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Rocky Mountain Spotted Fever in a patient treated with anti-TNF-alpha inhibitors

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Rocky Mountain Spotted Fever in a patient treated with anti-TNF-alpha inhibitors
Rana M Mays1 MD, Rachel A Gordon2 MD, K Celeste Durham3 MD, Whitney J LaPolla2 MD, Stephen K Tyring1 MD PhD
Dermatology Online Journal 19 (3): 7

1. Center for Clinical Studies, Webster, Texas
2. Center for Clinical Studies, Houston, Texas
3. University of Texas Medical School at Houston, Houston, Texas


Rocky Mountain Spotted Fever (RMSF) is a tick-bourne illness, which can be fatal if unrecognized. We discuss the case of a patient treated with an anti-TNF-alpha inhibitor for rheumatoid arthritis who later developed a generalized erythematous macular eruption accompanied by fever. The clinical findings were suggestive of RMSF, which was later confirmed with serology. Prompt treatment with doxyclycine is recommended for all patients with clinical suspicion of RMSF.

Case report

A 60-year-old man from southeast Texas presented with complaints of fever, malaise, frontal headache, and a diffuse non-pruritic eruption for the last week. He had a history of rheumatoid arthritis (RA) for which he was previously on etanercept therapy. However, after the emergence of severe pustular palmo-plantar psoriasis, his etanercept was discontinued and he was started on adalimumab. This regimen was continued approximately 7 months when this new eruption developed. Past medical history in addition to RA was significant for palmo-plantar psoriasis (drug induced) and seasonal allergies. The patient denied history of travel, sick contacts, or exposure to HIV or hepatitis. Physical examination revealed an otherwise healthy-appearing male in no apparent distress. He was febrile with a temperature of 103 F; other vital signs were within normal limits. Examination of the skin revealed diffuse small blanching erythematous macules on the trunk, back, and bilateral lower extremities (Figure 1). A slightly larger excoriated erythematous papule with mild surrounding edema was noted on the posterior neck (Figure 2). Laboratory evaluation was notable for mild leukocytosis (11.1 thousand/uL, normal= 3.8-10.8 thousand/uL); serum chemistry and liver function panel were unremarkable.

Figure 1Figure 2
Figure 1. Small erythematous macules on the trunk, back, and lower extremities.

Figure 2. Erythematous excoriated papule with mild surrounding edema on posterior neck.

Given the history and clinical presentation, the diagnosis of Rocky Mountain Spotted Fever (RMSF) was considered. The patient was started on doxycycline 100 mg PO twice daily, pending further testing. A shave biopsy of the excoriated lesion (Figure 2) revealed papillary edema and a mixed infiltrate of mononuclear cells and eosinophils consistent with persistent arthropod assault reaction. Serology for RMSF demonstrated a positive IgG titer of 1:1024 (normal ≤ 1:64). On further discussion, the patient noted a recent history of tick bite on his posterior neck a few days prior to presentation. The patient’s symptoms and cutaneous eruption resolved within days of beginning doxycycline. He completed a total of 30 days of treatment and had no signs or symptoms at a one month follow-up. The patient’s palmo-plantar psoriasis eventually resolved and he currently continues on adalimumab monotherapy with acceptable control of his RA. It is uncertain whether the patient’s clinical presentation and symptoms were stunted given the concurrent anti-TNF alpha immunosuppressant therapy. Although the incidence of RMSF has not been reported to be affected by concurrent anti-TNF alpha therapy, it is possible that the patient’s timing and severity of symptoms and response to therapy may be altered given the suppression of the appropriate immune response. In this case, the patient presented with a one-week history of generalized symptoms; it is possible that his symptoms had been more severe disease upon presentation given his immunosuppression. Given the concurrent immunosuppression, the patient was treated with a full 30-day course of antibiotics and clinical findings were evaluated after that time to determine if continuation of therapy was warranted. Repeat serology was not performed.

RMSF is a zoonotic tick-borne illness caused by Rickettsia rickettsii, a Gram negative obligate intracellular bacteria [2, 3]. RMSF is transmitted by Dermacentor variabilis, the American dog tick, found in central and southern US, and by Dermacentor andersoni, the Rocky Mountain wood tick found in the western regions of the US. Transfer of the organism into the bloodstream occurs via the saliva or feces of the tick and usually occurs with a longer feeding (> 6 hours). RMSF is the most common of rickettsial diseases and is known to be the most lethal tick-borne infection in the US [1]. The disease is endemic to all regions of the United States. However, the highest prevalence of disease has been reported in North Carolina, Oklahoma, Tennessee, Arkansas, South Carolina, Maryland, and Virginia [2, 3]. From 1997-2002, the estimated incidence of RMSF in the US was 2.2 cases per million people [5], with a large majority of the cases occurring from April to September [1, 3, 4]. The actual incidence of RMSF is probably much higher with low reporting owing to factors such as empiric treatment without serologic confirmation [6, 7].

RMSF is a curable disease if diagnosed and treated in the early stages. However it carries a high risk of fatality with late treatment and/or diagnosis [1, 8]. Serious sequelae include cardiovascular compromise, hypovolemic shock, meningoencephalitis, coma, and death [8]. The incubation period is 5-10 days post tick-bite, with some cases reported as late as 14 days after bite [3, 9]. The classic presentation includes a triad of fever, rash, and headache. However, these features occur concurrently in only 3 percent of cases [4, 5, 6]. The classic eruption is characterized by erythematous blanching macules that evolve into petechia or purpura. The typical distribution is wrists and ankles with later extension to the trunk, palms, and soles. Cutaneous manifestations occur an average of 3-6 days after initial symptoms and petechia may not always be present [9]. Nausea, vomiting, and abdominal pain are common and a misdiagnosis of gastrointestinal disease is possible [10]. After introduction into the bloodstream, R. rickettsii adheres to and replicates in the endothelial cells of small to medium-size blood vessels causing a lymphohistiocytic vasculitis [3, 6]. Subsequent vascular endothelial dysfunction and increased vessel permeability lead to edema and activation of the inflammatory cascade in almost any organ system and may result in complications such as digital gangrene, myocarditis, acute renal failure, meningoencephalitis, cerebral edema, and ARDS [3, 6].

T diagnosis of RMSF is challenging for even the most experienced clinicians. The initial diagnosis is suspected based on clinical findings but should be confirmed with laboratory testing. RMSF should be considered in all febrile patients with a known or possible history of tick exposure [6]. Tick bites are usually painless and frequently go unnoticed [3]. Therefore, clinical suspicion should prompt the physician to initiate prophylactic therapy. On biopsy of macular lesions, R. rickettsii can be identified via Geimsa or Gimenez staining, direct immunofluorescence, and/or immunohistochemical staining [6, 7]. Biopsy of the petechia may also demonstrate a characteristic perivascular lymphohistiocytic infiltrate [6]. Serologic testing with IgM or IgG titers to R. rickettsii (> 1:64) is the most common confirmatory method for RMSF diagnosis. Frequently IgM and IgG titers are not positive within the first 7 to 14 days of disease. According to Paddock et al, up to 25 percent of patients will not have positive titers > 64 at the end of the second week of disease. Therefore, immunohistochemical staining should be considered in severe cases in which the diagnosis has not been established [7]. Seroconversion usually occurs by the end of the second week, but may take up to 4 weeks in some patients [8]. If RMSF is suspected clinically, treatment should be initiated immediately, regardless of titer results. Abnormalities such as leukopenia, thrombocytopenia, and elevated liver enzymes may aid in the diagnosis, although are not always present [3].

Doxycycline is the treatment of choice for RMSF [8]. It is most effective if initiated within the first five days of symptoms and can significantly reduce mortality [4, 11]. Initiation of antibiotics after 5-7 days of presentation is often futile; there is an associated 23 percent mortality rate with delayed treatment as compared to 4 percent with prompt treatment [10, 11]. The standard duration of treatment is 7-14 days but this can vary depending on resolution of clinical symptoms [3]. Doxycycline is also first line therapy in children according to the American Pediatric Society and the Center for Disease Control and Prevention (CDC) [3, 4, 12] because other agents can increase the risk of fatality. Recommended dosing for adults is 100 mg every 12 hours; dosing in children less than 45 kg (100 lbs.) should be 2.2 mg/kg body weight given twice a day [4]. The recommended dose and duration of doxycycline for RMSF in pediatric patients has not been shown to cause staining of permanent teeth [3, 4, 13]. In patients who are pregnant and/or severely allergic to doxycycline, chloramphenicol is an alternative agent, although less efficacious [4, 13]. Treatment should be initiated immediately, even if cutaneous manifestations are not present, because a rash may not develop in all cases and may not appear until 3 to 5 days into the illness [4, 9, 11]. Prevention of RMSF can be achieved with measures to avoid tick exposure and prompt tick removal.

In conclusion, RMSF should be considered in febrile patients with potential tick exposure in endemic areas of the US. Diagnosis is based on clinical symptoms and the classic blanching macular eruption. Given the high mortality associated with delayed therapy, antibiotics should be initiated promptly pending confirmatory testing.


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