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Chikungunya’s turn

Highly debilitating viral infection spreads across Brazil

A painful virus: copies of chikungunya observed under an electron microscope

Photo Joshua E. Cogan / Pan American Health Organization-PAHO Illustration based on Henri Matisse / Jazz, 1947 A painful virus: copies of chikungunya observed under an electron microscopePhoto Joshua E. Cogan / Pan American Health Organization-PAHO Illustration based on Henri Matisse / Jazz, 1947

While attention was focused on the Zika virus and its devastating effects on fetal brains, quietly spreading across Brazil was another infectious agent, one that causes an illness that for most people is much more painful and debilitating. In mid-2014, two varieties of the chikungunya virus reached two regions of Brazil almost simultaneously. In late May, a lineage that originates in Africa arrived in Feira de Santana, Bahia, while an Asian lineage that has been associated with a chikungunya epidemic in the Americas landed in the municipality of Oiapoque, Amapá State. This was the onset of a slow and steady invasion that escalated sharply this year (see graph).

By December 2014, eight cities, in addition to Brasilia, had recorded 3,657 suspected cases of chikungunya fever. The figure has multiplied since then, as the problem has swept across Brazil.  In 2015, 38,332 probable cases were reported in 696 municipalities, and concern is rising that the infection will jeopardize the Brazilian healthcare system’s ability to provide care. In the first half of 2016 alone, 138,000 cases of chikungunya were recorded in 2,054 cities. By April 2016, suspected cases of the fever totaled 64,000, surpassing Zika infections in the Northeast by 36%.

“In April, I was at Giselda Trigueiro Hospital in Natal to get to know the symptoms of Zika better, but there was nothing but cases of chikungunya,” says infectologist Marcos Boulos, professor at the University of São Paulo School of Medicine (FM-USP). Boulos, who currently heads the Office for Disease Control of the São Paulo State Department of Health, watched as three people were seen for chikungunya in a little over an hour and a half that morning. “They came in bent over from the joint pain, and their fingers were so swollen that they couldn’t close their hands,” the doctor reports.

The chikungunya infection resembles the sickness caused by both Zika and dengue fever, which is why an accurate diagnosis is only possible through molecular (polymerase chain reaction [PCR]) assays or immunoassays. However, Brazil’s public health system does not yet offer either test.  Transmitted by the bite of mosquitoes from the genus Aedes – especially A. aegypti, which is plentiful throughout Brazil – the three diseases usually cause fever, a red rash over the body, and headache, along with muscle and joint pain (see Pesquisa FAPESP Issue nº 239).

Swollen joints and intense joint pain, possibly related to the multiplication of the virus, are generally what prompt a physician to suspect chikungunya, which in the Makonde language, spoken by peoples in Tanzania and Mozambique, means “those who are doubled over.” The term is an allusion to the fact that people who have been infected by the virus tend to walk with their bodies contracted and bent forward in an effort to relieve their discomfort.

The first confirmed outbreak of chikungunya occurred in Tanzania in 1952, although suspicions are that the virus, which belongs to the family Togaviridae and the genus Alphavirus, had already been circulating in Africa for two centuries. For a long time, the illness was considered a public health problem of the East, since it remained confined to eastern Africa, Southeast Asia, and the region bordering on the Indian Ocean. Only in the past 10 years has chikungunya become a global concern, as those regions witnessed an upsurge in outbreaks and the virus arrived in the Caribbean.

It all happened fast. After the first cases of domestic transmission had been reported on the island of Saint Martin in late 2013, the Asian lineage of the virus swept quickly across the Americas.  In a little over a year, the virus was in 43 countries and territories of the region and had infected 1.4 million people. This was the variety that entered Amapá, probably via French Guiana, triggering cases in towns of northern Brazil.

It may have been a Brazilian who traveled from Angola to visit his family in Bahia in May 2014 who introduced Brazil to the variety of the virus that circulates in eastern Africa and has now spread over much of Brazil. The man was staying in Feira de Santana, the second largest city in the state, and on May 28 he went to the emergency room complaining of a high fever and joint pain. Laboratory tests eliminated the initial suspicion of dengue. Genetic analyses later performed by the team of virologist Pedro Vasconcelos of the Evandro Chagas Institute in Pará, confirmed that the problem had been caused by the African variety of chikungunya, which differs from the lineage circulating in Amapá.

Chikungunya_246In the weeks following his visit, a number of the man’s relatives were bitten by infected mosquitoes and presented signs of chikungunya, which raged through the city. In the early days of the outbreak, researchers from the Oswaldo Cruz Foundation (Fiocruz) in Bahia and the State University of Feira de Santana (UEFS) began working with colleagues at Oxford University in England; together, they identified two waves of disease transmission. In the beginning, from June to December 2014 – a period when there are fewer mosquitoes – cases were concentrated in the neighborhood of George Américo, where the first infected family lived. The second wave struck between January and September 2015, keeping pace with the dissemination of dengue and Zika in the town, as the researchers reported in a paper published in PLOS Currents: Outbreaks in February 2016. According to the team, the phase during which the virus becomes established has ended. Breeding grounds of transmission can now be found in a number of neighborhoods and there is the risk that the infection might become endemic in the region.

Chronic pain
By early 2016, 5,363 suspected cases of chikungunya had been identified in Feira de Santana, driving the city’s public health system to the verge of collapse.  “We are doing follow-up on dozens of people who still suffer joint pain four to six months after falling ill,” says infectologist Rivaldo Venâncio da Cunha of Fiocruz in Mato Grosso do Sul.

Since the start of the outbreak in Bahia, Cunha has been traveling to Feira de Santana and Riachão do Jacuípe, another hard-hit town in the state, to analyze cases. According to Cunha, people who contract chikungunya generally use the health system more often than those who contract Zika or dengue. “Following a dengue outbreak or epidemic, the strain on the healthcare network gradually lessens,” he explains. But not with chikungunya. “Because of the pain and inflammation, people come back for office visits almost weekly, for months. This would disrupt any healthcare system.”

International research indicates that joint pain is more severe early on in the infection and tends to become chronic in people over the age of 45. In a variable proportion of these patients, the problem can persist for a year or more. A 1980s study showed that 12% of people who had chikungunya continued to present symptoms three years later. In another study, released in 2009, researchers spent 15 months following the health of 147 residents of Reunion Island, in the Indian Ocean, who had caught chikungunya. Their findings? Six out of 10 reported feeling pain even that long after the infection.

“In Brazil, chikungunya cases seem to be more common in poorer regions,” says virologist Renato Pereira de Souza, who is with the Adolfo Lutz Institute in São Paulo. “When the infection hits the family provider, it creates a serious economic problem.” In early June 2016, Souza attended an international virology meeting in São José do Rio Preto, where a number of experts expressed concern over the risk that chikungunya could become a problem during Brazil’s 2016-2017 summer.

There are grounds for this suspicion. The virus is now found in one-third of Brazilian municipalities, including the largest two, São Paulo and Rio de Janeiro; the Aedes mosquito inhabits and procreates in almost every corner of the country; and the population has never had contact with the virus (people apparently develop lasting immunity following infection).

Another feature of the Brazilian outbreak strengthens the fear that things might get worse. Despite the sharp upswing in cases observed in 2016, the virus is still spreading more slowly in Brazil than elsewhere. “Chikungunya outbreaks are usually explosive,” says infectologist Benedito Lopes da Fonseca of the Ribeirão Preto campus of USP. About a year and a half ago, he prepared his laboratory to identify the infection, and in early 2015 he diagnosed two imported cases. “I expected it to arrive before Zika,” states Fonseca, who is working with the municipal Health Department to set up a chikungunya surveillance system.

“We’ve noticed a slow increase in the number of cases in other regions of the country,” says Souza. “Winter is a time of apprehension but an important moment for gathering forces and resources to combat the mosquito.” Cunha adds: “This is the time for organizing the health network to serve the ill, since few things are as predictable as the infestation of Aedes every summer.”

There is as yet no vaccine against the virus and treatment is palliative, based on analgesics and other medications.  Experts believe that doctors have to be trained to make the proper diagnosis, especially in critical cases. “We’ve seen many cases of myocarditis and an inordinately high death rate in the Northeast,” states infectologist Kleber Luz, who is with the Federal University of Rio Grande do Norte (UFRN). Luz is also an advisor on patient care for the Ministry of Health and accompanied the 2013 outbreak of chikungunya in Martinique, which he felt was a milder version of the disease than what circulates in Brazil. He suspects that a portion of the deaths are attributable to improper patient management and the use of anti-inflammatory drugs, which should be avoided in the acute stage. “We have to investigate what’s happening,” he says.

Artistic representation of the Zika virus, which can damage the brain of a developing fetus and cause microcephaly

Adapted from Manuel Almagro Rivas / Wikimedia Commons Artistic representation of the Zika virus, which can damage the brain of a developing fetus and cause microcephalyAdapted from Manuel Almagro Rivas / Wikimedia Commons

Vaccines protect monkeys against Zika

Three potential vaccine formulas against the Zika virus have proven effective and safe in tests on monkeys. In an article published in late June 2016 in the journal Nature, Brazilian and U.S. researchers reported the protective efficacy of two classes of vaccines in mice, one made from the inactivated virus and the other, called a plasmid DNA vaccine, from two Zika genes (see Pesquisa FAPESP Issue nº 245). The same team presented the results of the subsequent round of tests in the August 4, 2016, issue of the journal Science. This was the last phase before human trials, which are expected to begin in the next few months.

“These are important results because they show that it’s possible to protect against Zika in monkeys, an animal whose defense system resembles the human’s system more than the mouse’s,” says Brazilian immunologist Rafael Larocca, researcher at the Harvard Medical School Center for Virology and Vaccine Research (CVVR). Larocca is a member of Dan Barouch’s team and, alongside his colleague Peter Abbink, one of the principal authors of the two studies.

In the latest tests, researchers vaccinated rhesus monkeys with either a single dose or one dose plus a booster, using one of three formulas: the inactivated virus, the DNA vaccine, or a recombinant rhesus adenovirus expressing Zika genes. All three displayed the same ability to block subsequent Zika infection.

The inactivated virus formula provided quite broad protection. Monkeys that were treated with this and later infected with Zika did not present the virus in their blood, urine, cerebrospinal fluid, or vaginal secretions. “This type of protection is relevant because of the risk of sexual transmission,” says neuroimmunologist Jean Pierre Peron, USP researcher. Peron and virologist Paolo Zanotto, also of USP, contributed to the articles and are members of the São Paulo Zika Network, a task force of São Paulo researchers that is investigating the virus, with the support of FAPESP.

Scientific articles
NUNES, R. F. et al. Epidemiology of chikungunya virus in Bahia, Brazil, 2014-2015. PLOS Currents: Outbreaks. February 1, 2016.
TEIXEIRA, M. G. et al. East/Central/South African genotype chikungunya virus, Brazil, 2014. Emerging Infectious Diseases. May 2015.
MORRISON, C. R.; PLANTE, K. S. and HEISE, M. T. Chikungunya virus: Current perspectives on a reemerging virus. Microbiology Spectrum. May 13, 2016.
ABBINK, P. et al. Protective efficacy of multiple vaccine platforms against Zika virus challenge in rhesus monkeys. Science. August 4, 2016.