Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne Bunyaviridae positive stranded RNA viral disease reported from more than 30 countries in Africa, Asia, South-East Europe, and the Middle-East. Hyalomma tick bites, human-to-human transmission, and contact with blood or tissues from viremic livestock are the routes of disease transmission to human beings. However, occupational exposure poses the highest risk to humans and the majority of human cases are workers in livestock industry, agriculture, slaughterhouses, and veterinary practice,1–4 a fact that explains the rarity of the disease among children and adolescents. Previous reports presented clinical manifestations of CCHF mostly among adult patients.3–10 To our knowledge, clinical and epidemiologic characteristics of CCHF in children and adolescents have not been addressed to date.
We retrospectively studied clinical and epidemiologic and laboratory features of CCHF among children and adolescents from a highly endemic region of Iran.
MATERIALS AND METHODS
A retrospective study was conducted and the records of 277 confirmed cases of CCHF seen between June 1996 and September 2006 from 2 referral university hospitals in the Systan-Baluchestan province (in southeastern Iran) were reviewed. Children and adolescents younger than 18 years with confirmed CCHF were included. Suspected cases of CCHF were those who had clinical signs and symptoms of CCHF (high-grade fever, severe headache, muscle pain, nausea, vomiting, severe headache, or bleeding tendency), positive history of exposure (residence or outdoor activities in an endemic area, receipt of a tick bite, exposure to tick splashing, contact with suspected cases of CCHF, or contact with fresh blood or other tissues of livestock or game animals), and suggestive laboratory data during the first 5 days of illness (a platelet count of <150,000 platelets/mm3 and a WBC count of <3000 or >9000 cells/mm3). The first serum sample was obtained when a diagnosis of CCHF was suspected. Second and third samples were collected 5 and 10 days later, when possible. Suspected cases of CCHF who tested positive for CCHF virus-specific IgM by enzyme-linked immunosorbent assay (n = 21; 61.8%) and/or genomic segments of the CCHF virus by reverse transcriptase polymerase chain reaction (n = 24; 70.6%)11,12 were recognized as confirmed cases of CCHF. Viral culture was not part of routine diagnostic assessments of patients.
All suspected cases of CCHF were treated with oral ribavirin as recommended by the World Health Organization13 in the following regimen: 30 mg/kg as an initial loading dose, then 15 mg/kg every 6 hours for 4 days, and then 7.5 mg/kg every 8 hours for 6 days. The total duration of treatment was 10 days. Those patients who had nausea and vomiting received ribavirin by nasogastric tube. Ribavirin was administered in the form of tablets (200 mg).
Demographic characteristics, residing area (urban versus rural), history of tick bite or contact with animal blood or carcasses, clinical and laboratory features, and survival of these patients were reviewed.
Continuous variables were compared between groups using the nonparametric Mann-Whitney U test. The Fisher exact test was used to evaluate the significance of the relationship between 2 dichotomous variables. To elucidate factors associated with the survival, a multivariate analysis was performed and a regression model with a forward, stepwise (likelihood ratio) method was built. Confidence intervals for odds ratios and the Wald test P values were calculated. Statistical significance was set at P < 0.05.
A total of 34 nonadult confirmed CCHF patients were studied. The mean age of the studied subjects was 13.3 ± 4.6 (range, 5.0–18.0) years. Fourteen (41.2%) patients were 12-year-old or younger. Twenty-three (67.6%) study subjects and almost all children (13 of 14; 92.9%) were males. History of tick bite was obtained in 8 (23.5%) patients, and contact with animal blood or carcasses in 14 (41.2%). Twenty-nine (85.3%) subjects resided in rural areas.
The presenting symptoms and signs are shown in Table 1. The median time interval between onset of symptoms and hospital admission was 3 days (range, 2–6 days). Although this interval was significantly higher in fatal than survived cases when an equal variance between groups was assumed (P = 0.033), nonparametric test could not approve the significance of difference (P = 0.066; Table 2). In nonfatal patients, the median hospital stay was 9 days (range, 6-14 days).
The case-fatality ratio was 26.5% (9 of 34). In fatal cases, the median time from onset of symptoms until death was 7 days (range, 5–11 days). In univariate analyses, impaired consciousness, petechia, hemorrhagic manifestations, and jaundice were more frequent in those who died than in survivors. Those who survived received treatment with ribavirin sooner than those who did not (Table 2). However, an initial presentation with impaired consciousness (odds ratio, 35.0; 95% confidence interval, 4.1–297.7; P = 0.001) was the only factor that was independently associated with higher mortality in multivariate analysis. The 2 log likelihood (−2LL) of 14.29, Nagelkerke R2 of 0.76, and insignificant Hosmer-Lemeshow test indicated that the model used for multivariate analysis did fit the data.
The case-fatality ratio attributable to CCHF ranged from 2.8% to 80% in different studies from various geographical regions.3–10 The case-fatality ratio among children and adolescents in the present study was 26.5% despite treatment with oral ribavirin. In a previous study in the same region, Mardani et al9 reported a significantly lower fatality ratio of CCHF in adults who received ribavirin than in an historic cohort who did not receive ribavirin (11.6% versus 58.3%). Although several studies have suggested that ribavirin is efficient for treatment of CCHF,8,9,14–16 current literature lacks strong evidence in form of randomized controlled trials. The univariate but not the multivariate analysis of the current study showed that fatal cases received ribavirin significantly later than nonfatal cases. There was also a longer time interval between disease onset and hospital admission in fatal than survived subjects, although the difference was not significant in the nonparametric test. However, the presented insignificance could be because of a relatively small number of fatal cases in comparison to survivors (9 versus 25).
The time interval between disease onset and admission (median, 4 days) in the studied children and adolescents of the current study was shorter than the corresponding average interval in patients from Turkey (5.5 days),8 Pakistan (4.3 days),5 and the UAE (3.5 days).17 Although it may be because of variations in the local health systems, those who were presented sooner for admission in this study may suggest early onset of a severe disease in children and adolescents. Additionally, in fatal cases of this study, death occurred about 1 week after onset of symptoms that may suggest a fast deterioration of general condition in children and adolescents with CCHF.
To our knowledge, the presenting signs and symptoms of CCHF have not been addressed in children and adolescents in particular before. We found clinical manifestations in the studied population almost similar to previous nonage-specific reports.3–10 Nevertheless, jaundice was evident in about half of the studied children and adolescents and was infrequent in other studies.3–10 Moreover, no laboratory finding could independently predict survival which was in contrast with other reports that suggested different laboratory severity criteria for CCHF.6,10,18 Indeed, it was only impaired consciousness that was independently associated with a fatal outcome in the studied children and adolescents. Congruently, other investigators7,10 indicated a markedly more frequent early presentation with impaired consciousness in fatal than survived cases. Other variables that showed significant difference in univariate analyses between fatal cases and survivors cannot be considered as risk factors as multivariate analysis could not prove their independent association.
In conclusion, clinical manifestations of CCHF among children and adolescents are almost similar to those in adults. Impaired consciousness at presentation was the only factor that was independently associated with a fatal outcome. Because most of the mortalities occurred during the first week of disease onset, a fast deterioration of general condition in infected children and adolescents can be suggested.
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