in France: Apparent Limited Spread within Swine Populations Despite Serological Evidence of Breeding Sow Exposure. Viruses 2019, 12, 25. [Google Scholar] [CrossRef]
  19. Silveira, S.; Falkenberg, S.M.; Kaplan, B.S.; Crossley, B.; Ridpath, J.F.; Bauermann, F.B.; Fossler, C.P.; Dargatz, D.A.; Dassanayake, R.P.; Vincent, A.L.; et al. Serosurvey for Influenza D Virus Exposure in Cattle, United States, 2014-2015. Emerg. Infect. Dis. 2019, 25, 2074–2080. [Google Scholar] [CrossRef]
  20. Smith, D.B.; Gaunt, E.R.; Digard, P.; Templeton, K.; Simmonds, P. Detection of influenza C virus but not influenza D virus in Scottish respiratory samples. J. Clin. Virol. 2016, 74, 50–53. [Google Scholar] [CrossRef]
  21. White, S.K.; Ma, W.; McDaniel, C.J.; Gray, G.C.; Lednicky, J.A. Serologic evidence of exposure to influenza D virus among persons with occupational contact with cattle. J. Clin. Virol. 2016, 81, 31–33. [Google Scholar] [CrossRef] [PubMed]
  22. Ritchey, M.B.; Palese, P.; Kilbourne, E.D. RNAs of influenza A, B, and C viruses. J. Virol. 1976, 18, 738–744. [Google Scholar] [CrossRef] [PubMed]
  23. Compans, R.W.; Bishop, D.H.; Meier-Ewert, H. Structural components of influenza C virions. J. Virol. 1977, 21, 658–665. [Google Scholar] [CrossRef] [PubMed]
  24. Cox, N.J.; Kendal, A.P. Presence of a segmented single-stranded RNA genome in influenza C virus. Virology 1976, 74, 239–241. [Google Scholar] [CrossRef]
  25. Lamb, R.A.; Choppin, P.W. The gene structure and replication of influenza virus. Annu. Rev. Biochem. 1983, 52, 467–506. [Google Scholar] [CrossRef]
  26. Chen, W.; Calvo, P.A.; Malide, D.; Gibbs, J.; Schubert, U.; Bacik, I.; Basta, S.; O’Neill, R.; Schickli, J.; Palese, P.; et al. A novel influenza A virus mitochondrial protein that induces cell death. Nat. Med. 2001, 7, 1306–1312. [Google Scholar] [CrossRef]
  27. Jagger, B.W.; Wise, H.M.; Kash, J.C.; Walters, K.A.; Wills, N.M.; Xiao, Y.L.; Dunfee, R.L.; Schwartzman, L.M.; Ozinsky, A.; Bell, G.L.; et al. An overlapping protein-coding region in influenza A virus segment 3 modulates the host response. Science 2012, 337, 199–204. [Google Scholar] [CrossRef]
  28. Herrler, G.; Compans, R.W.; Meier-Ewert, H. A precursor glycoprotein in influenza C virus. Virology 1979, 99, 49–56. [Google Scholar] [CrossRef]
  29. Herrler, G.; Nagele, A.; Meier-Ewert, H.; Bhown, A.S.; Compans, R.W. Isolation and structural analysis of influenza C virion glycoproteins. Virology 1981, 113, 439–451. [Google Scholar] [CrossRef]
  30. Sugawara, K.; Ohuchi, M.; Nakamura, K.; Homma, M. Effects of various proteases on the glycoprotein composition and the infectivity of influenza C virus. Arch. Virol. 1981, 68, 147–151. [Google Scholar] [CrossRef]
  31. Matrosovich, M.N.; Matrosovich, T.Y.; Gray, T.; Roberts, N.A.; Klenk, H.D. Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium. J. Virol. 2004, 78, 12665–12667. [Google Scholar] [CrossRef] [PubMed]
  32. Herrler, G.; Durkop, I.; Becht, H.; Klenk, H.D. The glycoprotein of influenza C virus is the haemagglutinin, esterase and fusion factor. J. Gen. Virol. 1988, 69, 839–846. [Google Scholar] [CrossRef] [PubMed]
  33. Pekosz, A.; Lamb, R.A. Cell surface expression of biologically active influenza C virus HEF glycoprotein expressed from cDNA. J. Virol. 1999, 73, 8808–8812. [Google Scholar] [CrossRef] [PubMed]
  34. Kitame, F.; Sugawara, K.; Ohwada, K.; Homma, M. Proteolytic activation of hemolysis and fusion by influenza C virus. Arch. Virol. 1982, 73, 357–361. [Google Scholar] [CrossRef]
  35. Ohuchi, M.; Ohuchi, R.; Mifune, K. Demonstration of hemolytic and fusion activities of influenza C virus. J. Virol. 1982, 42, 1076–1079. [Google Scholar] [CrossRef]
  36. Rogers, G.N.; Herrler, G.; Paulson, J.C.; Klenk, H.D. Influenza C virus uses 9-O-acetyl-N-acetylneuraminic acid as a high affinity receptor determinant for attachment to cells. J. Biol. Chem. 1986, 261, 5947–5951. [Google Scholar]
  37. Rosenthal, P.B.; Zhang, X.; Formanowski, F.; Fitz, W.; Wong, C.H.; Meier-Ewert, H.; Skehel, J.J.; Wiley, D.C. Structure of the haemagglutinin-esterase-fusion glycoprotein of influenza C virus. Nature 1998, 396, 92–96. [Google Scholar] [CrossRef]
  38. Matsuzaki, Y.; Sugawara, K.; Furuse, Y.; Shimotai, Y.; Hongo, S.; Mizuta, K.; Nishimura, H. Neutralizing Epitopes and Residues Mediating the Potential Antigenic Drift of the Hemagglutinin-Esterase Protein of Influenza C Virus. Viruses 2018, 10, 417. [Google Scholar] [CrossRef]
  39. Zhang, W.; Zhang, L.; He, W.; Zhang, X.; Wen, B.; Wang, C.; Xu, Q.; Li, G.; Zhou, J.; Veit, M.; et al. Genetic Evolution and Molecular Selection of the HE Gene of Influenza C Virus. Viruses 2019, 11, 167. [Google Scholar] [CrossRef]
  40. Liu, R.; Sheng, Z.; Lin, T.; Sreenivasan, C.; Gao, R.; Thomas, M.; Druce, J.; Hause, B.M.; Kaushik, R.S.; Li, F.; et al. Genetic and antigenic characteristics of a human influenza C virus clinical isolate. J. Med. Virol. 2020, 92, 161–166. [Google Scholar] [CrossRef]
  41. Matsuzaki, M.; Sugawara, K.; Adachi, K.; Hongo, S.; Nishimura, H.; Kitame, F.; Nakamura, K. Location of neutralizing epitopes on the hemagglutinin-esterase protein of influenza C virus. Virology 1992, 189, 79–87. [Google Scholar] [CrossRef]
  42. Sugawara, K.; Nishimura, H.; Hongo, S.; Muraki, Y.; Kitame, F.; Nakamura, K. Construction of an antigenic map of the haemagglutinin-esterase protein of influenza C virus. J. Gen. Virol. 1993, 74, 1661–1666. [Google Scholar] [CrossRef] [PubMed]
  43. Koutsakos, M.; Illing, P.T.; Nguyen, T.H.O.; Mifsud, N.A.; Crawford, J.C.; Rizzetto, S.; Eltahla, A.A.; Clemens, E.B.; Sant, S.; Chua, B.Y.; et al. Human CD8(+) T cell cross-reactivity across influenza A, B and C viruses. Nat. Immunol. 2019, 20, 613–625. [Google Scholar] [CrossRef] [PubMed]
  44. Elliott, R.M.; Yuanji, G.; Desselberger, U. Polypeptide synthesis in MDCK cells infected with human and pig influenza C viruses. J. Gen. Virol. 1984, 65, 1873–1880. [Google Scholar] [CrossRef]
  45. Elliott, R.M.; Yuanji, G.; Desselberger, U. Protein and nucleic acid analyses of influenza C viruses isolated from pigs and man. Vaccine 1985, 3, 182–188. [Google Scholar] [CrossRef]
  46. Yokota, M.; Nakamura, K.; Sugawara, K.; Homma, M. The synthesis of polypeptides in influenza C virus-infected cells. Virology 1983, 130, 105–117. [Google Scholar] [CrossRef]
  47. Hongo, S.; Sugawara, K.; Nishimura, H.; Muraki, Y.; Kitame, F.; Nakamura, K. Identification of a second protein encoded by influenza C virus RNA segment 6. J. Gen. Virol. 1994, 75, 3503–3510. [Google Scholar] [CrossRef]
  48. Nakada, S.; Graves, P.N.; Palese, P. The influenza C virus NS gene: Evidence for a spliced mRNA and a second NS gene product (NS2 protein). Virus Res. 1986, 4, 263–273. [Google Scholar] [CrossRef]
  49. Alamgir, A.S.; Matsuzaki, Y.; Hongo, S.; Tsuchiya, E.; Sugawara, K.; Muraki, Y.; Nakamura, K. Phylogenetic analysis of influenza C virus nonstructural (NS) protein genes and identification of the NS2 protein. J. Gen. Virol. 2000, 81, 1933–1940. [Google Scholar] [CrossRef]
  50. Kohno, Y.; Muraki, Y.; Matsuzaki, Y.; Takashita, E.; Sugawara, K.; Hongo, S. Intracellular localization of influenza C virus NS2 protein (NEP) in infected cells and its incorporation into virions. Arch. Virol. 2009, 154, 235–243. [Google Scholar] [CrossRef]
  51. Muraki, Y.; Furukawa, T.; Kohno, Y.; Matsuzaki, Y.; Takashita, E.; Sugawara, K.; Hongo, S. Influenza C virus NS1 protein upregulates the splicing of viral mRNAs. J. Virol. 2010, 84, 1957–1966. [Google Scholar] [CrossRef]
  52. Pachler, K.; Vlasak, R. Influenza C virus NS1 protein counteracts RIG-I-mediated IFN signalling. Virol. J. 2011, 8, 48. [Google Scholar] [CrossRef] [PubMed]
  53. Paragas, J.; Talon, J.; O’Neill, R.E.; Anderson, D.K.; Garcia-Sastre, A.; Palese, P. Influenza B and C virus NEP (NS2) proteins possess nuclear export activities. J. Virol. 2001, 75, 7375–7383. [Google Scholar] [CrossRef] [PubMed]
  54. Peng, G.; Hongo, S.; Muraki, Y.; Sugawara, K.; Nishimura, H.; Kitame, F.; Nakamura, K. Genetic reassortment of influenza C viruses in man. J. Gen. Virol. 1994, 75, 3619–3622. [Google Scholar] [CrossRef] [PubMed]
  55. Peng, G.; Hongo, S.; Kimura, H.; Muraki, Y.; Sugawara, K.; Kitame, F.; Numazaki, Y.; Suzuki, H.; Nakamura, K. Frequent occurrence of genetic reassortment between influenza C virus strains in nature. J. Gen. Virol. 1996, 77, 1489–1492. [Google Scholar] [CrossRef] [PubMed]
  56. Matsuzaki, Y.; Sugawara, K.; Furuse, Y.; Shimotai, Y.; Hongo, S.; Oshitani, H.; Mizuta, K.; Nishimura, H. Genetic Lineage and Reassortment of Influenza C Viruses Circulating between 1947 and 2014. J. Virol. 2016, 90, 8251–8265. [Google Scholar] [CrossRef] [PubMed]
  57. Matsuzaki, Y.; Sugawara, K.; Mizuta, K.; Tsuchiya, E.; Muraki, Y.; Hongo, S.; Suzuki, H.; Nakamura, K. Antigenic and genetic characterization of influenza C viruses which caused two outbreaks in Yamagata City, Japan, in 1996 and 1998. J. Clin. Microbiol. 2002, 40, 422–429. [Google Scholar] [CrossRef] [PubMed]
  58. Matsuzaki, Y.; Mizuta, K.; Kimura, H.; Sugawara, K.; Tsuchiya, E.; Suzuki, H.; Hongo, S.; Nakamura, K. Characterization of antigenically unique influenza C virus strains isolated in Yamagata and Sendai cities, Japan, during 1992–1993. J. Gen. Virol. 2000, 81, 1447–1452. [Google Scholar] [CrossRef]
  59. Matsuzaki, Y.; Muraki, Y.; Sugawara, K.; Hongo, S.; Nishimura, H.; Kitame, F.; Katsushima, N.; Numazaki, Y.; Nakamura, K. Cocirculation of two distinct groups of influenza C virus in Yamagata City, Japan. Virology 1994, 202, 796–802. [Google Scholar] [CrossRef]
  60. Matsuzaki, Y.; Sugawara, K.; Abiko, C.; Ikeda, T.; Aoki, Y.; Mizuta, K.; Katsushima, N.; Katsushima, F.; Katsushima, Y.; Itagaki, T.; et al. Epidemiological information regarding the periodic epidemics of influenza C virus in Japan (1996-2013) and the seroprevalence of antibodies to different antigenic groups. J. Clin. Virol. 2014, 61, 87–93. [Google Scholar] [CrossRef]
  61. Matsuzaki, Y.; Abiko, C.; Mizuta, K.; Sugawara, K.; Takashita, E.; Muraki, Y.; Suzuki, H.; Mikawa, M.; Shimada, S.; Sato, K.; et al. A nationwide epidemic of influenza C virus infection in Japan in 2004. J. Clin. Microbiol. 2007, 45, 783–788. [Google Scholar] [CrossRef] [PubMed]
  62. Ohyama, S.; Adachi, K.; Sugawara, K.; Hongo, S.; Nishimura, H.; Kitame, F.; Nakamura, K. Antigenic and genetic analyses of eight influenza C strains isolated in various areas of Japan during 1985-9. Epidemiol. Infect. 1992, 108, 353–365. [Google Scholar] [CrossRef] [PubMed]
  63. Howard, L.M.; Johnson, M.; Gil, A.I.; Pekosz, A.; Griffin, M.R.; Edwards, K.M.; Lanata, C.F.; Grijalva, C.G.; Williams, J.V.; Group, R.-P. A novel real-time RT-PCR assay for influenza C tested in Peruvian children. J. Clin. Virol. 2017, 96, 12–16. [Google Scholar] [CrossRef] [PubMed]
  64. Matsuzaki, Y.; Ikeda, T.; Abiko, C.; Aoki, Y.; Mizuta, K.; Shimotai, Y.; Sugawara, K.; Hongo, S. Detection and quantification of influenza C virus in pediatric respiratory specimens by real-time PCR and comparison with infectious viral counts. J. Clin. Virol. 2012, 54, 130–134. [Google Scholar] [CrossRef] [PubMed]
  65. Claas, E.C.; Sprenger, M.J.; Kleter, G.E.; van Beek, R.; Quint, W.G.; Masurel, N. Type-specific identification of influenza viruses A, B and C by the polymerase chain reaction. J. Virol. Methods 1992, 39, 1–13. [Google Scholar] [CrossRef]
  66. Hirsila, M.; Kauppila, J.; Tuomaala, K.; Grekula, B.; Puhakka, T.; Ruuskanen, O.; Ziegler, T. Detection by reverse transcription-polymerase chain reaction of influenza C in nasopharyngeal secretions of adults with a common cold. J. Infect. Dis. 2001, 183, 1269–1272. [Google Scholar] [CrossRef]
  67. Coiras, M.T.; Perez-Brena, P.; Garcia, M.L.; Casas, I. Simultaneous detection of influenza A, B, and C viruses, respiratory syncytial virus, and adenoviruses in clinical samples by multiplex reverse transcription nested-PCR assay. J. Med. Virol. 2003, 69, 132–144. [Google Scholar] [CrossRef]
  68. Ramos, A.P.; Herrera, B.A.; Ramirez, O.V.; Valdes, C.S.; Hernandez, A.G.; Gonzalez, G.; Baez, G.G. Detection of influenza C during an outbreak at an internal school, using a molecular tool; Havana, Cuba, September 2006. Int. J. Infect. Dis. 2008, 12, e129–e130. [Google Scholar] [CrossRef]
  69. Muradrasoli, S.; Mohamed, N.; Belak, S.; Czifra, G.; Herrmann, B.; Berencsi, G.; Blomberg, J. Broadly targeted triplex real-time PCR detection of influenza A, B and C viruses based on the nucleoprotein gene and a novel "MegaBeacon" probe strategy. J. Virol. Methods 2010, 163, 313–322. [Google Scholar] [CrossRef]
  70. Pabbaraju, K.; Wong, S.; Wong, A.; May-Hadford, J.; Tellier, R.; Fonseca, K. Detection of influenza C virus by a real-time RT-PCR assay. Influenza Other Respir. Viruses 2013, 7, 954–960. [Google Scholar] [CrossRef]
  71. Minuse, E.; Quilligan, J.J., Jr.; Francis, T., Jr. Type C influenza virus. I. Studies of the virus and its distribution. J. Lab. Clin. Med. 1954, 43, 31–42. [Google Scholar]
  72. Andrews, B.E.; McDonald, J.C. Influenza virus C infection in England. Br. Med. J. 1955, 2, 992–994. [Google Scholar] [CrossRef]
  73. Hilleman, M.R.; Werner, J.H.; Gauld, R.L. Influenza antibodies in the population of the USA; an epidemiological investigation. Bull. World Health Organ. 1953, 8, 613–631. [Google Scholar]
  74. Dykes, A.C.; Cherry, J.D.; Nolan, C.E. A clinical, epidemiologic, serologic, and virologic study of influenza C virus infection. Arch. Intern. Med. 1980, 140, 1295–1298. [Google Scholar] [CrossRef]
  75. Manuguerra, J.C.; Hannoun, C.; Aymard, M. Influenza C virus infection in France. J. Infect. 1992, 24, 91–99. [Google Scholar] [CrossRef]
  76. Manuguerra, J.C.; Hannoun, C.; Saenz Mdel, C.; Villar, E.; Cabezas, J.A. Sero-epidemiological survey of influenza C virus infection in Spain. Eur. J. Epidemiol. 1994, 10, 91–94. [Google Scholar] [CrossRef] [PubMed]
  77. Salez, N.; Melade, J.; Pascalis, H.; Aherfi, S.; Dellagi, K.; Charrel, R.N.; Carrat, F.; de Lamballerie, X. Influenza C virus high seroprevalence rates observed in 3 different population groups. J. Infect. 2014, 69, 182–189. [Google Scholar] [CrossRef] [PubMed]
  78. Nishimura, H.; Sugawara, K.; Kitame, F.; Nakamura, K.; Sasaki, H. Prevalence of the antibody to influenza C virus in a northern Luzon Highland Village, Philippines. Microbiol. Immunol. 1987, 31, 1137–1143. [Google Scholar] [CrossRef] [PubMed]
  79. Jennings, R. Respiratory viruses in Jamaica: A virologic and serologic study. 3. Hemagglutination-inhibiting antibodies to type B and C influenza viruses in the sera of Jamaicans. Am. J. Epidemiol. 1968, 87, 440–446. [Google Scholar] [CrossRef] [PubMed]
  80. Kaji, M.; Hiromatsu, Y.; Kashiwagi, S.; Hayashi, J.; Oyama, S.; Katagiri, S.; Homma, M. Distribution of antibodies to influenza C virus. Kurume Med. J. 1983, 30, 121–123. [Google Scholar] [CrossRef] [PubMed]
  81. Motta, F.C.; Luiz, M.O.; Couceiro, J.N. Serological analysis reveals circulation of influenza C viruses, Brazil. Rev. Saude Publica 2000, 34, 204–205. [Google Scholar] [CrossRef]
  82. Takao, S.; Toyota, A.; Shimazu, Y.; Fukuda, S.; Noda, M.; Tokumoto, S. Seroepidemiological survey of influenza C virus in Hiroshima Prefecture, Japan. Jpn. J. Infect. Dis. 2000, 53, 246–247. [Google Scholar]
  83. Yano, T.; Maeda, C.; Akachi, S.; Matsuno, Y.; Yamadera, M.; Kobayashi, T.; Nagai, Y.; Iwade, Y.; Kusuhara, H.; Katayama, M.; et al. Phylogenetic analysis and seroprevalence of influenza C virus in Mie Prefecture, Japan in 2012. Jpn. J. Infect. Dis. 2014, 67, 127–131. [Google Scholar] [CrossRef]
  84. Fraser, P.K.; Shell, G.N.; Hatch, L.A.; Forster, J.M. Influenza C in a naval recruit population. Lancet 1959, 1, 1259–1260. [Google Scholar] [CrossRef]
  85. Kauppila, J.; Ronkko, E.; Juvonen, R.; Saukkoriipi, A.; Saikku, P.; Bloigu, A.; Vainio, O.; Ziegler, T. Influenza C virus infection in military recruits--symptoms and clinical manifestation. J. Med. Virol. 2014, 86, 879–885. [Google Scholar] [CrossRef]
  86. Nesmith, N.; Williams, J.V.; Johnson, M.; Zhu, Y.; Griffin, M.; Talbot, H.K. Sensitive Diagnostics Confirm That Influenza C is an Uncommon Cause of Medically Attended Respiratory Illness in Adults. Clin. Infect. Dis. 2017, 65, 1037–1039. [Google Scholar] [CrossRef]
  87. Ting, P.J.; Seah, S.G.; Lim, E.A.; Liaw, J.C.; Boon-Huan, T. Genetic characterisation of influenza C viruses detected in Singapore in 2006. Influenza Other Respir. Viruses 2016, 10, 27–33. [Google Scholar] [CrossRef]
  88. Seah, S.G.; Lim, E.A.; Kok-Yong, S.; Liaw, J.C.; Lee, V.; Kammerer, P.; Metzgar, D.; Russell, K.L.; Tan, B.H. Viral agents responsible for febrile respiratory illnesses among military recruits training in tropical Singapore. J. Clin. Virol. 2010, 47, 289–292. [Google Scholar] [CrossRef]
  89. Benkouiten, S.; Charrel, R.; Belhouchat, K.; Drali, T.; Salez, N.; Nougairede, A.; Zandotti, C.; Memish, Z.A.; al Masri, M.; Gaillard, C.; et al. Circulation of respiratory viruses among pilgrims during the 2012 Hajj pilgrimage. Clin. Infect. Dis. 2013, 57, 992–1000. [Google Scholar] [CrossRef]
  90. Chakraverty, P.; Adhami, Z.; Wise, R.; Mathews, R.S. Influenza C virus in the United Kingdom. J. Infect. 1984, 8, 177–178. [Google Scholar] [CrossRef]
  91. Katagiri, S.; Ohizumi, A.; Homma, M. An outbreak of type C influenza in a children’s home. J. Infect. Dis. 1983, 148, 51–56. [Google Scholar] [CrossRef]
  92. Calvo, C.; Garcia-Garcia, M.L.; Centeno, M.; Perez-Brena, P.; Casas, I. Influenza C virus infection in children, Spain. Emerg. Infect. Dis. 2006, 12, 1621–1622. [Google Scholar] [CrossRef]
  93. Akinloye, O.M.; Ronkko, E.; Savolainen-Kopra, C.; Ziegler, T.; Iwalokun, B.A.; Deji-Agboola, M.A.; Oluwadun, A.; Roivainen, M.; Adu, F.D.; Hovi, T. Specific viruses detected in nigerian children in association with acute respiratory disease. J. Trop. Med. 2011, 2011, 690286. [Google Scholar] [CrossRef]
  94. Calvo, C.; Garcia-Garcia, M.L.; Borrell, B.; Pozo, F.; Casas, I. Prospective study of influenza C in hospitalized children. Pediatr. Infect. Dis. J. 2013, 32, 916–919. [Google Scholar] [CrossRef]
  95. Principi, N.; Scala, A.; Daleno, C.; Esposito, S. Influenza C virus-associated community-acquired pneumonia in children. Influenza Other Respir. Viruses 2013, 7, 999–1003. [Google Scholar] [CrossRef]
  96. Odagiri, T.; Matsuzaki, Y.; Okamoto, M.; Suzuki, A.; Saito, M.; Tamaki, R.; Lupisan, S.P.; Sombrero, L.T.; Hongo, S.; Oshitani, H. Isolation and characterization of influenza C viruses in the Philippines and Japan. J. Clin. Microbiol. 2015, 53, 847–858. [Google Scholar] [CrossRef]
  97. Shimizu, Y.; Abiko, C.; Ikeda, T.; Mizuta, K.; Matsuzaki, Y. Influenza C Virus and Human Metapneumovirus Infections in Hospitalized Children With Lower Respiratory Tract Illness. Pediatr. Infect. Dis. J. 2015, 34, 1273–1275. [Google Scholar] [CrossRef]
  98. Jelley, L.; Levy, A.; Deng, Y.M.; Spirason, N.; Lang, J.; Buettner, I.; Druce, J.; Blyth, C.; Effler, P.; Smith, D.; et al. Influenza C infections in Western Australia and Victoria from 2008 to 2014. Influenza Other Respir. Viruses 2016, 10, 455–461. [Google Scholar] [CrossRef]
  99. Fritsch, A.; Schweiger, B.; Biere, B. Influenza C virus in pre-school children with respiratory infections: Retrospective analysis of data from the national influenza surveillance system in Germany, 2012 to 2014. Euro Surveill 2019, 24. [Google Scholar] [CrossRef]
  100. Njouom, R.; Monamele, G.C.; Ermetal, B.; Tchatchouang, S.; Moyo-Tetang, S.; McCauley, J.W.; Daniels, R.S. Detection of Influenza C Virus Infection among Hospitalized Patients, Cameroon. Emerg. Infect. Dis. 2019, 25, 607–609. [Google Scholar] [CrossRef]
  101. Gouarin, S.; Vabret, A.; Dina, J.; Petitjean, J.; Brouard, J.; Cuvillon-Nimal, D.; Freymuth, F. Study of influenza C virus infection in France. J. Med. Virol. 2008, 80, 1441–1446. [Google Scholar] [CrossRef]
  102. Onyango, C.O.; Njeru, R.; Kazungu, S.; Achilla, R.; Bulimo, W.; Welch, S.R.; Cane, P.A.; Gunson, R.N.; Hammitt, L.L.; Scott, J.A.; et al. Influenza surveillance among children with pneumonia admitted to a district hospital in coastal Kenya, 2007–2010. J. Infect. Dis. 2012, 206, S61–S67. [Google Scholar] [CrossRef]
  103. Thielen, B.K.; Friedlander, H.; Bistodeau, S.; Shu, B.; Lynch, B.; Martin, K.; Bye, E.; Como-Sabetti, K.; Boxrud, D.; Strain, A.K.; et al. Detection of Influenza C Viruses Among Outpatients and Patients Hospitalized for Severe Acute Respiratory Infection, Minnesota, 2013–2016. Clin. Infect. Dis. 2018, 66, 1092–1098. [Google Scholar] [CrossRef]
  104. Anton, A.; Marcos, M.A.; Codoner, F.M.; de Molina, P.; Martinez, A.; Cardenosa, N.; Godoy, P.; Torner, N.; Martinez, M.J.; Ramon, S.; et al. Influenza C virus surveillance during the first influenza A (H1N1) 2009 pandemic wave in Catalonia, Spain. Diagn. Microbiol. Infect Dis. 2011, 69, 419–427. [Google Scholar] [CrossRef]
  105. Buonagurio, D.A.; Nakada, S.; Fitch, W.M.; Palese, P. Epidemiology of influenza C virus in man: Multiple evolutionary lineages and low rate of change. Virology 1986, 153, 12–21. [Google Scholar] [CrossRef]
  106. Kawamura, H.; Tashiro, M.; Kitame, F.; Homma, M.; Nakamura, K. Genetic variation among human strains of influenza C virus isolated in Japan. Virus Res. 1986, 4, 275–288. [Google Scholar] [CrossRef]
  107. Adachi, K.; Kitame, F.; Sugawara, K.; Nishimura, H.; Nakamura, K. Antigenic and genetic characterization of three influenza C strains isolated in the Kinki district of Japan in 1982–1983. Virology 1989, 172, 125–133. [Google Scholar] [CrossRef]
  108. Matsuzaki, Y.; Takao, S.; Shimada, S.; Mizuta, K.; Sugawara, K.; Takashita, E.; Muraki, Y.; Hongo, S.; Nishimura, H. Characterization of antigenically and genetically similar influenza C viruses isolated in Japan during the 1999-2000 season. Epidemiol. Infect. 2004, 132, 709–720. [Google Scholar] [CrossRef]
  109. Roy Mukherjee, T.; Mukherjee, A.; Mullick, S.; Chawla-Sarkar, M. Full genome analysis and characterization of influenza C virus identified in Eastern India. Infect. Genet. Evol. 2013, 16, 419–425. [Google Scholar] [CrossRef]
  110. Tanaka, S.; Aoki, Y.; Matoba, Y.; Yahagi, K.; Mizuta, K.; Itagaki, T.; Katsushima, F.; Katsushima, Y.; Matsuzaki, Y. The dominant antigenic group of influenza C infections changed from c/Sao Paulo/378/82-lineage to c/Kanagawa/1/76-lineage in Yamagata, Japan, in 2014. Jpn. J. Infect. Dis. 2015, 68, 166–168. [Google Scholar] [CrossRef]
  111. Potdar, V.A.; Hinge, D.D.; Dakhave, M.R.; Manchanda, A.; Jadhav, N.; Kulkarni, P.B.; Chadha, M.S. Molecular detection and characterization of Influenza ‘C’ viruses from western India. Infect. Genet. Evol. 2017, 54, 466–477. [Google Scholar] [CrossRef] [PubMed]
  112. Bello, S.; Minchole, E.; Fandos, S.; Lasierra, A.B.; Ruiz, M.A.; Simon, A.L.; Panadero, C.; Lapresta, C.; Menendez, R.; Torres, A. Inflammatory response in mixed viral-bacterial community-acquired pneumonia. BMC Pulm. Med. 2014, 14, 123. [Google Scholar] [CrossRef] [PubMed]
  113. Bellinghausen, C.; Rohde, G.G.U.; Savelkoul, P.H.M.; Wouters, E.F.M.; Stassen, F.R.M. Viral-bacterial interactions in the respiratory tract. J. Gen. Virol. 2016, 97, 3089–3102. [Google Scholar] [CrossRef]
Table 1. Summary of clinical characteristics of patients infected with influenza C virus.
Table 1. Summary of clinical characteristics of patients infected with influenza C virus.
ManuscriptLocationAge RangeMedian Age (yrs)NHospitalizedFever (%)Rhinorrhea/RhinitisCoughWheezeHeadacheDiarrheaVomitingLower Resp
Moriuchi et al., 1991 [12]Japan2 m to 11 y1 yr20-16 (80)5 (25)15 (75)1 (5)-3 (15)3 (15)5 (25)
Matsuzaki et al., 2006 [1]Japan<1 to 13 y-17029 (17)153 (90)105 (62)126 (74)21 (12)10 (6)17 (10)24 (14)-
Gouarin et al., 2008 * [101]France4 m to 74 y-1812 (67)13 (93)8 (57)10 (71)2 (14)-4 (29)5 (36)-
Anton et al., 2011 [104]Spain1 to 60 y20.512-10 (83)-10 (83)-4 (33)---
Salez et al., 2014 [77]France; Reunion Island; UK<1 to 49 y3.212-9 (75)5 (42)7 (58)----4 (33)
Howard et al., 2017 [63]Peru<3 y-39-24 (62)35 (90)34 (87)0---1 (3)
Thielen et al., 2018 [103]United States<6 m to >18 y1.77059 (84)33 (47)29 (41)42 (60)16 (23)6 (9)8 (11)20 (29).
* 14 patients had available clinical information; - = not reported
Table 2. Summary of co-infections seen in patients with influenza C virus (ICV) infection.
Table 2. Summary of co-infections seen in patients with influenza C virus (ICV) infection.
PathogenN
Rhinovirus/Enterovirus20
Respiratory syncytial virus16
Adenovirus11
Influenza A virus6
Influenza B virus4
Parainfluenza virus (1–4)9
Human metapneumovirus6
Coronavirus (229E, NL63)3
Rotavirus2
Chlamydia pneumoniae1
Moraxella catarrhalis1
Bordetella parapertussis1
Mumps virus1
Rubella virus1
Herpes simplex virus1
Total ICV (+)278
Sources: [1,12,101,103]
Back to TopTop