Epidemiological and clinical features of erythema infectiosum in children in Novi Sad from 2000 to 2009

Background/Aim. Erythema infectiosum (EI) is a common childhood illness, caused by human parvovirus B19. It occurs sporadically or in epidemics and is characterized by mild constitutional symptoms and a blotchy or maculopapular lacy rash on the cheeks (slapped-cheek) spreading primarily to the extremities and trunk. The aim of our study was to analyse the epidemiological and clinical characteristics of erythema infectiosum in children. Methods. This study included 88 children observed in the Department of Dermatology of the Institute for Child and Youth Health Care of Vojvodina, in Novi Sad, during the period January 2000–December 2009. We compared the data about the clinical characteristics during and after the outbreak of EI observed from December 2001 to September 2002. The data were retrieved from the hospital database. Results. During the study period, EI was detected in 88 children (44 females and 44 males), 0.213% of the total number of 41,345 children observed in the Department of Dermatology. An outbreak of erythema infectiosum was observed from December 2001 to September 2002, with the peak frequency in April and May 2002 and 39 diagnosed cases, and stable number of cases from 2005 to 2009 (a total of 49 diagnosed cases). The average age of infected children was 7.59 ± 3.339. Eleven (12.5%) children were referred from primary care pediatricians with the diagnosis of urticaria or rash of allergic origin. The most constant clinical sign was reticular exanthema on the limbs, present in 100% of the cases, followed by 89.77% of cheek erythema. Pruritus was present in 9.09% of the children, mild constitutional symptoms in 5.68% and palpable lymph glands in 3.41% of the children. In all the cases the course of the disease was without complications. Conclusion. The results of this study confirm the presence of EI (the fifth disease) in our area with a mild course in the majority of patients. Since the diagnosis of EI is usually based on clinical findings, continuing medical education of primary health care pediatricians is essential for reducing the number of misdiagnosed cases.

the peak frequency in April and May 2002 and 39 diagnosed cases, and stable number of cases from 2005 to 2009 (a total of 49 diagnosed cases).The average age of infected children was 7.59 ± 3.339.Eleven (12.5%) children were referred from primary care pediatricians with the diagnosis of urticaria or rash of allergic origin.The most constant clinical sign was reticular exanthema on the limbs, present in 100% of the cases, followed by 89.77% of cheek erythema.Pruritus was present in 9.09% of the children, mild constitutional symptoms in 5.68% and palpable lymph glands in 3.41% of the children.In all the cases the course of the disease was without complications.

Conclusion.
The results of this study confirm the presence of EI (the fifth disease) in our area with a mild course in the majority of patients.Since the diagnosis of EI is usually based on clinical findings, continuing medical education of primary health care pediatricians is essential for reducing the number of misdiagnosed cases.

Introduction
Erythema infectiosum (EI) is an acute childhood illness, characterized by blotchy or maculopapular rash starting on cheeks, spreading to extremities and the trunk, giving a typical slapped cheek appearance and lacy configuration on limbs.Constitutional symptoms are mild 1,2 .The disease is caused by human parvovirus B19 (Pv B19), the route of natural transmission is presumably the respiratory route, and parenteral and transplacental transmission have been proved, as well.A receptor molecule for B19 is glycolipid antigen on the erythrocyte surface, and hosts with the decreased production or increased destruction of red blood cells (such as hemolytic anemia or pure red cell aplasia due to various causes) are prone to aplastic crises and protracted severe anemia upon infection with human Pv B19 [2][3][4] .In immunocompromised hosts the course of Pv B19 infection can be severe, even caused by hemophagocytic syndrome 4 .Acute infection during pregnancy can result in hydrops fetalis (risk estimated in 10% of cases) 5 .The incubation period is 4-14 days, during which patients are infectious, only prior to the onset of the rash 6,7 .
EI usually develops suddenly, prodromal symptoms are mild or may be absent.The course of the disease is threephasic: facial "slapped-cheeks" rash, followed by lacy or reticular rash of the upper extremities and an evanescence/recrudescence stage.Eruption is pruritic in about 15% of children.EI usually lasts for 2 weeks, but can recur with mechanical, physical or emotional triggers.The diagnosis of EI is usually made on the basis of the characteristic clinical features.The differential diagnosis includes the other viral rashes (rubella, measles, enteroviral infection), scarlet fever, cheek erysipelas, hypersensitivity reaction (urticaria, drug reaction or allergic exanthemata) and collagen vascular diseases (systemic lupus erythematosus).Due to the mild course only symptomatic treatment is necessary (antipyretics, antihistamines) 1,7,8 .

Methods
This retrospective study was conducted in the Department of Dermatology, Institute for Child and Youth Health Care of Vojvodina in Novi Sad, as tertiary referral center for the South Ba ka region in the Province Vojvodina.Age, sex distribution, the presence of constitutional symptoms and clinical characteristics of the disease were retrieved from the medical records of all EI patients diagnosed between January 2000 and December 2009.The data from the period 2005-2009, and those previously published for the period 2000-2004 were compared 9 .
All the patients were diagnosed by one of the dermatologists (authors), based on the clinical findings in the majority of cases.A total of 12 patients (2 during the period of 2005-2009) serum samples were additionally analyzed using SERION ELISA (enzyme-linked immunosorbent assay) classic parvovirus B19 IgG/IgM quantitative and qualitative tests for identification of specific antibodies against human parvovirus B19.Complement-fixing reactions (CFR) to viruses (Rubella, Adenovirus, Coxsackie virus) were performed in 5 children, with constitutional symptoms and palpable lymph nodes.

Results
During the study period (from the beginning of 2000 to the end of 2009), at the Department of Dermatology, the total number of first visits was 41,345 and erythema infectiosum was diagnosed in 88 children (0.213%). Figure 1 shows the number of patients during a 10-year period.Patients with EI were not observed within 2000, and sporadic cases emerged by the end of 2001.A sudden outbreak was noted from December 2001 to September 2002 with the highest number of cases recorded in April and May, 2002 9 .In a subsequent 5 year period (2005-2009) EI was diagnosed in 49 children, 22 girls and 27 boys, average age being 7.98 ± 3.554 years.During a total period of 10 years, the average age of EI patients was 7.59 ± 3.339 years, with the majority of patients in the 5-10 years group, and equal sex ratio (44 girls and 44 boys affected).
During the whole study period 11 children (12.5%) were referred from primary care pediatricians with the diagnosis of urticaria or rash of allergic origin, 7 during the pe- riod of outbreak and 4 patients (8.16%) during the second period.These children were on diet and recevied oral antihistamines, while 5 of them (5.68%) had been prescribed parenteral corticosteroid treatment, 2 (4.08%) in the second period after the outbreak.Mild pruritus was present in 8 (9.09%) of the children and mild constitutional symptoms were present in only 5 (5.68%) of the children.All the patients had typical clinical picture, and atypical forms of the disease were not recorded in the studied pediatric population (ie, papular-purpuric gloves and socks syndrome or acropetechial syndrome) (Figure 2).The most constant clinical sign was reticular exanthema on upper extremities, present in 100% of the cases, followed by intensive erythema of the cheeks (slapped-cheek appearance) in 79 (89.77%).Exanthema on trunk and extremities was present in 12 (13.63%)children.One (1.14%) patient had palmar and plantar erythema.Occipital lymphadenopathy was present in 3 (3.41%)children.Clinical findings of EI patients from the study period 2005-2009 are presented in Table 1.All the 12 tested children were positive for IgM antibodies against human parvovirus B19, confirmative of the acute Pv B19 infection.
CFR assays for Rubella, Adenovirus and Coxsackie were negative in all the five children tested.On control examination after 14 days rash was resolved in all the patients, while physical examination showed normal results.

Discussion
Infection with PvB19 is ubiquitous and occurs worldwide.EI is common, mildly contagious, and occurs sporadically or in epidemics 1 .The rise in the number of EI patients noted during the period December 2000 to May 2002, with the peak in April and May 2001, was not repeated in the later study period when an average number of patients was relatively stable 9 .That is in concordance with data form the literature on EI epidemics occurring in cyclical fashion, every 4-7 years, with more frequent outbreaks in winter and spring 3,6,8,9 .Localized outbreaks among schoolchildren are common 6 .The first outbreak of EI in Serbia was reported from October 1987 to May 1988 that occurred among school children in part of Belgrade 10 .The majority of our EI patients were 5-10 years old, that is in concordance with literature data 1 .No gender difference in susceptibility to EI was noted in the literature, similar to our case series 5 .Lacy exanthema on proximal extremities was the most prominent symptom noted in all our patients, that disagrees with the study by Revilla et al. 11 where erythema of the cheeks (slapped-cheek appearance) was the most frequent one.Lacy exanthema of the extremities was the most frequent in the study by Bukumirovi et al. 10 , and in our previous report, also 9 .Palmar and plantar erythema occurs only rarely in EI 6 .In our study it was present only in one boy during the 2001-2002 outbreak, and in was not observed a later period 9 .None of the children had any further complications.In a similar study by Rewilla et al. 11 the illness had a mild course.The only difference in clinical presentation of EI patients between the two study periods is that exanthema affecting both trunk and limbs occurred more frequently during the study period 2005-2009 than in the previous 5 years (18.37% and 7.69% correspondingly) 9 .
In our study lymph nodes enlargement was present in 3.41% of the patients (occipital lymph nodes), and in those children serological analyses for Rubella, Adenovirus and Coxsackie virus were performed, proved negative in all of them.In all 12 tested serum samples Pv B19 infection was serologically detected.According to the literature, laboratory proof of Pv B19 infection is not necessary in cases with characteristic clinical picture and uncomplicated course in previously healthy children 1,7,8 .Therefore, EI should not be a diagnostic problem because of its characteristic presentation and the course of the illness.EI description as "geographical map with lakes" as the most picturesque of all the rashes, together with phasic course with slapped cheeks or sun-burnt facial aspect preceding rash, are pathognomonic, and seen only in this disease 1,7,8 .However, the number of patients had been referred to the Institute because of suspected allergic rash, and a relatively large proportion of children (12.15%) had been previously prescribed antihistamine and corticosteroid treatment and  elimination diet.Even though EI is not a rare disease, it appears periodically every 4-7 years in the form of sporadic epidemics lasting for several months, that could be the reason not to be easily recognized among primary health care physicians.Albeit, during 2001/2002 outbreak when 18% of children were referred from primary care as suspect allergic reaction, in the period 2005-2009 proportion of unrecognized cases decreased to 8%.That is an encouraging result pointing that previous epidemics increased awareness and enhanced recognition of EI among non-dermatologists 9 .

Conclusion
The results of this study confirm the presence of EI (the fifth disease) in our area with a mild course in the majority of patients.Since the diagnosis of EI is usually based on clinical findings, the continuing medical education of primary health care pediatricians is essential for reducing the number of misdiagnosed cases.Further studies within longer observation periods and larger groups of patients are necessary to determine the epidemiological and clinical characteristics of erythema infectiosum in Serbia.

Fig. 1 -
Fig. 1 -The number of patients with erythema infectiosum in a 10-year research period.