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Fever and High-Grade Parasitemia Following Splenectomy
By Shaili Gupta, MD and Carlos Torres-Viera, MD
Dr Gupta is a fellow in Infectious Diseases and Dr. Torres-Viera is a Clinical Instructor in Internal Medicine/ Infectious Diseases, Yale School of Medicine, New Haven CT.
Drs. Gupta and Torres-Viera report no financial relationships relevant to this field of study.
A 59-year-old man was admitted to the hospital in July 2006, with a 10-day history of fevers, malaise, muscle aches, back pain and progressive weakness. Two days prior to admission, he had developed slurred speech and jaundice.
His past medical history was significant for glioblastoma multiforme of right temporal lobe, which had been treated with surgical resection, chemotherapy and external beam radiation. He underwent a splenectomy 4 years previously for treatment of hypersplenism. He lived in eastern Connecticut and over the previous 2 months, had spent a significant amount of time with his dogs in the backyard.
On physical examination, his temperature was 101.1°F, pulse 106 bpm, and blood pressure 110/57 mm Hg. Skin exam did not reveal a rash, sclera were icteric, lungs were clear to auscultation, heart sounds were tachycardic without any murmur, and abdomen was soft and nontender with a moderately enlarged liver. He was somnolent and confused, with slurred speech, but without other focal neurological deficits or signs of meningeal irritation. Laboratory findings were impressive for thrombocytopenia, leukocytosis, acute renal failure, hyperbilirubinemia, metabolic acidosis, and high serum LDH, creatine kinase, and liver enzymes. Peripheral blood smear revealed intra- and extraerythrocytic. Babesia with 60%-75% parasitemia (Figure 1).
The patient was admitted to the intensive care unit, and started on clindamycin, quinine and doxycycline. Ceftriaxone was given until Lyme serologies were found to be negative. Exchange transfusion was performed within 2 hours of admission with a fall of the parasitemia to 2%. Clinical response was evident by improvement in mental status, resolution of myalgias and defervescence. Laboratory values also improved. Serology and blood smears for Ehrlichia species remained negative. Viral hepatitis serologies, VDRL, CMV Ag, EBV IgM, CMV Ag, Parvovirus B19 IgM and HIV were negative.
On hospital day 5, he developed hyperexcitability, delirium, nausea, vomiting, followed by extreme somnolence. He was found to be persistently hypoglycemic (blood glucose 32-55 mg/dL) despite continuous intravenous glucose infusion. Electrocardiogram revealed prolonged Q-T intervals (433-439 msec). Quinine toxicity was suspected. Therapy was changed to atovaquone and azithromycin with subsequent improvement of symptoms and dysglycemia. Doxycycline was continued. On day 8, fevers recurred (101-102°F) with confusion, myalgias, diarrhea, and mild coagulopathy (INR 1.87). The level of babesia parasitemia increased to 10%. Exchange transfusion was repeated with reduction of parasitemia to <1%. Azithromycin dose was increased to 500 mg daily and he was continued on atovaquone and doxycycline for triple-drug therapy of babesiosis. Progressive rise in liver enzymes, especially alkaline phosphatase was noted with a value of 748 U/liter on hospital day 25. Right upper quadrant ultrasonography revealed biliary sludge. Azithromycin was discontinued, as a likely cause of cholestasis, and the patient was restarted on clindamycin (atovaquone and doxycycline were continued) with resolution of his cholestatic picture. The patient showed resolution of his symptoms and was discharged home on hospital day 29 taking a triple-antibiotic regimen. His Babesia PCR test remained positive and he was continued on treatment for a total of 60 days when given his persistently negative blood smear his treatment was discontinued. Ten months after the initial diagnosis, the patient remains asymptomatic. Repeated peripheral smears have not shown any evidence of ongoing Babesia parasitemia.
B. microti typically causes a subclinical or mild illness characterized by malaise, fever, anorexia, myalgias, and headache. In most instances, specific therapy is not required. In asplenic or immunocompromised patients, however, illness may be severe, with hemolytic anemia, renal dysfunction, and pulmonary involvement. With subclinical infection being the rule, blood transfusions have become an important means of transmission. B. microti has been shown to have a tropism for mature erythrocytes1-3 as reticulocytes do not readily take up the parasite. This may be one reason why asplenic patients, who have impaired destruction of mature RBCs, are more susceptible to severe infections.
The most reliable and definitive diagnostic test is direct visualization of parasitized red blood cells. With low-grade parasitemia, closer inspection of multiple blood smears is usually required to locate a few infected erythrocytes. Once treatment is initiated, many of the intraerythrocytic inclusions may represent nonviable parasites. Elevation of IgM and IgG antibodies against Babesia may be found in acute phase sera followed during convalescence. PCR detection of B. microti was initially described as a diagnostic method in 1992.4 In 1996, a double blind study comparing PCR with blood smear and inoculation of small animals was conducted on 41 asymptomatic participants who lived in an endemic region, and 19 patients were diagnosed with acute babesiosis based on clinical features and serological assays.5 The sensitivity of thin blood smear, hamster inoculation and PCR were 84%, 74% and 95% respectively and the specificity for all 3 was 100%.5 However, PCR can remain positive even after clearance of parasitemia and resolution of symptoms. This has been thought to potentially represent viable subclinical infections based upon a prospective study on 46 Babesia-infected subjects, 22 of whom received treatment, while 24 did not.6 B. microti DNA persisted for more than three months in 25 percent of the untreated subjects , but in none of the treated subjects. IgG antibody and subjective symptoms also persisted longer when babesial DNA could be detected by PCR.
In our patient, both symptoms and antibody levels correlated more closely to the parasitemia clearance, than the detection of babesial DNA by PCR. The persistently positive PCR in our patient, in the absence of symptoms and with declining antibody titers, likely represented the detection of nonviable DNA by PCR. Diagnosis of acute as well as persistent or relapsed babesiosis must incorporate clinical assessment along with any of the common diagnostic modalities, including blood smears, PCR and serology,.
The treatment of Babesia infections is based on a combination of drugs with the two main regimens being oral clindamycin (600 mg every 8 hours) with quinine (650 mg every 8 hours), or atovaquone (750 mg every 12 hours) with azithromycin (500 mg on day 1, then 250 mg/day thereafter). For high-grade parasitemia, quinine /clindamycin combination therapy had been the most evaluated, in era prior to exchange transfusions.7 Atovaquone and azithromycin were compared with clindamycin and quinine in a prospective, nonblinded, randomized trial of 58 adult patients with non-life-threatening babesiosis.8 The median level of parasitemia in these patients was only 0.5%. Atovaquone plus azithromycin was found to be better tolerated and equally effective in clearing parasitemia and resolving symptoms compared to the combination of quinine and clindamycin. In immunocompromised patients with babesiosis, successful outcome has been reported using atovaquone combined with higher doses of azithromycin (600-1000 mg per day).9 Such high dose of azithromycin can cause significant cholestasis, as noted in our patient. Triple-drug therapy ,with addition of doxycycline, has been successful in a case of refractory babesiosis. A severely immunosuppressed HIV-infected patient with chronic babesiosis who did not respond to clindamycin and quinine, improved with clindamycin, doxycycline, and azithromycin, although the infection was not eradicated.10 For parasitemias >10% causing significant hemolysis, renal, hepatic or pulmonary decompensation, exchange transfusion remains the therapy of choice, in conjunction with antimicrobial agents.11
In our patient, parasitemia apparently had cleared by week 4 of therapy with atovaquone, doxycycline and high-dose azithromycin. However, the patient still had significant fatigue and rising antibody titers. Subsequently, the patient was continued on clindamycin, atovaquone and doxycycline until resolution. These 3 drugs in combination have not been described for use in babesiosis previously.
The mechanisms of drug actions during treatment of babesiosis may explain the applicability of the triple-drug therapy used in our patient. In each of the 2 common regimens, one drug acts as the principal antiparasitic agent, while the second agent facilitates the former. Atovaquone's antibabesial effects involve inhibition of mitochondrial electron transport, but when used alone it is not as effective as in combination therapy, as animal studies showed recrudescence of parasitemia when treated with atovaquone alone, and clearance of the infection with combination therapy using atovaquone and azithromycin.12 Azithromycin inhibits RNA-dependent protein synthesis at the chain elongation step and binds to the 50S ribosomal subunit resulting in blockage of transpeptidation. Quinine depresses oxygen uptake and carbohydrate metabolism and intercalates into DNA, disrupting the parasite's replication and transcription. Clindamycin reversibly binds to 50S ribosomal subunits preventing peptide bond formation thus inhibiting bacterial protein synthesis. Doxycycline also is an inhibitor of protein synthesis.
Therefore, atovaquone and quinine work at the mitochondrial and nuclear levels in these parasites, while clindamycin and azithromycin potentiate the opsonization and phagocytosis of the Babesia by disrupting babesial protein synthesis. The latter agents cause changes in cell wall surfaces, decrease adherence of the parasite to host cells and facilitate intracellular killing of organisms by the former two agents. This might explain the increased activity of combination therapy using an intracellular antiparasitic agent with one of the protein synthesis inhibitors.