One Confirmed and 2 Suspected Cases of Heartland Virus Disease

Abstract

Heartland virus is a tickborne phlebovirus first identified in Missouri in 2009; 11 human cases have been reported in the literature. Reported hallmarks of infection have included fever, malaise, anorexia, gastrointestinal complaints, thrombocytopenia, neutropenia, and aminotransferase elevations. We report 1 confirmed and 2 suspected cases and discuss implications for case-finding.

Heartland virus (HRTV) disease is a tickborne infection discovered in 2009 [1]. To date, 11 human cases have been reported in the literature [1–6]. HRTV is a phlebovirus that has been detected in humans, other mammals, or Amblyomma americanum (Lone Star) ticks throughout the central and southeastern United States [7] and is closely related genetically to the severe fever with thrombocytopenia syndrome virus (SFTSV) described in China, Japan, and Korea beginning in 2009 [8].

All 11 published HRTV cases had fever; most also reported fatigue, weakness, and headache. Nausea, diarrhea, myalgia, and arthralgia also have been observed. All cases manifested thrombocytopenia, and most also had neutropenia and moderate liver enzyme elevations. Of the 11 cases, 9 were hospitalized and 4 died; all were males > 50 years of age, and most were > 65 years of age.

We report 1 confirmed and 2 suspected cases of HRTV disease and discuss their implications for recognition of HRTV disease.

CONFIRMED CASE

On 1 September 2019, a 73-year-old retired infectious disease physician in active good health living on a small farm in central Tennessee noted that a right hip skin irritation present for 3 days was actually an embedded nymphal tick (species unknown), which he removed. He often finds crawling ticks, including Lone Star, and typically experiences 3–6 tick implantations each growing season.

On 5 September, the patient had a sudden onset of illness marked by weakness, nearly complete loss of appetite, and lassitude; the patient commented that “it felt like a virus.” There was no evident fever. The patient was cared for by his wife, a registered nurse, who also noted the absence of fever. By 10 September the patient began to regain his appetite and felt sufficiently improved to leave the house that day for an appointment.

On 12 September the patient attended a previously scheduled annual physical examination, in the course of which specimens were submitted for laboratory analysis (Table 1). Results available on 16 September revealed thrombocytopenia, leukopenia, and mild liver enzyme elevations. Based on these results and the clinical history, the patient suspected HRTV infection and contacted colleagues at the Tennessee Department of Health (TDH) to arrange for HRTV-specific testing; a serum specimen was submitted to TDH on September 18 for forwarding to the Centers for Disease Control and Prevention (CDC). Serum submitted on 12 September was reported negative on 16 September for Ehrlichia, Lyme, and Rocky Mountain spotted fever (RMSF) antibodies (LabCorp tests 164722, 258004, and 016667, respectively).

During the second week following illness onset, the patient continued gradually to improve. Appetite was better but not yet normal; he experienced early satiety and felt somewhat weak and slightly unstable. He was able to do chores in the mornings but needed to work at his desk or rest in the afternoon. Weight loss during the illness was > 5 kg. After initially worsening, the thrombocytopenia, leukopenia, and liver enzyme results improved slowly (Table 1). By 4 weeks after onset of illness, the patient felt entirely well. The thrombocytopenia resolved by 10 October and all laboratory results had normalized by 8 November.

The serum specimen obtained 17 days after illness onset was reported by the CDC as negative for HRTV and for Bourbon virus by reverse-transcription polymerase chain reaction (RT-PCR) and plaque reduction neutralization test (PRNT) but as positive by microsphere immunoassay for HRTV immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies. Based on the negative RT-PCR and PRNT, it was thought that the antibody results were false positives. However, a convalescent serum sample submitted on 6 November demonstrated that the patient had developed neutralizing antibodies (HRTV IgG titer, 1:2560 by PRNT), confirming recent HRTV infection.

SUSPECTED CASES

A consulting hematologist reported attending 2 patients in recent months with similar clinical and laboratory findings whose illnesses resolved without definitive diagnosis. Medical records could be retrieved for 1 of these, a 21-year-old woman with mild lupus erythematosus treated with hydroxychloroquine who had tick exposures in the Nashville area. Her febrile illness began 8 August 2019. She was hospitalized on 10 August with an oral temperature of 38.9°C (102.0°F). Laboratory results included platelets, 72 000/µL; neutrophils, 390/µL; aspartate aminotransferase, 463 units/L; alanine aminotransferase, 210 units/L (Supplementary Table 1). Her fever abated 14 August; she was discharged 16 August, and felt normal by 19 August. Antibody assays for RMSF and Ehrlichia were negative; no HRTV test was conducted. She moved and is lost to follow-up.

Discussion

The spectrum of tickborne diseases was further expanded in 2009 with the discovery of 2 viruses that were distant geographically but closely related genetically, HRTV in Missouri [1] and SFTSV in Xinyang City, China [8]. By 2014, > 3500 cases of SFTSV infection had been described in China [9], whereas it was reported in 2019 [6] that the CDC was aware of > 40 cases of HRTV infection, some in females. Based on reported cases, the clinical severity of the 2 diseases appears to be generally similar, but it would seem that SFTSV infection is much more common in China than is HRTV infection in the United States (US). However, the incidence of each infection may not be as different as it might appear. By 2017, nearly 2 dozen studies of SFTSV seroprevalence had been published [10]. The Chinese studies showed a pooled seroprevalence of 4.3% (range by study, 0.23%–9.17%); seroprevalence rates varied substantially by geographic locale, occupation (farmer vs not), proximity to other cases, and year (higher after 2012), but not by sex or age [10].

In contrast, to date there is only 1 published study of HRTV seroprevalence. Based on data collected in 2013, it was found that 12 (2.5%) of 487 tested donors were positive for HRTV IgG; 7 (1.4%) had HRTV neutralizing antibodies by PRNT [11]. After adjustment based on US Census data, it was estimated that 0.9% (95% confidence interval [CI], .4%–4.2%) of blood donors in northwestern Missouri were seropositive for HRTV antibody [11]. There has also been 1 study of SFTSV seroprevalence among blood donors in China. Based on data collected in 2012, it was found that 80 (0.54% [95% CI, .05%–.77%]) of 14 752 blood donors in Xinyang City, China, were seropositive for IgM or IgG SFTSV antibodies [12]. Thus, based on these 2 studies of seroprevalence among blood donors, there is no reason to believe that HRTV is less prevalent than SFTSV; it may simply be less thoroughly studied. The Chinese blood donor study also found that 2 of 9960 (0.02% [95% CI, 0–.07%]) tested donors were positive by RT-PCR for SFTSV RNA, suggesting current or very recent infection that presumably was asymptomatic, given the routine screening undergone by blood donors. Indeed, a 2016 serosurvey in Xinyang City, China, found SFTSV-specific IgM in 12 of 1463 (0.8%) surveyed individuals, none of whom manifested signs or symptoms of illness, further supporting the possibility of asymptomatic SFTSV infection [13].

It is well known that initial data regarding an emerging infectious disease are biased toward more severe cases, and only later is the full spectrum of clinical and asymptomatic infection recognized. This process is undoubtedly under way for both SFTSV and HRTV, and the cases presented herein contribute to broadening the recognized spectrum of HRTV disease. All previously reported cases of HRTV disease developed substantial fever during the course of their illnesses, and fever is listed first as a required element in the surveillance case definition posted on the CDC website [14]. Our confirmed case, in contrast, had no known fever. One other reported case had no fever at presentation [5]; his subsequent fever may have been due to nosocomial infection. Along with the Missouri serosurvey results [11], our 2 suspected cases, 1 of whom had clinical and laboratory findings typical of HRTV disease and negative diagnostic results for likely alternative diagnoses, suggest strongly the existence of undiagnosed clinical infections.

Although Heartland virus infection is uncommon, clinical illness is striking, with prominent anorexia and malaise (our confirmed case described it as the most profound illness of his life) along with thrombocytopenia, leukopenia, neutropenia, and mild to moderate aminotransferase elevations. In reported cases, illness onset occurred 1–14 days after the tick was noted and removed [1, 3, 4, 6].

Diagnostic testing of compatible cases is available through state health departments. Even more useful than increased diagnostic awareness, however, would be additional seroprevalence studies conducted by public health authorities, blood banks, or others to characterize the prevalence of HRTV (such an effort is under way in Tennessee) and elucidate the rate of asymptomatic infection. In addition, surveillance case definitions should be modified to recognize that fever is a common, but not mandatory, element of HRTV disease.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Acknowledgments. The authors thank Dr Tim Jones, Chief Medical Officer at the Tennessee Department of Health, and Drs David Aronoff and William Schaffner, Vanderbilt University Medical Center, Nashville, Tennessee, for their guidance and assistance. The authors also thank the staff of the Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, for the performance of the Heartland virus and related assays.

Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

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