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An atypical course of coxsackievirus A6 associated hand, foot and mouth disease in extremely low birth weight preterm twins
Journal of Clinical Virology 65 (2015) 20–22
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Case report
An atypical course of coxsackievirus A6 associated hand, foot and mouth disease in extremely low birth weight preterm twins Andrea HL Bruning a,∗,1 , Sabine MG van der Sanden b,∗∗,1 , Amber E ten Hoedt c , Katja C Wolthers b , Anton H van Kaam c,2 , Dasja Pajkrt a,2 a
Department of Pediatric Infectious Diseases, Emma Children’s Hospital, Academic Medical Center, Amsterdam, The Netherlands Department of Medical Microbiology, Laboratory of Clinical Virology, Academic Medical Center, Amsterdam, The Netherlands c Department of Neonatology, Emma Children’s Hospital, Academic Medical Center, Amsterdam, The Netherlands b
a r t i c l e
i n f o
Article history: Received 29 December 2014 Received in revised form 13 January 2015 Accepted 28 January 2015 Keywords: Coxsackievirus A6 Hand, foot and mouth disease Preterm
a b s t r a c t The incidence of coxsackievirus A6 (CV-A6) associated hand, foot and mouth disease (HFMD) has reportedly increased since 2008 with sometimes severe complications. We here describe an atypical course of CV-A6-associated HFMD in extremely low birth weight twins. The CV-A6-strains are genetically closely related to international strains isolated from HFMD outbreaks. © 2015 Elsevier B.V. All rights reserved.
1. Why this case is important? Hand, foot and mouth disease (HFMD) is a common viral disease caused by human enteroviruses, mostly affecting infants and young children below 5 years of age. The most prominent symptoms include fever and a variety of skin lesions, such as maculopapular or vesicular eruptions in the oral cavity and on the distal extremities, buttocks and genital [1]. HFMD can be caused by multiple different serotypes of human enteroviruses of which enterovirus 71 and coxsackievirus (CV) A16 are most often associated with major outbreaks of HFMD worldwide [2]. However, since 2008 coxsackievirus A6 (CV-A6) has been causing HFMD outbreaks in Europe, South-East Asia and America. CV-A6 infection seems to be associated with atypical presentations such as epididymitis and more severe disease than the classic HFMD [3]. Although HFMD usually follows a benign and self-limiting course, severe or even lethal manifestations, such as paralytic
∗ Corresponding author at: Department of Pediatric Infectious Diseases, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel: +31 20 5668668; fax: +31 20 6912231. ∗∗ Corresponding author at: Department of Medical Microbiology, Laboratory of Clinical Virology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel.: +31 20 5668424. E-mail addresses: [email protected] (A.H. Bruning), [email protected] (S.M.v.d. Sanden). 1 Contributed equally as first authors. 2 Contributed equally as last authors. http://dx.doi.org/10.1016/j.jcv.2015.01.020 1386-6532/© 2015 Elsevier B.V. All rights reserved.
poliomyelitis, encephalitis, meningitis, myocarditis and neonatal sepsis-like systemic infections have been described [4]. Risk factors associated with severe HFMD include onset of illness in the first days of life, lack of specific antibodies, detection of virus in blood, specific infecting serotype (e.g. group B CV and echovirus 11), and prematurity [5]. In this report we described for the first time a case of CV-A6 in extremely low birth weight preterm twins.
2. Case description A dichorionic diamniotic pair of twins was born at a gestational age of 24 weeks and 2 days. Both twins had an uneventful start with an Apgar score of 8 after 5 min. Twin 1, a girl, weighed 535 g and twin 2, a boy, 740 g. Both infants were managed on non-invasive respiratory support and recurrent episodes of apnea of prematurity were treated with caffeine in combination with doxapram. At the age of 4 weeks, the twin girl was mechanically ventilated for 48 h during a period of sepsis caused by a Acinetobacter species, that was treated with gentamicin for 7 days. At the age of 1 month both infants developed vesicles on both their feet, without any other clinical signs of illness (Fig. 1). Further enquiry revealed that their mother had not been feeling well and had developed vesicles on her hands, feet and face 4 days prior to onset of the skin lesions in the twins. She had recently been into contact with two nieces, who also had vesicles on their hands and in their mouth. An enterovirus was detected by PCR in vesicle fluid from the mother and in vesicle fluid, pharynx, and stool samples from both
A.H. Bruning et al. / Journal of Clinical Virology 65 (2015) 20–22
21
Fig. 1. Clinical manifestations of CV-A6 in the preterm twins.
children. These enteroviruses were typed as CV-A6 by analysis of the viral VP1 capsid nucleotide sequences [6]. In addition, CV-A6 was detected in eye fluid in the twin boy and from plasma in the twin girl. Blood infection biomarkers, including white blood cell count and C-reactive protein levels, remained within the normal range. The skin lesions resolved within six days. Weekly repeated enterovirus PCR on pharynx samples obtained from the mother and both infants turned negative after, respectively, 2 and 3 weeks. Both infants were discharged home at a postnatal age of 3 months and showed no abnormalities at neurodevelopmental follow-up at 15 months.
3. Other similar and contrasting cases in the literature and discussion Despite the presence of two important risk factors for serious HFMD, namely extremely preterm birth and isolation of CV-A6 from blood, the course of CV-A6 infection in the presented cases was very mild. The mother of the preterm twins had also relatively mild symptoms of HFMD with minimal malaise and vesicular skin lesions. This is in contrast to reports from other countries such as the United States, Finland and France, where CV-A6 is reported as the causative agent of severe, atypical causes of HFMD [7–10]. Partial VP1 capsid nucleotide sequences (∼300 nts) of viral strains isolated from the twins differed only one nucleotide from that of the strain isolated from the mother. This high percentage of sequence homology suggests that the CV-A6 transmission occurred within the family. Phylogenetic analysis including Genbank CV-A6 reference strains isolated globally, showed that the strains isolated from the family clustered within one of the two main genetic clusters (0–8% nt diversity, Fig. 2). This cluster also included strains isolated during outbreaks of CV-A6 in Finland (2008) and France (2010) [7–9]. The close genetic relation of the strains isolated from the twins with strains from Finland and France indicates that CVA6 epidemiology has an international character. Close monitoring of circulation of this virus and its clinical manifestations is recommended to fully understand the broad spectrum of CV-A6 associated disease.
Fig. 2. Genetic relationship of CV-A6-strains isolated from the family (indicated with a black circle) and CV-A6 Genbank reference strains isolated globally. The tree was constructed on the basis of partial VP1 nucleotide sequences (204 nt) using the neighbor-joining method. Enterovirus 71 strain BrCr was used as outgroup. Bootstrap analysis was performed using 1000 pseudoreplicates. Only bootstrap values >70 are displayed. Sequences obtained from the Twin-mother’s vesicle fluid, and from throat swaps from the twin-girl and boy were included in the analysis.
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A.H. Bruning et al. / Journal of Clinical Virology 65 (2015) 20–22
Funding None. Competing interests None declared. Ethical approval Not required. References [1] B. Di, Y. Zhang, H. Xie, X. Li, C. Chen, P. Ding, P. He, D. Wang, J. Geng, L. Luo, Z. Bai, Z. Yang, M. Wang, Circulation of Coxsackievirus A6 in hand–foot–mouth disease in Guangzhou, 2010–2012, Virol. J. 11 (2014) 157. [2] K. Kaminska, G. Martinetti, R. Lucchini, G. Kaya, C. Mainetti, Coxsackievirus A6 and hand, foot and mouth disease: three case reports of familial child-to-immunocompetent adult transmission and a literature review, Case Rep. Dermatol. 2 (2013) 203–209. [3] T. Vuorinen, R. Österback, J. Kuisma, P. Ylipalosaari, Epididymitis caused by cosackievirus A6 in association of hand, foot and mouth disease, J. Clin. Microbiol. 52 (2014) 4412–4413.
[4] J.F. Chen, R.S. Zhang, X.H. Ou, F.M. Chen, B.C. Sun, The role of enterovirus 71 and coxsackievirus A strains in a large outbreak of hand, foot, and mouth disease in 2012 in Changsha, China, Int. J. Infect. Dis. 28 (2014) 17–25. [5] M.J. Abzug, Presentation, diagnosis, and management of enterovirus infections in neonates, Paediatr. Drugs 6 (2004) 1–10. [6] K. Benschop, R. Minnaar, G. Koen, H. van Eijk, K. Dijkman, B. Westerhuis, R. Molenkamp, K. Wolthers, Detection of human enterovirus and human parechovirus (HPeV) genotypes from clinical stool samples: polymerase chain reaction and direct molecular typing, culture characteristics, and serotyping, Diagn. Microbiol. Infect. Dis. 68 (2010) 166–173. [7] S. Blomqvist, P. Klemola, S. Kaijalainen, A. Paananen, M.L. Simonen, T. Vuorinen, M. Roivainen, Co-circulation of coxsackieviruses A6 and A10 in hand, foot and mouth disease outbreak in Finland, J. Clin. Virol. 48 (2010) 49–54. [8] A. Mirand, C. Henquell, C. Archimbaud, S. Ughetto, D. Antona, J.L. Bailly, H. Peigue-Lafeuille, Outbreak of hand, foot and mouth disease/herpangina associated with coxsackievirus A6 and 10A infections in 2010, France: a large citywide, prospective observational study, Clin. Microbiol. Infect. 18 (2012) E110–E118. [9] M.A. Bracho, F. Gonzalez-Candelas, A. Valero, J. Cordoba, A. Salazar, Enterovirus co-infections and onychomadesis after hand, foot, and mouth disease, Spain, 2008, Emerg. Infect. Dis. 17 (2011) 2223–2231. [10] H.M. Feder Jr, N. Bennett, J.F. Modlin, Atypical hand, foot, and mouth disease: a vesiculobullous eruption caused by coxsackie virus A6, Lancet Infect. Dis. 14 (2014) 83–86.
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Case report
An atypical course of coxsackievirus A6 associated hand, foot and mouth disease in extremely low birth weight preterm twins Andrea HL Bruning a,∗,1 , Sabine MG van der Sanden b,∗∗,1 , Amber E ten Hoedt c , Katja C Wolthers b , Anton H van Kaam c,2 , Dasja Pajkrt a,2 a
Department of Pediatric Infectious Diseases, Emma Children’s Hospital, Academic Medical Center, Amsterdam, The Netherlands Department of Medical Microbiology, Laboratory of Clinical Virology, Academic Medical Center, Amsterdam, The Netherlands c Department of Neonatology, Emma Children’s Hospital, Academic Medical Center, Amsterdam, The Netherlands b
a r t i c l e
i n f o
Article history: Received 29 December 2014 Received in revised form 13 January 2015 Accepted 28 January 2015 Keywords: Coxsackievirus A6 Hand, foot and mouth disease Preterm
a b s t r a c t The incidence of coxsackievirus A6 (CV-A6) associated hand, foot and mouth disease (HFMD) has reportedly increased since 2008 with sometimes severe complications. We here describe an atypical course of CV-A6-associated HFMD in extremely low birth weight twins. The CV-A6-strains are genetically closely related to international strains isolated from HFMD outbreaks. © 2015 Elsevier B.V. All rights reserved.
1. Why this case is important? Hand, foot and mouth disease (HFMD) is a common viral disease caused by human enteroviruses, mostly affecting infants and young children below 5 years of age. The most prominent symptoms include fever and a variety of skin lesions, such as maculopapular or vesicular eruptions in the oral cavity and on the distal extremities, buttocks and genital [1]. HFMD can be caused by multiple different serotypes of human enteroviruses of which enterovirus 71 and coxsackievirus (CV) A16 are most often associated with major outbreaks of HFMD worldwide [2]. However, since 2008 coxsackievirus A6 (CV-A6) has been causing HFMD outbreaks in Europe, South-East Asia and America. CV-A6 infection seems to be associated with atypical presentations such as epididymitis and more severe disease than the classic HFMD [3]. Although HFMD usually follows a benign and self-limiting course, severe or even lethal manifestations, such as paralytic
∗ Corresponding author at: Department of Pediatric Infectious Diseases, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel: +31 20 5668668; fax: +31 20 6912231. ∗∗ Corresponding author at: Department of Medical Microbiology, Laboratory of Clinical Virology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel.: +31 20 5668424. E-mail addresses: [email protected] (A.H. Bruning), [email protected] (S.M.v.d. Sanden). 1 Contributed equally as first authors. 2 Contributed equally as last authors. http://dx.doi.org/10.1016/j.jcv.2015.01.020 1386-6532/© 2015 Elsevier B.V. All rights reserved.
poliomyelitis, encephalitis, meningitis, myocarditis and neonatal sepsis-like systemic infections have been described [4]. Risk factors associated with severe HFMD include onset of illness in the first days of life, lack of specific antibodies, detection of virus in blood, specific infecting serotype (e.g. group B CV and echovirus 11), and prematurity [5]. In this report we described for the first time a case of CV-A6 in extremely low birth weight preterm twins.
2. Case description A dichorionic diamniotic pair of twins was born at a gestational age of 24 weeks and 2 days. Both twins had an uneventful start with an Apgar score of 8 after 5 min. Twin 1, a girl, weighed 535 g and twin 2, a boy, 740 g. Both infants were managed on non-invasive respiratory support and recurrent episodes of apnea of prematurity were treated with caffeine in combination with doxapram. At the age of 4 weeks, the twin girl was mechanically ventilated for 48 h during a period of sepsis caused by a Acinetobacter species, that was treated with gentamicin for 7 days. At the age of 1 month both infants developed vesicles on both their feet, without any other clinical signs of illness (Fig. 1). Further enquiry revealed that their mother had not been feeling well and had developed vesicles on her hands, feet and face 4 days prior to onset of the skin lesions in the twins. She had recently been into contact with two nieces, who also had vesicles on their hands and in their mouth. An enterovirus was detected by PCR in vesicle fluid from the mother and in vesicle fluid, pharynx, and stool samples from both
A.H. Bruning et al. / Journal of Clinical Virology 65 (2015) 20–22
21
Fig. 1. Clinical manifestations of CV-A6 in the preterm twins.
children. These enteroviruses were typed as CV-A6 by analysis of the viral VP1 capsid nucleotide sequences [6]. In addition, CV-A6 was detected in eye fluid in the twin boy and from plasma in the twin girl. Blood infection biomarkers, including white blood cell count and C-reactive protein levels, remained within the normal range. The skin lesions resolved within six days. Weekly repeated enterovirus PCR on pharynx samples obtained from the mother and both infants turned negative after, respectively, 2 and 3 weeks. Both infants were discharged home at a postnatal age of 3 months and showed no abnormalities at neurodevelopmental follow-up at 15 months.
3. Other similar and contrasting cases in the literature and discussion Despite the presence of two important risk factors for serious HFMD, namely extremely preterm birth and isolation of CV-A6 from blood, the course of CV-A6 infection in the presented cases was very mild. The mother of the preterm twins had also relatively mild symptoms of HFMD with minimal malaise and vesicular skin lesions. This is in contrast to reports from other countries such as the United States, Finland and France, where CV-A6 is reported as the causative agent of severe, atypical causes of HFMD [7–10]. Partial VP1 capsid nucleotide sequences (∼300 nts) of viral strains isolated from the twins differed only one nucleotide from that of the strain isolated from the mother. This high percentage of sequence homology suggests that the CV-A6 transmission occurred within the family. Phylogenetic analysis including Genbank CV-A6 reference strains isolated globally, showed that the strains isolated from the family clustered within one of the two main genetic clusters (0–8% nt diversity, Fig. 2). This cluster also included strains isolated during outbreaks of CV-A6 in Finland (2008) and France (2010) [7–9]. The close genetic relation of the strains isolated from the twins with strains from Finland and France indicates that CVA6 epidemiology has an international character. Close monitoring of circulation of this virus and its clinical manifestations is recommended to fully understand the broad spectrum of CV-A6 associated disease.
Fig. 2. Genetic relationship of CV-A6-strains isolated from the family (indicated with a black circle) and CV-A6 Genbank reference strains isolated globally. The tree was constructed on the basis of partial VP1 nucleotide sequences (204 nt) using the neighbor-joining method. Enterovirus 71 strain BrCr was used as outgroup. Bootstrap analysis was performed using 1000 pseudoreplicates. Only bootstrap values >70 are displayed. Sequences obtained from the Twin-mother’s vesicle fluid, and from throat swaps from the twin-girl and boy were included in the analysis.
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A.H. Bruning et al. / Journal of Clinical Virology 65 (2015) 20–22
Funding None. Competing interests None declared. Ethical approval Not required. References [1] B. Di, Y. Zhang, H. Xie, X. Li, C. Chen, P. Ding, P. He, D. Wang, J. Geng, L. Luo, Z. Bai, Z. Yang, M. Wang, Circulation of Coxsackievirus A6 in hand–foot–mouth disease in Guangzhou, 2010–2012, Virol. J. 11 (2014) 157. [2] K. Kaminska, G. Martinetti, R. Lucchini, G. Kaya, C. Mainetti, Coxsackievirus A6 and hand, foot and mouth disease: three case reports of familial child-to-immunocompetent adult transmission and a literature review, Case Rep. Dermatol. 2 (2013) 203–209. [3] T. Vuorinen, R. Österback, J. Kuisma, P. Ylipalosaari, Epididymitis caused by cosackievirus A6 in association of hand, foot and mouth disease, J. Clin. Microbiol. 52 (2014) 4412–4413.
[4] J.F. Chen, R.S. Zhang, X.H. Ou, F.M. Chen, B.C. Sun, The role of enterovirus 71 and coxsackievirus A strains in a large outbreak of hand, foot, and mouth disease in 2012 in Changsha, China, Int. J. Infect. Dis. 28 (2014) 17–25. [5] M.J. Abzug, Presentation, diagnosis, and management of enterovirus infections in neonates, Paediatr. Drugs 6 (2004) 1–10. [6] K. Benschop, R. Minnaar, G. Koen, H. van Eijk, K. Dijkman, B. Westerhuis, R. Molenkamp, K. Wolthers, Detection of human enterovirus and human parechovirus (HPeV) genotypes from clinical stool samples: polymerase chain reaction and direct molecular typing, culture characteristics, and serotyping, Diagn. Microbiol. Infect. Dis. 68 (2010) 166–173. [7] S. Blomqvist, P. Klemola, S. Kaijalainen, A. Paananen, M.L. Simonen, T. Vuorinen, M. Roivainen, Co-circulation of coxsackieviruses A6 and A10 in hand, foot and mouth disease outbreak in Finland, J. Clin. Virol. 48 (2010) 49–54. [8] A. Mirand, C. Henquell, C. Archimbaud, S. Ughetto, D. Antona, J.L. Bailly, H. Peigue-Lafeuille, Outbreak of hand, foot and mouth disease/herpangina associated with coxsackievirus A6 and 10A infections in 2010, France: a large citywide, prospective observational study, Clin. Microbiol. Infect. 18 (2012) E110–E118. [9] M.A. Bracho, F. Gonzalez-Candelas, A. Valero, J. Cordoba, A. Salazar, Enterovirus co-infections and onychomadesis after hand, foot, and mouth disease, Spain, 2008, Emerg. Infect. Dis. 17 (2011) 2223–2231. [10] H.M. Feder Jr, N. Bennett, J.F. Modlin, Atypical hand, foot, and mouth disease: a vesiculobullous eruption caused by coxsackie virus A6, Lancet Infect. Dis. 14 (2014) 83–86.