A large natural history study examining the neurologic, neurodevelopmental and other clinical outcomes of Zika virus infection in infants and young children has begun in rural Guatemala. It will focus on those infected with Zika virus after birth rather than those infected congenitally. The study is being conducted by the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health, in partnership with FUNSALUD (Fundacion para la Salud Integral de los Guatemaltecos) Center for Human Development in Coatepeque, Guatemala, a nonprofit foundation dedicated to improving the health and human development of families and communities in the southwest region of Guatemala. Researchers in Guatemala and the United States, including NIAID scientists, designed the study; NIAID is funding the research.
Most people with Zika virus infection have no symptoms or only a mild illness. However, Zika virus infection during pregnancy can result in congenital Zika syndrome, which is a pattern of birth defects that includes severe microcephaly (in which a baby’s head is smaller than expected), decreased brain tissue, damage to the back of the eye, joints with limited range of motion, and excess muscle tone restricting body movement. There are also reports of infants born to Zika virus-infected mothers appearing healthy at birth but later experiencing slowed head growth during the first year and developing postnatal microcephaly. These observations indicate that Zika virus infection has the potential to affect early brain development, but the full spectrum of possible consequences is not yet known.
Zika virus transmission is ongoing in parts of Guatemala, according to the Pan American Health Organization. In addition, a continuing University of Colorado surveillance study characterizing the incidence and pattern of dengue virus in children in the study area (southwestern Guatemala) has confirmed active Zika virus transmission and high Zika virus infection rates in children with fever.
“This natural history study of Zika among Guatemalan children promises to yield valuable insights into acute and longer-term outcomes of infection,” said NIAID Director Anthony S. Fauci, M.D. “It is imperative that we understand the potential neurologic and neurodevelopmental outcomes of Zika virus infection in children infected in infancy and early childhood.”
Flor M. Munoz, M.D., an investigator with the NIAID-funded Vaccine and Treatment Evaluation Unit (VTEU) at Baylor College of Medicine, and Edwin J. Asturias, M.D., of the University of Colorado Department of Pediatrics and Center for Global Health, will lead the trial, in collaboration with Antonio Bolaños, M.D., medical director at the FUNSALUD clinic, where the study will occur. The Emory VTEU Research Laboratory, under the direction of Mark Mulligan, M.D., will perform the laboratory testing for the study. Dr. Bolaños has noted that the study is important to families in Guatemala because “it will help provide access to the early diagnosis of Zika for families in this rural area of Guatemala, while helping us uncover whether this virus can interfere with the normal development of young children.”
“For many impoverished children in our country, any Zika effect on their neurodevelopment will add burden to their futures,” Bolaños added.
In addition to Dr. Bolaños, other FUNSALUD investigators, nurses and laboratory technicians will participate in the study, which will also help enhance future Guatemalan medical research capacity.
The trial was reviewed and approved by the Guatemalan Ministry of Health, National Ethics Committee and will be implemented in full compliance with Guatemalan and U.S. regulations that govern clinical research. It will enroll approximately 1,200 infants and children under five years of age. This will include a cohort of 300 children who have postnatally acquired Zika and/or dengue virus infection and were included in the recent University of Colorado surveillance study conducted at FUNSALUD. The trial will also enroll a new cohort of approximately 500 newborns who have not had Zika virus infection, along with their mothers and siblings. The sibling cohort will include approximately 400 children under age five.
Study investigators will monitor the infants, children and mothers for at least one year during home visits, phone calls and clinic appointments. Participants will regularly provide body fluid samples and undergo screenings for potential new Zika, dengue and chikungunya virus infections. They will also undergo regular physical, neurologic, neurodevelopmental, hearing, and eye examinations. Study clinicians will counsel families that choose to enroll their children as participants in the study on how to best prevent Zika infection, as well as other mosquito-borne illnesses. This counseling will include explaining how to remove standing water in and around the home and how to properly use mosquito nets, insect repellents and protective clothing to prevent as many mosquito-borne diseases as possible.
Researchers hope to compare the neurodevelopmental, neurologic, and clinical outcomes of Zika virus-infected children with those who remain uninfected. Participants will be screened for microcephaly, encephalitis (inflammation of the brain), Guillain-Barré syndrome (a rare nervous system disorder), seizures, neurodevelopmental delays, hearing loss, eye problems, and other neurologic issues.
The study aims to classify these outcomes among children with or without symptoms of Zika virus infection and compare them to the outcomes of other viral infections, such as dengue or chikungunya. Investigators also will examine levels of Zika virus nucleic acid and neutralizing antibodies in participants to see if certain thresholds correlate with specific clinical, neurologic or neurodevelopmental outcomes.
Secondary goals of the study are to characterize the effect of prior maternal dengue virus infection in Zika virus-infected infants and to evaluate if maternal infection (or children’s own previous dengue virus infections) could result in more severe Zika virus disease in children via antibody-dependent enhancement, or ADE. ADE occurs when antibodies developed in response to a previous viral infection bind to, but do not neutralize, a new infecting virus. Investigators also will determine how long Zika virus RNA persists in body fluids in infants and young children and in maternal breast milk. Their goals are to learn whether lingering virus affects clinical and neurologic outcomes and to determine any potential for virus transmission.
Enrollments will continue until the target number of participants has been reached; the study is expected to take three years to complete but preliminary results could be available in one year. It is anticipated that the study findings will help inform global public health practices and assist Guatemalan health officials as they seek to understand the risks associated with early childhood Zika infection and design health care programs that will provide Zika-related health care of benefit to Guatemalan children and families.