Painful, mosquito-borne diseases are no longer limited to distant, exotic locales. As the climate warms, U.S.-based labs should expect more orders to test for the mosquito-borne viruses that cause chikungunya, dengue fever, and West Nile virus (WNV). Cases of the former two could skyrocket, due to warmer weather, air travel to areas where they are endemic—particularly the Caribbean and Central and South America—and Americans’ near-total lack of immunity, according to experts. Similarly, WNV, already the leading cause of domestically acquired arboviral disease in the U.S., is poised to propagate further.
Aedes aegypti and Aedes albopictus mosquitoes transmit both chikungunya and dengue, while many more species serve as vectors for WNV; in 2012, the U.S. Centers for Disease Control and Prevention (CDC) identified 54 as carriers. After a long history in Sub-Saharan Africa, chikungunya landed for the first time in the Western Hemisphere—on the Caribbean island of Saint Martin—in 2013. In 2015, it became a nationally notifiable disease in the U.S., and at CLN press time, 126 cases in 26 states had been reported to CDC. Dengue is endemic world-wide but has not been a major problem in the continental U.S., with nearly all reported cases acquired elsewhere by travelers and immigrants. However, the Caribbean—including Puerto Rico—and Mexico are considered dengue high-risk areas.
“In any place with either of the two types of mosquitoes that transmit dengue and chikungunya, there’s risk for local transmission,” said Hollis J. Batterman, MD, laboratory medical director at San Juan Capistrano, California-based Focus Diagnostics, a subsidiary of Quest Diagnostics. Florida and states that border Mexico have had dengue outbreaks in the past and could have significant cases of chikungunya, she pointed out, urging laboratorians to prepare themselves for questions from clinicians practicing in these regions and from those with sick patients recently returned from affected locales.
Clinicians who are both familiar with the diseases and get good travel histories can probably distinguish chikungunya from dengue—both of which cause fever and disabling joint pain—but only lab testing will confirm the diagnosis. Distinguishing them is important. While patients rarely die from chikungunya, dengue has a fatality rate of up to 10%, according to CDC.
Chikungunya generally causes worse joint pain than dengue, and swelling. The pain may linger for months or years. Those at risk for serious disease—which may involve heart, nerve, and skin complications as well as hemorrhage—include newborns exposed in the womb, small children, adults older than 65, and people with chronic diseases such as hypertension or diabetes. In contrast, dengue does not involve joint swelling. However, those sick with dengue a second time are at risk for fatal hemorrhagic fever and require close monitoring.
There is no drug to treat either disease other than anti-inflammatory drugs to control symptoms. Severely ill patients need hospitalization for supportive care, including hydration therapy or transfusion.
Ideally, patients should have tests for both chikungunya and dengue, said Batterman. If cost is an issue, test for dengue first because it can be more serious, and supportive treatment is more time-sensitive, added Scott Weaver, PhD, director of the Institute for Human Infections and Immunity and scientific director of the Galveston National Laboratory at the University of Texas Medical Branch in Galveston.
For both diseases, polymerase chain reaction (PCR) tests are useful in the first days of symptom onset, but less so after several days or a week because viral levels in the blood diminish. At that point, immunoglobulin M (IgM) is the better test for both diseases, according to Batterman and Weaver. Chikungunya RNA is detectable in the blood at symptom onset but declines to undetectable levels within 7 days, while IgM isn’t uniformly detectable until 5 days after onset (Clin Vaccine Immunol 2015;22:291–7).
CDC recommends testing for both chikungunya and dengue in symptomatic patients returning from areas where these viruses have been detected. CDC’s testing algorithm includes PCR for acute specimens taken before day 5 or 6 of illness and IgM testing for samples taken after day 5 or 6, said Robert Lanciotti, PhD, chief of the Diagnostic and Reference Laboratory at CDC’s Arbovirus Diseases Branch in Fort Collins, Colorado. “Labs can send specimens to CDC for confirmation of their initial testing, or if they do not have a chikungunya test up and running they can send specimens here as long as the testing is indicated by travel,” he said. Turnaround time is about 2 weeks.
Focus Diagnostics delivers results in 1 to 2 days for chikungunya PCR, and 1 to 3 days for chikungunya serology, once the lab receives samples, according to Batterman. Commercial serology kits for chikungunya are also available, but recent research comparing them showed certain enzyme-linked immunoassay IgM tests had specificity as low as 88% and sensitivity as low as 79% (Emerg Infect Dis 2014;20:2129–32).
The possibility of cross-reactivity is a drawback to serology, noted Adnan Alatoom, MD, PhD, assistant professor of pathology at the University of Texas (UT) Southwestern Medical Center in Dallas, associate director of UT Southwestern and Parkland Hospital microbiology laboratories, and director of the UT Southwestern virology lab. He suggested confirming serology results with tests that use neutralizing antibodies, usually available at reference laboratories, state public health laboratories, or the CDC.
West Nile Virus Still Around
Differential diagnoses for both chikungunya and dengue include malaria, for which most labs can perform blood smears, and WNV. While it hasn’t been making as many headlines as chikungunya, WNV is a more significant health threat in most of the country, especially among patients age 65 or older, who have the highest risk of severe disease with complications including encephalitis and meningitis, according to Weaver.
Only 20% of those infected with WNV develop fever, headache, vomiting, body, and joint pains, according to Alatoom. Most of these patients recover completely; however, less than 1% develop neuroinvasive disease such as encephalitis, meningitis, or myelitis that cause fever, headache, neck stiffness, coma, disorientation, seizures, tremors, or paralysis.
Laboratorians should encourage clinicians to diagnose WNV with serology—IgM and immunoglobin G—because when patients present, the viral load usually is too low to detect with PCR, according to Lanciotti and Alatoom. However, noted Alatoom, clinicians may request detection of WNV RNA by PCR for patients with early disease who have negative serology, and in immunocompromised patients who fail to produce detectable amounts of antibodies. Alatoom prefers testing cerebral spinal fluid (CSF) instead of blood because CSF better reflects neuroinvasive disease. His research showed that in 25 WNV patients with neuroinvasive disease, 15 had positive IgM in both serum and CSF, while just 10 had positive IgM in serum only (Diagn Microbiol Infect Dis 2014;78:132–6).
Vaccines: The Next Frontier
Even as chikungunya still is emerging in the U.S., researchers, including Weaver, are developing chikungunya vaccines. Some have gone through Phase 1 clinical testing, but going forward requires tremendous investment. “You need hundreds of millions of dollars to take vaccines through the Food and Drug Administration. So you want certainty about prevalence for clinical trials,” said Weaver, explaining that confidence in incidence figures allows researchers to plan and budget for studies. Prevalence is now difficult to determine both because chikungunya is often misdiagnosed as dengue and because surveillance usually diminishes after epidemics peak. Development of a reliable, affordable, point-of-care test would aid with surveillance and in planning studies abroad, while also enabling U.S. labs “to detect imported cases and prevent the virus from gaining a foothold,” Weaver added.
Some researchers are working toward that goal. A rapid immunochromatographic assay tested recently in three southeast Asian countries and Senegal had a sensitivity of 89.4%, specificity of 94.4%, and results that agreed with PCR findings 91.1% of the time (J Clin Microbiol 2015;53:382–8).
During the wait for quicker diagnostics and vaccines, labs should educate clinicians about assays’ kinetics and the importance of using a patient’s history—including symptoms, travel, and epidemiology—to make good testing decisions, advised Batterman. She added, “Know when to expect PCR and antibody tests to be positive. Advise your clinicians.”
Deborah Levenson is a freelance writer in College Park, Maryland.