Tickborne diseases other than Lyme in the United States

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Tickborne diseases are increasing in the United States, and the geographic range of tick vectors is expanding. Tickborne diseases are challenging to diagnose, as they present with vague symptoms such as fever, constitutional symptoms, and nonspecific laboratory abnormalities. A high degree of clinical suspicion is required to make a diagnosis, as patients often do not recall a tick bite. The availability of laboratory testing for tickborne diseases is limited, especially in the acute setting. Therefore, if a tickborne disease is suspected, empiric therapy should often be initiated before laboratory confirmation of the disease is available. This article summarizes the most common non-Lyme tickborne diseases in the United States.


  • Tickborne illnesses should be considered in patients with known or potential tick exposure presenting with fever or vague constitutional symptoms in tick-endemic regions.
  • Given that tick-bite history is commonly unknown, absence of a known tick bite does not exclude the diagnosis of a tick-borne illness.
  • Starting empiric treatment is usually warranted before the diagnosis of tickborne illness is confirmed.
  • Tick avoidance is the most effective measure for preventing tickborne infections.



Ticks are responsible for most vector-borne infections in the United States. Most infections occur between April and October, when tick populations peak.1 However, infections can occur year-round.2,3

Tick bites are often unnoticed because the ticks are small when they are at the infective stage of their life cycle, and their attachment is characteristically painless and often in intertriginous body sites.1 Therefore, absence of a known tick bite never precludes the diagnosis of a tickborne infection.1,4,5

Although rural outdoor activities are recognized risk factors, tickborne infections also occur in urban areas.6 Thus, the lack of classic epidemiologic clues does not rule out a diagnosis of tickborne infection.

In most cases, tickborne illnesses present with nonspecific symptoms such as fever, malaise, headache, nausea, and myalgia. Accurate diagnosis of tickborne diseases can be challenging due to the similar clinical manifestations and overlapping geographic distributions of potential tick vectors.1

This review summarizes the epidemiology, clinical features, treatment, and prevention of the most prevalent non-Lyme tickborne diseases of the United States: Rocky Mountain spotted fever (RMSF), other spotted fever group rickettsial (SFGR) infections, ehrlichiosis, babesiosis, tickborne relapsing fever, Borrelia miyamotoi infection, southern tick-associated rash illness (STARI), tularemia, and tickborne viral infections.


Rocky Mountain spotted fever
RMSF (Table 1) is caused by Rickettsia rickettsii, an obligate intracellular gram-negative coccobacillus.7,8

Dermacentor variabilis, the American dog tick, is the major vector in the southern and eastern United States, and D andersoni, the Rocky Mountain wood tick, is the most common vector in the western United States.4,7,8Rhipicephalus sanguineus, the brown dog tick, has also been found to transmit RMSF in Arizona.9,10

While most infections in humans are transmitted by tick bite, rare cases of RMSF are contracted through exposure to infective tick hemolymph during tick removal, parenteral inoculation or infectious aerosols in laboratory settings, and blood transfusion.7,8

Geographic distribution of nationally notifiable tickborne diseases

Figure 1. Geographic distribution of nationally notifiable tickborne diseases, 2015.

The geographic distribution of RMSF is restricted to the Western Hemisphere. Within the United States, cases of RMSF have been reported in nearly every state.4 However, RMSF is most prevalent in North Carolina, Tennessee, Missouri, Arkansas, and Oklahoma (Figure 1).1

RMSF is both the most common and the most likely cause of death among rickettsial infections in the United States.4,7,8 Most cases occur in children ages 5 to 9.10,11 The case-fatality rate is over 20% without antimicrobial therapy but less than 1% with timely and appropriate antibiotic treatment.7,8

Clinical manifestations of Rocky Mountain spotted fever

RMSF is transmitted after only 2 to 20 hours of tick attachment, and symptoms begin 3 to 12 days after inoculation.1,7,8 Unlike many other species that cause SFGR infection, R rickettsii does not cause an eschar at the site of inoculation.7,12

The classic triad of RMSF is fever, headache, and a rash. This triad is present in only 3% of early infections, but the prevalence increases to 60% to 70% by 2 weeks after the tick bite.1,7 Other common initial symptoms include generalized malaise, weakness, and myalgia.7,8,12 Gastrointestinal symptoms are common, and RMSF can be misdiagnosed as gastroenteritis, particularly in children.8

A rash usually occurs. It is due to systemic vasculitis and endothelial injury and often presents 2 to 5 days after the onset of fever, which can delay diagnosis.7,12,13 It usually progresses from macular to petechial and begins on the ankles, forearms, and wrists, spreading centripetally to the trunk and face and often including the palms and soles.7 Large areas of ecchymosis, ulceration, and (uncommonly) gangrene may occur as lesions coalesce.7,8 The 10% of patients who do not develop a rash (“spotless” fever) tend to have a poorer prognosis due to delayed diagnosis.8

Risk factors for severe disease include delay or lack of appropriate treatment, extremes of age, Native American descent, glucose-6-phosphate dehydrogenase deficiency, and immunocompromised states.1,10,11,13 Complications from the widespread Rickettsia-induced vasculitis may include a septic or toxic shock-like syndrome and neurovascular, cardiac, respiratory, and renal damage.7,11 Without appropriate therapy, death occurs 7 to 15 days after symptom onset.8

Laboratory evaluation may reveal thrombocytopenia and anemia.7 Leukocytosis or leukopenia may be present.8 Hyponatremia, elevated aminotransferase levels, elevated creatine kinase levels, prolonged coagulation times, and decreased fibrinogen may also be present.7,8

Diagnosis of Rocky Mountain spotted fever

No diagnostic studies are available for the acute phase of RMSF. Therefore, a high suspicion of RMSF is essential, and treatment should be started as soon as RMSF is suspected. Confirmatory testing can retrospectively validate a clinical diagnosis.4,7,11

Serologic testing with an immunofluorescence antibody assay remains the principal diagnostic test for RMSF, and paired testing (during the acute and convalescent phases) has a sensitivity of 94%.4 A 4-fold or greater increase in antibody titer (with a minimum titer of 1:64) between acute and convalescent samples is considered diagnostic of acute infection.4,7,8 Serology is often negative early in the disease course.4,7,8 The assay cross-reacts with other SFGR species, however.4,8

Amplification of R rickettsii DNA by polymerase chain reaction (PCR) from blood or biopsy sites can be done in some research settings, but its utility is limited because of low sensitivity early in the course of the infection.4,7

Immunohistochemical staining of a skin biopsy or autopsy specimen is a highly specific diagnostic test performed at a limited number of laboratories, though it has a sensitivity of only 60% to 92%.4,7,8

Cell culture can also be performed, but only in biosafety level 3 (scale of 1 to 4) laboratories.1

Treatment of Rocky Mountain spotted fever

Prompt initiation of antibiotic therapy greatly improves prognosis.1,13,14

Doxycycline for 7 days is the treatment of choice for RMSF, including in pregnant patients with life-threatening disease and in children.4,7,8,15,16

Tetracycline can also be used.

Chloramphenicol is an alternative treatment for pregnant patients with mild to moderate disease or those patients with a severe hypersensitivity reaction to doxycycline.1,4,7,9,15,16 In the United States, chloramphenicol is currently available only in an intravenous formulation.

Fever typically subsides within 24 to 48 hours of starting treatment.4,8 Failure to clinically improve within 48 hours suggests an alternative diagnosis.1,4 Long-term complications of severe infection may include hearing loss, blindness, and amputation of digits or extremities due to gangrene.1,8 Persistence of disease beyond acute infection has not been observed.1


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