The Facts About Zika

Several members of Congress wrote to government officials about the recent Zika virus outbreak in Brazil and a suspected rise there in the number of microcephaly cases. But some of those letters overstated what’s known about these two phenomena.

• Sen. Kirsten Gillibrand claimed: “Over 4,000 babies in Brazil … have been born in the last year with microcephaly.” As of Jan. 29, Brazil’s Health Ministry reported 4,180 suspected cases, but only 270 were confirmed. The remaining cases were either under investigation (3,448) or discarded (462).
• Sen. Richard Blumenthal said those 4,000 cases in Brazil “have been linked to the outbreak of the Zika virus.” As of Jan. 29, only six of the 270 confirmed babies with microcephaly had tested positive for Zika. Health officials say evidence strongly suggests a link between Zika and microcephaly, but they also emphasize the link hasn’t been scientifically confirmed.

The senators were reacting to the Zika virus’ spread through the Americas, including Brazil, and a rise in the number of suspected cases of microcephaly. Microcephaly is normally thought of as a rare neurological condition, where an infant’s head is substantially smaller than the heads of other children of the same age and sex. However, the condition often signifies a deeper problem — abnormal brain development.

Doctors in Brazil began noticing a possible increase in microcephaly cases around August 2015, as reported by the New York Times. The Zika virus likely spread to the country roughly a year earlier.

Researchers in Brazil theorize that the virus initially spread to their country during the FIFA World Cup tournament in July 2014. But a group of scientists in French Polynesia believe Zika may have spread from their country to Brazil during the Va’a World Sprint Championship canoe race held in Rio de Janeiro in August 2014.

There is plenty of concern among groups such as the World Health Organization and the Centers for Disease Control and Prevention. But the concern, in part, arises from a lack of knowledge about Zika and its potential causal link to microcephaly. We’ll explain what’s known about that possible relationship and the cases in Brazil so far.

Update, April 14: On April 13, the CDC confirmed that “Zika virus is a cause of microcephaly and other severe fetal brain defects.”   

Counting Cases of Microcephaly

On Jan 28., Gillibrand, a Democrat from New York, wrote a letter to Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, urging the institute “to prioritize research into developing diagnostic tests, vaccines and therapeutic drugs to fight the continued spread of the Zika virus.” In her letter, she claimed: “Over 4,000 babies in Brazil … have been born in the last year with microcephaly.”

But according to information provided by Brazilian authorities, that’s inaccurate.

From Oct. 22, 2015, to Jan. 29, 2016, Brazil’s Ministry of Health reported 4,180 suspected cases of microcephaly, which included 3,448 cases under investigation, 270 confirmed cases and 462 discarded cases.

The fact that more cases have been discarded than confirmed shows that diagnosing microcephaly is not straightforward.

According to the Mayo Clinic, microcephaly is broadly defined as “a rare neurological condition in which an infant’s head is significantly smaller than the heads of other children of the same age and sex.” The syndrome is usually “the result of the brain developing abnormally in the womb or not growing as it should after birth.”

Different organizations and doctors have different definitions for “significantly,” however.

As the Centers for Disease Control and Prevention explains: “Although a universally accepted definition of microcephaly does not exist, microcephaly is most often defined as head circumference … greater than 2 standard deviations below the mean, or less than the 3^rd percentile based on standard growth charts.”

A review article published by the American Academy of Neurology in 2009 provides similar information: “Microcephaly is an important neurologic sign but there is nonuniformity in its definition and evaluation.” The article, though, also points to two standard deviations from the norm as the most often used definition.

The condition can be rooted in different causes, including chromosomal abnormalities, decreased oxygen to the fetal brain, infections during pregnancy, alcohol or drug abuse during pregnancy, and malnutrition.

Evidence of microcephaly can be found as early as the latter stages of the second trimester using an ultrasound, says the CDC. The condition can also be diagnosed after a baby is born. After birth, doctors will measure the circumference of a baby’s head.

If the baby’s head falls within a range that is below what its pediatrician defines as normal for its age, the doctor may request additional tests. A CT or MRI scan can provide information about the development of the newborn’s brain. These tests may be needed to confirm microcephaly in infants.

Early diagnosis does have the potential to lead to false diagnosis. According to National Institute of Neurological Disorders and Stroke: “Some children with microcephaly will have normal intelligence and a head that will grow bigger, but they will track below the normal growth curves for head circumference.”

The difficulty with definitively diagnosing microcephaly has lead some to question whether Brazil underreported cases in the past — and whether they overreported their 2015 cases as well.

For context, the Associated Press and the New York Times write that out of 3 million births in 2014, Brazilian doctors reported only about 150 cases of microcephaly. But 150 cases is surprisingly small for a country the size of Brazil. For comparison, Margaret Honein, a CDC epidemiologist, told the AP the United States “has an estimated 2,500 cases of microcephaly a year” out of 4 million births.

Researchers at the Latin American Collaborative Study of Congenital Malformations (ECLAMC) have also questioned Brazil’s past and present recording of microcephaly cases, reported Nature.

On Dec. 30, Jorge Lopez-Camelo and Ieda Maria Orioli, researchers at ECLAMC, published a report outlining how Brazilian authorities may have underreported cases of the neurological condition in the past and how they might be overreporting cases today.

For example, the ECLAMC report stated that defining microcephaly as a head size two standard deviations smaller than the norm “includes necessarily a large number of normal individuals.”

The authors also told Nature that the current “surge might largely be attributed to the intense search for cases of the birth defect, and misdiagnoses, because of heightened awareness in the wake of the possible link with Zika.”

In a Q&A on its website, the CDC says: “The baseline prevalence of congenital microcephaly [in Brazil] is difficult to determine because of underreporting, and the inconsistency of clinical criteria used to define microcephaly.” It adds that while “population-based estimates of congenital microcephaly in Brazil vary, the number of infants with microcephaly currently being reported in Brazil is greater than would be expected.”

Regardless, Gillibrand was inaccurate when she definitively wrote: “Over 4,000 babies in Brazil … have been born in the last year with microcephaly.” According to Brazil’s current count, only 270 cases have been confirmed.

The Possible Zika-Microcephaly Link

On Jan. 29, Blumenthal, a Democrat from Connecticut, wrote a letter to President Obama urging the administration to “increase funding for research related to combatting” Zika. In his letter, Blumenthal wrote: “More than 4,000 cases of microcephaly and birth deformities in infants in Brazil have been linked to the outbreak of the Zika virus.” That claim is inaccurate.

As previously mentioned, there have only been 270 confirmed cases of microcephaly, not “more than 4,000.” Also, while scientists and public health authorities have seen a correlated increase in reported cases of both microcephaly and Zika in Brazil, they stress that a causal link has yet to be established. As of Jan. 29, only six of the 270 confirmed babies with microcephaly also tested positive for Zika.

For example, on Jan. 28, when reporters asked about “the numbers” supporting a causal link between Zika to microcephaly, Dr. Anne Schuchat, the principal deputy director of the CDC, wasn’t able to give hard numbers. Instead, she said it’s “an ongoing investigation, information is being gathered.”

Blumenthal would have been correct if he had said — as the White House wrote on its website — that Zika “may be linked” to microcephaly.

As of Feb. 5, the World Health Organization reported that “Brazilian national authorities estimate that between 497,593 and 1,482,701 cases of Zika virus infection have occurred since the outbreak began” around August 2014.

The Zika virus is primarily spread through mosquito bites, in particular the Aedes species, which also spreads the dengue and chikungunya viruses. However, there have been cases of the Zika virus transmission through sexual contact, including one probable case in 2011, a possible case in 2015 and a confirmed case in Texas on Feb. 2, 2016.

According to the CDC, “about 1 in 5 people infected with Zika virus become ill.” Of the people who do become ill, the symptoms are usually mild, often include “fever, rash, joint pain, or conjunctivitis (red eyes)” and last “several days to a week.” The virus “usually remains in the blood of an infected person for about a week but it can be found longer in some people.”

Since Zika often entails a silent to mild infection, it is difficult to conclusively diagnose by symptoms alone.

To be clear, Blumenthal does have reason to raise concern about the possible link between Zika and microcephaly.

As Dr. Margaret Chan, director general of the WHO, said on Jan. 28, the possible link to more serious conditions like microcephaly changed the risk profile of Zika from “a mild threat to one of alarming proportions.”

At this point in time, scientists and health officials believe the increase in reported cases of Zika and microcephaly are positively correlated — meaning, when reported cases of Zika went up in certain areas, an increase in reported cases of microcephaly followed.

Health officials strongly suspect a causal link, though they have little direct evidence to support it — as of Jan. 29, only six babies have had microcephaly and tested positive for Zika in Brazil.

Scientists also have some understanding of the mechanism behind how Zika could, in theory, lead to microcephaly. Though they stress much still needs remains unclear about this mechanism. As Nature reports, “many researchers say that epidemiological data alone will not convince them of a link between Zika and microcephaly; they would like to see evidence of how and why the virus causes the condition. With this in mind, scientists are developing animal models to investigate Zika’s effects on the body.”

Based on what is known, on Feb. 1, the WHO declared the Zika outbreak a public health emergency. During a speech in Geneva announcing the news, Chan emphasized the need to “coordinate international efforts” to better understand the relationship between Zika and microcephaly. The New York Times reported that an “emergency designation from the W.H.O. can prompt action and funding from governments and nonprofits around the world.”

On Feb. 2, Dr. Anthony Costello, WHO director for maternal, child and adolescent health, also said the organization has set a global response unit for Zika “using all the lessons we’ve learned from the Ebola crisis.” The New York Times reported that the WHO’s decision to declare Zika a public health emergency may have been influenced by the criticism it received for “its tardiness in declaring Ebola an international emergency” during the 2014 outbreak.

Due to the possible transmission and microcephaly-Zika link, the CDC also issued travel precautions to certain countries, including Brazil, for pregnant women or women who are trying to become pregnant. While they haven’t issued a formal travel notice, the WHO says that: “Travellers should take the basic precautions … to protect themselves from mosquito bites.”

According to the CDC, “a mother already infected with Zika virus near the time of delivery can pass on the virus to her newborn around the time of birth, but this is rare.” It also writes “it is possible that Zika virus could be passed from a mother to her baby during pregnancy. We are studying how some mothers can pass the virus to their babies.”

Thomaz Gollop, a fetal medicine specialist who runs his own clinic in São Paulo, told us by email that he believes a “causal relationship” had been established in the six microcephalic babies who tested positive for Zika.

But he also said: “We do not have a prospective scientific study to state with scientific reasoning that it was in fact, the Zika virus that caused these defects. However the suspicion is very strong!”

In order to confirm a causal link, scientists and health officials, like those at the CDC and NIH, have said that they would need to find and study more cases where contracting Zika during pregnancy may have led to babies with microcephaly and brain defects. But, as previously mentioned, some researchers also want more mechanistic evidence before they definitively say Zika causes microcephaly.

Some mechanistic evidence supporting the theory that Zika causes microcephaly does already exist, however.

When G.W.A. Dick, a researcher at the National Institute for Medical Research in the United Kingdom at the time, first described the virus in 1952, he found that: “Zika virus is highly neurotropic in mice and no virus has been recovered from tissues other than the brains of infected mice.” Neurotropic means “affecting the nervous system.” Dick also wrote that: “Neuronal degeneration, cellular infiltration and areas of softening are present in [Zika] infected mouse brains.”

In 1971, T.M. Bell, a researcher at Newcastle General Hospital in the U.K. at the time, and colleagues, also found that “pathological changes in the brain are correlated with growth of the [Zika] virus.”

To be clear, Bell and Dick’s work is still evidence for a causal link between Zika and brain defects – but on the cellular level instead of the individual or population level. But when researchers find evidence for cellular-level causal links, this provides them with clues about the mechanisms behind how one variable may lead to another.

This research also was conducted in mice and not humans. While viruses can affect different organisms differently, scientists often use mouse models to perform experiments that otherwise wouldn’t be permitted on humans. But Dick and Bell’s work does show that Zika has the mechanistic potential to cause microcephaly.

Health officials may have also seen a similar spike in microcephaly cases during a Zika outbreak in French Polynesia in 2013-14.

The WHO says a Zika outbreak was reported for the first time in Yap in 2007, but it wasn’t until the French Polynesian outbreak in 2013 that “national health authorities reported potential neurological and auto-immune complications of Zika virus disease” during the French Polynesia outbreak.

As the New York Times reported: “French Polynesia is the only area outside of Brazil to be affected by a Zika outbreak in which public health officials have identified an increase in the number of fetuses and babies with unusually small heads.”

Reason for Doubt

But the ECLAMC report pointed out (page 7) that the investigation of a possible Zika-microcephaly link during the French Polynesian outbreak took place in November 2015, after Brazil declared a state of emergency. For this reason, the report says the investigation is “not an independent event.” Since Zika only circulates in the body for a short period, this also makes retroactive analysis of an outbreak difficult.

As previously mentioned, diagnosing microcephaly isn’t straightforward. But Zika isn’t the easiest to diagnose either.

In the report summary (pages 9-10), Lopez-Camelo and Orioli point out that identifying the Zika virus in the blood is difficult due to its short circulation period. Its similarity with the dengue virus also makes definitive diagnosis problematic. Reuters and The Scientist have also written about the difficulties of testing for Zika using current serological, or blood-testing, tools.

During roughly the week of infection, when the virus is still present in the body, health officials can use a test that identifies Zika by its ribonucleic acid. Since every virus has its own specific RNA — or every organism for that matter — the test has a high degree of accuracy.

After that first week though, health officials have to test for Zika antibodies. The immune system produces antibodies in response to viruses and other pathogens. But a virus’ antibodies aren’t as specific to it as its RNA, so this method sometimes “cross-reacts” with dengue antibodies. And dengue is widespread in Brazil.

However, researchers worldwide are currently working to develop better diagnostic tests for Zika. Fauci, for example, told reporters on Jan. 28 that the NIH is working to develop “diagnostic platforms that can rapidly determine if a patient is infected with Zika or has been infected either recently or in the past, and distinguish it from other viruses, particularly Dengue infection.”

Lavinia Schüler-Faccini, a researcher at the Federal University of Rio Grande do Sul in Brazil, told us by email that, in the six microcephalic babies that did test positive for Zika, “the virus genetic material was identified by RT-PCR” — that is, through Zika RNA. She also told us these were “severe cases of stillborns or babies that died shortly after birth — where a chronic and generalized infection was present.”

Despite the severity of the microcephaly cases where researchers did find the Zika virus present, Lopez-Camelo and Orioli question Brazil’s overall numbers.

Lopez-Camelo and Orioli also reviewed microcephaly records in Brazil dating back to 1967 and compared those numbers to reports in 2015. On average, Brazil sees roughly two cases of microcephaly for every 10,000 births. But the Brazilian state of Pernambuco tends to see more cases each year – 10 on average, according to the Pan American Health Organization, a regional office of WHO.

In 2015, 147,597 babies were born in Pernambuco. Based on the historical data, the researchers estimated that the maximum number of expected cases of microcephaly would be around 45 for that number of births and without any potential influence of Zika. Yet in 2015 Pernambuco officials reported 1,153 cases, according to the ECLAMC report.

If Zika had been infecting people at rates similar to the 2007 outbreak in Micronesia, which includes Yap Island, the virus could potentially explain an additional 353 cases of microcephaly – not an additional 1,108 cases, the authors say. This, among other findings, gave Lopez-Camelo and Orioli reason to question Brazil’s numbers.

The Jury’s Still Out

The point is, much is still not known about the possible relationship between the Zika virus and microcephaly. There is evidence that the two conditions are positively correlated within certain areas of Brazil and possibly French Polynesia. While strongly suspected, scientists and health officials have little direct evidence to support a causal link, but that’s due, in part, to the nature of Zika and microcephaly diagnosis. Lastly, Zika does appear to target the brain, but some scientists say much more mechanistic research needs to be done to confirm a causal link between the virus and microcephaly.

In short, much is still unknown about Zika, microcephaly and their possible link. The WHO declared the outbreak a public health emergency for precisely this reason — to “coordinate international efforts” to better understand the two conditions’ potential relationship and to control Zika’s spread.

As a result, Blumenthal was inaccurate when he said that the Zika outbreak “has been linked” with “4,000 cases” of microcephaly in Brazil. The jury is still out on the Zika-microcephaly link – and the numbers behind it.