New phlebovirus associated with severe febrile illness in Missouri
Abstract & Commentary
By Dean L. Winslow, MD, FACP, FIDSA. Chairman, Department of Medicine, Santa Clara Valley, Medical Center; Clinical Professor, Stanford University School of Medicine. Dr. Winslow is a consultant for Siemens Diagnostic.
This article originally appeared in the October 2012 issue of Infectious Disease Alert. It was edited by Stan Deresinski, MD, FACP, FIDSA, and peer reviewed by Timothy Jenkins, MD. Dr. Deresinski is Clinical Professor of Medicine, Stanford University, and Dr. Jenkins is Assistant Professor of Medicine, University of Colorado, Denver Health Medical Center. Dr. Deresinski does research for the National Institutes of Health, and is an advisory board member and consultant for Merck, and Dr. Jenkins reports no financial relationships relevant to this field of study.
Synopsis: Two men presented to a hospital in northwestern Missouri in June 2009 with fever, fatigue, diarrhea, thrombocytopenia and leukopenia. Both had a history of frequent recent tick bites. A novel phlebovirus was isolated in cell culture from patient blood. Electron microscopy revealed virus particles consistent with Bunyaviridae. Sequencing identified the viruses as novel members of the phlebovirus genus.
Source: McMullan LK, et al. A new phlebovirus associated with severe febrile illness in Missouri. New Eng Jrl Med 2012;367:834-41.
Two men (one age 57 with no prior significant illnesses and one age 67 with type 2 diabetes) from northwestern Missouri presented separately to a hospital with illnesses characterized by fever, fatigue, diarrhea, thrombocytopenia and leukopenia. Hepatic transaminase levels subsequently became elevated in both patients, peaking between 8 and 10 days. Both reported frequent tick bites with most recent tick exposure 5-7 days prior to onset of illness. The patients were initially suspected of having ehrlichiosis and were given doxycycline pending diagnostic studies. Both patients eventually recovered from their illnesses but had symptoms of fatigue for as long as 2 years following their acute illnesses.
Blood samples sent to CDC were negative by PCR for Ehrlichia and rickettsiae of the spotted fever group. Subsequent serologic studies were negative for antibodies to spotted fever group rickettsiae and typhus. Leukocytes collected from the patients on day 2 of hospitalization were inoculated into DH82 cells and showed cytopathic effect, which was transferable to fresh DH82 cells. Electron microscopy revealed enveloped particles averaging 86 nm in diameter, typical of a virus in the Bunyaviridae family. RNA isolated from infected cell cultures was sequenced using next-generation sequencing and was found to be similar to phleboviruses in the Bunyaviridae family. Sequences from the two patients were similar, but not identical, suggesting that the two patients were infected independently. Phylogenetic analysis showed clustering of these two new viruses with other tickborne viruses most closely related to severe fever with thrombocytopenia syndrome virus (SFTSV). Viral RNA of the novel virus was also detected in bone marrow from the second patient. Both patients demonstrated IgG antibody to the novel virus by ELISA more than 2 years following their acute illnesses.
One of the main reasons I decided to become an infectious diseases specialist when I was doing my Medicine residency during the 1970s was because I really enjoyed the challenge of trying to figure out what was wrong with very sick (usually febrile) patients. It was also during my internship that I cared for a patient with severe multi-lobar pneumonia who had recently attended a convention of the American Legion at the Bellevue-Stratford hotel in Philadelphia (about 2 years later the CDC finally identified the etiologic agent Legionella pneumophila). The next year I cared for a 14-year-old girl who developed a faint sunburn-like rash, fever, and multi-system organ failure shortly after beginning to use a newly marketed super-absorbent tampon (vaginal culture did grow Staphylococcus aureus, and a few months later other cases of menstrual TSS were identified in the U.S.). At the end of my fellowship training, Mike Gottlieb in Los Angeles described the first cases of Pneumocystis pneumonia in young gay men and we knew we were dealing with another new infectious disease (AIDS). During my career, the identification of new syndromes and newly recognized etiologic agents of disease has continued with great regularity (Hantavirus pulmonary syndrome, SARS, pandemic H1N1 and many others come to mind).
This is an interesting case report which while not completely fulfilling Koch's postulates, almost certainly represents a newly recognized tick-borne viral infection in North America. Many of the clinical and laboratory manifestations of this illness are similar to the also recently described SFTS bunyavirus illness seen in China.1 Although the two patients described in the case report had severe illness, the spectrum of disease and extent of subclinical infection associated with this newly recognized phlebovirus is unknown. Also, while it is most likely that the common tick, Amblyomma americanum, is the vector for this virus, limited sampling of ticks in Missouri did not reveal the virus.
Coincidentally, Toscana virus (another phlebovirus originally isolated in 1971 in Tuscany) was recently shown to be responsible for 15% of cases of aseptic meningitis between July and October in northern Italy.2 Since this latter virus has been recognized previously as a common cause of aseptic meningitis in the Mediterranean basin, its recognition recently in northern Italy may be a reflection of changing ecology related to global climate change.
1. Yu X-J, et al. Fever with thrombocytopenia associated with a novel bunyavirus in China. New Eng Jrl Med 2011;364:1523-32.
2. Vocale C, et al. Toscana virus infections in northern Italy: Laboratory and clinical evaluation. Vector-borne and Zoonotic Diseases 2012;12:526-9.