Tafenoquine for Relapsing Babesiosis: A Case Series.

BACKGROUND: Relapsing babesiosis often occurs in highly immunocompromised patients and has been attributed to the acquisition of resistance against drugs commonly used for treatment such as atovaquone, azithromycin, and clindamycin. Tafenoquine, which is approved for malaria prophylaxis and presumptive antirelapse treatment of Plasmodium vivax malaria, has shown activity against Babesia microti in several animal models of acute infection and in a single human case of relapsing babesiosis. Here, we report 5 cases of relapsing babesiosis treated with tafenoquine, including the previous case, and begin to define the conditions for optimal use of tafenoquine in relapsing babesiosis. METHODS: A definitive diagnosis of babesiosis was made by microscopic examination of Giemsa-stained thin blood smears or a real-time polymerase chain reaction (PCR) that targets the parasite 18S rRNA gene. Clearance of B. microti infection was ascertained by use of blood smear and real-time PCR. RESULTS: Tafenoquine was initiated with a loading dose of 600 mg. A weekly maintenance dose consisted of 200 mg or 300 mg; the lower dose was associated with a delayed clearance of B. microti. In 2 cases, all antimicrobial agents but tafenoquine were discontinued prior to clearance of infection. In 2 other cases, clearance was achieved while tafenoquine was administered along with other antimicrobial agents. In 3 of these 4 cases, tafenoquine was used in combination with atovaquone-proguanil. Other agents included atovaquone, azithromycin, and/or clindamycin. In 1 case, tafenoquine was administered alone and failed to prevent relapse. CONCLUSIONS: Tafenoquine can be a useful adjunct for the treatment of highly immunocompromised patients experiencing relapsing babesiosis caused by B. microti.

Cardiac Complications of Human Babesiosis.

BACKGROUND: Human babesiosis is a worldwide emerging tick-borne disease caused by intraerythrocytic protozoa. Most patients experience mild to moderate illness, but life-threatening complications can occur. Although cardiac complications are common, the full spectrum of cardiac disease and the frequency, risk factors, and outcomes in patients experiencing cardiac complications are unclear. Accordingly, we carried out a record review of cardiac complications among patients with babesiosis admitted to Yale-New Haven Hospital over the last decade to better characterize cardiac complications of babesiosis. METHODS: We reviewed the medical records of all adult patients with babesiosis admitted to Yale-New Haven Hospital from January 2011 to October 2021, confirmed by identification of Babesia parasites on thin blood smear and/or by polymerase chain reaction. The presence of Lyme disease and other tick-borne disease coinfections were recorded. RESULTS: Of 163 enrolled patients, 32 (19.6%) had ≥1 cardiac complication during hospitalization. The most common cardiac complications were atrial fibrillation (9.4%), heart failure (8.6%), corrected QT interval prolongation (8.0%), and cardiac ischemia (6.8%). Neither cardiovascular disease risk factors nor preexisting cardiac conditions were significantly associated with the development of cardiac complications. The cardiac complication group had a greater prevalence of high-grade parasitemia (>10%) (P < .001), longer median length of both hospital (P < .001) and intensive care unit stay (P < .001), and a higher mortality rate (P = .02) than the group without cardiac complications. CONCLUSIONS: Cardiac complications of acute babesiosis are common and occurred in approximately one-fifth of this inpatient sample. Further investigation is needed to elucidate the relationship between babesiosis severity and cardiac outcomes.

Broad Antimicrobial Resistance in a Case of Relapsing Babesiosis Successfully Treated With Tafenoquine.

We describe a case of relapsing babesiosis in an immunocompromised patient. A point mutation in the Babesia microti 23S rRNA gene predicted resistance to azithromycin and clindamycin, whereas an amino acid change in the parasite cytochrome b predicted resistance to atovaquone. Following initiation of tafenoquine, symptoms and parasitemia resolved.

Neurologic Complications of Babesiosis, United States, 2011-2021.

Babesiosis is a globally distributed parasitic infection caused by intraerythrocytic protozoa. The full spectrum of neurologic symptoms, the underlying neuropathophysiology, and neurologic risk factors are poorly understood. Our study sought to describe the type and frequency of neurologic complications of babesiosis in a group of hospitalized patients and assess risk factors that might predispose patients to neurologic complications. We reviewed medical records of adult patients who were admitted to Yale-New Haven Hospital, New Haven, Connecticut, USA, during January 2011-October 2021 with laboratory-confirmed babesiosis. More than half of the 163 patients experienced >1 neurologic symptoms during their hospital admissions. The most frequent symptoms were headache, confusion/delirium, and impaired consciousness. Neurologic symptoms were associated with high-grade parasitemia, renal failure, and history of diabetes mellitus. Clinicians working in endemic areas should recognize the range of symptoms associated with babesiosis, including neurologic.

Transfusion-transmitted Babesia spp.: a changing landscape of epidemiology, regulation, and risk mitigation.

Babesia spp. are tick-borne parasites with a global distribution and diversity of vertebrate hosts. Over the next several decades, climate change is expected to impact humans, vectors, and vertebrate hosts and change the epidemiology of Babesia. Although humans are dead-end hosts for tick-transmitted Babesia, human-to-human transmission of Babesia spp. from transfusion of red blood cells and whole blood-derived platelet concentrates has been reported. In most patients, transfusion-transmitted Babesia (TTB) results in a moderate-to-severe illness. Currently, in North America, most cases of TTB have been described in the United States. TTB cases outside North America are rare, but case numbers may change over time with increased recognition of babesiosis and as the epidemiology of Babesia is impacted by climate change. Therefore, TTB is a concern of microbiologists working in blood operator settings, as well as in clinical settings where transfusion occurs. Microbiologists play an important role in deploying blood donor screening assays in Babesia endemic regions, identifying changing risks for Babesia in non-endemic areas, investigating recipients of blood products for TTB, and drafting TTB policies and guidelines. In this review, we provide an overview of the clinical presentation and epidemiology of TTB. We identify approaches and technologies to reduce the risk of collecting blood products from Babesia-infected donors and describe how investigations of TTB are undertaken. We also describe how microbiologists in Babesia non-endemic regions can assess for changing risks of TTB and decide when to focus on laboratory-test-based approaches or pathogen reduction to reduce TTB risk.

Frequency and Geographic Distribution of Borrelia miyamotoi, Borrelia burgdorferi, and Babesia microti Infections in New England Residents.

BACKGROUND: Borrelia miyamotoi is a relapsing fever spirochete that relatively recently has been reported to infect humans. It causes an acute undifferentiated febrile illness that can include meningoencephalitis and relapsing fever. Like Borrelia burgdorferi, it is transmitted by Ixodes scapularis ticks in the northeastern United States and by Ixodes pacificus ticks in the western United States. Despite reports of clinical cases from North America, Europe, and Asia, the prevalence, geographic range, and pattern of expansion of human B. miyamotoi infection are uncertain. To better understand these characteristics of B. miyamotoi in relation to other tickborne infections, we carried out a cross-sectional seroprevalence study across New England that surveyed B. miyamotoi, B. burgdorferi, and Babesia microti infections. METHODS: We measured specific antibodies against B. miyamotoi, B. burgdorferi, and B. microti among individuals living in 5 New England states in 2018. RESULTS: Analysis of 1153 serum samples collected at 11 catchment sites showed that the average seroprevalence for B. miyamotoi was 2.8% (range, 0.6%-5.2%), which was less than that of B. burgdorferi (11.0%; range, 6.8%-15.6%) and B. microti (10.0%; range, 6.5%-13.6%). Antibody screening within county residence in New England showed varying levels of seroprevalence for these pathogens but did not reveal a vectoral geographical pattern of distribution. CONCLUSIONS: Human infections caused by B. miyamotoi, B. burgdorferi, and B. microti are widespread with varying prevalence throughout New England.

Epidemiology of Hospitalized Patients with Babesiosis, United States, 2010-2016.

Babesia spp. are tickborne parasites that cause the clinical infection babesiosis, which has an increasing incidence in the United States. We performed an analysis of hospitalizations in the United States during 2010-2016 in which babesiosis was listed as a diagnosis. We used the National Inpatient Sample database to characterize the epidemiology of Babesia-associated admissions, reflecting severe Babesia-related disease. Over a 7-year period, a total of 7,818 hospitalizations listed babesiosis as a primary or secondary admitting diagnosis. Hospitalizations were seasonal (71.2% occurred during June-August) and situated overwhelmingly in the Northeast and Midwest. The patients were predominantly male and of advanced age, which is consistent with the expected epidemiology. Despite a higher severity of illness in more than (58.5%), the mortality rate was low (1.6%). Comparison with state reporting data suggests that the number of hospitalized persons with babesiosis increased modestly during the observation period.

Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA): 2020 Guideline on Diagnosis and Management of Babesiosis.

The purpose of this guideline is to provide evidence-based guidance for the most effective strategies for the diagnosis and management of babesiosis. The diagnosis and treatment of co-infection with babesiosis and Lyme disease will be addressed in a separate Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR) guideline [1]. Recommendations for the diagnosis and treatment of human granulocytic anaplasmosis can be found in the recent rickettsial disease guideline developed by the Centers for Disease Control and Prevention [2]. The target audience for the babesiosis guideline includes primary care physicians and specialists caring for this condition, such as infectious diseases specialists, emergency physicians, intensivists, internists, pediatricians, hematologists, and transfusion medicine specialists.

Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA): 2020 Guideline on Diagnosis and Management of Babesiosis.

The purpose of this guideline is to provide evidence-based guidance for the most effective strategies for the diagnosis and management of babesiosis. The diagnosis and treatment of co-infection with babesiosis and Lyme disease will be addressed in a separate Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR) guideline [1]. Recommendations for the diagnosis and treatment of human granulocytic anaplasmosis can be found in the recent rickettsial disease guideline developed by the Centers for Disease Control and Prevention [2]. The target audience for the babesiosis guideline includes primary care physicians and specialists caring for this condition, such as infectious diseases specialists, emergency physicians, intensivists, internists, pediatricians, hematologists, and transfusion medicine specialists.

Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.

Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.

Tick hypersensitivity and human tick-borne diseases.

Immune-mediated hypersensitivity reactions to ticks and other arthropods are well documented. Hypersensitivity to ixodid (hard bodied) ticks is especially important because they transmit infection to humans throughout the world and are responsible for most vector-borne diseases in the United States. The causative pathogens of these diseases are transmitted in tick saliva that is secreted into the host while taking a blood meal. Tick salivary proteins inhibit blood coagulation, block the local itch response and impair host anti-tick immune responses, which allows completion of the blood meal. Anti-tick host immune responses are heightened upon repeated tick exposure and have the potential to abrogate tick salivary protein function, interfere with the blood meal and prevent pathogen transmission. Although there have been relatively few tick bite hypersensitivity studies in humans compared with those in domestic animals and laboratory animal models, areas of human investigation have included local hypersensitivity reactions at the site of tick attachment and generalized hypersensitivity reactions. Progress in the development of anti-tick vaccines for humans has been slow due to the complexities of such vaccines but has recently accelerated. This approach holds great promise for future prevention of tick-borne diseases.

Parasite burden and red blood cell exchange transfusion for babesiosis.

BACKGROUND: The association between parasite burden and end-organ dysfunction in subjects with Babesia microti infection has not been extensively studied, nor has the optimal role of red blood cell exchange (RCE) transfusion in babesiosis treatment. This retrospective chart review evaluates the associations between parasitemia, end-organ dysfunction, and outcomes in babesiosis patients treated with antimicrobial agents and RCE compared to those treated with antimicrobial agents alone. MATERIALS AND METHODS: We evaluated adults (≥18 years of age) with laboratory-confirmed babesiosis who were admitted between 2011 and 2017 to Yale New Haven Hospital, located in a Babesia-endemic region of the Northeastern United States. Patient demographics, parasitemia levels, clinical and laboratory indicators of end-organ dysfunction, and outcomes were examined. RESULTS: Ninety-one subjects (mean age 65.1 years, 69.2% male) were studied. Subjects were stratified according to peak parasitemia: <1% (n = 34), 1-5% (n = 24), 5-10% (n = 15), and >10% (n = 18). Laboratory measures indicating degrees of hemolysis, coagulopathy, and pulmonary, renal and hepatic dysfunction differed significantly across peak parasitemia levels. Median length of hospital stay increased with each successive peak parasitemia level (P < .001). These results indicate a strong association between peak parasitemia level and disease severity. Nineteen subjects underwent RCE, all with peak parasitemia ≥9% and some degree of end-organ dysfunction. CONCLUSIONS: Babesia microti parasitemia is closely associated with disease severity, though not all subjects with end-organ dysfunction had high-grade parasitemia. Our data suggest that the use of parasitemia >10%, coupled with clinical status, is a reasonable indicator for RCE in babesiosis patients.

Clofazimine, a Promising Drug for the Treatment of Babesia microti Infection in Severely Immunocompromised Hosts.

BACKGROUND: Persistent and relapsing babesiosis caused by Babesia microti often occurs in immunocompromised patients, and has been associated with resistance to antimicrobial agents such as atovaquone. Given the rising incidence of babesiosis in the United States, novel drugs are urgently needed. In the current study, we tested whether clofazimine (CFZ), an antibiotic used to treat leprosy and drug-resistant tuberculosis, is effective against B. microti. METHODS: Mice with severe combined immunodeficiency were infected with 107B. microti-infected erythrocytes. Parasites were detected by means of microscopic examination of Giemsa-stained blood smears or nested polymerase chain reaction. CFZ was administered orally. RESULTS: Uninterrupted monotherapy with CFZ curtailed the rise of parasitemia and achieved radical cure. B. microti parasites and B. microti DNA were cleared by days 10 and 50 of therapy, respectively. A 7-day administration of CFZ delayed the rise of parasitemia by 22 days. This rise was caused by B. microti isolates that did not carry mutations in the cytochrome b gene. Accordingly, a 14-day administration of CFZ was sufficient to resolve high-grade parasitemia caused by atovaquone-resistant B. microti parasites. CONCLUSIONS: Clofazimine is effective against B. microti infection in the immunocompromised host. Additional preclinical studies are required to identify the minimal dose and dosage of CFZ for babesiosis.

Seroprevalence of Borrelia burgdorferi, B. miyamotoi, and Powassan Virus in Residents Bitten by Ixodes Ticks, Maine, USA.

We conducted a serosurvey of 230 persons in Maine, USA, who had been bitten by Ixodes scapularis or I. cookei ticks. We documented seropositivity for Borrelia burgdorferi (13.9%) and B. miyamotoi (2.6%), as well as a single equivocal result (0.4%) for Powassan encephalitis virus.

Repeat exchange transfusion for treatment of severe babesiosis.

We report a case of severe babesiosis presenting with 43% parasitemia in a 73-year-old splenectomized woman on etanercept for rheumatoid arthritis. She initially was treated aggressively with clindamycin and quinine and exchange transfusion. Despite a post-exchange drop in parasitemia to 7.6%, it rebounded to 11.4% on hospital day 5 accompanied by new onset high fevers and hypoxia. She improved after a second exchange transfusion and ultimately resolved her infection after 12 weeks of antibabesial antibiotics. Although exchange transfusion is commonly used in immunocompromised hosts, there is a dearth of information about repeat exchange transfusion, including the risk for and outcome of repeat exchange. We performed a literature search for other cases of repeat exchange transfusion for severe Babesia microti infection and compared our case with those in other published reports.

Human Babesiosis Caused by a Babesia crassa-Like Pathogen: A Case Series.

Background: Human babesiosis is an emerging health problem in China. Methods: Babesia were identified in ticks, sheep, and humans in northeastern China using polymerase chain reaction (PCR) followed by genetic sequencing. We enrolled residents who experienced a viral-like illness after recent tick bite or were healthy residents. We defined a case using the definition for babesiosis developed by the US Centers for Disease Control and Prevention. Results: A Babesia crassa-like agent was identified in Ixodes persulcatus and Haemaphysalis concinna ticks using PCR followed by sequencing. The agent was characterized through phylogenetic analyses of the 18S rRNA gene, the ß-tubulin gene, and the internal transcribed spacer region. We tested sheep as a possible reservoir and found that 1.1% were infected with the B. crassa-like agent. We screened 1125 human participants following tick bites using B. crassa-specific PCR and identified 31 confirmed and 27 suspected cases. All the patients were previously healthy except for 1 with an ovarian tumor. Headache (74%), nausea or vomiting (52%), and fever (48%) were the most common clinical manifestations of confirmed cases. Six of 10 cases remained PCR positive for B. crassa-like infection 9 months after initial diagnosis. Asymptomatic infections were detected in 7.5% of 160 local residents. Conclusions: We identified B. crassa-like infection in people in northeastern China that caused mild to moderate symptoms. The possibility of more severe disease in immunocompromised patients and of transmission through the blood supply due to asymptomatic infections justifies further investigation of this reported infection.

BmGPAC, an Antigen Capture Assay for Detection of Active Babesia microti Infection.

Human babesiosis is an emerging zoonotic infectious disease caused by intraerythrocytic protozoan parasites of the genus Babesia Most cases of human babesiosis are caused by Babesia microti and often manifest in individuals over the age of 50 years or in patients with a compromised immune system. Patients who develop symptomatic B. microti infections usually experience months of asymptomatic infection after the acute infection has resolved. About one-fifth of B. microti-infected adults never develop symptoms. These asymptomatically infected individuals sometimes donate blood and thus can transmit B. microti through blood transfusion. Current assays for detection of active B. microti infections can be used to screen donor blood prior to transfusion, but they rely primarily on microscopy or PCR methods, which have sensitivity and technical limitations. Here we report the development of an antigen capture enzyme-linked immunosorbent assay (BmGPAC) based on a major secreted immunodominant antigen of B. microti (BmGPI12/BmSA1), and we provide evidence that this assay is superior for detection of active B. microti infections, compared to available microscopy methods and serological assays. The assay has been evaluated using supernatants of B. microti-infected erythrocytes cultured in vitro, sera from B. microti-infected laboratory mice, and sera from wild mice and human patients. Our data suggest that the BmGPAC assay is a reliable assay for detection of active B. microti infections and is superior to real-time PCR and antibody assays for diagnosis of acute B. microti infections, screening of the blood supply, and epidemiological surveys of humans and animal reservoir hosts.

Superior real-time polymerase chain reaction detection of Babesia microti parasites in whole blood utilizing high-copy BMN antigens as amplification targets.

BACKGROUND: Babesiosis is a zoonotic disease transmitted to humans by the bite of infected ticks and caused by apicomplexan parasites, most commonly Babesia microti. Additionally, blood and blood products collected from asymptomatically infected blood donors may cause transfusion-transmitted infections in recipients. Highly sensitive molecular assays that detect parasite nucleic acid are needed for laboratory diagnosis and to identify and defer clinically silent but parasitemic blood donors. STUDY DESIGN AND METHODS: Here we report the development and analytical and clinical characterization of a real-time polymerase chain reaction (RT-PCR)-based assay for the detection of B. microti genomic DNA in whole blood. We evaluate the detection of Babesia parasites using two separate targets, the traditional18S ribosomal subunit gene (Bm18S) and members of the abundant BMN family of seroreactive antigens (BmBMN). RESULTS: Analytical sensitivity determination using a probit analysis demonstrated an analytical sensitivity of 30.9 parasites/mL for 18S amplification and 10.0 parasites/mL for BMN amplification The BMN primer set also demonstrates superior sensitivity for serial dilution panels prepared from clinically diagnosed Babesia-infected blood samples, generally detecting 10-fold more dilute nucleic acid. CONCLUSIONS: Cumulatively, our data demonstrate that RT-PCR detection of the BMN family of seroreactive antigens reflects a sensitive and superior assay for the detection of B. microti in whole blood samples.

Transfusion-transmitted babesiosis: is it time to screen the blood supply?

PURPOSE OF REVIEW: This review summarizes the current status of blood screening to prevent transfusion-transmitted babesiosis (TTB). RECENT FINDINGS: Babesia microti has recently been determined to be the most common transfusion-transmitted pathogen in the United States. Patients who acquire TTB often experience severe illness with an associated mortality rate of about 20%. Recent studies have demonstrated that laboratory screening using B. microti antibody and/or PCR assays can effectively identify infectious blood donors and that this approach may offer a cost- effective means of intervention. Pathogen inactivation methods may offer an alternative solution. None of these methods has yet been licensed by US Food and Drug Administration, however, and current efforts to prevent TTB rely on excluding blood donors who report having had babesiosis. SUMMARY: TTB imposes a significant health burden on the United States population. Further research is needed to better inform decisions on optimal screening strategies and reentry criteria, but given the acute need and the currently available screening tools, initiation of blood donor screening to prevent TTB should be given high priority.