Colorado tick fever

Colorado tick fever (CTF) is a rare, self-limited viral infection caused by the Colorado tick fever virus (CTFV), a coltivirus in the genus Coltivirus and family Spinareoviridae, primarily transmitted to humans through the bite of infected Rocky Mountain wood ticks (Dermacentor andersoni) in the mountainous regions of the western United States and Canada.^[1][2] The virus was first isolated in 1943 from a febrile patient in Colorado, marking the identification of this tick-borne pathogen endemic to elevations between 4,000 and 10,000 feet above sea level.^[2] Symptoms typically emerge after an incubation period of 1 to 14 days and include high fever, chills, severe headache, myalgia, and lethargy, often following a characteristic biphasic pattern in about half of cases where fever subsides briefly before recurring.^[3][4] While most infections are mild and resolve with supportive care such as rest and hydration, rare complications can involve the central nervous system, and fatigue may persist for weeks; no specific antiviral treatment or vaccine exists.^[3][5] CTF is maintained in nature through a cycle involving ticks and small mammals like squirrels, chipmunks, and mice, with the virus passing transstadially (from larva to nymph to adult) and transovarially within tick populations, enabling its persistence in endemic areas.^[1][2] Human cases are uncommon, with only 223 reported to the CDC from 2003 to 2022 across 10 western states where it is notifiable, peaking in spring and summer when adult ticks are most active; underreporting is likely due to its mild nature and lack of national surveillance.^[6][7] Transmission is not person-to-person but can rarely occur via blood transfusion or perinatally from mother to infant.^[1] Diagnosis relies on clinical history of tick exposure in endemic areas combined with serological or PCR testing of blood samples, as the virus can be detected in erythrocytes during acute illness.^[4] Prevention focuses on tick avoidance through measures such as wearing long clothing, using EPA-approved repellents containing DEET or permethrin, and performing thorough tick checks after outdoor activities in wooded or grassy habitats at risk elevations.^[8] Prompt removal of attached ticks with fine-tipped tweezers reduces transmission risk, as the virus requires at least several hours of feeding to infect.^[8] Recent research highlights ongoing surveillance needs, with studies detecting CTFV in ticks from recreational sites in Colorado, Wyoming, and Utah, underscoring its persistence despite declining reported cases possibly due to improved prevention or diagnostic challenges.^[9][10]

Etiology and transmission

Virology

Colorado tick fever virus (CTFV) is the etiologic agent of Colorado tick fever and the type species of the genus Coltivirus within the family Spinareoviridae in the order Reovirales.^[11][12] First isolated in 1943 from the blood of a febrile patient in Colorado, CTFV represents a key arbovirus in the Reoviridae family, distinguished by its tick-borne nature and segmented genome.^[13][14] The genus also includes Eyach virus, a related coltivirus identified in Europe. The virion of CTFV is non-enveloped and icosahedral, with a diameter of 60-80 nm and two concentric capsid layers enclosing a core approximately 50 nm in diameter.^[11][15] Its genome comprises 12 segments of double-stranded RNA (dsRNA), totaling about 29 kb, which is among the largest in the Reoviridae family.^[16][17] The segments range in size from approximately 675 to 4,350 base pairs and encode 13 viral proteins, including structural components like outer capsid proteins and non-structural proteins essential for viral processes.^[18][13] Replication of CTFV takes place entirely in the cytoplasm of infected host cells, where it is characteristically associated with granular matrices, arrays of filaments, and viral inclusion bodies.^[19] The virus enters cells via receptor-mediated endocytosis, followed by uncoating and transcription of the dsRNA segments by the viral RNA-dependent RNA polymerase to produce mRNA.^[18] These mRNAs are translated into viral proteins, which facilitate genome replication and assembly of new virions within cytoplasmic factories.^[11] In tick vectors, CTFV persists through transstadial transmission across larval, nymphal, and adult stages, enabling its perpetuation in vector populations without vertical transmission to eggs.^[20] The complete genome sequence of the prototypic Florio strain of CTFV was determined in 2000, providing insights into segment-specific functions.^[18] For example, segment 9 (1,884 bp) encodes two proteins via a termination codon read-through mechanism: the structural protein VP9, a component of the virion, and the non-structural protein VP9', which localizes to the cytoplasm and may contribute to viral replication or assembly.^[21] Other segments encode key enzymes, such as the RNA-dependent RNA polymerase (VP1) essential for transcription and replication, highlighting the segmented genome's role in coordinated viral protein expression.^[22] As an arbovirus, CTFV maintains an enzootic cycle between ticks and rodent reservoirs, with human infections occurring incidentally via tick bites and no sustained person-to-person spread except in rare blood transfusion cases.^[1]

Vector and transmission

The primary vector for Colorado tick fever is the Rocky Mountain wood tick, Dermacentor andersoni, a hard-bodied tick species prevalent in the western United States and Canada. Adult ticks, which measure approximately 5 mm in length when unfed, are most active during spring and early summer, typically from March to July, when they quest for hosts in grassy or shrubby habitats.^[23][12] The tick life cycle consists of egg, larva, nymph, and adult stages, with each feeding stage requiring a blood meal from a vertebrate host. Larval and nymphal ticks acquire the Colorado tick fever virus during feeding on viremic rodents, such as squirrels, chipmunks, and mice, which serve as the principal amplifying hosts in the enzootic cycle. The virus persists in the tick population through transstadial transmission, moving from the larval to the nymphal stage and then to the adult stage during molting, but transovarial transmission to eggs does not occur, ensuring that newly hatched larvae are uninfected.^[12][24] Transmission to humans primarily happens via the bite of an infected adult tick, as larvae and nymphs rarely feed on people; the virus is injected into the host through the tick's saliva as it feeds. These ticks favor elevations between 4,000 and 10,000 feet in wooded and shrubby areas, where environmental conditions support their survival and activity. Rare non-vector transmissions have been documented, including via blood transfusion from an infected donor and perinatally from mother to fetus, though person-to-person spread is otherwise absent. There is no evidence of mechanical transmission by other insects or dissemination through fomites.^[12][25]

Clinical presentation

Signs and symptoms

Colorado tick fever typically has an incubation period of 1–14 days following the bite of an infected tick, with an average duration of 3–6 days.^[3][26][27] The illness usually begins abruptly with a high fever that can reach up to 104°F (40°C), accompanied by chills, severe headache, myalgia (particularly in the legs and back), profound fatigue, and general malaise. Laboratory findings often include leukopenia (white blood cell count below 4,000/μL) and moderate thrombocytopenia.^[4][28][29] Approximately 50% of cases exhibit a characteristic biphasic fever pattern, in which the initial fever persists for 2–3 days before remitting for another 2–3 days, followed by a recurrence of fever; this pattern is often associated with leukopenia, defined as a white blood cell count below 4,000/μL.^[3][4][30] Other common symptoms include sore throat, nausea, vomiting, and abdominal pain, while a maculopapular rash occurs in fewer than 10% of cases.^[4][3] The total duration of acute illness is generally 7–10 days, though fatigue and weakness may linger for several weeks afterward.^[31][3] In rare instances, complications such as meningitis can arise.^[4]

Complications

Neurological complications from Colorado tick fever are rare, occurring more frequently in children (up to 10% of pediatric patients). These may include aseptic meningitis, encephalitis, or meningoencephalitis, presenting with symptoms such as stiff neck, confusion, and photophobia, particularly in young children or immunocompromised individuals.^[3][32][33] Common laboratory findings include moderate thrombocytopenia and leukopenia, which typically resolve without intervention; however, rare bleeding tendencies may arise due to platelet reduction.^[4][34][35] Other rare effects include pericarditis, pneumonitis, orchitis, or gastrointestinal hemorrhage. Additionally, the use of aspirin in children during the febrile phase carries a risk of Reye's syndrome, a serious condition involving liver and brain swelling, alongside potential exacerbation of bleeding due to thrombocytopenia.^[4][27][36] Long-term effects are generally mild, with some adults experiencing persistent fatigue or asthenia lasting several weeks to months, though no evidence exists of chronic infection or a carrier state.^[27][37][15] Mortality from Colorado tick fever is extremely low and rare (<1%), and most patients achieve full recovery without sequelae.^[10][7]

Diagnosis

Clinical evaluation

Clinical evaluation of suspected Colorado tick fever (CTF) begins with a thorough history to identify risk factors and exposure. Clinicians should inquire about recent travel or outdoor activities in endemic areas, particularly the Rocky Mountains and western U.S. states including Arizona, Colorado, Idaho, Montana, New Mexico, Oregon, South Dakota, Utah, Washington, Wyoming, and parts of Canada, during the peak transmission season from April to July.^[4][38] A history of potential tick exposure from the Rocky Mountain wood tick (Dermacentor andersoni) is crucial, although bites are often unnoticed due to the tick's feeding behavior.^[4] Patients may report a biphasic or "saddleback" fever pattern, with initial symptoms appearing 1–14 days (typically 3–4 days) after exposure, followed by a brief remission and recurrence.^[39][38] Physical examination findings in CTF are generally nonspecific and do not provide pathognomonic signs. Common observations include high fever (often up to 104°F or 40°C), tachycardia, chills, severe myalgias, and headache, reflecting a flu-like illness.^[4][39] A rash is rare and, when present, typically maculopapular or petechial; notably, the absence of rash in most cases helps differentiate CTF from Rocky Mountain spotted fever.^[4][40] Other occasional findings may include pharyngitis, conjunctival injection, or mild lymphadenopathy, but severe signs like organomegaly are uncommon.^[39] Suspicion for CTF should arise in patients from or visiting western U.S. or Canadian endemic regions who present with flu-like illness following outdoor exposure, such as hiking or camping.^[4][38] The differential diagnosis includes other viral infections like dengue, influenza, or enterovirus, as well as tick-borne diseases such as tularemia or Lyme disease.^[4][39] A key initial clue may be leukopenia on complete blood count, prompting further consideration of CTF over bacterial etiologies.^[39] Confirmatory laboratory tests are essential for definitive diagnosis.^[4]

Laboratory tests

Laboratory diagnosis of Colorado tick fever (CTF) relies on serological, molecular, and supportive tests to confirm infection and differentiate it from similar illnesses. Serological testing detects virus-specific antibodies in serum, with IgM enzyme-linked immunosorbent assay (ELISA) used for acute-phase detection, as IgM antibodies typically appear 14–21 days after illness onset. IgG antibodies, also assessed via ELISA or indirect fluorescent antibody (IFA) methods, peak during convalescence at 2–4 weeks post-onset, and a fourfold or greater rise in IgG titer between acute and convalescent samples is considered confirmatory.^[4][41] Molecular detection via reverse transcription polymerase chain reaction (RT-PCR) on blood or serum identifies CTFV RNA, offering high sensitivity during the first week of illness when viremia persists. This method is particularly valuable for early diagnosis, as antibody responses may be delayed.^[4][42] Viral isolation, though rarely performed clinically due to its hazardous nature and requirement for Biosafety Level 3 (BSL-3) facilities, involves culturing the virus in Vero cells or inoculating suckling mice; it is primarily reserved for research purposes.^[15][43] Supportive laboratory findings include complete blood count (CBC) results showing leukopenia in most cases, often followed by relative lymphocytosis and atypical lymphocytes, as well as moderate thrombocytopenia; liver enzymes are typically normal. These hematologic changes reflect CTFV's tropism for hematopoietic progenitor cells but are nonspecific.^[4] Diagnostic testing is available through select commercial laboratories, state health departments, or the CDC's Arbovirus Diagnostic Laboratory, with clinicians advised to contact local health authorities for specimen submission guidance.^[4]

Management

Treatment

There is no specific antiviral treatment for Colorado tick fever (CTF), and management focuses on supportive care to alleviate symptoms and prevent complications.^[5] Patients are advised to rest, maintain adequate hydration, and use over-the-counter analgesics such as acetaminophen or ibuprofen to control fever, headache, and myalgias associated with the characteristic biphasic fever pattern.^[39] Aspirin should be avoided, particularly in children, due to the risk of Reye's syndrome in viral illnesses.^[44] Hospitalization is reserved for severe cases involving significant dehydration, persistent high fever, or complications, where intravenous fluids and close monitoring are provided.^[5] Corticosteroids are generally not recommended unless specific complications arise, and patients should be monitored for potential secondary bacterial infections, though antibiotics are not routinely used.^[39] Experimental therapies like ribavirin have shown antiviral activity in animal models but lack proven efficacy in humans and are not standard.^[45] With supportive care, the prognosis is excellent, and most patients experience full recovery within 1 to 2 weeks, though fatigue may persist for several weeks in some cases.^[15]

Prevention

Prevention of Colorado tick fever (CTF) primarily involves personal protective measures to avoid bites from the Rocky Mountain wood tick, Dermacentor andersoni, the primary vector, as no vaccines or specific prophylactic medications are available.^[5] Experimental vaccines, such as a formalin-inactivated version tested in humans during the 1940s and 1950s, were developed but never advanced to widespread use due to challenges in production and efficacy. Public health efforts emphasize education on tick avoidance in endemic areas of the western United States and Canada.^[46] To minimize exposure, individuals should wear light-colored clothing that covers the arms, legs, and feet, including long sleeves, long pants tucked into socks, and closed-toe shoes when entering tick habitats such as wooded or grassy areas.^[47] Treating clothing, gear, and boots with 0.5% permethrin provides long-lasting protection against tick attachment, remaining effective through multiple washings; permethrin should not be applied directly to skin.^[47] Insect repellents registered by the Environmental Protection Agency (EPA) are recommended for skin application, with N,N-diethyl-meta-toluamide (DEET) at concentrations of 20–30% offering effective repellency for several hours.^[48] Alternatives include picaridin or IR3535, which are equally effective and have a lower odor; oil of lemon eucalyptus (OLE) or para-menthane-3,8-diol (PMD) can be used for children over 3 years old.^[47] DEET and similar repellents should not be applied to children under 2 months of age, and sunscreen should be applied before repellent. Behavioral strategies further reduce risk, such as avoiding wooded, brushy, or high-grass areas known to harbor ticks, particularly during peak activity from March to September at elevations of 4,000–10,000 feet.^[46] Staying on cleared trails, walking in the center of paths, and conducting thorough tick checks daily—focusing on the scalp, ears, armpits, groin, and behind the knees—help detect and remove ticks before they attach.^[47] Showering within 2 hours of returning indoors can wash off unattached ticks.^[49] If a tick is found attached, prompt removal is essential to prevent transmission, which typically requires the tick to feed for several hours. Use clean, fine-tipped tweezers to grasp the tick as close to the skin's surface as possible, then pull upward with steady, even pressure without twisting or jerking to avoid leaving mouthparts embedded.^[49] After removal, clean the bite area and hands thoroughly with rubbing alcohol, iodine scrub, or soap and water; dispose of the tick by placing it in alcohol, sealing it in a bag, or flushing it down the toilet.^[49] Avoid folklore methods like using petroleum jelly, nail polish, or heat, as they may cause the tick to regurgitate and increase infection risk.^[49] Monitor the bite site and overall health for symptoms such as fever or rash for 1–14 days post-removal, and seek medical attention if illness develops.^[3] Individuals with confirmed CTF infections should defer blood or bone marrow donation for 6 months after recovery to prevent transmission.^[5]

Epidemiology

Geographic distribution and incidence

Colorado tick fever is endemic to the western mountainous regions of the United States and Canada, primarily occurring at elevations between 4,000 and 10,000 feet where the vector tick thrives in coniferous forests and shrublands.^[50] In the United States, cases are concentrated in six states: Montana (42% of reported cases), Wyoming (21%), Oregon (16%), Colorado (9%), Utah (7%), and Idaho (2%), with infections acquired across 42 counties in these areas.^[27] Additional states with sporadic reports include Washington, northern New Mexico, and California.^[46] In Canada, the disease is reported in the western provinces of British Columbia and Alberta, particularly in southern Rocky Mountain regions.^[40] The disease is rare, with 148 confirmed cases reported in the United States from 2013 to 2022, averaging approximately 15 cases per year and a national incidence of 0.04 cases per million population.^[27] This represents a decline from historical peaks; for instance, annual reports averaged 50–100 cases in the 1990s, with 864 cases documented from 1985 to 1995, compared to over 200 cases per year during 1970–1984.^[29] Earlier peaks occurred in the mid-20th century, including 552 cases from 1948 to 1959 across 10 western states and 1,767 cases from 1956 to 1965, primarily in Colorado and Wyoming counties.^[29] The reduction in recent decades is attributed to increased public awareness, changes in land use affecting tick habitats, and likely underreporting due to the illness's mild nature and challenges in diagnosis.^[27] Possible cases were first noted in the 19th century, with the disease clearly described as a distinct entity in the early 20th century and the virus isolated in the 1940s.^[51] Seasonally, 98% of cases have illness onset from April through July, peaking in May and June when adult Rocky Mountain wood ticks are most active in seeking hosts.^[27] In the United States, Colorado tick fever is a nationally notifiable condition, tracked by the Centers for Disease Control and Prevention (CDC) through the National Notifiable Diseases Surveillance System (NNDSS) and ArboNET for arboviral diseases, with reporting required in 10 states as of 2023: Arizona, Colorado, Idaho, Montana, New Mexico, Oregon, South Dakota, Utah, Washington, and Wyoming.^[6][27]

Risk factors and trends

Colorado tick fever primarily affects individuals engaged in outdoor activities in the Rocky Mountain region, with cases showing a median age of 55 years (range: 1–84 years) and approximately 65% occurring in males.^[27] Higher incidence is observed among campers, hikers, hunters, and outdoor workers who spend extended time in tick-infested areas such as grassy or brushy woodlands at elevations above 4,000 feet.^[46] Children and the elderly may experience more severe outcomes due to age-related vulnerabilities, though overall disease severity remains low in most cases.^[27] Incidence has remained stable at low levels from 2003 to 2022, with a median of 11 cases reported annually to the CDC (range: 3–37 cases) as of 2022 and no major outbreaks documented.^[6] This pattern aligns with seasonal peaks in spring and early summer, when adult Rocky Mountain wood ticks are most active. However, climate change may contribute to future increases by expanding tick habitats to higher elevations and northern latitudes, potentially broadening the geographic range of the virus.^[52] Factors modifying disease severity include immunosuppression, which can lead to rare complications such as encephalitis or prolonged viremia in affected individuals.^[53] Transfusion transmission is possible due to persistent viremia lasting up to several months, yet routine screening of blood donors in endemic areas is not performed, as no FDA-licensed test exists for this purpose.^[54] Public health strategies emphasize education on tick avoidance to mitigate cases, given the disease's non-contagious nature precludes herd immunity.^[8] Ongoing surveillance and awareness campaigns target high-risk populations to maintain low transmission rates.^[10]