Can tumor necrosis factor α blockade predispose to severe babesiosis?
Article first published online: 31 JAN 2007
Copyright © 2007 by the American College of Rheumatology
Arthritis Care & Research
Volume 57, Issue 1, pages 179–181, 15 February 2007
How to Cite
Taiwo, B., Lee, C., Venkat, D., Tambar, S. and Sutton, S. H. (2007), Can tumor necrosis factor α blockade predispose to severe babesiosis?. Arthritis & Rheumatism, 57: 179–181. doi: 10.1002/art.22479
- Issue published online: 31 JAN 2007
- Article first published online: 31 JAN 2007
- Manuscript Accepted: 8 MAY 2006
- Manuscript Received: 24 JAN 2006
- NIH. Grant Number: K12-RR-017707
Babesiosis is a zoonosis caused by Babesia species, an intracellular protozoan transmitted by Ixodes scapularis (deer tick). Babesiosis is not a reportable disease in the US; therefore, its exact incidence is unknown. However, there are published cases of babesiosis occurring in several areas of the US, with the highest numbers reported in the southern New England states, southern New York, Wisconsin, and Minnesota. Most reported cases are caused by Babesia microti; however, rarely cases have also been attributed to Babesia divergens, a Babesia species from Washington state (WA-1-type), and a Babesia species from Missouri (MO1) (1). A previously arcane diagnosis, babesiosis is likely to increase in incidence and geographic distribution in part due to human encroachment on wild life for recreation and habitation (2). B microti infections are sometimes subclinical and self-limiting, but severe systemic symptoms and even fatal disease may occur in persons with compromised ability to clear the parasite. Specific immune deficiency states associated with severe babesiosis include anatomic or functional asplenia, malignancy, and use of immunosuppressive drugs including high-dose corticosteroids (3, 4). Here we describe a patient who developed severe babesiosis while receiving etanercept for management of longstanding rheumatoid arthritis (RA).
A 67-year-old man with RA who was a long-time resident of Chicago, Illinois spent 9 days with friends at a private vacation camp in northern Wisconsin in the middle of July 2005. He engaged in many outdoor activities at the camp site and recalled brushing off numerous ticks from his body. He presented to our institution 5 weeks later with 3 days of intermittent fever, chills, and sweating. Other accompanying symptoms included nausea, anorexia, mild lightheadedness, and bilateral fronto-temporal headache. The remainder of his systemic review was negative. He denied any sick contacts.
The patient's RA was diagnosed in November 2002. He initially received methotrexate, which was stopped because of nodulitis. Leflunomide, azathioprine, and infliximab were also administered on separate occasions, but the patient experienced inadequate control of his RA prior to his current regimen (50 mg subcutaneous injections of etanercept weekly combined with 5 mg of prednisone daily), which was started in March 2005. Other chronic medical problems included diet-controlled diabetes (last glycosylated hemoglobin 6.5%), peripheral neuropathy, depression, hypertension, Hashimoto thyroiditis in remission, attention deficit disorder, and prostatectomy for prostate cancer (prostate-specific antigen was 0 ng/ml 1 month prior to presentation).
The patient's vital signs at the time of presentation showed a temperature of 38.4°C, a blood pressure of 125/77 mm Hg, a regular pulse of 74/minute, respiration of 18/minute, and oxygen saturation of 96% on room air. He appeared anxious but otherwise had a normal physical examination, including absence of any remarkable joint synovitis. Initial laboratory data revealed a white cell count of 6.9 × 103/μl (52% neutrophils, 30% monocytes, 18% lymphocytes, 0% eosinophils, and 0% basophils), hemoglobin of 15 gm/dl, hematocrit of 44.6%, platelet count of 60 × 103/μl, normal electrolytes, creatinine of 1.3 mg/dl, an alanine aminotransferase of 52 units/liter, and an aspartate aminotransferase of 40 units/liter. The initial peripheral smear showed a paucity of platelets without schistocytes, morulae, or intraerythrocytic parasites. Screening for disseminated intravascular coagulation was negative. Given the potential concern for an infectious source of the patient's fevers, etanercept was discontinued, but prednisone was continued to maintain control of his RA.
During his initial hospital course, blood culture, serum human immunodeficiency virus (HIV) RNA, and serologies for HIV, Epstein-Barr virus, hepatitis C virus, and cytomegalovirus were negative. A computed tomography scan of the abdomen and pelvis was normal with the presence of a normal-sized spleen. The patient declined a lumbar puncture because of his concerns over the potential for bleeding. On hospital day 4, the patient developed shortness of breath and oxygen saturation dropped to 87% on room air, requiring supplemental oxygen; however, a chest radiograph was negative. Repeat hemoglobin, hematocrit, platelet count, and white cell count were 12.1 gm/dl, 34.4%, 22 × 103/μl, and 2.6 × 103/μl, respectively. Total bilirubin increased to 1.5 mg/dl (direct 0.4 mg/dl) and lactate dehydrogenase increased to 425 units/liter. The patient was empirically started on doxycycline 100 mg twice daily for possible ehrlichiosis.
On hospital day 5, repeat microscopic examination of Giemsa-stained thin blood smear showed intraerythrocytic forms (Figure 1) with occasional tetrads/maltese cross formations that were consistent with babesiosis. Subsequently, the B microti polymerase chain reaction (PCR; forward primer 5′-tccaacttcgacatggtcca-3′ and reverse primer 5′- accgttacgccagagtttgc-3′ performed by Specialty Laboratories, Valencia, CA) was positive, and therefore a test for B microti antibodies was not performed. In addition, ehrlichiosis and Lyme serologies were negative. A bone marrow biopsy specimen showed mild immaturity of myeloid elements, normal erythroid elements, and normal megakaryocyte morphology. Blast cells were normal in number and fungal stains were negative. Doxycycline was discontinued and clindamycin and quinine were started for treatment of babesiosis. However, this antibiotic regimen was stopped on the second day of treatment because the patient developed severe nausea, dizziness, and hearing impairment, which were suggestive of cinchonism. His treatment was changed to azithromycin and atovaquone, which were well tolerated. Intraerythrocytic forms on peripheral smears cleared by the fourth day of anti-Babesia therapy. The patient's hemoglobin and hematocrit levels reached a nadir of 8.4 gm/dl and 23.9%, respectively, on hospital day 8. He was discharged on hospital day 9, by which time his platelet count had normalized and the respiratory symptoms had resolved. Our patient completed a 10-day course of azithromycin and atovaquone postdischarge. The patient remained clinically asymptomatic in terms of his RA during the hospital course.
Four weeks later, at a followup visit to the infectious diseases clinic, the patient reported feeling well and had normal hemoglobin level, hematocrit level, platelet count, and white blood cell count. He was also seen in the rheumatology clinic the following week because of recrudescent morning stiffness accompanied by pain and swelling of his hands and wrists. Etanercept was reintroduced, which was followed by resolution of his joint symptoms. Four months following the reinitiation of etanercept, our patient remained asymptomatic in terms of his RA, and his hemoglobin level, hematocrit level, platelet count, and white blood cell count were normal at 14.7 gm/dl, 43.6%, 311 × 103/μl, and 5.6 × 103/μl, respectively.
To our knowledge, this is the first reported case of babesiosis identified in a patient receiving etanercept, an anti–tumor necrosis factor (anti-TNF) agent, for the treatment of RA. However, our patient may also have been at increased risk for severe babesiosis in part due to his age. In addition, corticosteroid use has also been implicated as a risk factor for severe babesiosis, but the patient's daily dose of prednisone was low and was less than physiologic levels of endogenous steroids. An association between the immunologic effects of etanercept and predisposition to severe clinical manifestations of babesiosis, as suggested by this case, is plausible based on the known functions of TNF. However, definitive determination of a causal relationship requires adequately powered and controlled studies. TNFα is an inflammatory cytokine that is primarily produced by activated macrophages and in smaller quantities by T lymphocytes, B lymphocytes, fibroblasts, and endothelial cells. TNFα acts through cellular receptors (TNF receptor 1 and TNF receptor 2) to exert biologic activities that include cellular proliferation and differentiation, apoptosis, cytotoxicity, inflammation, and immune modulation. Thus, a large quantity of TNF is potentially deleterious and mediates immunoinflammatory disorders. Physiologic quantities of TNF, however, play a central role in the defense against intracellular bacteria, viruses, and parasites, mainly through its recruitment of eosinophils and macrophages to the sites of infection. TNF is also capable of killing and controlling the proliferation of intracellular parasites (5).
The mechanisms through which B microti is controlled in a newly infected host are incompletely understood. However, TNFα appears to have important immunologic roles in handling such an infection, in addition to the role of a functioning spleen. For example, macrophages release TNF when they are exposed to B microti (6). Secondly, experimental inoculation of mice with B microti resulted in an increase in the splenic expression of TNFα, with peak titers occurring a few days after peak parasitemia (7). Our understanding of the pathogenesis of B microti needs to be improved; however, like other intracellular organisms, the immune response to B microti may be influenced by numerous factors.
Immune response modifiers are a broad group of agents that control disease by modulating the body's immune response. One of these agents is etanercept, a recombinant dimeric p75 TNF receptor that is linked and fused to the Fc region of IgG1. It does not affect TNF production or serum level; rather, it competitively prevents TNFα and TNFβ from binding to their cell surface receptors. Etanercept is approved by the Food and Drug Administration for the treatment of RA, juvenile RA, psoriatic arthritis, and ankylosing spondylitis. It has also been found to be effective in the treatment of many other rheumatologic and dermatologic conditions, including psoriasis, sarcoidosis, Behçet's disease, Langerhans' cell histiocytosis, and cicatricial pemphigoid (8). Despite the clinical utility of etanercept, and other agents similar to it, their use is not without risk as their potential to interfere with the protective immunologic functions of TNF is well recognized. For example, there are several reports of severe tuberculosis, fungal infections, infections caused by other intracellular pathogens, and sepsis in association with TNF blockade (8–10), although a causative role has not been established in all cases. Given the purported immunologic role of TNFα in controlling intracellular parasitic infections, B microti may be another example of an infectious organism that may cause more fulminant clinical manifestations in some patients treated with anti-TNF agents. In our patient, the discontinuation of entanercept, the timely diagnosis of babesiosis, and the institution of definitive therapy likely prevented further clinical deterioration.
Another caveat illustrated by the current case is the presence of anemia and thrombocytopenia in the setting of active babesiosis and anti-TNFα use. Mild to severe hemolytic anemia and thrombocytopenia are common findings described in cases of babesiosis (11). Conversely, anti-TNFα agents can affect the growth of hematopoietic stem cells and potentially result in peripheral cytopenias. Despite the absence of any clear causal relationship, pancytopenia including aplastic anemia, albeit uncommon, have been reported in association with etanercept use (12). In our patient, anemia stabilized and thrombocytopenia improved after institution of appropriate antibiotic treatment of babesiosis. The patient remained hematologically stable following subsequent rechallenge with anti-TNFα therapy. Therefore, the onset of new cytopenias in patients with RA should prompt clinicians to also consider other causes of hematologic abnormalities beyond those potentially due to adverse effects of anti-TNFα therapy.
It is likely that the use of IRMs, as well as the incidence and geographic distribution of babesiosis will increase in the future. Physicians practicing in places where human babesiosis is endemic should consider this diagnosis when patients present with suggestive clinical symptoms or laboratory findings. Laboratory testing that may be useful in establishing a diagnosis of babesiosis includes microscopic examination of Giemsa-stained thin blood smear, Babesia antibody studies, and PCR testing. Meanwhile, patients who reside or recreate in such places should be advised to undertake measures that reduce exposure to I scapularis. A comprehensive reference on preventive measures is provided by the Centers for Disease Control and Prevention (13). Such advice may be particularly germane to individuals receiving anti-TNFα agents.
The authors wish to acknowledge Dr. Rowland Chang who provided outpatient care and helpful information for this work, and Linda Kuksuk who assisted us in the clinical parasitology laboratory.
Dr. Taiwo had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. Drs. Taiwo and Sutton.
Acquisition of data. Drs. Taiwo, Venkat, Tambar, and Sutton.
Analysis and interpretation of data. Drs. Taiwo, Lee, Venkat, and Sutton.
Manuscript preparation. Drs. Taiwo, Lee, Venkat, and Sutton.
- 2Babesia species. In: MandellG, BennettD, DolinR, editors. Principles and practice of infectious diseases. Pennsylvania: Elsevier Inc: Philadelphia; 2005. p. 3209–14., .
- 13Centers for Disease Control and Prevention. Spotlight: tick tips. URL: http://www.cdc.gov/ncidod/ticktips2005.