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Babesiosis and Other Protozoan Diseases
Babesiosis
Babesiosis is a tick-borne, malaria-like disease caused by sporozoan parasites of the genus Babesia that infect red blood cells.
Epidemiology
With few exceptions, Babesia spp are transmitted by ixodid ticks. Thus, wherever humans are intensely exposed to hard-bodied ticks, babesiosis should be part of the differential diagnosis for a patient presenting with fever and hematologic abnormalities.
Three worldwide epidemiologic patterns are apparent. The first involves the rodent-maintained Babesia microti , which is a species complex distributed across the Holarctic. About 2000 cases of B. microti babesiosis are reported each year, mostly from the northeastern United States and upper Midwestern states, compared with an average of about 26,000 cases of Lyme disease ( Chapter 296 ), but babesiosis is thought to be underreported. The vector for both B. microti and Lyme disease ( Chapter 296 ) is the deer tick, Ixodes dammini , also known as northern populations of I. scapularis . As a result, concurrent babesiosis and Lyme disease is common. Immunocompetent as well as immunocompromised individuals are at risk. Within the last decade, B. microti has been increasingly reported in an expanded distribution in the United States from its original foci in coastal New England and the Upper Midwest, and it is possible that babesiosis cases eventually may be found wherever Lyme disease is intensely zoonotic. In addition, cases of B. microti or B. microti –like babesiosis have been reported in Australia, Canada, China, Germany, Japan, Mexico, Poland, Spain, South Africa, and Taiwan; the vectors for these have not been definitively identified.
The second pattern is represented by cases of babesiosis due to Babesia divergens , B. divergens –like, or closely related species (e.g., Babesia venatorum ) that have been reported from Asia and Europe. Almost all clinical cases in Europe have been in splenectomized patients who reside in sites where castor bean ticks ( Ixodes ricinus ) and deer are common. Babesia crassa and B. venatorum babesiosis recently have been found to be endemic in northeastern China, and B. microti babesiosis is endemic in southern China on the Myanmar border. A few cases of Babesia divergens –like infections (referred to as MO-1) have been described in the United States.
The third pattern of babesiosis involves sporadic cases due to diverse Babesia spp, including Babesia duncani (WA-1) and CA-type parasites of the western United States; a Babesia motasi –like infection (KO-1) in Korea; and unidentified or poorly characterized Babesia spp from China, Colombia, Egypt, India, Mexico, Mozambique, and South Africa. Molecular phylogenetic methods provide evidence that human babesiosis may be caused by many of the known Babesia spp., as well as by non- Babesia piroplasms such as the related parasite Anthemosoma garnhami .
The known zoonotic tick vectors ( I. dammini, I. ricinus ) have marked seasonal periods of activity (May to August), and the majority of reported cases are acquired during these times, however, babesiosis may be diagnosed at any time of the year.
More than 250 cases of transfusion-acquired babesiosis due to B. microti and three due to B. duncani have been reported, but the actual number of cases is thought to be much greater. Babesiosis is one of the most commonly reported transfusion-transmitted diseases ( Chapter 162 ) in the United States, and the number of such cases is increasing, including those ending in death. Cases occur throughout the year, and about 10% of cases occur in nonendemic areas because Babesia -infected blood is exported to nonendemic areas or persons become infected in endemic areas and subsequently donate blood in nonendemic areas. A few cases of transplacentally transmitted babesiosis also have been reported.
Pathobiology
The pathophysiology of Babesia infection is directly related to the development of parasitemia. Peripheral blood parasitemias of 70% or greater have been reported, although most cases sustain parasitemias on the order of 0.5 to 5%.
Excessive production of pro-inflammatory cytokines seems to best explain the most common clinical manifestations, which include fever, fatigue, sweats, chills, headache, anorexia, myalgia, nausea, vomiting, and pallor. Such findings are not seen when erythrocyte lysis is due to noninfectious causes, which suggests that the release of merozoites serves as a trigger for the pro-inflammatory cascade. Elevated serum concentrations of TNF as well as of interferon-γ, interleukins 2 and 6, E-selectin, vascular cell adhesion molecule 1, and intracellular cell adhesion molecule 1 are detected during the acute phase of human B. microti infection and return to baseline within 3 months after resolution of infection.
Severe illness caused by infection with Babesia includes a complex array of metabolic abnormalities and organ dysfunction. Cardiac and pulmonary disease are the most common complications in patients who experience severe Babesia infection, with up to 20% of patients suffering from noncardiogenic pulmonary edema. Pro-inflammatory cytokines contribute to the pulmonary complications of Babesia infection. Disseminated intravascular coagulation and heart failure are even more frequently observed. It is also likely that lung and other end-organ disease is mediated, at least in part, by vascular stasis.
Clinical Manifestations
About 25% of B. microti infections in adults and 50% of cases in children are subclinical. Most people experience a mild to moderate illness that persists for about 1 week. Manifestations include a gradual onset of malaise, anorexia, fatigue, fever (temperature as high as 40° C), sweats, and myalgia. Nausea, vomiting, headache, shaking chills, emotional lability, depression, confusion, delirium, impaired consciousness, hemoglobinuria, and hyperesthesia can also occur. Findings on physical examination may consist of fever, pallor, splenomegaly, and hepatomegaly. Laboratory abnormalities include anemia, thrombocytopenia, and leukopenia. Parasitemia generally ranges from barely detectable on blood smear to 5% in previously healthy people, but it may reach 85% in asplenic and other immunocompromised patients. Serum levels of lactate dehydrogenase, bilirubin, and aminotransferases are commonly elevated in more severe cases. Persistent relapsing illness may occur in highly immunocompromised patients who fail to clear the infection for months or more than a year despite multiple courses of antibiotics.
Severe babesiosis usually manifests as an acute onset of illness with hemoglobinuria, a persistent nonperiodic high fever (temperature of 40° to 41° C), shaking chills, intense sweats, headaches, and myalgia, as well as lumbar and abdominal pain. Vomiting and diarrhea may occur. Pulmonary, renal, or liver failure may develop rapidly. In fatal cases, patients become comatose with multiorgan failure. Severe disease occurs only in individuals with asplenia, malignancy, HIV, organ transplants, immunosuppressive treatment, or age younger than 2 months or older than 50 years. About a third of treated asplenic babesiosis patients without a history of autoimmune disease may suffer warm autoimmune hemolytic anemia ( Chapter 146 ) that requires immunosuppressive treatment.
Cases of babesiosis caused by B. divergens tend to be severe, at least in part because they are primarily reported in immunocompromised patients. Almost all European patients who have experienced B. divergens infection have been splenectomized, and about a third died. B. duncani , B. venatorum , and B. divergens –like infections also have often been reported in immunocompromised hosts with a similarly severe course of illness. In contrast, the clinical course of B. venatorum infection in 48 immunocompetent patients in northeastern China was similar to that of B. microti infection, with full recovery of all patients, including seven patients who were admitted to the hospital.
Diagnosis
The diagnosis of babesiosis is based on epidemiologic and clinical findings and confirmed by laboratory testing. It should be considered in patients who live or travel in Babesia endemic regions or who have received a blood transfusion within the previous 6 months and whose clinical findings are consistent with babesiosis.
The two primary laboratory tests for confirmation of babesiosis infection are microscopic visualization of parasites on a Giemsa-stained thin blood smear and the detection of Babesia DNA on a polymerase chain reaction (PCR) assay. Microscopy can be performed more rapidly than PCR, so it is especially useful in patients who are severely ill with parasitemia above 1% and who need immediate diagnosis and therapy. PCR has greater sensitivity and is especially useful in cases with lower degrees of parasitemia. For B. microti babesiosis ( Fig. 324-1 ), examination of a slide for 10 minutes or as many fields as needed to tally 200 leukocytes (that are not infected but serve as a marker for effort) and repeated smears performed twice a day may be required. Standard Romanowsky stains (Giemsa, Wright) using malaria protocols are optimal. Artifactual inclusions are limited mainly to stain precipitates (which can be determined by their presence in the plasma spaces between cells), Howell-Jolly or Heinz bodies ( Chapter 143 ), or platelets superimposed on erythrocytes, which always have a light-colored halo when visualized this way. Babesia spp have clearly defined chromatin with a lighter-colored cytoplasm ( Fig. 324-2A ) and may be mistaken for early malarial trophozoites. Neither malarial nor babesial rings have hemozoin (malarial pigment), so this feature cannot distinguish between the two. Paired piriform parasites, arranged in a v , are suggestive of B. divergens or B. divergens –like infection ( Fig. 324-2B ). Rings of all sizes may be seen in all species. Multiple parasites may frequently be seen in single erythrocytes, as well as clumps of extracellular parasites. Tetrad forms ( Fig. 324-2C ) and Maltese cross forms ( Fig. 324-2D ), which are diagnostic but are rarely seen in B. microti babesiosis, seem to be more common with B. duncani or CA-type infections.
Serologic testing is useful to help confirm B. microti infection, but patients with a positive antibody test should have the diagnosis confirmed by a thin blood smear or PCR to diagnose acute infection. The indirect immunofluorescence test, using antigen from infected hamster red cells, is sensitive and specific and is currently the serologic method of choice. A four-fold rise in B. microti antibody titer in paired acute and convalescent serum samples is most useful to corroborate B. microti infection. The presence of parasite-specific IgM may suggest that the patient has an acute infection even in the absence of readily demonstrable parasitemia. Serology is not generally useful for B. divergens babesiosis (although the immunofluorescence test is generally sensitive and specific), given its fulminant natural history.
Serology for B. duncani is complicated by a high rate of false positives, and specificity depends on carefully establishing a diagnostic threshold dilution. Antigens for the other Babesia spp infecting humans are not available. Because parasitemia occurs before an antibody response and because the doubling time of B. divergens can be as short as 8 hours, serologies are not helpful for prompt decision-making.
The known vectors for human babesiosis are ticks that also transmit the agents of Lyme disease ( Chapter 296 ), human granulocytic anaplasmosis (Chapter 302), Borrelia miyamotoi infection ( Chapter 297 ), Ehrlichia muris –like infection ( Chapter 302 ), and tick-borne encephalitis virus ( Chapter 352 ). Thus, coinfections should be considered in all patients with babesiosis. Acute illness in patients coinfected with Lyme disease and babesiosis is more severe and more persistent than in patients experiencing Lyme disease alone.
Treatment
Treatment should be initiated immediately on the basis of clinical suspicion and initial results on PCR testing or microscopy. However, incidental finding of parasites (e.g., during a manual CBC, or at a blood donation center that proactively performs screening) in an otherwise healthy individual requires monitoring but may not require treatment.
Therapy for mild to moderate B. microti infection, which typically occurs in immunocompetent individuals, should consist of the combination of atovaquone (750 mg orally twice daily for 7 to 10 days) and azithromycin (500 to 1000 mg initial dose followed by 250 mg orally daily for 7 to 10 days) ( Table 324-1 ), , which clears parasitemia as effectively as the combination of clindamycin (600 mg orally every 8 hours for 7 to 10 days) plus quinine (650 mg orally every 8 hours for 7 to 10 days) with fewer side effects. For immunocompromised hosts, the azithromycin dose should be increased to 600 to 1000 mg orally daily for 7 to 10 days. For severe babesiosis (which usually occurs in immunocompromised patients or patients over age 50 years), a 7- to 10-day course of the combination of atovaquone (750 mg orally twice daily) and azithromycin (500 mg intravenously once a day) is recommended. An alternative combination is clindamycin (600 mg every 6 hours intravenously) and quinine (650 mg orally every 8 hours).
TABLE 324-1
TREATMENT REGIMENS FOR ADULTS PATIENTS WITH BABESIOSIS
Adapted from Krause PJ, Auwaerter PG, Bannuru RR, et al. Clinical practice guidelines by the Infectious Diseases Society of America (IDSA): 2020 Guideline on Diagnosis and Management of Babesiosis. Clin Infect Dis . 2021;72:e49-e64.
| PATIENT CATEGORY | TREATMENT REGIMEN |
|---|---|
| Ambulatory patients: mild to moderate disease | Preferred:
Alternative:
|
| Hospitalized patients: acute severe disease † | Preferred:
Alternative:
|
| Hospitalized patients: step-down therapy (transition to oral therapy) | Preferred:
Alternative:
|
| Highly immunocompromised patients | Start with one of the regimens recommended for hospitalized patients with acute severe disease and follow with one of the step-down regimens, but treat for at least 6 consecutive weeks, including 2 final weeks during which parasites are no longer detected on the peripheral blood smear. When oral azithromycin is used, a 500 to 1000 mg daily dose should be considered. If infection relapses, consider an experimental regimen with combinations that include doxycycline, proguanil, pentamidine, or trimethoprim-sulfamethoxazole under expert guidance |
IV = intravenous.
∗ Clindamycin plus quinine is preferred when parasitemia and symptoms have failed to respond to atovaquone plus azithromycin.
† Exchange transfusion should be considered for patients who have high-grade parasitemia (>10%) or moderate to high-grade parasitemia plus: severe hemolytic anemia or severe pulmonary, renal, or hepatic compromise.
Treatment may occasionally fail in high-risk patients or in patients who must discontinue quinine because of side effects, such as severe tinnitus and gastrointestinal distress, or because of antibiotic resistance to atovaquone and azithromycin. A prolonged course of treatment may be required to clear parasitemia in certain immunocompromised patients, including patients with B-cell lymphoma ( Chapter 171 ) or other conditions treated with rituximab, patients with malignancy who also are asplenic ( Chapter 154 ), patients with organ or stem cell transplantation, and patients with HIV/AIDS. In such cases, expert consultation is suggested to design combination therapy for immunocompromised patients with one or more of the following regimens: atovaquone, azithromycin, and clindamycin; atovaquone plus clindamycin; atovaquone/proguanil plus azithromycin; or atovaquone, azithromycin, clindamycin, and quinine. Dosing for these antimicrobial combinations should be based on doses recommended for other infections (informed by allergic history, renal function, and other relevant considerations for the specific patient) and/or from the few case reports for which they have been used. Once an effective combination demonstrates clinical improvement and reduction in parasitemia, it should be continued for at least 6 weeks and 2 weeks beyond the time when Babesia can no longer be visualized on blood smear or blood samples become PCR negative. Other drugs have been demonstrated to be effective against B. microti in laboratory models (e.g., robenidine, primaquine, artesunate, clofazimine, tafenoquine, and endochin-like quinolones) but await clinical trials.
Partial or complete red cell exchange transfusion (1 to 3 blood volumes) should be considered in addition to antibiotic treatment in severely ill patients with parasitemias in excess of 10%, evidence of severe hemolysis, or organ compromise. Apheresis reduces parasitemia and may help reduce pathogenic circulating inflammatory host factors or products liberated by the parasite, but its effect on patients’ outcomes is uncertain.
Prevention
Prevention depends on reducing the risk for tick bites. Immunocompromised individuals should be especially careful to use personal protection and may even consider avoiding highly endemic sites such as coastal New England and Long Island in the United States during May through August, when the risk is the greatest. Use of repellants such as DEET or application of permethrin to clothing will greatly reduce tick attachment. Such products should be applied to shoes, socks, and trouser cuffs. Wearing light-colored long pants and tucking the cuffs into socks will also help prevent ticks from gaining access to attachment sites. As with the agent of Lyme disease, ticks must be attached at least 36 to 48 hours before a sufficient inoculum of Babesia sporozoites is delivered. Daily examination for attached ticks should be performed; the best method is to feel for new bumps on a soapy body in the shower. Any attached ticks should be promptly removed by simple traction, which is best accomplished with the use of tweezers (see Fig. 302-3 ).
Community-level prevention should focus on public education about the risks of tick-borne infection, reducing the habitat for ticks (brush removal and landscaping around yards), or reducing the reproductive hosts for the tick. Deer reduction will reduce the abundance of the deer tick vector for B. microti babesiosis. Screening blood donations for B. microti antibodies and B. microti DNA (using PCR) can decrease the risk of transfusion-associated babesiosis.
Prognosis
The case-fatality rate for B. microti babesiosis has been estimated to be 6 to 9% in hospitalized patients but may be as high as 20% in immunocompromised hosts, including patients who acquire the infection through blood transfusion. Based on Medicare data, about 1% of patients older than 65 years of age die within 30 days of diagnosis.
Among survivors, long-term sequelae have not been reported if patients were adequately treated. In most patients who complete a full treatment regimen, B. microti DNA becomes undetectable by PCR within 3 months. Infection does not, however, imply protective immunity, although subsequent infections are usually limited in duration and intensity. Recrudescent infections have been reported, mainly in immunocompromised individuals.
Enteric Protozoa
The gastrointestinal and urogenital tracts may contain representatives of the four major groupings of protozoa (amebae, sporozoa, flagellates, and ciliates). Diarrhea and other lower gastrointestinal signs and symptoms may be caused by diverse protozoa. Specific clinical diagnosis is difficult because expert clinical parasitology support is required to determine whether an agent that has been detected in a stool sample is a pathogenic species. However, new point-of-care antigen detection tests, or nucleic acid amplification tests (NAAT) are sensitive and specific when they can be used. Identification is necessary because treatment options differ by the agent. With the exception of Trichomonas vaginalis infection (sexually transmitted), all of the enteric protozoa are acquired by the ingestion of food or materials contaminated by human feces; a small subset may have extraintestinal manifestations. Given a shared mode of transmission (fecal-oral), demonstrating the presence of any one of these protozoa within a stool sample from a patient is justification for an intensified search for those that are recognized as clinically significant pathogens ( Entamoeba histolytica [ Chapter 323 ], Giardia lamblia/intestinalis [ Chapter 322 ], Cyclospora cayetanensis , Cystoisospora belli , and Cryptosporidium parvum/hominis [ Chapter 321 ]). Common luminal intestinal protists that are frequently detected during stool analyses for ova and parasites (e.g., Blastocystis hominis, Dientamoeba fragilis, Iodamoeba bütschlii, Entamoeba coli , and Endolimax nana) are thought to be microbes that interact with the intestinal microbiome ( Chapter 257 ) and that any health impacts are likely because of their tendency to induce or serve as markers for dysbiosis, not because they themselves directly cause clinical manifestations.
Cryptosporidiosis ( Chapter 321 ), giardiasis ( Chapter 322 ), and amebiasis ( Chapter 323 ) are discussed in separate chapters. Trichomoniasis and coccidian enteritis are discussed here because they are relatively common infections.
Trichomoniasis
Epidemiology
Trichomonas vaginalis is among the most prevalent of all pathogenic protozoa and is one of the most common sexually transmitted infections ( Chapter 264 ) in the United States and likely worldwide. The World Health Organization estimates that over 150 million incident cases of trichomoniasis occur annually worldwide, thereby making trichomoniasis more common than chlamydia (about 130 million annual cases; Chapter 294 ) or gonorrhea (about 90 million cases; Chapter 275 ). In the United States, the Centers for Disease Control and Prevention estimate 6.9 million incident cases per year, with trichomoniasis infection rates seven-fold higher in Black women as compared with non-Hispanic White women. T. vaginalis can be passed from infected mothers to their newborn daughters, but it is seldom symptomatic in girls before menarche. The parasite is able to survive for some time in moist environments, and nonvenereal transmission, although uncommon, can occur. Trichomoniasis, like other sexually transmitted diseases, may increase the likelihood of transmission of HIV ( Chapter 353 ).
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