Adenovirus Infection in Immunocompetent Children



Annals of Virology and Research

Central 

Bringing Excellence in Open Access

Case Series

Adenovirus Infection in Immunocompetent Children: Not Always as Innocent as Assumed Moniek S. Corcoran1*, Inge HM van Loo2,3, Foekje F. Stelma4, and Gijs ThJ van Well1,5

*Corresponding author Moniek S. Corcoran, Department of Pediatrics, Maastricht University Medical Center, PO Box 5800, 6202 AZ, Maastricht, the Netherlands, Tel: 31- 43-387 -7264. Fax: 31-43-387- 5246; Email: Submitted: 24 June 2016 Accepted: 11 August 2016 Published: 13 August 2016 Copyright © 2016 Corcoran et al. OPEN ACCESS

1

Department of Pediatrics, Maastricht University Medical Center, The Netherlands 2 Department of Medical Microbiology, Maastricht University Medical Center, The Netherlands 3 CAPHRI, School for Public Health and Primary Care, Maastricht University, The Netherlands 4 Department of Medical Microbiology, Radboud University Medical Center, The Netherlands 5 NUTRIM, School for Nutrition, Toxicology and Metabolism, Maastricht University, The Netherlands

Keywords • Human adenovirus • Clinical presentation • Typing • PCR • Children

Abstract Adenovirus infection of respiratory or gastro-intestinal epithelial tissues is a common disease, frequently occurring in childhood. These infections mostly cause mild febrile respiratory and/or gastro-intestinal disease. Specific adenoviral subtypes may cause sepsis-like disease or central nervous system infections with severe symptoms and sequelae. The goal of this paper is to describe the clinical presentation of different adenoviral infections in children and to stress that these often assumed innocent infections of childhood may also present as severe disease even in immunocompetent children. We present four different clinical presentations in relation to adenovirus types and summarize the relevant literature on species-specific clinical presentation in immunocompetent children. We conclude that clinical presentation of adenovirus infection in childhood is often speciesspecific and might present with severe symptoms mimicking serious bacterial infection. Viral diagnostic testing is important to differentiate between bacterial and viral disease in terms of disease progression and prognosis and may diminish unnecessary or prolonged antibiotic treatment. The use of semi quantitative molecular diagnostic methods (i.e. polymerase chain reaction and genotyping) may be used to discriminate between colonization and infection.

ABBREVIATIONS BOOP: Bronchiolitis Obliterans with Organizing Pneumonia; CNS: Central Nervous System; CRP: C-Reactive Protein; CSF: Cerebrospinal Fluid; Ct-value: Cycle Threshold Value; HAdV: Human Adenovirus; HR-CT: High Resolution Computer Tomography; ORS: Oral Rehydration Solution; PICU: Pediatric Intensive Care Unit; PCR: Polymerase Chain Reaction

INTRODUCTION

Human adenovirus (HAdV) is a double-stranded DNA virus belonging to the family of Adenoviridae and the genus of Mastadenovirus. There are currently 70 described types of HAdV, divided over 7 species (A-G) [1-3]. Some studies on HAdV respiratory infections show seasonal variation with a peak in early winter [4,5]. While other studies however, describe peaks in the summer period or different peaks every year [6,7]. For gastrointestinal infections seasonal variation is not clear, with one study

showing a peak in winter months and other studies showing a year round infection [8,6]. Transmission of the virus occurs by inhalation of aerosols from infected individuals, via the fecal-oral route and by direct conjunctival inoculation [1]. HAdV infection establishes an immune response of the innate and adaptive immune system. Eventually HAdV specific T-cells are produced, which show cross-reactivity with different HAdV species. This leads to a wide HAdV immunity in the course of life [1]. After primary infection HAdV persists in a latent state in lymphoid, intestinal and respiratory tissue [1]. In immunocompromised children, latency frequently leads to reactivation causing severe systemic disease [9]. In immunocompetent children prolonged asymptomatic shedding has been reported [8]. Risk groups for (severe) adenovirus infections are children, elderly and immunocompromised individuals. In children, HAdV mainly affects young children under the age of five [10,11]. In upper respiratory tract infections, HAdV accounts for up to 15% of known causative agents and in lower respiratory tract infections

Cite this article: Corcoran MS, van Loo IHM, Stelma FF, van Well GT (2016) Adenovirus Infection in Immunocompetent Children: Not Always as Innocent as Assumed. Ann Virol Res 2(2): 1017.

Corcoran et al. (2016) Email: 

Central 


for up to 5% [12]. HAdV is isolated in up to 18% of children with fever and respiratory symptoms [4,13]. In young children up to 20% of gastroenteritis cases is caused by HAdV [14-18]. As we will discuss later, clinical manifestation is often related to specific HAdV species [11], although differentiation based on clinical presentation is not always obvious. Species identification is done by either serotyping when cell culture is used or genotyping when molecular diagnostic methods e.g. polymerase chain reaction (PCR) are used.

HAdV infection usually causes mild respiratory and/or gastro-intestinal disease. Children often present with fever, cough, rhinorrhea, conjunctivitis, diarrhea and/or vomiting. Less common presentations are lower respiratory tract infection, encephalitis, meningitis, hepatitis, nephritis and myocarditis [19]. More severe clinical presentations usually occur in immunocompromised children or children with an extensive medical history [20]. In rare cases, HAdV can cause sepsis-like disease leading to multiple organ failure with high morbidity and mortality rates, also in children with a normal immune status [10,21].

Case 2 A 7-month-old, previously healthy girl presented at the emergency department with fever, purulent conjunctivitis, cough and respiratory distress. She also developed diarrhea. The days before presentation she experienced symptoms of rhinorrhea. Her oxygen saturation in room air was 84% and oxygen therapy was started with good effect. Laboratory analysis revealed a C-reactive protein (CRP) level of 40 mg/L and leukocyte count of 16.5 10e9/L. Cultures of blood, conjunctival secretions and nasopharyngeal swabs did not show growth of pathogenic bacteria. All the specimens were then tested for HAdV with viral culture and immunofluorescence techniques and returned positive for HAdV type 3, now known to belong to species B. With supportive care, consisting of oxygen therapy and nasogastric tube feeding during one week she recovered without any sequelae.

Case 3

Case 1

A boy, two years of age and known with episodes of viral induced wheezing, was admitted to a general hospital with signs of respiratory tract infection and diarrhea. He quickly deteriorated and developed respiratory insufficiency, despite the fact that both antibiotic and corticosteroid therapy were started. After intubation and stabilization he was transported to the nearest pediatric intensive care unit (PICU). He was mechanically ventilated with high pressures. Because of severe bronchospastic episodes, endotracheal and intravenously salbutamol was administered. Laboratory analyses showed a remarkably high CRP of 218 mg/L and signs of hepatitis (alanine aminotransferase 78 E/l, aspartate aminotransferase 48 E/l, gamma-glutamyl transferase 141 E/l and alkaline phosphatase 157 E/l). Chest X-ray examination showed bilateral infiltrative changes. Cultures of blood, feces and sputum returned negative for pathogenic bacteria. Viral culture of sputum, conjunctival secretions and feces was positive for HAdV type 3, belonging to species B, and viremia was confirmed with a positive HAdV PCR of 6,5 10e4 copies/mL in blood. Ventilatory support could gradually be decreased and after 10 days of mechanical ventilation the patient was successfully extubated. He remained in need of high oxygen levels and even after discharge he chronically remained in need of 1-3L/min O2 via a nose tube and later non-invasive mechanical ventilation. Because the prolonged severity of his pulmonary disease was not fully understood a HR-CT was performed on day 11 after onset of symptoms. This showed severe bronchiectasis. Underlying pre-existing causes were excluded. Follow-up showed progressive lung disease because of bronchiolitis obliterans with organizing pneumonia (BOOP). We concluded that this severe sequela was caused by the HAdV infection.

A 10-month-old girl, without a relevant medical history was admitted to the pediatric ward with fever and signs of dehydration due to persisting diarrhea and vomiting. Upon admission she was treated with ORS administered by a nasogastric tube. After three days she improved and was no longer suffering from ongoing gastro-intestinal fluid losses and was discharged. PCR tested positive for HAdV species F DNA in a fecal sample, with a Ct-value of 26.

An 18-month-old boy was admitted to the PICU after febrile convulsions and subsequent respiratory insufficiency. He had a history of diarrhea, vomiting and high fever since 2 days. He was intubated and ventilated mechanically for 2 days and was also in need of inotropic therapy for 2 days, because of low blood pressures and oliguria, which was not anticipated. The chest X-ray showed consolidation of the right lung. The CRP level was 134 mg/L with a leukocyte count of 5.6 10e9/L. Cultures

In one study on immunocompetent children, presenting with adenoviral infection 44% of children received antibiotics from their primary care physician prior to admission in hospital and 30% of admitted patients were empirically treated with antibiotics [6]. A study in the Netherlands, where antibiotic prescription generally is low, showed that in 57.4% children who received antibiotics prescribed by their primary care physician for fever and respiratory symptoms, a virus was diagnosed in their nasopharyngeal swab [22]. Critical clinical assessment and awareness combined with sensitive molecular diagnostic techniques could potentially avoid unnecessary prescription of antibiotics, which could possibly influence the ongoing development of antibiotic resistance.

In this paper we describe four cases with different clinical presentations of HAdV infection in immunocompetent children. We put these different cases in perspective of what is studied on subtype specific clinical presentations and summarize what is reported on the relation between HAdV species and different clinical presentations in children with a normal immune status. Diagnostic methods are based on either cell culture and serotyping in the older cases and molecular diagnostic methods and genotyping in the more recent cases. HAdV infections in immunocompromised patients are well studied [1,23] and beyond the scope of this article.

CASES

Ann Virol Res 2(2): 1017 (2016)

Case 4

2/6


Central 


of blood, CSF, sputum and feces where negative for pathogenic bacteria. Sputum from the endotracheal tube showed a positive viral culture and by immunofluorescence technique HAdV type 2, belonging to species C was identified. All other body specimens, including CSF tested negative for HAdV. Antibiotics were continued for 7 days. He recovered without neurological or pulmonary sequelae.

and further studies are needed to help improve the clinical relevance of these results. In case one the Ct-value of 26 makes the diagnosis of HAdV gastroenteritis likely, however not certain. Distinction between colonization or viral shedding and infection might be possible by establishing clinical cut-off values using semi-quantitative molecular methods, as described before in rotavirus gastroenteritis [14].

OVERVIEW AND DISCUSSION

Respiratory tract infections

This paper describes four immunocompetent children with HAdV infection presenting with different clinical characteristics. These cases illustrate that HAdV may present on a spectrum varying from mild to severe and even life threatening disease, mimicking serious bacterial infection. In the literature many similar cases have been described in immunocompromised children [23]. We will discuss and summarize the recent literature and present what is known on the relation between HAdV species and their clinical presentation in immunocompetent children. For gastro-intestinal- and respiratory tract infections we will discuss the diagnostic challenges and make the point of the importance of differentiating between colonization and infection when using highly sensitive molecular diagnostic techniques.

Adenoviral upper and lower respiratory tract infections are common in young children. HAdV is isolated in up to 18% of children with fever and respiratory symptoms [4,13]. In a longitudinal study 27% of upper respiratory tract infection episodes were caused by HAdV [27]. As shown in case two, common clinical presentation of HAdV respiratory tract infection consists of fever, rhinorrhea, cough and respiratory distress, often accompanied with conjunctivitis, known as pharyngoconjunctivitis [6,11].

Clinical features of different adenovirus types

Currently 70 HAdV types have been described, based on serology for neutralizing antibodies [2,1,3]. They are divided over 7 phylogenetic species. Species A (type 12,18, 31 and 61), F (type 40 and 41) and G (type 52) mainly cause gastroenteritis. Species B (type 3, 7, 11, 14, 16, 21, 34, 35, 50, 55 and 66), C (type 1, 2, 5, 6 and 57) and E (type 4) usually infect the respiratory system and species D (type 8, 9, 10, 13, 15, 17, 19, 20, 22-30, 32, 33, 36-39, 42-49, 51, 53, 54, 56, 58-60, 63-67,69 and 70) more specifically causes conjunctivitis [24,1,25,2,3]. The exact association between species or type and clinical expression is however not completely differential, and overlap in clinical presentation does occur.

Gastroenteritis

As presented in case one; HAdV is frequently detected in feces of children presenting with vomiting, diarrhea and fever. This mainly occurs in children between the ages of 6 to 24 months [18]. Up to 20% of young children admitted to hospital with symptoms of gastroenteritis tested positive for HAdV [1418]. Most common HAdV types causing gastroenteritis are 40 and 41 belonging to species F [15,17,26,18]. Type 52, belonging to species G, was recently discovered to also specifically cause gastroenteritis [24]. HAdV types 1,2 (species C),7 (species B), 19 (species D),18 and 31 (species A) however are also frequently detected in children with gastroenteritis, but are less specific [15,18]. Another study also detected type 3 (species B), type 5 (species C) and type 12 (species A) HAdV, in children with gastroenteritis [17]. These latter types are mainly known to cause respiratory disease and are nevertheless frequently detected in feces of children with gastroenteritis [14,17]. This might reflect prolonged gastro-intestinal shedding of HAdV after initial respiratory infection. Moreover, using PCR, HAdV has also been detected in up to 41.7% of fecal samples of asymptomatic children [8]. Is this primary infection, post-infectious shedding or colonization? The interpretation of these findings is difficult Ann Virol Res 2(2): 1017 (2016)

One study performed in Hong Kong found that HAdV types 2, 3, 5 and 7, belonging to species B and C, are most prevalent in adenoviral upper respiratory tract infections in children [6]. Concomitant involvement of the gastro-intestinal tract is however not uncommon [6,12]. Tonsillitis is a common finding on physical examination. Up to 52% of adenoviral tonsillitis patients present with an exudative form mimicking bacterial infection [28,29].

In hospitalized children with a lower respiratory tract infection HAdV was detected in 15.7% to 30% of children [5,4,30]. One study showed 50% of co-infections with other viruses when detecting HAdV [4]. In lower respiratory tract infections respiratory distress with tachypnea is often observed and may be severe. As shown in case three, this may even lead to respiratory failure with need for mechanical ventilation. Moreover, lower respiratory tract infections caused by HAdV sometimes result in severe chronic pulmonary sequelae, such as BOOP, illustrated by case three. HAdV types isolated from children with lower respiratory tract infection belong to species C (1,2,5, and 6) and B (3,7, and 21) [31,6,32,13,11]. One study determined that HAdV bronchiolitis in young children in Hong Kong was mainly caused by type 2 and pneumonia in older children (3-5 years of age) by type 3 [6]. HAdV type 3 and 7 (species B) are specifically associated with the development of BOOP, a rather severe pulmonary complication of adenoviral lower respiratory tract infection [33,6,34]. Finding HAdV in respiratory specimens by highly sensitive molecular methods should always be interpreted in relation to clinical symptoms. HAdV may cause severe illness, but may also cause asymptomatic infections. In fact, in the study of Singleton et al. HAdV was detected in up to 16% of the samples from asymptomatic children [30]. This emphasizes the need for a method to improve clinical interpretation of these results, preferably quantitatively.

CNS infection and CNS involvement in HAdV infections with other origin

It is not common for HAdV to cause CNS infections. However, cases are described showing severe infections with neurological involvement in young immunocompetent children [21]. The most

3/6


Central 


common presentation of adenoviral CNS infection is encephalitis, followed by encephalopathy, meningitis, meningo-encephalitis and cerebellitis [21]. In one case with encephalitis HAdV type 5 belonging to species C was isolated from post-mortem acquired brain tissue [35]. Another paper described a case of sudden death in a child, who turned out to have suffered from adenoviral meningitis [36]. A case series detected HAdV type 6 (species C), 7 (species B) and 12 (species A) in CSF from children presenting with meningo-encephalitis [37]. Besides primary CNS infections, 3.3% of all HAdV respiratory infections present with signs of CNS involvement [19]. In almost one quarter of those children a lumbar puncture was performed, but HAdV was not detected in CSF [19]. This might explain the severe presentation of case four with a febrile seizure without proven CNS infection. Studies evaluating all children presenting with febrile seizures, demonstrated the presence of HAdV in 3.4 to18.4% of the cases [38,39]. A relative risk of 4.3 was calculated for developing a febrile seizure following febrile illness by HAdV [38]. HAdV, detected in the isolates of these children, mainly showed type 3, 2 and 1 (in order of detected frequency, species B and C respectively). Another case series described encephalopathy caused by HAdV type 7 (species B) in children presenting with symptoms of gastro-intestinal or respiratory infection [40].

Sepsis-like disease

In immunocompetent children, HAdV type 3, 7 and 21 (species B) have been described as the cause of severe clinical disseminated disease involving liver (as in case three), kidney and heart [10]. Moreover, HAdV can also present with sepsislike disease, including petechiae [41], or a diffuse erythematous rash with edema [42], mimicking severe bacterial illness. Type 3, 7 (species B) and 5 (species C) are known to cause severe disseminated disease with a sepsis-like presentation in immunocompetent children [43,44,10], as also shown in the patient in case four, who was in need of inotropic support. Systemic treatment of HAdV with cidofovir is still under discussion because of the often severe adverse effects, especially on kidney function, and is currently only indicated for severe infections in immunocompromised children [23].

Mimicking bacterial disease

HAdV is known to present with prolonged high fever with an average of 5 days [6,45]. HAdV not only mimics bacterial disease by its clinical presentation. Other markers that usually guide us in the direction of bacterial infection such as high CRP and high erythrocyte sedimentation rate (ESR) can also be markedly elevated in HAdV infection. Up to 56% of all HAdV positive children had CRP levels higher than 40 mg/L [19,11]. HAdV has been known to cause significantly higher CRP levels than other viral respiratory infections [46]. Concomitant with our cases, with a maximum CRP level of 218 mg/L in case three, another case series showed CRP elevation of up to 191 mg/L [45]. ESR was shown to be elevated >30 mm/h in 62.5% of type 1 (species C), 80.6% of type 2 (species C) and 33.3% of type 3 (species B) HAdV infection [11]. In this study mean ESR was higher in type 1 and 2 compared to type 3 infections. HAdV commonly presents with a persistent high neutrophil count [6]. Ann Virol Res 2(2): 1017 (2016)

All these markers make discrimination from bacterial disease very hard. Molecular testing could provide rapid results thereby making distinction easier.

CONCLUSION

Although not frequent, HAdV infection in immunocompetent children may present with severe clinical symptoms, thereby mimicking severe bacterial disease. Besides awareness for the often species-specific disease presentation, testing for HAdV could also decrease prescription or cessation of antibiotic therapy in an early stage of disease. Currently, molecular diagnostic techniques (e.g. PCR) are the preferred method of testing and will provide rapid results with a high sensitivity. Positive test results for HAdV in CSF and blood are confirmatory for disease, although this is not so clear for positive results of feces and respiratory tract specimens. In these specimens positive HAdV PCR results may also be found due to asymptomatic shedding or prolonged shedding after infection because of increased analytical sensitivity of molecular techniques. By using semi-quantitative real-time PCR results for these samples, we should be able to determine clinically relevant cut-off values in future research. This will improve distinction between colonization and infection and therefore enhance interpretation of molecular findings in critically ill children.

We conclude that clinical presentation of adenovirus infection in childhood is often species-specific and might present with severe symptoms mimicking serious bacterial infection. Viral diagnostic testing is important to differentiate between bacterial and viral disease in terms of disease progression and prognosis and may diminish unnecessary or prolonged antibiotic treatment. The use of semi quantitative molecular diagnostic methods and genotyping may be used to discriminate between colonization and infection.

REFERENCES

1. Lion T. Adenovirus infections in immunocompetent and immunocompromised patients. Clin Microbiol Rev. 2014; 27: 441462. 2. Hage E, Gerd Liebert U, Bergs S, Ganzenmueller T, Heim A. Human mastadenovirus type 70: a novel, multiple recombinant species D mastadenovirus isolated from diarrhoeal faeces of a haematopoietic stem cell transplantation recipient. J Gen Virol. 2015; 96: 2734-2742. 3. Singh G, Zhou X, Lee JY, Yousuf MA, Ramke M, Ismail AM, et al. Recombination of the epsilon determinant and corneal tropism: Human adenovirus species D types 15, 29, 56, and 69. Virology. 2015; 485: 452-459. 4. Garcia-Garcia ML, Calvo C, Pozo F, Villadangos PA, Perez-Brena P, Casas I. Spectrum of respiratory viruses in children with communityacquired pneumonia. Pediatr Infect Dis J. 2012; 31: 808-813.

5. Wang H, Zheng Y, Deng J, Wang W, Liu P, Yang F, et al. Prevalence of respiratory viruses among children hospitalized from respiratory infections in Shenzhen, China. Virol J. 2016; 13: 39. 6. Chau SK, Lee SL, Peiris MJ, Chan KH, Chan E, Wong W, et al. Adenovirus respiratory infection in hospitalized children in Hong Kong: serotypeclinical syndrome association and risk factors for lower respiratory tract infection. Eur J Pediatr. 2014; 173: 291-301.

7. Chen Y, Liu F, Wang C, Zhao M, Deng L, Zhong J, et al. Molecular Identification and Epidemiological Features of Human Adenoviruses

4/6


Central 


Associated with Acute Respiratory Infections in Hospitalized Children in Southern China, 2012-2013. PloS one. 2016; 11: e0155412.

8. Corcoran MS, van Well GT, van Loo IH. Diagnosis of viral gastroenteritis in children: interpretation of real-time PCR results and relation to clinical symptoms. Eur J Clin Microbiol Infect Dis. 2014; 33: 16631673. 9. Kosulin K, Geiger E, Vecsei A, Huber WD, Rauch M, Brenner E et al. Persistence and reactivation of human adenoviruses in the gastrointestinal tract. Clin Microbiol Infect. 2015.

10. Munoz FM, Piedra PA, Demmler GJ. Disseminated adenovirus disease in immunocompromised and immunocompetent children. Clin Infect Dis. 1998; 27: 1194-1200. 11. Tabain I, Ljubin-Sternak S, Cepin-Bogovic J, Markovinovic L, Knezovic I, Mlinaric-Galinovic G. Adenovirus respiratory infections in hospitalized children: clinical findings in relation to species and serotypes. Pediatr Infect Dis J. 2012; 31: 680-684.

12. Hong JY, Lee HJ, Piedra PA, Choi EH, Park KH, Koh YY, et al. Lower respiratory tract infections due to adenovirus in hospitalized Korean children: epidemiology, clinical features, and prognosis. Clin Infect Dis. 2001; 32: 1423-1429. 13. Rojas LJ, Jaramillo CA, Mojica MF, Escalante MP, Delgado P. Molecular typing of adenovirus circulating in a Colombian paediatric population with acute respiratory infection. Epidemiol Infect. 2012; 140: 818822.

14. Corcoran MS, van Loo IH, Wolffs PF, van Well GT. Interpretation of real-time PCR diagnosing fecal viruses in children: a prospective casecontrol study. Pediatr Infect Dis J. 2013; 32: 1402-1403. 15. Moyo SJ, Gro N, Kirsti V, Matee MI, Kitundu J, Maselle SY et al. Prevalence of enteropathogenic viruses and molecular characterization of group A rotavirus among children with diarrhea in Dar es Salaam Tanzania. BMC Public Health. 2007; 7: 359.

16. Raboni SM, Damasio GA, Ferreira CE, Pereira LA, Nogueira MB, Vidal LR et al. Acute gastroenteritis and enteric viruses in hospitalised children in southern Brazil: aetiology, seasonality and clinical outcomes. Mem Inst Oswaldo Cruz. 2014; 109: 428-435. 17. Ren Z, Kong Y, Wang J, Wang Q, Huang A, Xu H. Etiological study of enteric viruses and the genetic diversity of norovirus, sapovirus, adenovirus, and astrovirus in children with diarrhea in Chongqing, China. BMC Infect Dis. 2013; 13: 412.

18. Verma H, Chitambar SD, Varanasi G. Identification and characterization of enteric adenoviruses in infants and children hospitalized for acute gastroenteritis. J Med Virol. 2009; 81: 60-64. 19. Huang YC, Huang SL, Chen SP, Huang YL, Huang CG, Tsao KC et al. Adenovirus infection associated with central nervous system dysfunction in children. J Clin Virol. 2013; 57: 300-304.

20. Gupta P, Tobias JD, Goyal S, Hervie P, Harris JB, Sadot E et al. Prolonged mechanical support in children with severe adenoviral infections: a case series and review of the literature. J Intensive Care Med. 2011; 26: 267-272. 21. Reyes-Andrade J, Sanchez-Cespedes J, Olbrich P, Falcon L, SanchezGanfornina I, Tebruegge M, et al. Meningoencephalitis due to adenovirus in a healthy infant mimicking severe bacterial sepsis. Pediatr Infect Dis J. 2014; 33: 416-419. 22. Kool M, Monteny M, van Doornum GJ, Moll HA, Berger MY. Respiratory virus infections in febrile children presenting to a general practice out-of-hours service. Eur J Gen Pract. 2015: 21: 5-11.

23. Tebruegge M, Curtis N. Adenovirus: an overview for pediatric infectious diseases specialists. Pediatr Infect Dis J. 2012; 31: 626-627. Ann Virol Res 2(2): 1017 (2016)

24. Jones MS 2nd, Harrach B, Ganac RD, Gozum MM, Dela Cruz WP, Riedel B, et al. New adenovirus species found in a patient presenting with gastroenteritis. J Virol. 2007; 81: 5978-5984. 25. Tebruegge MC, Curtis N. Adenovirus Infection in the Immunocompromised Host. In: Hot Topics in Infection and Immunity in Children VI. Advances in Experimental Medicine and Biology. New York: Springer. 2009; 153-174.

26. Shimizu H, Phan TG, Nishimura S, Okitsu S, Maneekarn N, Ushijima H. An outbreak of adenovirus serotype 41 infection in infants and children with acute gastroenteritis in Maizuru City, Japan. Infect Genet Evol. 2007; 7: 279-284.

27. Chonmaitree T, Revai K, Grady JJ, Clos A, Patel JA, Nair S, et al. Viral upper respiratory tract infection and otitis media complication in young children. Clin Infect Dis. 2008; 46: 815-823. 28. Cheng CC, Huang LM, Kao CL, Lee PI, Chen JM, Lu CY, et al. Molecular and clinical characteristics of adenoviral infections in Taiwanese children in 2004-2005. Eur J Pediatr. 2008; 167: 633-640.

29. Dominguez O, Rojo P, de Las Heras S, Folgueira D, Contreras JR. Clinical presentation and characteristics of pharyngeal adenovirus infections. Pediatr Infect Dis J. 2005; 24: 733-734. 30. Singleton RJ, Bulkow LR, Miernyk K, DeByle C, Pruitt L, Hummel KB, et al. Viral respiratory infections in hospitalized and community control children in Alaska. J Med Virol. 2010; 82: 1282-1290.

31. Barrero PR, Valinotto LE, Tittarelli E, Mistchenko AS. Molecular typing of adenoviruses in pediatric respiratory infections in Buenos Aires, Argentina (1999-2010). J Clin Virol. 2012; 53: 145-150. 32. Ghasemi Y, Makvandi M, Samarbafzadeh AR, Nejati A, Najafifard S, Neisi N et al. Serotype determination of adenoviruses in children with respiratory infection. Indian J Pediatr. 2014; 81: 639-643.

33. Carballal G, Videla C, Misirlian A, Requeijo PV, Aguilar Mdel C. Adenovirus type 7 associated with severe and fatal acute lower respiratory infections in Argentine children. BMC Pediatr. 2002; 2: 6.

34. Murtagh P, Giubergia V, Viale D, Bauer G, Pena HG. Lower respiratory infections by adenovirus in children. Clinical features and risk factors for bronchiolitis obliterans and mortality. Pediatr Pulmonol. 2009; 44: 450-456. 35. Chatterjee NK, Samsonoff WA, Balasubramaniam N, Rush-Wilson K, Spargo W, Church TM. Isolation and characterization of adenovirus 5 from the brain of an infant with fatal cerebral edema. Clin Infect Dis. 2000; 31: 830-833.

36. Krous HF, Chadwick AE, Miller DC, Crandall L, Kinney HC. Sudden death in toddlers with viral meningitis, massive cerebral edema, and neurogenic pulmonary edema and hemorrhage: report of two cases. Pediatr Dev Pathol. 2007; 10: 463-469. 37. Kelsey DS. Adenovirus meningoencephalitis. Pediatrics. 1978; 61: 291-293.

38. Chung B, Wong V. Relationship between five common viruses and febrile seizure in children. Arch Dis Child. 2007; 92: 589-593. 39. Tang J, Yan W, Li Y, Zhang B, Gu Q. Relationship between common viral upper respiratory tract infections and febrile seizures in children from Suzhou, China. J Child Neurol. 2014; 29: 1327-1332.

40. Straussberg R, Harel L, Levy Y, Amir J. A syndrome of transient encephalopathy associated with adenovirus infection. Pediatrics. 2001; 107.

41. Schneider H, Adams O, Weiss C, Merz U, Schroten H, Tenenbaum T. Clinical characteristics of children with viral single- and co-infections and a petechial rash. Pediatr Infect Dis J. 2013; 32: 186-191.

5/6


Central 


42. Bojang K, Walters MD. Toxic shock-like syndrome caused by adenovirus infection. Arch Dis Child. 1992; 67: 1112-1114.

43. Ladisch S, Lovejoy FH, Hierholzer JC, Oxman MN, Strieder D, Vawter GF, et al. Extrapulmonary manifestations of adenovirus type 7 pneumonia simulating Reye syndrome and the possible role of an adenovirus toxin. J Pediatr. 1979; 95: 348-355. 44. Levy Y, Nitzan M, Beharab A, Zeharia A, Schoenfeld T, Nutman J, et al. Adenovirus type 3 infection with systemic manifestation in apparently normal children. Isr J Med Sci. 1986; 22: 774-778.

45. Shike H, Shimizu C, Kanegaye J, Foley JL, Burns JC. Quantitation of adenovirus genome during acute infection in normal children. Pediatr Infect Dis J. 2005; 24: 29-33. 46. Lee CY, Wu MC, Ho CL, Lai CC, Chou TY, Chan YJ. Design and application of a real-time polymerase chain for the detection and subsequent characterization of respiratory adenoviral infections. J Med virol. 2014; 86: 2128-2133.

Cite this article Corcoran MS, van Loo IHM, Stelma FF, van Well GT (2016) Adenovirus Infection in Immunocompetent Children: Not Always as Innocent as Assumed. Ann Virol Res 2(2): 1017.

Ann Virol Res 2(2): 1017 (2016)

6/6