**Acknowledgements**

*Biochemical Testing - Clinical correlation and Diagnosis*

white matter junction [80, 86].

is initially pruritic and maculopapular, following a vesicular phase until crushing occurs, usually about 5 days later [84]. Finally, the rash in ZIKV infection is pruritic, descending, and maculopapular, beginning proximally and spreading to the

Nonspecific intrauterine US findings in TORCH infections are intrauterine growth restriction, abnormal fluid imbalance (ascites, hydrops, pericardial effusion, pleural effusion, and oligo-polyhydramnios), hepatosplenomegaly and hepatic calcifications, echogenic bowel, echogenic kidneys, and limb deformities [80, 85]. Cerebral brain calcification, although relatively common in most of these infections, can be an important distinguishing factor due to its location [80, 85]. In congenital toxoplasmosis, the calcifications are diffuse and widely distributed, and in rubella, they are at basal ganglia [80, 85]. In CMV congenital infection, the calcifications are usually punctate and periventricular or cortical [80, 85]. Conversely, in ZIKV, the calcifications are larger and denser, usually appearing at the gray and

As well as seen with maternal clinical signs and intrauterine US findings, TORCH congenital infection can also produce a similar neonatal clinical presentation, although the features rarely occur simultaneously [87, 88]. The common clinical features include growth retardation, prematurity, jaundice, anemia, hepatosplenomegaly, microcephaly, cerebral calcifications, chorioretinitis, cataracts, microphthalmia, and others [87, 88]. However, clinical findings are more associated, although not exclusively, with a determined etiological agent. Cardiac lesions and deafness have been described in CMV and rubella congenital infections. Cicatricial skin lesions and limb hypoplasia are seen in varicella virus congenital infection [87]. Petechial or purpuric form exanthema (blueberry muffin spot) is typical of CMV infection [80, 82]. Chorioretinitis, hydrocephalus, and cerebral calcifications comprise the characteristic triad of congenital toxoplasmosis [89]. Finally, clinical signs of CZS can also be found in other TORCH infections. Cranial ZIKV morphology and brain anomalies can occur in congenital CMV infection [75]. Congenital contractures can appear in congenital rubella, varicella, and Coxsackie B infections [75]. Neurologic sequelae are seen in most TORCH infections [75]. Ocular anomalies, such as pigmentary mottling and chorioretinal scars, can manifest differently in each of these congenital infections. In rubella, the pigment mottling is usually diffused compared with the focal pigment mottling seen in Zika virus infection (**Figure 4B**) [77]. Chorioretinal lesions in toxoplasmosis can present with active exudative retinitis or regressed macular or peripapillary retinal scar [77]. In ZIKV congenital infection, chorioretinal lesions are atrophic and colobomatouslike and are found in the macula or retinal periphery (**Figure 4A**) [77]. Optic nerve hypoplasia, commonly seen in ZIKV congenital infection, is seldom seen in rubella,

toxoplasmosis, herpes, and CMV congenital infections [77].

Human clinical diagnosis of ZIKV infection in regions where other arboviruses circulate, mainly DENV and CHIKV, has become a daunting task; therefore, laboratory confirmation is crucial for conclusive diagnosis. Detection of virus genome by RT-qPCR is helpful and demonstrated to be a reliable tool; however, the limited window for virus detection, low viral load, and stability restricted the use of these methodologies. Antibody screening is also hampered by cross-reactivity among

Due to impact of ZIKV infection, especially for pregnant women, a confident ZIKV serology test is urgently needed, and this will promote a better prenatal

extremities with resolution occurring within 1–4 days of onset [14, 74].

**94**

**6. Conclusions**

other flaviviruses.

We thank Fernandes Figueira Institute Pediatric Infectious Disease Team for helpful discussions during this work and field expertise from ZIKVIRUSIFF Cohort study registered on clinicaltrials.gov with identifier NCT03255369.

This work was partially supported by Fernandes Figueira Institute Research Program (Programa de Incentivo à Pesquisa II), Rio de Janeiro State Research Grant (Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro—grant E-26/201.840/2017), National Research Grant (Conselho Nacional de Desenvolvimento Científico e Tecnológico—grant 441098/2016-9), and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)— Finance Code 001.
