Age-dependent manifestations and case definitions of paediatric Zika: a prospective cohort study

Abstract

Background Paedeatric Zika remains an understudied topic. WHO and the Pan American Health Organization (PAHO) Zika case definitions have not been assessed in children. We aimed to characterise clinical profiles and evaluate the diagnostic performance of the WHO and PAHO case definitions in a large cohort of paediatric Zika cases. Methods From January, 2016 to February, 2017, encompassing the major 2016 Zika epidemic, participants in the Pediatric Dengue Cohort Study (PDCS) in Managua, Nicaragua, were encouraged to visit the study health centre at first indication of any illness. PDCS participants were aged 2-14 years, healthy at enrolment, and recruited before the initiation of the present study. Molecular and serological assays were used to test participants exhibiting any of four broad clinical profiles suspected of resulting from a symptomatic Zika virus infection. These clinical profiles were: fever and at least two of headache, retro-orbital pain, myalgia, arthralgia, rash, haemorrhagic manifestations, and leukopenia; fever and at least two of nausea or vomiting, rash, aches and pains, positive tourniquet test, leukopenia, and any dengue warning sign; undifferentiated fever without evident cause, with or without any other clinical finding; and afebrile rash with or without any other clinical finding. We characterised acute clinical findings (signs, symptoms, and complete blood counts) in both Zika cases and non-Zika cases. Findings We prospectively followed a cohort of about 3700 children, of which 1110 were deemed eligible for inclusion. Four participants with laboratory-confirmed Zika (three co-infections with dengue virus, one missing complete blood count data) and two participants who were non-Zika cases (missing complete blood count data) were excluded from analysis. We analysed 556 laboratory-confirmed Zika and 548 non-Zika cases. The WHO case definition captured 176 confirmed Zika cases, and the PAHO definition 109 confirmed Zika cases, who presented with the most clinical findings and a dengue-like clinical profile. The remaining two thirds of Zika cases, principally characterised by undifferentiated fever or afebrile rash, were missed. Among Zika cases, rash (n=440)-particularly generalised erythematous rash (n=334)-fever (n=333), leukopenia (n=217), and headache (n=203) were most common and peaked within 3 days of illness onset. The most common Zika presentation over the first week of illness was rash only (n=80). The sensitivity of Zika case definitions increased across paediatric age (from 11•3% to 56•1% for the WHO case definition and from 6•0% to 36•6% for the PAHO case definition), as the prevalence of most clinical findings (particularly arthralgia) increased with age, irrespective of previous dengue virus infection. Consequently, Zika manifested differently across paediatric age; older Zika cases presented with a dengue-like clinical profile while younger Zika cases presented with undifferentiated fever or afebrile rash. Interpretation We provide the most thorough description of paediatric Z...

Postnatal symptomatic Zika virus infections in children and adolescents: A systematic review

“…Of the ten studies, nine [ 39 – 42 , 44 , 46 , 47 , 49 ] reported on the presence of common signs and symptoms of ZIKV infections [ 17 ], while the remaining study reported only on the presence of neurological disorders [ 43 ]. The most frequently reported ZIKV symptoms among confirmed pediatric ZIKV cases were rash (prevalence range: 29–100%), fever (55–99%), conjunctivital involvement (11–64%), arthralgia (14–48%), myalgia (6–57%), and headache (21–50%) ( Table 1 ).…”

“…In the third study, a cohort study based in Nicaragua, Burger-Calderon and colleagues also noted that the clinical presentation of Zika virus infection differed across pediatric ages [ 39 ]. Among the 556 participants with confirmed ZIKV disease, older cases presented more frequently with arthralgia, myalgia, and headache.…”

“…Unsurprisingly, the signs most commonly reported in pediatric cases, fever and rash, were also most frequently used to identify potential ZIKV cases. Findings from three studies describing symptoms by age suggested similar frequencies of signs, such as fever, rash and conjunctivitis across age groups, but lower frequencies of subjective pain-related symptoms, such as arthralgia and myalgia, in younger age groups, which is likely due to the difficulty of accurately identifying such self-reported symptoms in young children [ 39 , 44 , 45 ]. There was little evidence of severe outcomes among ZIKV patients, with only four studies (one case series [ 43 ] and three case reports [ 50 , 58 , 59 ]) reporting deaths among pediatric ZIKV patients.…”

“…Studies using a broader case definition and populations identified using cohort or national or county level surveillance data are likely to be more representative of symptomatic pediatric ZIKV infection. However, growing evidence suggests that standard case definitions, such as the PAHO and WHO definitions, have low sensitivity in pediatric populations and could lead especially to under-representation of the youngest children with ZIKV disease [ 39 , 44 , 45 ]. Furthermore, the signs and symptoms described in these studies may not be exhaustive, as atypical symptomatic ZIKV cases are unlikely to have been identified using routine surveillance systems.…”

Leveraging multiple data types to estimate the size of the Zika epidemic in the Americas

“…The Pan American Health Organization (PAHO) reported suspected and confirmed Zika cases for every country and territory in the Americas, but these reported cases vastly underestimate the total number of ZIKV infections due to inadequate surveillance, the non-specificity of ZIKV symptoms, and the high proportion of asymptomatic infections [11,19,20]. Underreporting is particularly an issue for pathogens such as ZIKV where the majority of infections are asymptomatic or produce only mild symptoms [21,22].…”