Heartland virus infection is due to a Phlebovirus (family Bunyaviridae), with cases reported (as of September 2018) from Arkansas, Georgia, Kansas, Illinois, Indiana, Kentucky, Missouri, North Carolina, Oklahoma, and Tennessee in the United States. The virus has been isolated in deer, raccoons, coyotes, and moose in at least 13 states in the United States (from Texas to North Carolina and Florida to Maine). Infection with Heartland virus is believed to occur after a bite from an infected Amblyomma americanum tick (lone star tick). As of 2017, more than 30 cases of Heartland virus infection have been reported. Typical patients are males older than 50 years, and deaths have occurred. All patients describe outdoor exposures, and most recalled prior tick bites. Symptom onset has occurred during May to September, coinciding with the time when ticks are active.

While the transmission of Heartland virus from ticks to humans has yet to be confirmed, detection of Heartland virus in field-collected ticks supports the role of ticks and subsequent bites in the development of disease in humans.

Fever is universally present in reported cases. The most common symptoms include fatigue and anorexia. Other symptoms include headache, nausea, myalgia, arthralgia, and diarrhea. Thrombocytopenia and leukopenia are commonly noted at presentation. Leukopenia can be progressive, and mild neutropenia has occurred. Progressive transaminitis without coagulopathy appears to be common. Mild anemia and hyponatremia have also been noted.

Complications of Heartland virus infection that may have contributed to death in one elderly patient include hypoxia and respiratory failure, hypotension, progressive cytopenia, acute kidney injury, gastrointestinal bleeding from gastric ulcers, and persistent encephalopathy.