REVIEW STEVE M. BLEVINS, MD RONALD A. GREENFIELD, MD* MICHAEL S. BRONZE, MD CME Assistant Professor of Medicine, Section Professor of Medicine, Section of Infectious Professor of Medicine, Section of Infectious CREDIT of General Internal Medicine, Department Diseases, Department of Medicine, University Diseases, Chair of Department of Medicine, of Medicine, University of Oklahoma of Oklahoma Health Sciences Center and the University of Oklahoma Health Sciences Center Health Sciences Center, Oklahoma City Oklahoma City Veterans Administration and the Oklahoma City Veterans Administration Medical Center Medical Center Blood smear analysis in babesiosis, ehrlichiosis, relapsing fever, malaria, and Chagas disease ■ ABSTRACT LOOD SMEAR ANALYSIS, while commonly B used to evaluate hematologic condi- Blood smear analysis is especially useful for diagnosing tions, is infrequently used to diagnose infec- five infectious diseases: babesiosis, ehrlichiosis, relapsing tious diseases. This is because of the rarity of fever due to Borrelia infection, malaria, and American diseases for which blood smear analysis is indi- trypanosomiasis (Chagas disease). It should be performed cated. Consequently, such testing is often in patients with persistent or recurring fever or in those overlooked when it is diagnostically impor- who have traveled to the developing world or who have tant. a history of tick exposure, especially if accompanied by Nonspecific changes may include mor- hemolytic anemia, thrombocytopenia, or phologic changes in leukocytes and erythro- 1 hepatosplenomegaly. cytes (eg, toxic granulations, macrocytosis). And with certain pathogens, identifying ■ KEY POINTS organisms in a peripheral blood smear allows for a rapid diagnosis. In the United States, malaria and American This paper discusses the epidemiology, trypanosomiasis principally affect travelers from the clinical manifestations, laboratory findings, developing world. and management of five infectious diseases in which direct visualization of the organism in the blood plays a major diagnostic role. Our Babesiosis, ehrlichiosis, and relapsing fever are intent is to summarize the clinical findings transmitted by ticks and may produce thrombocytopenia that should prompt blood smear analysis so and elevation of liver enzyme levels. that these uncommon conditions are not overlooked. Malaria and babesiosis cause hemolytic anemia and may be associated with hepatomegaly and splenomegaly. ■ BABESIOSIS Recurring fever is typical of malaria and Borrelia infection. Babesiosis, a tick-borne protozoal disease, occurs principally in the United States and Europe. Of the more than 100 species of Babesia, two account for almost all human dis- ease: B microti and B divergens. Both species are transmitted by Ixodes ticks, although patients often do not recall being bitten. The disease may rarely compli- *Dr. Greenfield has disclosed that he has received honoraria from the Astellas, Bristol-Myers cate blood transfusion. Most cases occur from Squibb, Cubicin, Gilead, Ortho-NcNeil, and Pfizer corporations for teaching and speaking. May to September, when tick exposure is CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 75 • NUMBER 7 JULY 2008 521 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. BLOOD SMEAR ANALYSIS BLEVINS AND COLLEAGUES Babesiosis leukopenia, and atypical lymphocytosis, is more common in high-risk patients. Hepatic transaminases may be elevated. Urinalysis may show proteinuria and hemoglobinuria. Acute respiratory distress syndrome has been reported in severe cases.7–10 B divergens infection: A serious but rare disease seen in Europe B divergens is found mainly in Europe. Altogether, fewer than 50 cases of infection have been reported in France, Spain, FIGURE 1. Babesia microti forming intra- Germany, Great Britain, Ireland, Yugoslavia, 11,12 erythrocytic rings (short arrow), exoery- and the former Soviet Union. Cattle are throcytic rings (long arrow) and a “Maltese the principal reservoir of infection. cross” (red arrow) (Giemsa stain, original Infection with B divergens causes a rare but magnification ×100). devastating disease mainly in asplenic people, usually resulting in coma and death. No cases highest. The incubation period varies from 1 of subclinical infection have been reported. to 4 weeks. The clinical course is fulminant, and hemolyt- ic anemia is common.2,3 Common in the Northeast, usually asymptomatic Suspect babesiosis in endemic areas B microti infection occurs predominantly in in cases of prolonged ‘flu’ the United States. Rodents, especially the Babesiosis should be considered when a white-footed mouse, are the principal reser- patient residing in or traveling from an voir.2,3 Endemic areas, where seropositivity endemic area presents with a prolonged flu- Suspect rates range from 4% to 21%, include the like illness and hemolysis, with or without babesiosis in coastal areas and islands off of Massachusetts, organomegaly and jaundice. particularly Cape Cod, Nantucket, and The diagnosis is made by finding intraeryth- New England in Martha’s Vineyard; the islands near New York rocytic parasites on a Giemsa-stained blood prolonged ‘flu’ City, especially Long Island, Shelter Island, smear (FIGURE 1). Thin smears are preferred to and Fire Island; Block Island, off the coast of thick smears for visualizing the organism. Levels and hemolysis Rhode Island; and certain areas in of parasitemia may range from less than 1% to Connecticut.4 WA-1, a species that is mor- more than 80% of erythrocytes. High levels of phologically identical to B microti, is emerging parasitemia occur mainly in asplenic patients. in California and Washington.5,6 At low levels of parasitemia, meticulous blood Infection with B microti is usually asymp- smear examination is required. tomatic. Elderly and immunosuppressed peo- The protozoa may resemble the rings of ple, especially those without a spleen or with malaria parasites. Distinguishing traits include impaired cellular immunity, are more likely to exoerythrocytic organisms; the absence of pig- become ill. Symptoms, including fever, mented granules in infected red blood cells; malaise, headache, nausea, and generalized and a “maltese cross,” a rare pattern produced aching, may last weeks to months. by tetrads of Babesia merozoites.13 An infected About one-fourth of patients with erythrocyte may contain up to eight parasites. babesiosis are coinfected with the Lyme dis- Serologic and polymerase chain reaction ease bacterium (Borrelia burgdorferi) and often tests are useful when the organism is not visi- have more severe illness.3 ble.14,15 Hepatomegaly, splenomegaly, jaundice, and dark urine are common findings in Treat patients with severe disease patients with symptoms. Severe hemolysis, Most patients with B microti infection have a often accompanied by thrombocytopenia, mild illness that resolves without treatment. 522 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 75 • NUMBER 7 JULY 2008 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. Treatment is recommended for those with HGA follows that of Lyme disease, because severe infection and in those with high-level the two diseases share the same tick vector. parasitemia. Agents with consistent activity against B microti include clindamycin Acute onset of fever and myalgias (Cleocin), azithromycin (Zithromax), ato- HME and HGA have an incubation period of vaquone (Mepron), doxycycline (Vibramycin), 1 to 2 weeks. The symptoms are similar and and quinine (Quinamm). Combination thera- are usually acute, ranging from mild to severe. py with either clindamycin and quinine or Most patients have fever, chills, malaise, azithromycin and atovaquone is recommended. headache, and myalgias. Many also have nau- B divergens infection has been successfully sea, vomiting, cough, and arthralgias. treated with a combination of clindamycin, Symptoms are similar to those in Rocky quinine, and exchange transfusion.16 Mountain spotted fever (caused by Rickettsia rickettsii), except that rash is uncommon in ■ EHRLICHIOSIS HME (seen in approximately a third of patients) and rare in HGA.23–25 Neurologic Ehrlichiosis, nicknamed Rocky Mountain findings, such as altered sensorium and neck “spotless” fever, is a seasonal, tick-borne dis- stiffness, may be accompanied by lymphocytic ease caused by obligate intracellular bacteria. pleocytosis and elevated protein levels in the Bacteria of the genus Ehrlichia grow within the cerebrospinal fluid.26 Subclinical and sub- cytoplasmic vacuoles of leukocytes and cause acute presentations (eg, a fever lasting up to 2 mainly zoonotic infections. Several species, months) are uncommon. No chronic cases especially Ehrlichia chaffeensis and Anaplasma have been reported. phagocytophilum, are recognized as human The estimated death rate is 1% to 10%, pathogens.17,18 E chaffeensis infects mononu- and hospitalization rates are as high as 60%. clear cells, causing a condition known as Most deaths occur in the elderly, often follow- human monocytic ehrlichiosis (HME). A ing such complications as congestive heart phagocytophilum infects neutrophils, produc- failure,27 cardiac tamponade, respiratory or ing a condition called human granulocytic renal failure, seizures, and coma. Patients with Ehrlichiosis: anaplasmosis (HGA). human immunodeficiency virus infection also Rocky Deer are the principal reservoir for E chaf- have a poor prognosis. Convalescence may be feensis19; white-footed