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Tick-borne diseases in the United States: Rocky Mountain spotted fever and Colorado tick fever. A review.

The historical, clinical, ecological, and epidemiological features of Rocky Mountain spotted fever and Colorado tick fever, the two important tick-borne diseases in the United States, are reviewed. Rocky Mountain spotted fever, once considered a disease of the past, has again become a measurable public health problem. Its nationwide incidence has steadily increased since 1960 and has reached record proportions in 1976. The various factors responsible for this trend as well as for the mortality rates, which in spite of availability of effective antibiotics ranges from 5 to 10%, are discussed. Education of the public about ticks and their potential role as vectors of Rickettsia rickettsii and/or Colorado tick fever virus, and about the clinical manifestations of Rocky Mountain spotted fever, is considered the best means for preventing high incidence and mortality from these diseases.

Antibodies, Viral

Co-circulation of multiple Colorado tick fever virus genotypes.

Colorado tick fever (CTF) virus, family Reoviridae, genus Orbivirus, contains 12 genes distinguishable by polyacrylamide gel electrophoresis (PAGE). Multiple genotypes of CTF virus were isolated at 3 field sites in Colorado in 1985. Five genotypes were found at Campos Cabin, 2 at Drake, and 6 at Rocky Mountain National Park. Virus isolations were made in 1985 from 6 patients with CTF. These isolates were distinct from each other and the field isolates. Although the CTF isolates were different by PAGE profile, the majority of the 12 genes were highly conserved among the 1985 isolates and a Florio isolate (FMA). Only genes 4 and 6 were variant among the 1985 CTF isolates and FMA, and no unique genes were identified. In 1986, a follow-up field survey was done at the Campos Cabin site. Of the 3 CTF PAGE genotypes obtained, 2 exhibited PAGE profiles which were different from the 1985 isolates. One isolate may have resulted from the reassortment of genes from 2 of the isolates circulating at Campos Cabin in 1985.

Animals

Establishment of reverse genetics systems for Colorado tick fever virus.

The Colorado tick fever virus (CTFV), which has 12-segmented double-stranded RNA genomes, is a pathogenic arbovirus that causes severe diseases in humans. However, little progress has been made in the analysis of replication mechanisms and pathogenicity. This virological constraint is due to the absence of a reverse genetics system for CTFV; therefore, we aimed to establish the system. Initially, the efficacy of CTFV replication was investigated in various cell lines. CTFV was found to grow in many cell types derived from different hosts and organs. Subsequently, BHK-T7 cells stably expressing T7 RNA polymerase were transfected with plasmids encoding each of the 12 CTFV gene segments, expression plasmids encoding all CTFV proteins, and a vaccinia virus RNA-capping enzyme. Following transfection, the cells were co-cultured with Vero or HeLa cells. Using this system, we rescued monoreassortants and recombinant viruses harboring peptide-tagged viral proteins. Furthermore, an improved system using Expi293F cells expressing T7 RNA polymerase was established, which enabled the generation of recombinant reporter CTFVs. In conclusion, these reverse genetics systems for CTFV will greatly contribute to the understanding of viral replication mechanisms, pathogenesis, and transmission, ultimately facilitating the development of rational treatments and candidate vaccines.

Animals

Experimental Colorado tick fever virus infection in Colorado mammals.

One hundred and twenty-four small mammals of six species were inoculated with three strains of Colorado tick fever (CTF) virus to define viremia and neutralizing (N) antibody responses. Adult Eutamias minimus and Eutamias embrinus, and juvenile Peromyscus maniculatus and Spermophilus lateralis, were highly susceptible to development of viremic infection. Adult S. lateralis and P. maniculatus were moderately susceptible (greater than or equal to 50% viremic). Five Sylvilagus nuttalli did not become viremic following experimental inoculation. Spermophilus richardsoni was also relatively resistant (less than or equal to 50% viremic). The longest duration of viremia (mean 15.8 days) and highest peak viremia levels (mean peak titer 10(3.9 plaque-forming units per ml) occurred in E. minimus. Adult E. umbrinus, juvenile S. lateralis, and juvenile P. maniculatus had moderate viremias. Adult S. lateralis and S. richardsoni often had short viremias during which virus was only intermittently detectable. N antibody production was most rapid in E. minimus in comparison with other species. In addition, N antibody persisted for 1 year in this species. In other species, many animals lost detectable antibody 5-11 months after infection. No significant differences were found in patterns of infection between three CTF virus strains. We conclude that of the six species inoculated, E. minimus is the best experimental host for CTF virus.

Animals

An overview of Colorado tick fever.

Certain features of Colorado tick fever (CTF) virus and the disease it causes may be relevant to studies on bluetongue virus (BTV), or other orbiviruses. Rapid and easy detection of viral antigen in infected tissues and peripheral blood cells by immunofluorescence staining facilitate diagnosis of the disease. The prolonged (3-4 months) viremia is due to persistent intracellular infection, particularly of erythrocytes, in which the virus is protected from antibody or other host defense mechanisms. This results in more efficient maintenance of the virus cycle in nature, but might lead to adverse effects in the human host. Clues to understanding chronic viral infections or viral immunosuppression might be gained by further research on CTF and other orbiviruses.

Animals

Colorado tick fever: clinical, epidemiologic, and laboratory aspects of 228 cases in Colorado in 1973-1974.

During 1973 and 1974, we looked for cases of Colorado tick fever throughout Colorado; 228 cases were identified. Although 90% of the patients reported exposure to ticks before illness, only 52% were aware of an actual tick bite. Typical symptoms of fever, myalgia, and headache were common, but gastrointestinal symptoms were also prominent in 20% of the patients. Twenty percent were hospitalized; no deaths or permanent sequelae were noted. Persistent viremia (greater than or equal to 4 weeks) was found in about half of the cases; this finding was not associated with the occurrence of prolonged symptoms (greater than or equal to 3 weeks), which were also reported in half of the cases. One patient became reinfected with the virus. Increasing tourism in endemic areas and the frequent occurrence of prolonged or biphasic illnesses provide the potential for patients with Colorado tick fever to seek medical care anywhere in the United States.

Adolescent

Antigenic variants of Colorado tick fever virus.

Twenty strains of Colorado tick fever (CTF) virus, isolated from ticks, mammals and humans, and two antigenic relatives of CTF virus were compared in cross-neutralization tests. Viruses were tested using single-inoculation sera prepared in hamsters. Antigenic variation, as measured by differences detected in the neutralization test, was noted among the virus isolates identified as strains of CTF virus. The virus strains isolated from humans appeared to vary the most in serological reactions. The two antigenic relatives of CTF virus are clearly distinct from strains of CTF and are different from each other. Antigenic relationships between these two viruses were established using two sets of single-inoculation antisera and both complement fixation and neutralization tests. Six distinct antigenic variants of CTF virus isolated from humans and the virus strain from ticks (75V1906) that showed the least antigenic variation, were tested against 49 coded serum pairs from clinically diagnosed cases of CTF. Significant differences were noted in the number of convalescent-phase sera that reacted with each virus strain and in the number of seroconversions observed with each test virus strain. Convalescent phase sera that reacted with multiple virus strains often varied significantly in antibody titre from one virus strain to another. This indicates that, in some instances, antibody was probably produced in response to infection by different antigenic variants of CTF virus.

Animals

Detection of Colorado tick fever virus by using reverse transcriptase PCR and application of the technique in laboratory diagnosis.

Colorado tick fever (CTF) virus elicits an acute illness in humans, producing nonspecific flu-like symptoms and a biphasic fever in approximately 50% of patients. The disease is transmitted by the adult Rocky Mountain wood tick (Dermacentor andersoni), and therefore incidence is limited by the habitat and life cycle of that vector. The early symptoms of infection are difficult to distinguish from those of several other agents, especially Rickettsia rickettsii. Serologic testing is usually unable to provide evidence of CTF viral infection during the acute phase because of the late appearance of the various antibodies. Here we report the development and clinical application of a test to diagnose this disease during the acute stages. Oligonucleotide primers to the S2 segment of CTF (Florio) virus were made, and these were used in the amplification of a 528-bp fragment of DNA, transcribed from the double-stranded CTF virus RNA template by reverse transcriptase PCR. RNAs processed from 16 CTF virus isolates yielded similar results when analyzed on agarose gels. These were distinguishable from their antigenic relatives Eyach, S6-14-03, and T5-2092 and from other coltiviruses and an orbivirus but not from the antigenically distinct CTF virus-related isolate 720896. A mouse model demonstrated the utility of this method with whole-blood specimens, and CTF virus was successfully detected in human sera from the initial day of the onset of symptoms to 8 days later. The reverse transcriptase PCR method is a promising tool for the early diagnosis of CTF viral infection, or for ruling out CTF virus as the etiologic agent, in order to facilitate appropriate medical support.

Adult

The ecology of Colorado tick fever in Rocky Mountain National Park in 1974. II. Infection in small mammals.

Field studies of Colorado tick fever (CTF) in small mammals in Rocky Mountain National Park (RMNP) in 1974 established that Eutamias minimus and Spermophilus lateralis were the most important hosts for CTF virus and were the source of virus for immature stages of the tick vector, Dermacentor andersoni. Other species (Peromyscus maniculatus, Spermophilus richardsonii, Eutamias umbrinus) are secondary hosts. The intensity of viral activity in rodents varied greatly from locality to locality. Highest rodent infection rates were found to occur in the Moraine Park area of RMNP. Lowest infection rates occurred above 3,290 meters in altitude at Rainbow Curve and on the tundra. The prevalence of infection in rodents was constant from April--July (5--6% of animals captured were viremic) and then declined to 1.7--2.5% in August and September coincident with a decline in nymphal tick ectoparasitism. Many animals were captured which were simultaneously viremic and antibody-positive. Under field conditions, neutralizing antibody seroconversion does not always occur.

Animals

Virus-induced leukopenia: Colorado tick fever as a human model.

Eight patients with Colorado tick fever were studied to determine whether alterations in the production of granulopoietic stimulatory or inhibitory factors (or both) could be found in association with the leukopenic state of the disease. The studies demonstrate that in the patients with Colorado tick fever the mononuclear cell production of colony-stimulating factor is decreased and that there is an increase in circulating inhibitory factors in the serum of such patients. The depressed mononuclear cell colony-stimulating activity does not appear to be reversible by addition of either endotoxin or normal human serum. Characterization of these serum inhibitory factors may facilitate understanding of leukopenia in human disease.

Adult

Survey for evidence of Colorado tick fever virus outside of the known endemic area in California.

A virus very similar or identical to Colorado tick fever (CTF) virus was recovered from the blood clot of one of 104 black-tailed jack rabbits (Lepus californicus) examined during a survey for various zoonotic agents in mammals and ticks from the University of California, Hopland Field Station, Mendocino County, California, 1974--79. This is the first reported isolation of a CTF-like virus from L. californicus, and only the second time such a virus has been found in northwestern California. Mendocino County is located far outside the known distributional ranges of the most common mammalian hosts of CTF virus and of Dermacentor andersoni, the only proven tick vector for man. The viral isolate is very similar to a CTF-like virus previously recovered from the blood and spleen of a western gray squirrel (Sciurus griseus) from San Luis Obispo County, an area also outside of the previously-known CTF area. Virus was not isolated from 14 additional species of mammals (354 specimens) or from eight species of ticks (4,487 individuals), but CTF-neutralizing antibodies were detected in 28 of 771 (3.6%) sera from seven of 15 mammalian species including significant titers (greater than or equal to 1:8) in two species and one subspecies not previously reported as natural hosts, i.e., brush mouse (Peromyscus boylii), pinyon mouse (P. truei), and Columbian black-tailed deer (Odocoileus hemionus columbianus). CTF indirect immunofluorescent antibodies also were detected in 26 of 129 (20.2%) sera belonging to four of five mammalian species tested. Neutralizing antibodies were found in sera of deer from other localities in Mendocino County, from a deer mouse from Napa County, and from a brush rabbit from Monterey County as well. These findings suggest that a virus identical or similar to CTF virus is widespread in northwestern-westcentral California, and that surveillance for human cases of CTF or a similar disease should be extended to cover this region.

Animals

Ecology of porcupines (Erethizon dorsatum) and Colorado tick fever virus in Rocky Mountain National Park, 1975-1977.

The involvement of porcupines, Erethizon dorsatum (L.), in the ecology of Colorado tick fever (CTF) virus in Rocky Mountain National Park was investigated from 1975 to 1977. Porcupine dens and feeding activity were found mostly on rocky knolls or on south-facing slopes within open stands of the montane coniferous forest, and 20 adult porcupines were trapped or captured by hand at those locations. An average of 24.6 +/- 5.4 adult Dermacentor andersoni Stiles ticks were found per animal (annual range, 17.5-31.4 ticks). The minimum CTF virus infection rate of the ticks removed from porcupines varied from 129 to 257, whereas for questing adult D. andersoni ticks from the same geographic area was 205 in 1976. No virus was isolated from the 20 animals, but 85% had neutralizing antibody against CTF virus. Porcupines utilize the same habitats described for the CTF ecosystem in Rocky Mountain National Park and appear to be an important host for adult D. andersoni.

Animals

The ecology of Colorado tick fever in Rocky Mountain National Park in 1974. III. Habitats supporting the virus.

Ecologic studies of small mammals in Rocky Mountain National Park (RMNP) were conducted in 1974 in order to identify the specific habitats within the Lower Montane Forest that support Colorado tick fever (CTF) virus. Data was collected on the abundance and distribution of 4 primary rodent species, tick infestation, CTF virus, and neutralizing antibody prevalence. Rodents were captured along transects crossing different habitats. Open stands of ponderosa pine and shrubs on dry, rocky surfaces were found to be important for maintaining CTF virus.

Animals

Diagnosis of Colorado tick fever virus infection by enzyme immunoassays for immunoglobulin M and G antibodies.

An immunoglobulin M (IgM) capture enzyme immunoassay technique was adapted for the detection of antibody to Colorado tick fever virus in sera from 84 individuals for whom diagnosis had been confirmed by virus isolation or neutralization test. Titers were compared with those for IgG and neutralizing antibodies in these Colorado tick fever cases. IgM antibody titers were higher than neutralizing antibody titers, but neither appeared until 1 to 2 weeks after the onset of illness. Neutralizing antibodies were detected earlier than IgM antibodies, and both were detected with greater frequency than IgG antibodies. Late-convalescent-phase sera contained both neutralizing and IgG antibodies, but IgM was all but undetectable by 2 months after onset. Although the neutralization test may remain the serological test of choice, the enzyme immunoassay for IgM antibody offers a simple and more rapid method of serodiagnosis; the enzyme immunoassay is, however, less sensitive than the neutralization test. Furthermore, because there was a sharp decline in IgM antibody after 45 days, the presence of IgM antibody in a single serum sample provides a basis for the presumptive serodiagnosis of recent Colorado tick fever virus infection.

Adolescent

Colorado tick fever in a resident of New York City.

When a traveler returns from abroad with a febrile illness, clinicians appropriately concern themselves with a potentially vast array of diagnostic exotica. The patient we describe herein did not leave the United States but nevertheless posed the same clinical dilemma after returning home to New York City from the western United States. This case of Colorado tick fever, acquired on the Utah-Colorado border and first expressed in Manhattan, serves as a useful reminder of the importance of taking a careful travel history for national as well as international travelers.

Antibodies, Viral

Teratogenic effects of Colorado tick fever virus in mice.

The teratogenic effects in mice of Colorado tick fever (CTF) virus, a human pathogen, were demonstrated. Various routes of inoculation, gestational periods, and dosages of virus were studied. The incidence of stillbirth and neonatal death increased significantly after inoculation of pregnant mice with CTF virus. CTF virus crossed the placenta and replicated to high titers in the placental and fetal tissues. Mice that survived the first six weeks of life had neutralizing antibody to CTF virus. Neutralization tests, in which pregnant mice were inoculated with both CTF virus and specific antiserum to CTF virus, validated the teratogenic effects of CTF virus in mice.

Animals