BORNE BY BUGS, DISEASES OF CONCERN. Heartland Virus

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1 BORNE BY BUGS, DISEASES OF CONCERN Steven R. Bolin, DVM, MS, PhD Department of Pathobiology and Diagnostic Investigation College of Veterinary Medicine Diagnostic Center for Population and Animal Health, Rm 265 Michigan State University Lansing, MI Heartland Virus In June of 2009, a new disease appeared in northwestern Missouri that affected two farmers living 60 miles apart. Both men had removed ticks from their bodies shortly before they developed fever, fatigue, anorexia, and non-bloody diarrhea. On admission to the hospital, both men showed low white bold cell count, low platelet count, and elevated liver aminotransferases. Antibiotic therapy was administered and samples of blood were sent to the CDC to test for known tick borne pathogens, and for unknown agents. After several days in the hospital, both men were discharged. Fatigue and anorexia lasted for weeks after discharge and both men suffered short term memory loss. Laboratory testing at the CDC resulted in the isolation of a virus. Further testing of viral infected cell cultures using electron microscopy showed an enveloped virus morphologically similar with viruses in the Bunyaviridae family. Using molecular techniques, the nucleic acid sequence of the viruses from both men were derived and found to be highly similar to each other. The virus was classified as a phlebovirus and genetic analyses showed that the virus was most closely related to the newly identified Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV). The SFTSV is considered the cause of a new disease of people in rural areas of China. The new virus isolated from the farmers in Missouri was termed Heartland virus (HRTV). When comparisons were made, it was found that the disease induced by HRTV and the disease induced by SFTSV were similar. Both diseases occurred in farmers or people living in rural areas, most of the affected people were over 50, ticks bites were a common factor, the affected people presented with signs and symptoms of fever, fatigue, anorexia, leukopenia, thrombocytopenia, and gastrointestinal signs. The mortality rate associated with SFTSV in China was 30%. The likely source of SFTSV in China was ticks, which were shown to carry the virus. Thus, it was speculated that the source of HRTV also was ticks and the most common tick in northwestern Missouri is Amblyomma americanum (A.a.), the lone star tick. Since those first 2 cases of HRTV infection in 2009, at least 7 additional cases have occurred. Missouri has had five more confirmed cases of HRTV infection that were non-fatal and there

2 have been single fatal cases reported from Tennessee and Oklahoma. In 2012, ticks were collected by drag, baited traps, or removal from animals in Missouri at the farms owned by the first two men infected with HRTV and at 10 other sites in the general area of the farms. Over 56,000 ticks were collected in April, June, and August. Included in the collection were 1,987 adults, 7,271 nymphs, and 45,760 larvae that were A.a.; 1,385 adults, 12 nymphs, and 6 larvae that were Dermacentor variabilis; and only 7 Ixodes dentatus ticks. The HRTV was detected only in A.a nymphs that had been collected at 2 of 12 total sites. Thus, the HRTV was found in A.a. ticks, as had been speculated after the first two cases of disease were described. To date, a potential reservoir host has not been identified. A serologic survey for antibody that might be induced by HRTV, or by an unknown similar virus, was performed using convenience samples of serum collected from farmed animals that were located in 29 counties in Minnesota. The laboratory test used was an ELISA manufactured in China for detection of antibody against the SFTVS nucleoprotein. It was assumed that since HRTV and SFTVS were genetically similar, that ELISA would detect antibody raised against HRTV or some other closely related phlebovirus. The ELISA identified 64 of 414 cattle, 10 of 92 goats, 6 of 48 sheep, 35 of 296 white-tailed deer, and 7 of 39 elk located in 24 of 29 counties with antibody against the SFTVS nucleoprotein. Chikungunya virus Chikungunya virus (CHIKV) is in the Semliki Forrest Virus complex of alphaviruses within the Togaviridae family of viruses. Three genetic cluster of CHIKV are recognized: Asian, West African, and Central/South/East African. CHIKV is responsible for periodic outbreaks of disease in Africa, in islands in the Indian Ocean, and in Southeast Asia. Signs and symptoms of disease begin about 3 to 7 days after being bitten by an Aedes mosquito that carries CHIKV. The disease commonly presents as fever accompanied by severe joint pain, often in the hands and feet. Headache, muscle pain, joint swelling, or rash also may occur. In most cases, the disease lasts about a week, but long term joint pain may occur in some people. Severe disease is seen in newborns, elderly, and people with existing chronic disease. A map of the distribution CHIKV in 2006 showed the virus in sub Saharan Africa, in countries and islands adjacent to or in the Indian Ocean, and countries and islands of Southeast Asia. From 2006 until 2013, an average of 28 people (range 5 to 65) a year in the U.S. were diagnosed with travel related CHIKV. In 2013, CHIKV appeared in the Caribbean islands and became established. The map showing the distribution of CHCKV in 2014 includes France and Italy, islands of the Caribbean, the U.S., several countries in Central America, and countries in northern South America. From January 1 to October 7, 2014, there were 1,337 reported cases of CHIKV in the U.S. Those cases were reported from most of the States in the Continental U.S. and Hawaii. Most of those cases were travel related and involved travel to the Caribbean islands.

3 Significantly, 11 cases in Florida did not have a history of travel and are presumed to be locally transmitted. Over 740,000 cases of CHIKV are suspected to have occurred in the Western Hemisphere as of October 2014, and it is highly likely that CHKV will continue to spread. The reservoir(s) for CHKV are still being identified. The laboratory based studies in the older literature mostly used the hemagglutination inhibition test to detect antibody against CHICK, which was reported to have been found in non-human primates, poultry, cattle, sheep, goats, pigs, horses, and dogs. Assuming the antibody was against CHIKV and not against some other related togavirus; those species likely had been infected with virus. Using virus isolation (gold standard) to detect active infection, non-human primates, striped ground squirrels, yellow bats, golden sparrows, and mice have been shown to be infected. Recently, animals on islands in the Indian Ocean that were involved in an outbreak of CHIKV in 2006 were sampled and tested for antibody against CHIKV, using ELISA, and/or tested for viral RNA, using PCR. The animals found positive were non-human primates and the ship rat (black rat). Animals tested and not found negative were cat, dog, horse, cattle, goat, sheep, pig, chicken, shrew, and Norway rat. We are waiting for similar studies to be done in the Americas. Ehrlichia muris-like agent In 2010, patients (humans) from northern Wisconsin and northeastern Minnesota presented with signs and symptoms similar to those associated with anaplasmosis, including fever, chills, headache, muscle pain, fatigue, confusion, and nausea. Diagnostics for Anaplasma phagocytophilum were negative, but a new organism termed Ehrlichia muris-like agent was detected in blood samples. The Ehrlichia muris-like agent is closely related to Ehrlichia muris of mice. The Ehrlichia are gram negative bacteria and, at that time, all Ehrlichia except Ehrlichia muris have been reported to infect people. In addition to mice, serologic surveys and PCR assays that had been done in Japan indicated that Ehrlichia muris may infect deer, monkeys, boars, bears, and dogs. In 2011, a retrospective survey of Ixodes scapularis ticks collected off plants in northern Wisconsin during the 1990 s revealed the presence of DNA from the Ehrlichia muris-like agent. Then, in 2012, it was reported that the Ehrlichia muris-like agent was detected in a dog. The dog was located in Minnesota and initially presented to a veterinary clinic with clinical signs of fever, abnormal gate, and apparent joint pain. Serologic testing showed antibody against Anaplasma phagocytophilum and treatment was initiated. The dog relapsed after treatment and had repeated episodes of vomiting and anorexia. Testing of blood from the dog, using several PCR assays for detection of blood-borne pathogens, led to the detection of the Ehrlichia muris-like agent In 2013, a surveillance study was reported in which 542 Ixodes scapularis ticks were collected off of dogs that were located in 26 counties in Wisconsin. The Ehrlichia muris-like agent was

4 detected using PCR assays in 20 ticks that had been collected in 8 counties. As of September of 2013, six persons in Minnesota or Wisconsin and one person in Michigan have been reported with laboratory confirmed infections with Ehrlichia muris-like agent. Borrelia miyamotoi Borrelia miyamotoi is a spirochete that is most closely related to the relapsing fever group of spirochetes. It is distantly related to the group of Borrelia spirochetes (burgdorferi, afzelii, garinii) that cause Lyme disease. Relapsing fever presents in people with influenza like symptoms with one or more relapses of fever and bacteremia. Borrelia miyamotoi was first described in Japan in 1995 and since then has been found in all species of ticks that carry the Lyme disease group of Borrelia. Ticks may concurrently carry B. miyamotoi and B. burgdorferi, but B. miyamotoi appears to be far less common. Although B. miyamotoi was known to be present in ticks, it was not associated with disease until a 2011 report that involved case studies of multiple patients with laboratory confirmed infection with B. miyamotoi. Those patients resided in an area of central Russia where Lyme disease and other tick-borne disease were prevalent. The Russian study included data from tick collections in the area of Russia where the patients resided and in areas of geographic proximity. Prevalence of B. miyamotoi in ticks from two separate collections was 0.9% of 442 and 6.4% of 394 ticks. A case definition was developed that included a history of tick bite followed by clinical manifestations of fever, headache, chills, fatigue, vomiting, and myalgia. Active infection was confirmed using species specific PCR assays for B. miyamotoi in samples of blood and the detection of anti-borreliae IgM in acute- and/or convalescent-phase serum samples. The study had 302 patients of which 51 were positive for an active infection B. miyamotoi and 46 of those patients had anti-borreliae IgM in their sera at time of presentation or at 2 weeks after presentation. The study made comparisons of patients with Lyme disease and patients infected with B. miyamotoi. The findings were that patients presented with symptoms of disease associated with B. miyamotoi later after tick bite than those patients with Lyme disease. Admission to a hospital after symptoms first appeared occurred sooner with B. miyamotoi and hospital stay was longer. Since publication of the Russian study, infection and disease associated with B. miyamotoi has been reported in an 80 year old woman that lived on a farm in New Jersey and was suffering from a progressive decline in mental status, patients with febrile disease in New Jersey (1) and Massachusetts (1), and three patients were being evaluated for Lyme disease in southern New England. In addition, a 70 year old patient presenting with slow cognitive processing, memory loss, and abnormal gait in the Netherlands was diagnosed with B. miyamotoi. Recent interest in B. miyamotoi has stimulated prevalence studies in ticks and bank voles in France and ticks in Canada. In the French study, B miyamotoi was found in 3% of 268 Ixodes ricinus ticks and 5.5%

5 of 72 bank voles. The Canadian study involved 4,938 I. scapularis ticks collected in The results showed B. miyamotoi was detected in <1% ticks from all provinces except Newfoundland, which had only negative results. The prevalence of other tick-borne disease agents varied among the provinces whereas the prevalence of B. miyamotoi was consistent among the provinces. In addition to voles, B. miyamotoi has been reported in wild turkeys in Tennessee, and in white-footed deer mice.