Infection with Ehrlichia chaffeensis is an acute and potentially fatal condition. Factors associated with severe infection are not yet completely clear. The role of tumor necrosis factor (TNF) in disease prevention and disease severity remains unclear. We present a case of rapid fulminant ehrlichiosis in a patient receiving etanercept, a TNF-blocking agent.
A 55-year-old man from Arkansas was diagnosed with seropositive rheumatoid arthritis 4 years prior and was being treated with weekly etanercept 50 mg subcutaneously, sulfasalazine 1500 mg twice a day, and hydroxychloroquine 400 mg once a day. He had not taken any steroids or other immunosuppressive agents for the past 2 years. He presented with a 6-day history of nausea and fever of up to 104°F and a rash on his ankles for 1 day. He worked in the timber industry and spent a large amount of time in the rural outdoors. He reported frequent tick bites. At presentation, he had a blood pressure of 76/56 mm Hg and was alert and oriented appropriately. He was noted to have a petechial rash on his ankles and feet and marked facial and truncal flushing. Examination also revealed a rapid irregular heart rate consistent with a prior diagnosis of atrial fibrillation. There was no appreciable hepatosplenomegaly. Neurologically, the patient had no deficits. Laboratory analysis revealed a white blood cell (WBC) count of 3400/μL, hemoglobin level of 15.1 g/dL, and a platelet count of 27,000/μL. His creatinine level was 2.0 mg/dL. His serum alanine aminotransferase (ALT) was 254 U/L, and his serum aspartate aminotransferase (AST) was 499 U/L. Two days before first developing fever, he had been seen by his rheumatologist and, at that time, had a WBC count of 5700/μL, a platelet count of 196,000/μL, serum creatinine of 1.2 mg/dL, ALT of 38 U/L, and AST of 32 U/L. Upon admission to the hospital, his etanercept was discontinued, and he was empirically started on broad-spectrum antibiotics including cefepime, vancomycin, and doxycycline along with supportive care. The patient improved on antibiotics within 24 hours. His WBC count quickly returned to within the reference range, as did his serum creatinine. His platelet count, ALT, and AST also returned to normal levels over the next several days. An assay for antibodies to Rickettsia rickettsii was negative, as was a tularemia agglutination assay. Serum antibodies to E. chaffeensis were detected (immunoglobulin G, 1:2048; immunoglobulin M, 1:160). A serum polymerase chain reaction analysis for E. chaffeensis was also positive. The cefepime and vancomycin were discontinued, and the patient was discharged home after 5 days of hospitalization to complete a 3-week course of doxycycline. His etanercept was held until after finishing the doxycycline.
Ehrlichia chaffeensis is a gram-negative obligate intracellular organism that is common in the southern and southeastern United States. The first reported case of human infection with what would become known as E. chaffeensis was in 1986 when a visitor to rural Arkansas returned home to Michigan and subsequently developed a febrile illness similar to Rocky Mountain spotted fever. Prominently featured were thrombocytopenia, elevated liver transaminase levels, renal insufficiency, and hypotension. The characteristic morulae of Ehrlichia were seen in the patient's peripheral blood smear.1 This agent of human ehrlichiosis was reported as a unique organism in 1991 and named E. chaffeensis.2 Human infection with E. chaffeensis is now known to be transmitted by the Lone Star tick, Amblyomma americanum, and the American dog tick, Dermacentor variabilis. Endemic areas coincide with the geographical distribution of these ticks, and the incidence of infection peaks every year between the months of April and October, when the ticks are most active.3
Patients with ehrlichiosis usually present with a febrile illness that has occurred for a period of days to a week. In some cases, there may not be a history of known tick bite. Symptoms may be mild and include only fever and malaise or may be severe and include nausea, diarrhea, acute renal failure, meningoencephalitis, disseminated intravascular coagulation, and death.4 In less than half of infected patients, there can be a maculopapular or petechial rash that starts on the hands and/or ankles and sometimes spreads to the trunk.4 Common laboratory abnormalities that may be seen include leukopenia, thrombocytopenia, elevated AST, and hyponatremia.3,4 In some patients, the disease is self-limited and resolves without requiring medical care. In others, disease can be acutely fulminant. The factors associated with more severe disease are not clear, but immunosuppression is felt to be a factor.4
Prompt diagnosis and initiation of treatment requires a high degree of suspicion, as confirmatory laboratory testing can be delayed because of performance at a reference laboratory. In highly endemic areas during "tick season," empirical antibiotic therapy with doxycycline is often given to any person that presents with the typical features. Prompt resolution of symptoms can be considered highly suggestive of a tick-borne infection. In cases that are less clear or more severe, various diagnostic testing can be attempted. In some cases of ehrlichiosis, the characteristic intracellular inclusion bodies, or morulae, can rarely be seen in a peripheral blood smear, usually in mononuclear cells. Serological tests for antibodies to E. chaffeensis can be helpful but may be negative in early disease. Repeat serology testing can be used to verify a 4-fold or greater rise in antibodies.5 Serum polymerase chain reaction detection for E. chaffeensis is available and can be quite useful for diagnosis.6 Polymerase chain reaction is especially useful during acute infection when the organism is more easily detectable in the blood.
Tumor necrosis factor α, a proinflammatory cytokine, plays a major role in controlling many intracellular organisms. Infection with E. chaffeensis is associated with production of Ehrlichia-antibody immune complexes that lead to increased production of TNF-α and other proinflammatory cytokines.7 Tumor necrosis factor α also plays a role in several autoimmune disorders, including inflammatory bowel disease and rheumatoid arthritis among others. Agents that inhibit TNF-α are becoming used with increasing frequency with many successful results. However, agents that decrease or inhibit TNF-α have also been associated with increased rates of various intracellular organisms including Mycobacteria, Histoplasma, Coccidioides, Listeria, and Nocardia.8 There are also now reports of infections with various other organisms such as Legionella, Bartonella, and Streptococcus pneumoniae 9-12 in patients receiving etanercept.
There are currently 3 available TNF-α blockers. Etanercept is a soluble recombinant TNF-α receptor that mimics TNF-α receptor 2. Etanercept binds TNF-α before it is able to bind to a functional TNF-α receptor.13 Two other agents, infliximab and adalimumab, are monoclonal antibodies to TNF-α. Etanercept has been associated with increased incidences of the above-mentioned pathogens but in smaller numbers than those seen with the other TNF-α inhibitory agents.8,14 Recent work15 suggests that etanercept inhibits T cell apoptosis and also leads to decreased levels of interleukin 10 production. Unlike infliximab and adalimumab, etanercept seems to have no role in T cell inhibition or production of interferon γ. This may explain why etanercept has less of an increased risk of infection than infliximab or adalimumab.
As E. chaffeensis is an intracellular organism, it is reasonable to consider the role of TNF-α in controlling this organism in humans and the role of TNF-α-inhibiting agents with respect to morbidity and mortality in ehrlichiosis. We could find only 1 published report of ehrlichiosis in a patient receiving a TNF-α inhibitor, specifically etanercept.16 Our case represents the second such case involving this agent. Ismail et al17 have reported on the role of TNF-α in mouse models of ehrlichiosis. In their models, infection with lethal strains of Ehrlichia was associated with increased TNF-α production by CD8+ T cells and a septic shock picture. Infections with less lethal strains led to decreased TNF-α production, milder disease, and better outcomes as did infections with lethal strains after prior challenge with a less lethal strain. Additional work by Ismail et al18 has shown that mice deficient in TNF receptors 1 and 2 had higher bacterial burdens, decreased hepatocyte damage, and prolonged survival, although all animals eventually succumb. Mice that had normal TNF receptors but were instead TNF-α deficient had increased hepatic damage and decreased length of survival when compared with the mice deficient in TNF receptors 1 and 2.
Our patient was also receiving sulfasalazine and hydroxychloroquine. Both of these agents also contribute to decreased levels of TNF-α.19,20 The role that these drugs, both alone and in conjunction with other anti-TNF-α agents, may play in ehrlichial infections remains unclear. However, to our knowledge, these 2 agents have not previously been associated with increased risk of ehrlichiosis.
Ehrlichiosis remains a serious, rapidly progressive, and potentially fatal infection. The interactions between the immune system and this organism are yet to be fully elucidated, especially in regard to the role of TNF-α. Definitive proof of an association between TNF-α inhibitors and ehrlichiosis has not been established. However, as TNF-α inhibitors are increasingly used for various conditions, the concern of opportunistic infections in these patients remains high. It remains to be seen whether E.chaffeensis will be included in the list of possible opportunistic infections in those patients receiving etanercept or similar agents.
1. Maeda K, Markowitz N, Hawley RC, et al. Human infection with Ehrlichia canis
, a leukocytic rickettsia. N Engl J Med
2. Anderson BE, Dawson JE, Jones DC, et al. Ehrlichia chaffeensis
, a new species associated with human ehrlichiosis. J Clin Microbiol
3. Schutze GE. Ehrlichiosis. Pediatr Infect Dis J
4. Walker DH, Dumler JS. Ehrlichia chaffeensis
(human monocytotropic ehrlichiosis), Anaplasma phagocytophilum
(human granulocytotropic anaplasmosis), and other Ehrlichieae. In: Mandell, et al, eds. Principles and Practice of Infectious Diseases
. Elsevier: Philadelphia; 2005:2310-2318.
5. Dawson JE, Fishbein DB, Eng TR, et al. Detection of Ehrlichia chaffeensis
with the indirect fluorescent antibody test: kinetics and specificity. J Infect Dis
6. Everett ED, Evans KA, Henry RB, et al. Human ehrlichiosis in adults after tick exposure. Diagnosis using polymerase chain reaction. Ann Intern Med
7. Lee EH, Rikihisa Y. Anti-Ehrlichia chaffeensis
antibody complexed with E. chaffeensis
induces potent proinflammatory cytokine mRNA expression in human monocytes through sustained reduction of IκB-alpha and activation of NF-κB. Infect Immun
8. Wallis RS, Broder MS, Wong JY, et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis
9. Tubach F, Rayaud P, Salmon-Ceron D, et al. Emergence of Legionella pneumophila
pneumonia in patients receiving tumor necrosis factor-alpha antagonists. Clin Infect Dis
10. Mathieu S, Vellin JF, Poujol D, et al. Cat scratch disease during etanercept therapy. Joint Bone Spine
11. Killingley B, Carpenter V, Flanagan K, et al. Pneumococcal meningitis and etanercept-chance or association? J Infect
12. Baghai M, Osmon DR, Wolk DM, et al. Multifocal septic arthritis and osteomyelitis caused by group A Streptococcus in a patient receiving immunomodulating therapy with etanercept. Pediatr Infect Dis J
13. Crum NF, Lederman ER, Wallace MR. Infections associated with tumor necrosis factor-α antagonists. Medicine
14. Shiff MH, Burmester GR, Kent JM, et al. Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis
15. Oluwabunmi YS, Sofer C, Stein DS, et al. Tumor-necrosis-factor blockers: differential effects on mycobacterial immunity. J Infect Dis
16. Stone JH, Dierberg K, Aram G, et al. Human monocytic ehrlichiosis. JAMA
17. Ismail N, Soong L, McBride JW, et al. Overproduction of TNF-α by CD8+type 1 cells and down-regulation of IFN-γ production by CD4+Th1 cells contribute to toxic shock-like syndrome in an animal model of fatal monocytotropic ehrlichiosis. J Immunol
18. Ismail N, Stevenson HL, Walker DH. Role of tumor necrosis factor α (TNF-α) and interleukin-10 in the pathogenesis of severe murine monocytotropic ehrlichiosis: increased resistance of TNF receptor p55- and p75-deficient mice to fatal ehrlichial infection. Infect Immun
19. Rodenburg RJ, Ganga A, van Lent PL, et al. The antiinflammatory drug sulfasalazine inhibits tumor necrosis factor α expression in macrophages by inducing apoptosis. Arthritis Rheum
20. Weber SM, Levitz SM. Chloroquine interferes with lipopolysaccharide-induced TNF-α gene expression by a nonlysosomotropic mechanism. J Immunol