e186 | www.pidj.com The Pediatric Infectious Disease Journal Volume32,Number5,May2013

Original StudieS

Background: Children with petechial rash are more likely to undergo inva-sive diagnostics, to be treated with antibiotics for potential bacterial infec-tion and to be hospitalized. However, viruses have also been associated with petechial rash. nonetheless, a systematic analysis of viral infections with modern available techniques as quantitative real-time polymerase chain reaction in the context of petechial rash is lacking. the purpose of this pedi-atric study was to prospectively uncover viral pathogens that may promote the emergence of petechiae and to analyze the correlation with the clinical characteristics and course.Methods: We conducted a prospective study in children (0 to 18 years) pre-senting with petechiae and signs or symptoms of infection at the emergency department between november 2009 and March 2012. in nasopharyngeal aspirates the following viruses were analyzed by quantitative real-time poly-merase chain reaction: cytomegalovirus, epsteinBarr virus, parvovirus B19, influenza a and B, parainfluenza viruses, human respiratory syncytial virus a and B, human metapneumovirus, rhinovirus, enterovirus, adenovi-rus, human coronavirus OC43, 229e, nl63 and human bocavirus.Results: a viral pathogen was identified in 67% of the analyzed 58 cases with petechial rash. Virus positive patients showed a significantly higher incidence of lower respiratory tract infections. Forty-one percent were viral coinfections, which were significantly younger than virus negative patients, had a higher leukocyte count and were hospitalized for a longer time.Conclusions: a petechial rash is frequently associated viral single- and coinfections and can rapidly be identified via quantitative real-time poly-merase chain reaction.

Key Words: petechiae, fever, viral infections, management, polymerase chain reaction

(Pediatr Infect Dis J 2013;32: e186e191)

Petechiae in children often pose a diagnostic dilemma lead-ing to an enhanced rate of hospitalizations, invasive proce-dures such as blood sampling for blood cultures, assessment of the inflammation parameters and lumbar punctures, as well as antibiotic treatment for possible sepsis or meningitis with bac-teria such as Neisseria meningitidis.16 in the past, the probabil-

ity of a severe bacteremia in children with petechiae and fever was estimated at 10% to 20% with the presence of skin hemor-rhages (diameter >2 mm) as a risk factor.2,3,5,6 in up to 72% of the patients with fever and a petechial rash, no causing pathogen was identified, whereas viruses were only identified in 11% to 15% of the cases.2

Human respiratory syncytial virus (rSV), epsteinBarr virus (eBV), cytomegalovirus (CMV), adenovirus, enterovirus (eV) and parvovirus B19 are reported to be associated with a pete-chial rash. the proportion of viral infections in children with pete-chiae and fever is understated.2,711 additionally, currently avail-able studies on children with a petechial rash (with the most recent being performed in 2001) noted an association between evolve-ment of petechiae in children and upper respiratory tract infec-tions (urtis) commonly caused by so called respiratory viruses as influenza types (inf) a, B and H1n1, parainfluenza type 1, 2 and 3, rSV, rhinovirus (rV), eV and adenovirus.3,1214 Moreover, previously unknown viruses as human metapneumovirus, human coronavirus and human bocavirus (HBoV) associated with urti and specific viral diagnostics have been discovered recently.1420 it is now possible to specifically detect viruses within hours with nucleic acid amplification tests as quantitative real-time polymer-ase chain reaction (q-PCr).3,15 Modern viral diagnostics might help further itemize the 45% of urti in children with a petechial rash as systematic analysis of the presence of viral pathogens in children with petechiae is lacking.2 the main aim of the study was to analyze prospectively the rate of viral (single and co-) infec-tions in children with a petechial rash applying q-PCr techniques of nasopharyngeal aspirates (nPas), to identify viruses associated with the emergence of petechiae and to correlate them with disease severity.

MATERIALS AND METHODS

Study Populationthe prospective clinical study was performed from novem-

ber 2009 to March 2012 at the university Childrens Hospital Mannheim, Heidelberg university and the Childrens Hospital St. annastiftkrankenhaus in ludwigshafen. identification and recruit-ment of patients was made by the responsible physician in the emergency department or the unit within the hospital after admis-sion. We included children between 0 and 18 years presented with a nonblanching rash not greater than 2 mm in diameter of unknown origin with signs and symptoms of an ongoing infection. Patients with thrombocytopenia, preexisting coagulation disorder, clinical vasculitis (purpuric lesion with a diameter of >2 mm), meningo-coccal disease or with primary or secondary immune dysfunction were excluded. Clinical data were prospectively collected using a standard data collection form. additional diagnostics apart from nasopharyngeal aspirates (nPa) as chest radiogram, blood sam-pling for laboratory parameters or blood cultures, analysis of the urine or lumbar puncture were not a study requirement. results of additional diagnostics were documented and analyzed within the study when available.

Copyright 2013 by lippincott Williams & WilkinsiSSn: 0891-3668/13/3205-0e186dOi: 10.1097/inF.0b013e318280618d

ClinicalCharacteristicsofChildrenWithViralSingle-and Co-infectionsandaPetechialRash

Henriette Schneider, MD,* Ortwin Adams, MD, Christel Weiss, ScD, Ulrich Merz, MD, Horst Schroten, MD,* and Tobias Tenenbaum, MD*

accepted for publication november 28, 2012.From the *Paediatric infectious diseases, university Childrens Hospital

Mannheim, Heidelberg university, Mannheim, germany; institute of Virol-ogy, university Childrens Hospital, Heinrich-Heine-university, dsseldorf, germany; department of Statistics, Medical Faculty Mannheim, Heidel-berg university, Mannheim, germany; and Childrens Hospital St. annas-tiftkrankenhaus, ludwigshafen, germany.

H.S. and O.a. contributed equally to this article and share first authorship.the concept of the study was honored in 2011 by the german Society of Paediat-

ric infectious diseases (dgPi) with an investigator award (5000 euro). the authors have no other funding or conflicts of interest to disclose.

address for correspondence: Henriette Schneider, Md, Paediatric infectious diseases, university Childrens Hospital Mannheim, Heidelberg university, theodor-Kutzer-ufer 13, 68167 Mannheim, germany. e-mail: henriette.schneider@medma.uni-heidelberg.de.

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Ethical Statementapproval was provided by the local ethics committees (Med-

ical Faculty of Mannheim, Heidelberg university [2009-323n-Ma] and Mainz [837.021.10 (7030)]). Written informed consent was obtained from parents and children (when possible according to their age) before any study procedures being performed.

Analysis of Nasopharyngeal AspiratesOn the day of admission or detection of petechial rash, nPas

were collected and evaluated in the institute of Virology in dssel-dorf with q-PCr for CMV, eBV, parvovirus B19, inf a and B, inf a H1n1 (H1n1), parainfluenza 1, 2 and 3, rSV a and B, human metapneumovirus, rV, eV (coxsackie a and B viruses and echo-viruses except for polioviruses 13), adenovirus, human corona-virus and HBoV. the quantification of the viruses was performed by a previously described 1-step real-time PCr method of which sensitivity and specificity have been demonstrated elsewhere.14,2123 in brief, the Quantitect Multiplex q-PCr kit (no. 204643, Qiagen, Hilden, germany) containing HotStartaq dna Polymerase was used for the assay. amplification was performed in an aBi7500 thermocycler using conditions as recommended by the manufac-turer of the multiplex rt-PCr kit. as standards, dna plasmids that encompass the amplified region were created and serially diluted after purification. Standard graphs of the CT values obtained from serial dilutions of the standards were constructed and the numbers of specific genomes were calculated by the software. nPa as a method for the detection of a viral infection was chosen as non-invasive procedure, of which reference values for the viral load in copies per milliliter (ml) of respiratory viruses exist.21 in cases in which lumbar puncture was performed, the cerebrospinal fluid was send for bacterial culture and analyzed with a standard commer-cial multiplex PCr (reverse Hybridization assay kit CnS, labo Bio-Medical Products B.V., the netherlands) for herpes simplex virus type 1, herpes simplex virus type 2, eV, CMV, varicella zoster virus, eBV, human John Cunningham virus, human herpes virus type 6 and Toxoplasma gondii.

StatisticsQualitative variables are presented as absolute and rela-

tive frequencies; quantitative parameters are given as mean and standard deviation or median and range. Clinical characteristics and laboratory variables have been compared using t tests of the pooled method (identical variances) and Satterthwaite method (dif-fering variances). For skewed distributed quantitative data, MannWhitney U test has been performed. to compare frequencies of 2 samples, test or Fishers exact test has been used, for ordinal scaled data Cochranarmitage trend test was preferred. a 2-sided P value 100 petechiae (P = 0.0247) between virus positive and virus negative patients (table 1). the distribution of petechiae did not differ sig-nificantly in virus positive and negative patients.

Blood samples were taken in the majority of the analyzed children (45/58; 78%) to examine full blood cell count and the C reactive protein value (14 virus negative and 31 virus positive patients) and revealed no significant difference between virus posi-tive and virus negative patients (table 2). Blood cultures were only analyzed in hospitalized children without any antibiotic treatment before admission. in 3 of 38 blood culture samples (8%), bacteria were detected (Flavimonas oryihabitans, Streptococcus agalac-tiae and coagulase negative staphylococci each in 1 patient). Only the patient with proven S. agalactiae infection received antibiotic treatment.

Identification of Viral Causes in Children With a Petechial Rash

in 39 of the 58 patients analyzed during the study period, at least 1 virus was detected within the nPa. the majority were single viral infections (23/39; 59%) whereas coinfections with 2 pathogens were as frequent as coinfections with >2 pathogens (each 8/39; 20.5%). Children with viral coinfections were signifi-cantly younger (2.3 2.16 years) than the children with a single viral infection (4.18 3.26 years) (P = 0.0440) (data not shown). Coinfections led to a significant higher hospitalization rate (15/16; 93.75%) compared with virus negative patients (12/19; 63%; P = 0.0472) (data not shown). interestingly, children with viral coinfections presented with a significant higher leukocyte count (12641 3274/l) compared with virus negative (8455 3155/l; P = 0.0063) and single viral infections (9393 4780/l; P = 0.0642) (data not shown).

the most frequent pathogens in association with a petechial rash were CMV and eBV (each 11/58; 18% of all patients) fol-lowed by eV and rV (each 8/58; 14% of all patients) and H1n1 and HBoV (each 5/58; 9% of all patients). eBV and CMV were frequently found as coinfections (only 1 single infection with eBV and CMV within the study collective). ten of 11 CMV positive patients (91%) and 9 of 11 eBV positive patients (82%) were hospitalized. CMV positive patients were with 2.07 2.53 years younger than virus negative (4.19 3.84 years; P = 0.01108) and

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CMV negative (4.57 4.88 years; P = 0.0208) patients. as to the laboratory findings, the CMV positive patients showed elevated platelet counts (297970 99617/l) compared with the CMV neg-ative patients (251142 70249/l; P = 0.0818) and a significant leukocytosis (13630 3337/l) compared with the CMV nega-tive (8455 3155/l; P = 0.0109) and all virus negative patients (9251 3979/l; P = 0.0043). Moreover, the eBV positive patients showed a significantly higher rate of lymphadenitis (3/11; 27%) compared with eBV negative patients (1/47; 2%; P = 0.0191) and virus negative patients (0/19; 0%; P = 0.0406). eV was detected in 5 cases as single and in 3 cases as coinfection. the eV positive patients were likely to present in summer (5/8; 63%) compared with eV negative patients (6/50; 12%; P = 0.0164) and 3 of 5 patients

(60%) received a lumbar puncture for neurological symptoms as febrile seizures, meningism or even meningitis. the majority of rV positive patients (7/8; 87.5%) was hospitalized. nine (23%) of the 39 virus positive patients were well appearing, treated as outpa-tients without antibiotics and scheduled for a clinical control on the consecutive days despite a high number of petechiae (6/67% had around 100 petechiae).

PCr-positive samples could qualitatively clearly be distin-guished from negative samples with mean viral loads ranging from 438 103 for coronavirus to 805 109 for adenovirus (Fig. 1), but it should be emphasized that there exist no clear cutoffs for clinical significant values for respiratory virus infections. especially adeno-virus, rSV and HBoV were found with a high viral load.

TABLE 2. Laboratory Findings in Children With or Without a Viral Infection and Petechial Rash

All Patients Positive Patients Negative Patients P

Total number 58 39 19Hemoglobin (g/dL) 12 1 12 1 12 2 0.7886Thrombocytes (/L) 257,556 82,567 260,197 87,981 25,1143 70,250 0.9614Leukocytes (/L) 10,080 4200 10,767 4446 8455 3155 0.5775Segmented neutrophils* 38 24 39 24 36 29 0.4302Banded neutrophils* 10 19 9 20 14 16 0.7628Lymphocytes* 35 23 36 21 33 30 0.7720Monocytes* 8 6 9 7 6 3 0.2971C reactive protein (mg/L) 23 34 20 25 31 49 0.9393INR 1.07 0.11 1.07 0.12 1.06 0.08 0.5735Ptt (s) 29 8 30 9 25 7 0.0638

*% of total leukocytes.

TABLE 1. Clinical Characteristics of All Patients, Virus Positive and Negative Patients With Petechiae

All Patients Positive Patients Negative Patients P

Total number 58 39 19Age (yr) 3.8 3.7 3.4 3.0 4.6 4.9 0.7972Gender Male 41 (71%) 26 (67%) 15 (79%) 0.3349 Female 17 (29%) 13 (33%) 4 (21%)Number of petechiae 100 14 (24.6%) 6 (15%) 8 (45%) 0.0247Symptoms Coughing 28 (48%) 21 (54%) 7 (37%) 0.2239 Vomiting 16 (28%) 11 (28%) 5 (26%) 0.8799 Diarrhea 14 (24%) 11 (28%) 3 (16%) 0.3495 Meningism 7 (12%) 4 (10%) 3 (16%) 0.6726 Swelling of joints 2 (3%) 1 (3%) 1 (5%) 1 Maximal temperature (C) at admission 38.3 1 38.8 1 38.5 1.3 0.8737Diagnosis URTI 20 (34%) 13 (33%) 7 (37%) 0.7919 Bronchitis 8 (14%) 8 (21%) 0 (0%) 0.0437 Pneumonia 2 (3%) 0 (0%) 2 (11%) 0.1034 Gastroenteritis 11 (19%) 8 (21%)* 3 (16%) 1 Lymphadenitis 4 (7%) 4 (10%) 0 (0%) 0.2921 Febrile seizure 3 (5%) 3 (8%) 0 (0%) 1 Meningitis 2 (3%) 1 (3%) 1 (5%) 1 Presumed sepsis 5 (9%) 2 (5%) 3 (17%) 0.3125 Others 14 (24%) 8 (21%) 6 (32%) 0.5141Invasive diagnostics Lumbar puncture 10 (17%) 5 (13%) 5 (26%) 0.2704Therapeutic strategies Antibiotics 17 (29%) 11 (28%) 6 (32%) 0.7911 Hospitalization rate 42 (72%) 30 (77%) 12 (63%) 0.271

*Of the patients with diarrhea, 4 were positive for an enteric virus (2 norovirus and 2 rotavirus).In 1 of the patients with presumed sepsis, blood cultures were positive for S. agalactiae.Of the patients who underwent a lumbar puncture, 1 of the virus positive and 2 of the virus negative patients underwent lumbar puncture for their young age

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Central Nervous System Symptoms in Children With Petechial Rash

as to central nervous system symptoms, 7 of the 58 (12%) presented with nuchal rigidity and 3 of the 58 (5%) with a febrile seizure. ten children (17%) received a lumbar puncture at admission. in 5 out of these, a virus was detected in the nPa (1 coinfection of H1n1, CMV, eBV and eV, 1 coronavirus, 2 single infections with eV and 1 coinfection of parainfluenza and CMV). all 7 children with meningism were hospitalized. Four of them (2 virus positive and 2 virus negative within the nPa) were treated with antibiotics. additionally, 4 children underwent lumbar puncture due to the presence of a petechial rash in combination either with their young age 2 mm were excluded from the study as they seem more likely to suffer from meningococcal disease.6 Main aim was to estimate the amount of viral pathogens within the nasopharynx measured with q-PCr analysis in the context of a petechial rash with a noninvasive procedure for which information about the viral load in disease exit. in 67% of the included patients, 1 or several viral pathogens have been detected. the viral loads in the nPa for the different viruses in this study (Fig. 1) were comparable to described viral loads for infections with respiratory viruses either in single or in coinfections and in a higher range than viral loads in healthy children.21,26 Still, there is no consensus in the literature on clinical significant values for respiratory infections. as a result of low case numbers for each pathogen viral load results have to be interpreted with caution. For rV, a previous prospective study with healthy children has shown that shedding of picornavirus rna was episodic with positive q-PCrs for 1 to 3 weeks followed by weeks of negative tests; chronic carriage did not occur.27 the mean viral load of the rV samples in our study was with 136 105 copies/ml equal or higher than viral loads found with other viruses (ie, influenza or parainfluenza) indicating that the detection of rV may be associated with an acute infection. Otherwise it cannot com-pletely be excluded that in some cases we detected rV rna from a previous episode of infection. Concerning herpesviruses (CMV and eBV), a critical point with the detection is the long lasting oral shedding after primary infection. in adults, CMV and eBV can be detected in 10%20% of asymptomatic individuals and is assumed to be more frequent during childhood.28 Consequently, a combi-nation of q-PCr of nPa with a serological analysis may help to differentiate between acute viral infection and reactivation. as our study was meant to apply as few additional invasive diagnostics in the children as possible, serological correlation with the findings, which was part of the study design, was not always possible. this might limit the interpretation of the study. Blood culture sampling

FIGURE 1. Meanviral loaddetectedinchildrenwithviral infectionsandpetechialrash.Thehighestviral loadvaluesweredetectedinchildrenwithadenovirus(AV),RSVandHBoVinfections.PVB19indicatesparvovirusB19;hMPV,humanmetap-neumovirus;HCoV,humancoronavirus;Para,parainfluenza.

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was performed in the hospitalized patients without prior antibiotic treatment (38/58; 66%) and revealed only 1 clinically relevant case of bacterial blood stream infection (S. agalactiae) in the study pop-ulation.

Between virus negative and virus positive patients with a petechial rash, there were no significant differences in clinical appearance, cardinal symptoms, diagnostic parameters, treat-ment and hospitalization rate despite the higher rate of bronchitis/bronchiolitis in virus positive patients and the number of pete-chiae (table 1). Patients with viral coinfections were significantly younger than virus negative patients, had a higher leukocyte count and were longer hospitalized.

interestingly, within the small subgroup of patients with central nervous system symptoms (10 patients), virus positive patients displayed the petechial rash in a more generalized fashion (head: 3/5; 60%; upper extremities: 2/5; 40%; trunk: 4/5; 80% and the lower extremities: 3/5; 60%), whereas in virus negative patients the rash was centered on the trunk (2/5; 40%) and lower extremities (3/5; 60%).

in previous studies, authors suggested to combine the clini-cal criteria general appearance and skin lesion (either petechiae or purpuric lesions) with the WBC to detect children with bacterial sepsis whereas viral pathogens were not investigated due to compli-cated virus diagnostics.4,15 applying these criteria (either general appearance, WBC and skin lesions or irritability, lethargy and low capillary refill) to our study population, all children with viral coinfections fulfill the criteria for bacterial septicemia/bacteremia and would receive an antibiotic treatment at least until bacterial cultures were proven negative.4,12 thus, our study provides evidence that also viral infections can lead to a reduced clinical appearance and an elevated WBC. due to efficient vaccination programs within europe and the united States, herd immunity and herd protection against Streptococcus pneumoniae, N. meningitidis and Haemophi-lus influenzae improved.2932 Consequently, the use of the clinical and diagnostic criteria (see above) set the era before the availabil-ity of elaborate viral diagnostics as q-PCr and before the imple-mentation of directed vaccination programs might lead nowadays in europe and the united States to an overestimation of bacterial infections in such children with a petechial rash.3,4,12 additional studies have to further clarify whether rather the infection with a specific pathogen or coinfections with different viruses determine the appearance of a petechial rash in children.

in our study, 17 (11 virus positive and 6 virus negative) children in total were treated with antibiotics due to suspicion of potential bacterial infection and/or young age. in the 11 virus posi-tive patients (8 viral single and 3 coinfections), viral infection fully accounted for the symptoms they presented and antibiotic treatment might have been dispensable. there is strong discordance about the suitable treatment for children with a petechial rash that are in a good general state of health and young aged children are more likely to be treated with antibiotics or to be admitted to hospital for a petechial rash even when their clinical condition is not reduced1,13

Petechial rash in children needs thorough examination to distinguish between life threatening diagnosis as fulminant sepsis and self-limiting viral infection. novel viral diagnostics as multi-plex q-PCr enables the rapid detection of viral causes and might avoid unnecessary antibiotic treatment, invasive diagnostics and hospitalizations.

ACKNOWLEDGMENTSWe are grateful for the support offered by the staff of the

2 childrens hospitals, the University Childrens Hospital Man-nheim, Germany Heidelberg University and the Childrens Hospi-tal St. Annastiftkrankenhaus in Ludwigshafen, Germany, and the

members of the working group of Prof. O. Adams in the Institute of Virology, University Childrens hospital, Heinrich-Heine-Univer-sity, Dsseldorf, Germany.

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