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Risk Factors for Severity of Chikungunya in Children: A Prospective Assessment

Pinzón-Redondo, Hernando MD; Paternina-Caicedo, Angel MSc; Barrios-Redondo, Katherine MD; Zarate-Vergara, Andrea MD; Tirado-Pérez, Irina MD; Fortich, Rossana MD; Alvis-Guzmán, Nelson PhD; Mattar, Salim PhD

The Pediatric Infectious Disease Journal: June 2016 - Volume 35 - Issue 6 - p 702–704
doi: 10.1097/INF.0000000000001135
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Chikungunya appeared during the second half of 2014 in Colombia. A prospective cohort study was carried to detect differences and severity between neonates and older children. Of 54 children with chikungunya, neonates had a higher viral load and greater frequency of severe laboratory and clinical findings.

Supplemental Digital Content is available in the text.

From the *Hospital Infantil Napoleón Franco Pareja and Universidad de Cartagena, Cartagena, Bolívar, Colombia; and Universidad de Córdoba, Montería, Córdoba, Colombia.

Accepted for publication November 6, 2015.

This study was funded by Hospital Infantil Napoleón Franco Pareja–La Casa del Niño. The authors have no other conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).

Address for correspondence: Angel Paternina-Caicedo, MD, MSc, Universidad de Cartagena, Cartagena, Bolívar, Colombia. E-mail: angel.paternina@gmail.com

Chikungunya (CHIK) virus infection is an emerging tropical disease.1 The chinkungunya virus is an alphavirus of the Togaviridae family transmitted by the mosquitoes Aedes aegypti and Aedes albopictus.2 This disease has spread to most tropical countries in the Americas; only Cuba, Argentina, Chile and Uruguay have not reported autochthonous transmission as of late 2015.3 Large outbreaks also occurred in La Réunion from 2004–2005 (a French island located in the Indian Ocean), India, France, Italy and Spain.4–7

CHIK can affect people at any age; however, pediatric and elderly patients are more likely to develop severe manifestations of the disease.5,8,9 In pediatric patients, only a few reports have shown clinical and laboratory manifestations of CHIK infection.7,10,11 The aim of this report is to characterize clinical and laboratory characteristics of neonatal and pediatric CHIK infection and to assess the severity in neonates compared with older pediatric age groups.

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METHODS

A prospective cohort study was carried out during the first Colombian outbreak of CHIK. According to the Colombian National Institute of Health,12 the Colombian outbreak started in Mahates (Bolivar, Colombia) and San Juan Nepomuceno (Bolivar, Colombia). The Hospital Infantil Napoleon Franco Pareja (HINFP), as the only university pediatric hospital in Cartagena, planned the present prospective research in children population. Cartagena is a middle-income city of ≈1 million inhabitants and 82,325 children below 5 years of age. Our data collection started on September 22 and continued until December 14 of 2014.

The Institutional Review Board of HINFP approved the research, and the Ethic committee of HINFP approved the protocol and publication of study results. Pediatric patients with suspected CHIK disease were eligible for inclusion. Patients with fever (≥38°C) were included in the assessment. Patients with fever >15 days or positive IgM and NS1 dengue tests were excluded from the study.

For children ≥1 year of age, fever, severe joint pain or swelling/edema, not explained by other disease, were enrolled in the study as a suspected case. For children <1 year of age with these symptoms, the first diagnosis was neonatal sepsis; hence, a full work-up was made to exclude other viral or bacterial diseases, including dengue. Once other diseases were excluded, we included children and proceeded to collect data and samples and stored it for laboratory analysis.

Sequence analyses based on phylogenetic analyses of genes NS1 and E2 revealed that Colombian CHIK is a strain closely related to the British Virgin Islands and to the Asian genotype (China and Philippines).13 Molecular analysis was performed by reverse transcriptase polymerase chain reaction on 59 acute patient sera that were collected within 1–5 days of appearance of symptoms. For a description of CHIK confirmation methods, see Mattar et al.13

A data collection form for all children with inclusion criteria was designed. Physicians and health personnel of the emergency ward were trained to be alert to possible cases of CHIK fever. Variables were assessed on the first day of symptoms and at emergency admission to HINFP (see Table, Supplemental Digital Content 1, http://links.lww.com/INF/C423).

A P < 0.05 was considered significant for all analyses. Categorical variables were reported in percentages and continuous variables in medians. Normality was assessed through the Shapiro-Wilk test. P values for categorical variables were assessed through χ2 or Fisher exact test, when appropriate. For continuous normal variables, one-way analysis of variance was used; for continuous non-normal variables, the Kruskal-Wallis test was carried out. Regression analyses with 95% confidence intervals were carried out.

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RESULTS

We tested 59 patients for CHIK by reverse transcriptase polymerase chain reaction, of whom 54 (91.5%) were positive. Negative patients were excluded from analysis.

Median age was 2.89 months (interquartile range, 1.18–50.63), and 30 children were male (55.6%). Median time with symptoms before emergency admission was 1 day (interquartile range, 1–3; range, 0–6). Twenty-four (44.4%) children were neonates, and 2 of these were 5 days old.

Respiratory rate was significantly decreased in infants <1 year old (P < 0.001) and increased in children >1 year old (P = 0.001). No other vital sign was significantly different in neonates from older patients.

Hemoglobin, hematocrit and white blood cell counts were significantly decreased in neonates compared with older children (P < 0.05). Decreased platelets (<100,000 cells/mm3) were found in 2 neonates (P = 0.040). For laboratory results, see Table, Supplemental Digital Content 1, http://links.lww.com/INF/C423.

Exanthema was generalized in all 54 children. Description of clinical signs present at emergency admission and in the first day of symptoms is shown in Table 1. Conjunctivitis, ascites, pleural effusion, macroscopic hematuria, hemoptysis, hematemesis, oral ulcers, stomatitis and hematomas were not found in any of the children at admission or on the first day of symptoms.

TABLE 1

TABLE 1

Median log-transformed viral loads comparing neonates, infants between 1 and 11 months and children older than 12 months with interquartile range are shown in the box plot of Figure, Supplemental Digital Content 2, http://links.lww.com/INF/C424. Absolute viral load (in log-scale) was lower as age increased, and for each 10% increase in age, log-viral load diminished 6.1% (95% confidence intervals: 1.5–10.5; P = 0.011). Temperature was also related to log-viral load. For each 10% increase in viral load, temperature increased 0.018% (95% confidence intervals: 0.002–0.035; P = 0.031). Figure, Supplemental Digital Content 3, http://links.lww.com/INF/C425, shows the association between log-viral load and body temperature.

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DISCUSSION

The main finding of our study is that CHIK was more severe and presented with increased viral load in neonates compared with older children. Fever and exanthema were the most frequent manifestation of pediatric CHIK. Also, arthralgia and arthritis were not easily diagnosed, especially in infants.

Previous studies in adults have shown other manifestations for diagnosis.7 These other manifestations (eg, edema, seizures, conjunctivitis) had low or very low frequency in our study; therefore, these signs are not valuable for diagnosis of pediatric CHIK.

Clinical presentation of CHIK disease varies according to age. Decreased platelets were not a key finding of the disease, and only neonates had thrombocytopenia at admission. Because thrombocytopenia is not a relevant pathologic feature of CHIK, this could aid in differentiating CHIK from dengue, especially in children ≥1 year of age.

Laoprasopwattana et al.14 showed that a key feature differencing between CHIK and dengue was a white blood cell count ≥5000 cells/mm3 for CHIK infection. We found increased white blood cell count in 11% of children and decreased cell count in 44% of our sample. Laoprasopwattana et al.14 found a 75% increase in white blood cell count ≥5000 cells per mm3 possibly because of age-dependent variations or the different sample sizes.

Neonates and infants under 1 year of age were more likely to have severe forms of CHIK and increased viral load in our study. This is important to set public health policies that would protect neonates, such as CHIK vaccination. Our study is relevant to the vaccine currently in phase II for CHIK infection. Neonates are the age group with the greatest relative economic and health burden of disease.15 This means that the target vaccination coverage in the population would have to be very high in order for the vaccine to cause an effect in neonates if vaccination is not administered at birth. Also, although mother-to-child transmission was rare in the outbreak in La Réunion,5 our cohort reported 2 confirmed infections within 5 days after birth. This finding strongly suggests that these neonates were infected at birth. Previous studies show that vertical transmission occurs if the mother is infected in labor.5

Limitations of our study have to be kept in mind. Sample size was not large, lacking enough statistical power to detect differences. Also, although because of the nature of the epidemic we could not collect all laboratory values, we reached ≈90% data completeness for most analyses, deeming the selection bias small.

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ACKNOWLEDGMENTS

We are deeply thankful to the clinical staff of Hospital Infantil Napoleón Franco Pareja–La Casa del Niño and Maria Auxiliadora Badillo-Viloria for their help in the realization of this research.

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REFERENCES

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12. Salud INd. Instituto Nacional de Salud. Chikungunya: Boletin Diario No 1.Chikungunya. 2014:Bogota: Instituto Nacional de Salud; 2.
13. Mattar S, Miranda J, Pinzon H, Tique V, Bolaños A, Aponte J, Arrieta G, Gonzalez M, Barrios K, Contreras H, Alvarez J, Aleman A. Outbreak of chikungunya virus in the North Caribbean area of Colombia: clinical presentation and phylogenetic analysis. J Infect Dev Ctries. 2015;9:1126–1132.
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    15. Castañeda-Orjuela C, Díaz-Jiménez D, Rodríguez-Castillo L, et al. PHS44-Medical care costs of Chikungunya Virus infection in a Pediatric Population in Colombia. Value in Health. 2015;18:A254–A255.
    Keywords:

    chikungunya fever; epidemiology; critical care; children

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