The early part of the 21st century has seen an unparalleled number of emerging infectious
disease events: West Nile virus across the Americas, severe acute respiratory syndrome
in China and beyond, chikungunya, avian influenza, Middle East respiratory syndrome
coronavirus, Ebola virus. So many in fact that perhaps we should no longer consider
them extraordinary.
The latest in this series of events is Zika virus (family Flaviviridae, genus Flavivirus),
a mosquito-borne pathogen that was first isolated from a sentinel rhesus monkey in
the Zika forest of Uganda in 1947, and identified in human beings in 1952. Since then
there have been occasional reports of Zika virus infection in human beings in Africa
and later in southeast Asia, characterised by the fever, arthralgia, and rash typical
of many arthropod-borne viruses (arboviruses). Phylogenetic studies suggest the virus
emerged in east Africa in the early part of the 20th century, later spreading to southeast
Asia.
1
In 2007 there was a small outbreak in Yap, Federated States of Micronesia, and in
2013 a larger outbreak in French Polynesia, with 28 000 cases recorded in the first
4 months. Since the first reports of Zika virus infection in Brazil in early 2015,
2
its rapid and explosive spread has resulted in an estimated 1·5 million cases with
4 million predicted across the continent by the end of the year, and the declaration
by WHO of a Public Health Emergency of International Concern.
Many mosquito-borne flaviviruses are zoonotic—for example, Japanese encephalitis virus
and West Nile virus, being transmitted naturally among animals, with human beings
coincidentally infected as dead end hosts. By contrast, Zika virus, like the four
dengue viruses, is transmitted between human beings by mosquitoes. Aedes aegypti is
the principle vector, although Aedes albopictus (the Asian tiger mosquito), which
is also found in southern Europe and parts of the USA might play a part too. In Brazil
the abundant numbers of Aedes spp mosquitoes and densely crowded populations of immunologically
naive individuals have probably contributed to this unprecedented situation. Why an
epidemic had not happened earlier, in the 60 years since Zika virus was first isolated,
is unclear. It is probably simply because the virus had not arrived on the continent.
Phylogenetic studies suggest the Brazilian strain originated in the Pacific islands,
3
and a viraemic traveller to an international canoe racing event in 2014, which included
Pacific nations as participants, is postulated to be the source.
3
For chikungunya virus, another arbovirus that has spread globally in recent years,
the rapid spread was associated with a crucial change on the virus E2 envelope glycoprotein
that increased its transmissibility by A albopictus mosquitoes enabling it to extend
its range.
4
Preliminary data for Zika virus suggest South American isolates are almost identical
to strains previously circulating in the Pacific region.
In the Polynesia Zika virus outbreak of 2013, an apparent increase in the incidence
of Guillain-Barré syndrome was noted,
5
and this also seems to be the case in Brazil, although details are scant. It is important
to distinguish this postinfectious or parainfectious syndrome from direct viral invasion
of the anterior horn cells in the spinal cord, which causes a poliomyelitis-like flaccid
paralysis that is usually irreversible.
6
The number of children reported born with microcephaly has also risen in Brazil, and
Zika virus has been detected in amniotic fluid, placental, or fetal tissue in babies
with nervous system malformations, including those stillborn or with microcephaly.
7
Abnormalities seen on CT scans include calcification in the periventricular parenchyma
and thalamic areas, and ventriculomegaly, lissencephaly, and pachygyria—the smooth
brains with reduced gyral ridges suggestive of cell migration abnormalities and first
trimester problems. Although strongly suspected, the causal relation between in-utero
exposure to Zika virus and microcephaly is yet to be established.
8
Infection in pregnancy might also result in infants born without microcephaly, but
with more subtle neurological and developmental abnormalities. The potential for Zika
virus transmission in semen and through blood transfusions is causing additional concern.
Several theories have been put forward to explain these new observations of neurological
complications. Could they relate to a high background prevalence of antibodies against
related flaviviruses, for example, after dengue infection, or yellow fever vaccination—an
antibody-dependent enhancement process similar to that seen in secondary dengue infection?
Does the microcephaly relate to toxins or nutritional deficiencies? Are these simply
rarer manifestations of the disease, which have now been recognised because there
are hundreds of thousands of infections? Zika virus is similar to dengue in that most
patients develop a syndrome of fever and rash, and there are many unrecognised infections.
For dengue, controversy over apparent neurological manifestations existed for more
than 80 years, until a well designed case-control study carefully excluded other possible
explanations of neurological disease, and proved a definitive link;
9
a whole range of neurological complications are now recognised.
10
Similar rigorous approaches are needed for Zika virus disease, as well as improved
diagnostic techniques.
The only intervention available for Zika virus is mosquito control, which, for Aedes
spp mosquitoes, is notoriously difficult to sustain. The full range of mosquito vectors
for Zika virus is not yet clear. Growing resistance to insecticides is an important
issue, and breeding site destruction and the prevention of bites might be better ways
forward. Unlike Ebola virus, for which there were vaccines on the shelf awaiting clinical
evaluation, for Zika virus the cupboard is bare—although investigators are working
hard to fill it. Understanding the range of neurological disease in Zika virus infection
is important not just for the individuals affected, but also to support policy decisions.
Experience with Japanese encephalitis in Asia has shown that development of a vaccine
is not enough: policy makers need to understand the burden of disease to help to guide
vaccine implementation.
11
This development and implementation will be some years off. For now there is an urgent
priority to understand the scale and full range of neurological disease associated
with Zika virus infection.
© 2016 Nature's Images/Science Photo Library
2016
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