Scandinavian Journal of Gastroenterology, 2006; 41: 693 699
ORIGINAL ARTICLE
Norovirus outbreak in a pediatric oncology unit
¨ BINGER2, ARNE SIMON1, OLIVER SCHILDGEN2, ANNA MARIA EIS-HU CAROLA HASAN1, UDO BODE1, STEPHAN BUDERUS3, STEFFEN ENGELHART4 & GUDRUN FLEISCHHACK1 1
Pediatric Hematology and Oncology, Children’s Hospital, University of Bonn, Bonn, Germany, 2Institute for Medical Microbiology and Immunology, Virology Section, Univeristy of Bonn, Bonn, Germany, 3Pediatric Gastroenterology, Children’s Hospital, University of Bonn, Bonn, Germany, and 4Institute for Hygiene and Environmental Medicine, Medical Center, University of Bonn, Germany
Abstract Objective. Norovirus (NV) is an etiologic agent of outstanding importance that can cause severe epidemic gastroenteritis in day-care centers, schools, nursing homes, and hospitals. Therefore NV requires foremost attention as a pathogen responsible for epidemics of gastroenteritis in immunocompromised inpatients. In this study, a NV outbreak in a pediatric oncology unit is described and the consequences for this high-risk population are discussed. Material and methods. Stool and vomitus samples from 11 patients were tested for NV and other relevant viruses during the outbreak by reverse transcriptase-polymerase chain reaction (RT-PCR) and/or enzyme-linked immunosorbent assay (ELISA) (whenever an appropriate ELISA was available). Norwalk virus PCR amplifications were sequenced and phylogenetic analysis was performed. Results. The index patient and the chain of infection were identified. Follow-up investigation surprisingly demonstrated viral shedding for a maximum of 140 days (median 23 days). Three patients experienced severe or lifethreatening symptoms, probably related to NV infection. Conclusions. In the event of an outbreak of gastroenteritis (involving two or more symptomatic patients) in a pediatric oncology unit, the search for NV in stool or vomitus specimens should be initiated in good time. As long as the data are limited regarding whether a detectable viral antigen or RNA in stools represents an infectious virus, patients have to be isolated as long as the diagnostic assays remain positive. During the acute phase of the illness, health-care workers should wear masks in addition to practicing meticulous hand hygiene with a disinfectant of proven activity against NV. Pediatric oncology patients must be closely monitored during follow-up investigations as they may shed the virus for months. There is some evidence from the outbreak described here that those patients face a greater risk of severe NV-related complications.
Key Words: Norovirus, outbreak, pediatric oncology
Introduction Initially described as ‘‘small round-structured viruses’’ in electron microscopy stool specimens in 1972 [1], Norovirus (NV) is the prototype strain of genetically and antigenically diverse single-stranded RNA viruses, classified in the genus ‘‘Norwalk-like viruses’’, family ‘‘Caliciviridae’’ [2]. NV is the most common cause of outbreaks of non-bacterial gastroenteritis [3]. NV was detected in 20% of all specimens (n /783) collected prospectively during investigations of outbreaks of acute gastroenteritis among Finnish children followed during the first two
years of life [4,5]. In our report we describe an outbreak of NV in a pediatric hematology and oncology unit and discuss the clinical consequences and obstacles in the management of epidemic NV infections in this high-risk population. Material and methods Clinical setting The Pediatric Hematology and Oncology Unit at the Children’s Hospital, Medical Center, University of Bonn is a separate 16-bed inpatient unit with 900
Correspondence: Arne Simon, MD, Children’s Hospital Medical Center, University of Bonn, Adenauerallee 119, DR-53113 Bonn, Germany. Tel: /49 22 8287 3254. Fax: /49 22 8287 3301. E-mail:
[email protected]
(Received 23 August 2005; accepted 19 October 2005) ISSN 0036-5521 print/ISSN 1502-7708 online # 2006 Taylor & Francis DOI: 10.1080/00365520500421694
694
A. Simon et al.
admissions and 50 newly diagnosed pediatric cancer patients per year. The unit covers all pediatric cancer diagnoses and treatment modalities, with the exception of allogenic stem-cell transplantation. An integral part of the inpatient care concept is a playroom where children of all ages and their parents can meet and take their meals together. There is a kitchen on the ward which can be used by the patients or their caregivers. The attending nurses and physicians follow written standard guidelines for hygiene precautions and for environmental disinfection, which is regularly done with a quaternary ammonium compound. Propanol (60%) is used routinely for hand hygiene procedures before and after each patient contact or before manipulation of critical items such as intravenous access devices. Since 2001, the incidence densities of nosocomial infections have been prospectively documented and analyzed with a computerized surveillance module developed by our group for the surveillance of nosocomial infections in pediatric cancer patients [6]. The surveillance activities of nosocomial gastroenteritis in this module focus on rotavirus infection [7] and Clostridium difficile -associated diarrhea and enterocolitis [8 10] as indicator events to measure the compliance with isolation, environmental disinfection, and hand hygiene precautions. Virological methods RNA extraction and reverse transcriptase-polymerase chain reaction (RT-PCR). Stool samples were diluted with phosphate buffered saline to a 10% stool suspension (w/v) and mixed. The suspension was clarified by centrifugation for 10 min at 3000 rpm in an Eppendorf 5416 centrifuge. The supernatant was used for RNA extraction using the QIAamp Viral RNA Mini Kit (Qiagen, Hilden, Germany) following the manufacturer’s instructions. The PCR was performed as described by Schreier et al. (2000) [11]. Briefly, one-tenth of the extracted RNA was reversely transcribed using AMV RT (Roche, Mannheim, Germany) and primer. The cDNA was partially amplified using primers 32 and 36 for the first PCR round and primers 33 and 35 for the second round. The PCR amplifications were carried out for 35 cycles (948C, 30 s; 428C, 30 s; 728C, 45 s; final step 728C, 3 min) using the Expand High Fidelity PCR system (Roche). DNA sequencing and phylogenetic analysis. PCR products were sequenced directly using primers 33 and 35 and cloned with the TopoTA kit (Invitrogen, Karlsruhe, Germany) and sequenced with T7 and T3 sequencing primers. The sequencing was performed with BigDye Terminator v1.1 Cycle Sequen-
cing kit and reactions were run on a genetic analyzer ABI Prism 310 (Applied Biosystems, Darmstadt, Germany) according to the manufacturer’s protocol. Alignment and phylogenetic trees were performed with the Vector NTI 9.0 software (Invitrogen) and the TreeView 1.6.6 program [12]. Accession numbers used for the alignment were: X86560 (Manchester), U95644 (Houston), U07611 (Hawaii), U04469 (Desert Shield), L07418 (Southampton), U22498 (Mexico), U46500 (Camberwell), X86557 (Lordsdale), AF093797 (Germany), and M87661 (Norwalk).
Results Description of the outbreak The time-course of the outbreak, which affected 11 patients and 2 relatives from 14 January to 20 February 2004, is plotted in Figure 1. The basic epidemiological data of the affected patients are described in Table I. The outbreak continued to spread and affected 9 patients (including the index patient) and two relatives until the attending physicians were notified of the NV etiology in a first report. The time-course of the outbreak, from 14 January to 20 February 2004 illustrated in Figure 1 also shows 9 additional symptomatic patients with NV infection identified in 2004. These additional cases were sporadic and did not result in further nosocomial transmission. Table I describes the basic epidemiological data of all 20 affected patients. Gastrointestinal disturbances with loose stools and vomiting are frequent symptoms in pediatric cancer patients. Thus, in 69/92 consecutively treated inpatients in 2004 (75%) at least one stool sample was tested for viral pathogens. In response to the first report notifying the attending physicians of the NV etiology of the outbreak, the agent for hand hygiene was immediately changed to a special product with certified activity against NV, which contains 95% (v/v) ethanol (Sterillium† ; Virugard, Bode Chemie, Hamburg, Germany). In addition, the use of masks when in close contact with symptomatic patients was recommended. All patients were tested for NV and were isolated in cohorts if positive. These measures stopped the outbreak. There were some sporadic NV cases in the next few months. Fortunately, no additional transmission from patient to patient was observed after the first outbreak had been contained. An analysis of all 246 stool samples from the pediatric oncology unit investigated in 2004 (repeats included) showed a rate of 28.9% positive specimens for NV, 3.3% for rotavirus, 0.8% for adenovirus, and
Norovirus in pediatric oncology
695
Figure 1. Time-course of the epidemic (newly diagnosed cases). Dark bars: symptomatic patients. Light bars: Symptomatic relatives. Arrow: Date of the first positive Norovirus result reported from the laboratory (08.02.). This was the time-point when additional measures were implemented: Use of masks and a particular disinfectant: Sterillium Virugard† , 95% (v/v) ethanol for hand hygiene.
1.6% for astrovirus. In all patients with a positive stool sample, the tests were repeated weekly until they became negative. Probably as a consequence of
the outbreak and the subsequent repeats (control stool samples in NV-infected patients), NV was the most prevalent etiologic agent detected. The inci-
Table I. Basic epidemiological data. Norovirus-positive patients (in 2004) Involved in the outbreak Nosocomially acquired NV cases in 2004 (start of symptoms at least 24 h after hospitalization) Male/female Age Median (min; max) Underlying illness (reason for admission) Acute lymphoblastic leukemia Non-Hodgkin’s lymphoma Chronic osteomyelitis Hemangioma Hemophilia Intrathoracic tumor (hemangioma) Malignant lymphophagocytosis Malignant histiocytosis Neuroblastoma Sarcoma Spherocytosis, rotavirus infection Wilms’ tumor Total no. of stool specimens tested in 2004 No. (%) of patients with at least one stool specimen tested for viral infection No. and proportion of positive results# (repeats included)§
20 patients; 21% of all patients admitted to the pediatric oncology unit* 11 patients and 2 relatives 15 patients (75% of all NV cases) 14/6 Months 43 (4; 288) No. 7 3 1 1 1 1 1 1 1 1 1 1 246 69/92
Norovirus Rotavirus Adenovirus Astrovirus Incidence of Norovirus infection/100 admissions (20/818) 2.6 Incidence density of Norovirus infection/1000 patient-days (20/4041) 5.2
(70%/30%) Years 3,5 (0.3; 24.0) Proportion (%) 35.0 15,0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 (100%) (75%) 71 (28.9%) 8 (3.3%) 2 (0.8%) 4 (1.6%) (818 admissions) (4041 inpatient-days)
Abbreviation: NV /Norovirus. * 20 of 92 consecutive patients treated in the unit experienced a NV infection in 2004. # Absolute no. of patients with rotavirus n /4; astrovirus n /2; adenovirus n /1. § In all patients with positive specimen stool samples were retested at least weekly until results turned negative.
696
A. Simon et al.
dence density of all NV infections in 2004 was 4.9/ 1000 inpatient days; the incidence density of all 15 nosocomially acquired NV cases in 2004 was 3.7/ 1000 inpatients days. In comparison, the incidence density of the nosocomially acquired rotavirus infections documented with the Onkopaed NI surveillance module was 0.99/1000 inpatient days (n /4) in 2004. The median WHO severity of illness grades for diarrhea and vomiting of all 20 patients infected with NV were high enough to justify hospital admission in this high-risk population (Table II). In addition, 90% showed fever, with a temperature /398C in 65%. In pediatric cancer patients, fever results in hospitalization and patients with febrile neutropenia have to be treated empirically. Seven patients (35%) had to receive parenteral nutrition and in 5 patients (25%) mostly infants and toddlers a nasogastric feeding tube was necessary for some weeks after the acute symptoms of NV infection subsided to guarantee sufficient oral nutrition. The course of three patients is discussed here in detail as they experienced severe complications related to NV infection. The first patient was an 8month-old boy with infant acute lymphoblastic leukemia. During induction chemotherapy, a comTable II. Clinical and laboratory data of 20 pediatric oncology patients infected with Norovirus. Item Neutropenia B/0.5 /109/l Diarrhea (WHO grading) Vomiting (WHO grading) Dehydration 5 10% body-weight Fever (T /388C) Temperature /398C Acidosis (pH B/7.28) and BE B/ /10 mmol/l Sodium/145 mmol/l/Sodium B/135 mmol/l Potassium B/3.5 mmol/l Hypoglycemia (B/60 mg/dl) C-reactive protein /20 mg/l First symptoms ]/24 h after admission (probably nosocomial infection) Intravenous antibiotics (empirical) Parenteral nutrition during NV infection Enteral feeding tube necessary after NV infection (feeding difficulties) Length of inpatient stay (d) Length of symptoms, related to NV infection (d)
No.
Proportion (%)
n /6 Median 3# Median 2§ N /6 N /18 N /13 N /0
30% Range 0 4 Range 0 3 30% 90% 65% 0%
N /3/ N /6 N /4 N /1 N /5 N /15
15%/30%
N /10 N /7
50% 35%
N /5
25%
20% 5% 25% 75%
Median 13 Range 1 68 Median 7 Range 1 140
Abbreviations: NV /Norovirus; BE /Base Excess. # /7 //4 h or hospitalization with i.v. hydration for more than 24 h. § 2 5 //24 h.
mon adverse event of the antineoplastic agent cytosine arabinoside is diarrhea. This patient was infected with NV and experienced life-threatening bleeding from his lower gastrointestinal tract (fresh blood in stools, drop of hemoglobin to a nadir of 7.3 g/dl, transfusion of platelets, fresh frozen plasma and erythrocyte concentrates). In response to this serious adverse event, we screened the database of the principal investigator of the Infant ALL 1999 Study and received the information that none of the prospectively documented patients in this protocol ever experienced a comparable complication during this treatment phase. The patient had to be given additional formula nutrition through a nasogastric tube; he shed NV for 13 days and recovered completely after 4 weeks. The second patient was a 17-month-old boy with a systemic form of Langerhans cell histiocytosis involving the skin, liver, spleen, lymph nodes, and the lung. He was still being breastfed when the NV infection occurred. The predominant clinical symptom of NV infection was a protracted diarrhea with failure to thrive, dehydration, loss of electrolytes, and peripheral edema as a consequence of hypoalbuminemia. The patient shed NV for 140 days and had to be given parenteral nutrition and albumin supplementation as an inpatient and, later, home parenteral nutrition through his Broviac catheter to maintain a sufficient nutritional status. After 4 months of protracted diarrhea, complicated by transient lactose malabsorption, the patient underwent a coloscopy with mucosal biopsies, which revealed a flattened mucosa with patchy hemorrhagic areas. The third patient was a 19-year-old man with metastatic desmoblastic rhabdomyosarcoma involving the whole abdominal cavity and retroperitoneal lymph nodes. In this patient, who remained negative for C. difficile toxin and for other gastrointestinal pathogens, enterocolitis with pronounced thickening of the colonic wall and intermittent severe lower abdominal pain developed, probably as a result of the NV infection. The patient recovered but experienced a two-sited colonic perforation with lifethreatening peritonitis and sepsis 4 months later. A causal relationship to the NV enterocolitis in his medical history could neither be proven nor excluded. Virological results Following the first detection of viral RNA in stool samples from symptomatic patients, PCR amplifications were sequenced directly or cloned and sequenced. Sequences were aligned as described above, and phylogenetic analysis was performed.
Norovirus in pediatric oncology The unrooted phylogenetic tree derived from sequences obtained during the first week of the acute NV infection from patients of the nosocomial outbreak described here is presented in Figure 2. All sequences are grouped in the same cluster as the one derived from the NV that infected the index patient (the first patient with gastroenteritis symptoms in the relevant cohort). However, sequences from virus strains of patients 9 and 10, the patients in whose stool samples virus RNA was detected after a delay, were grouped in the same cluster but somehow distant from the index sequence, probably because of virus evolution or the development of a quasispecies. The minimal length of viral shedding (pos. RT-PCR) in 12 patients with ]/2 positive results (median 23 days; range 3 140 days) is depicted in Figure 3. Discussion NV is a highly contagious organism and at least 50% of all persons exposed to this agent experience illness [13]. Some of the characteristics of NV, which predispose this agent to institutional outbreaks, are the low infectious dose (B/100 virus particles), prolonged asymptomatic shedding, and environmental stability (NV survives drying, freezing, and heating to 608C as well as 5/10 ppm chlorine in
697
water). Multiple genetic and antigenic types lead to substantial strain diversity and a lack of lasting immunity after infection. Reinfection can occur and childhood infection does not protect against disease in adulthood (Centers for Disease Control and Prevention (CDC) [13]). Health-care personnel are often affected and may serve as a vector of transmission in hospital outbreaks. Negative results for bacterial and parasitic pathogens, a percentage of cases with vomiting /50%, and a mean illness duration of 1260 h, as well as a median incubation period of 24 48 h have been established as the epidemiological criteria for suspecting a NV etiology in community outbreaks [13]. Young children are more prone than adults to develop vomiting if infected, and some patients present only vomiting without diarrhea. Index patients are difficult to identify as NV infected in a pediatric oncology population where chemotherapyinduced nausea and vomiting is a frequent adverse event. All other symptoms such as headaches (tension headaches), fever (bacterial infection or fever of unknown origin presenting as febrile neutropenia), and myalgia (adverse effects of treatment with vincristine and corticosteroids) are highly prevalent in this group of patients. NV is transmitted primarily by fecal-oral spread, but droplet and airborne [14] as well as fomite
U95644 X86560
patient 09
relative 1 patient 01
U46500
patients 2 -8/11
relative 2
X86557
AF093797 U07611
U04469 U22498 L07418
M87661
Figure 2. Unrooted phylogenetic tree* derived from 11 patients and 2 relatives with acute Norovirus infection. *Accession numbers used for the alignment were: X86560 (Manchester), U95644 (Houston), U07611 (Hawaii), U04469 (Desert Shield), L07418 (Southampton), U22498 (Mexico), U46500 (Camberwell), X86557 (Lordsdale), AF093797 (Germany), and M87661 (Norwalk). The tree indicates that patients were infected with the same virus subtype.
698
A. Simon et al. 3 4
Pts. with 2 or more positive results (n=12)
11
13
9
17 21
7
23 23
5
37 40
3
48 116
1
140 0
20
40
60
80
100
120
140
160
Minimal length of positive Noro-RNA stool results (days) (median 23 days) Figure 3. Minimal length of viral shedding (pos. RT-PCR) in 12 patients with ]/2 positive results.
transmission can occur and contribute to the rapid transmission pattern in health-care institutions [13], where the contaminated hands of health-care workers and non-critical items shared between patients during medical care may play an important role. In addition, patient-to-patient transmission can occur in playrooms, in hospital schoolrooms for inpatients, or in recreational areas of pediatric facilities [15]. A particular problem in pediatric oncology may be the contamination of a common vehicle by parents or kitchen personnel when preparing special foods for the patients on the ward, as cooking might not completely inactivate NV. Owing to its profound antigenic and genetic diversity and to the fact that NV cannot be cultivated in cell lines, simple and sensitive assays are still not available to detect the full spectrum of NV infection associated with institutional outbreaks. Diagnostic efforts of acceptable sensitivity and specificity rely on RT-PCR (detection limit 102 104 virus particles/ml stool or vomitus) and serological methods. Unfortunately, antibody assays are probably not reliable diagnostic methods in pediatric cancer patients receiving intensive anticancer treatment who are not able to mount a sufficient humoral immune response. Interestingly, NV status was not influenced by the administration of breast milk or intravenous immunoglobulins, and turned negative in patient no. 2 despite a severe shortage of T-helper cells (subpopulation analysis; TCD4 0.054 /109/l; normal age adjusted value /0.9 /109/l). Asymptomatic persons infected with the virus (a group that represents 30% of all cases) may shed the
virus in stools for a week and as early as 15 h after inoculation [13] Using RT-PCR in sequentially collected specimens, further evaluation will be required to determine whether the shedding of the viral genome for weeks or months has any epidemiological significance in the absence of clinical illness. The actual advice requested from the reference laboratory for NV in Germany (Robert Koch-Institute, Berlin) [16,17] was to declare those patients as contagious and to isolate them as long as the viral genome is detected. This results not only in an increased need for isolation resources [18] and additional monitoring efforts [19] but in substantial psychosocial consequences. These patients and their families are accustomed to sharing multiple social activities and contacts with others in the ward, rendering them more empowered and motivated to cope with the adverse consequences of their underlying disease and of the intensive chemotherapy. There is no antiviral agent available to treat NV-infected patients at high risk for complications. According to the clinical and histological observations of Kaufman et al. [20], Calicivirus infection in pediatric intestinal transplant recipients has clinical and histological features that overlap with allograft rejection. In a prospective study, NV enteritis was found in only one of 75 stem-cell transplant recipients [21]. It is crucial to collect clinical and environmental samples accurately in a timely manner and to collaborate with the laboratory during the outbreak investigation. Unfortunately, in our case, the management of the outbreak was hampered by the unavailability of a sensitive and specific diagnostic
699
Norovirus in pediatric oncology test that could be applied at the patient’s bedside. The first report from the laboratory relating the outbreak to NV in three patients was communicated to the pediatric oncology personnel 14 days after the first patient became symptomatic. Thus, a timely identification of the causative pathogen was not possible and all measurements to contain the outbreak could not be targeted early enough to the special requirements of NV.
and II in patients with acute gastroenteritis. J Clin Virol 2005;33:168 71. Simon A, Fleischhack G, Hasan C, Bode U, Engelhart S, Kramer MH. Surveillance for nosocomial and central linerelated infections among pediatric hematology-oncology patients. Infect Control Hosp Epidemiol 2000;21:592 6. Rogers M, Weinstock DM, Eagan J, Kiehn T, Armstrong D, Sepkowitz KA. Rotavirus outbreak on a pediatric oncology floor: possible association with toys. Am J Infect Control 2000;28:378 80. Burgner D, Siarakas S, Eagles G, McCarthy A, Bradbury R, Stevens M. A prospective study of Clostridium difficile infection and colonization in pediatric oncology patients. Pediatr Infect Dis J 1997;16:1131 4. Hanna H, Raad I, Gonzalez V, Umphrey J, Tarrand J, Neumann J, et al. Control of nosocomial Clostridium difficile transmission in bone marrow transplant patients. Infect Control Hosp Epidemiol 2000;21:226 8. Langley JM, LeBlanc JC, Hanakowski M, Goloubeva O. The role of Clostridium difficile and viruses as causes of nosocomial diarrhea in children. Infect Control Hosp Epidemiol 2002;23:660 4. Schreier E, Doring F, Kunkel U. Molecular epidemiology of outbreaks of gastroenteritis associated with small round structured viruses in Germany in 1997/98. Arch Virol 2000;145:443 53. Page RD. TreeView: an application to display phylogenetic trees on personal computers. Comput Appl Biosci 1996;12: 357 8. Centers for Disease Control and Prevention. ‘‘Norwalk-like viruses’’: Public health consequences and outbreak management. Morbid Mort Weekly Rep 2001;50(June 1; No. RR9):1 18. Marks PJ, Vipond IB, Regan FM, Wedgwood K, Fey RE, Caul EO. A school outbreak of Norwalk-like virus: evidence for airborne transmission. Epidemiol Infect 2003;131:727 36. Isakbaeva ET, Bulens SN, Beard RS, Adams S, Monroe SS, Chaves SS, et al. Norovirus and child care: challenges in outbreak control. Pediatr Infect Dis J 2005;24:561 3. Pusch D, Oh DY, Wolf S, et al. Detection of enteric viruses and bacterial indicators in German environmental waters. Arch Virol 2005;150:929 47. Hohne M, Schreier E. Detection and characterization of norovirus outbreaks in Germany: application of a one-tube RT-PCR using a fluorogenic real-time detection system. J Med Virol 2004;72:312 9. Langley JM, Hanakowski M, Bortolussi R. Demand for isolation beds in a pediatric hospital. Am J Infect Control 1994;22:207 11. Stelfox HT, Bates DW, Redelmeier DA. Safety of patients isolated for infection control. JAMA 2003;290:1899 905. Kaufman SS, Chatterjee NK, Fuschino ME, Morse DL, Morotti RA, Magid MS, Gondolesi GE, et al. Characteristics of human calicivirus enteritis in intestinal transplant recipients. J Pediatr Gastroenterol Nutr 2005;40:328 33. Chakrabarti S, Collingham KE, Stevens RH, Pillay D, Fegan CD, Milligan DW. Isolation of viruses from stools in stem cell transplant recipients: a prospective surveillance study. Bone Marrow Transpl 2000;25:277 82. /
[6]
/
/
[7]
/
[8]
Conclusion
/
/
[9]
From our experience with some severely complicated or protracted cases of NV infection in immunocompromised patients, we would advise our colleagues to search with rapid and sensitive methods for NV in stool or vomitus specimens as early as possible if an outbreak of gastroenteritis is suspected in two or more patients in a pediatric oncology unit. As long as data are limited regarding whether a detectable viral antigen or RNA represents an infectious virus, patients should be isolated (during the acute phase of the illness with health-care workers using masks in addition to the meticulous hand hygiene with a disinfectant of proven activity against NV) until diagnostic assays turn negative. Pediatric oncology patients must be closely monitored during follow-up investigations, as there is some evidence from our patients that they face a greater risk of NVrelated complications.
/
[11]
/
/
[13]
[14]
/
[15]
Arne Simon and Oliver Schildgen contributed equally to this publication.
/
[16]
/
[17]
References [1] Kapikian AZ. The discovery of the 27-nm Norwalk virus: an historic perspective. J Infect Dis 2000;181 Suppl 2:S295 302. [2] Matson DO, Szucs G. Calicivirus infections in children. Curr Opin Infect Dis 2003;16:241 6. [3] Moreno-Espinosa S, Farkas T, Jiang X. Human caliciviruses and pediatric gastroenteritis. Semin Pediatr Infect Dis 2004; 15:237 45. [4] Pang XL, Joensuu J, Vesikari T. Human calicivirus-associated sporadic gastroenteritis in Finnish children less than two years of age followed prospectively during a rotavirus vaccine trial. Pediatr Infect Dis J 1999;18:420 6. [5] Pang XL, Preiksaitis JK, Lee B. Multiplex real time RT-PCR for the detection and quantitation of norovirus genogroups I /
/
/
/
/
[18]
/
[19]
/
/
/
/
/
/
[20]
/
/
/
/
/
[12]
Acknowledgements
/
/
/
[10]
/
/
/
[21]
/
/
/
/
/
