Boustani MR, Lepore TJ, Gelfand JA, Lazarus OS.Acute respiratory failure in patients treated for babesiosis. Am J Respir Crit Care Med 1994;149:1689-91.
Case Rep_o_rt
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Acute Respiratory Failure in Patients Treated for Babesiosis MARIA R. BOUSTANI, TIMOTHY J. LEPORE, JEFFREY A. GELFAND, and DAVID S. LAZARUS Divisions of Pulmonary and Critical Care Medicine and Geographic Medicine and Infectious Diseases, Department of Medicine, New England Medical Center, and Tufts University School of Medicine, Boston, Massachusetts; and the Nantucket Cottage Hospital, Nantucket, Massachusetts
Babesiosis is a tick-borne protozoal disease with infrequent clinical complications. We report three cases of noncardiogenic pulmonary edema in patients from Nantucket Island, MA, with a history of Lyme disease and review the clinical presentation of babesiosis and its treatment. Respiratory complications in our patients, as well as in the four previously reported cases in the literature, occurred a few days after initiation of medical therapy. We hypothesize that the pathophysiology of the pulmonary edema is multifactorial, due to decreased deformability of the infected erythrocytes, increased cytoadherence of red blood cells in capillaries and venules, and a possible role of excessive production of certain cytokines, such as tumor necrosis factor and interleukin-1. Boustani MR, Lepore TJ, Gelfand JA, Lazarus OS. Acute respiratory failure in patients treated for babesiosis. Am J Respir Crit Care Med 1994;149:1689-91.
Babesiosis, a tick-borneprotozoal disease, usually has an uncomplicated clinical course in North America (1). The geographic distribution as well as the incidence of babesiosis have increased (2-4). Since the disease wasfirst described in humans,27 yr ago, only four cases of noncardiogenic pulmonary edema have been reported in association with it (5-8). Over the past 14 mo, however, we have encounteredan additional three cases of noncardiogenic pulmonary edema from Nantucket Island, MA. This suggests a change in the clinical course of babesiosis occurring simultaneously with an increase in the incidence of the disease in the northeastern United States.
CASE REPORTS Patient 1 A 65-yr-old woman with a medical history of Lyme disease complained of a productive cough, fever, headache, and periodic chills for 1 wk after a tick bite. She was treated with amoxicillin and ciprofloxacin with no effect. Her chest X-ray was normal. Inspection of a peripheral blood smear showed intraerythrocytic organisms consistent with Babesia. Laboratory values included a normal white blood cell count, mild anemia, decreased platelets, elevated lactate dehydrogenase level, and hyponatremia. She was treated with clindamycin (1.2 g intravenously every 12 h) and quinine (650 mg by mouth three times a day). Two days later, she complained of dyspnea, and her O2 saturation was 82%. Mechanical ventilation was instituted, requiring an F102 of 0.8 to maintain an arterial O2 saturation > 90%. A chest X-ray showed bilateral pulmonary infiltrates. The lungs were clear, and her heart examination was normal, without any evidence
(Received in original form August27, 7993and in revised form November4, 7993) Supported by National Institutes of Health Training Grant Hl07053 (Dr. Boustani) and a Parker B. Francis Scholarship in pulmonary research (Dr. lazarus). Correspondence and requests for reprints should be addressed to David S. lazarus, M.D., New England Medical Center, Pulmonary and Critical Care Division, 750 Washington Street, NEMC #257, Boston, MA 02111. Am
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of congestive heart failure. An electrocardiogram was normal. The red blood cell Babesia count was> 15% of the total erythrocyte count. Dynamic compliance was calculated to be 32 ml/cm H2O. A right-heart catheterization demonstrated a right atrial pressure of 12 mm Hg, pulmonary artery pressures of 45/17 mm Hg, pulmonary capillary wedge pressure of 16 mm Hg, cardiac output of 4.51 Umin/m 2, and systemic vascular resistance of 974dyne·slcm5 • An exchange transfusion was performed using 7 U each of packed red blood cells and fresh frozen plasma. The patient was successfully extubated on the seventh day. One month later, her chest X-ray and pulmonary function tests were normal.
Patient 2 A 40-yr-old man with a medical history of systemic arterial hypertension and Lyme disease had a 1-mo history of upper respiratory tract symptoms with sinusitis, rhinitis, pharyngitis, and mild fever. He was treated empirically with amoxicillin pending the results of Lyme titers. He improved transiently but developed recurrent fever, sweats, occipital headache, mild abdominal discomfort, anorexia, and malaise. On examination, he had only mild and tender hepatomegaly. His peripheral blood smear showed moderate levels of intraerythrocytic Babesia, and he was treated with quinine and clindamycin. The next day, he became increasingly dyspneic, with a sensation of chest tightness and a paroxysmal cough. Laboratory values showed a normal white blood cell count, mild anemia, normal platelet count, and elevated liver enzymes. Room air arterial blood gases demonstrated a Pa02 of 72 mm Hg. Chest X-ray revealed bilateral interstitial infiltrates, more prominent in the lower lobes. His estimated peripheral RBC Babesia count was 1% of his total erythrocyte count. Clindamycin (900 mg intravenously every 8 h), quinine (600 mg by mouth every 8 h), pentoxifylline (400 mg by mouth every 8 h), and one 500-mg intravenous dose of solumedrol were administered. However, his condition deteriorated, and he required mechanical ventilation. Arterial blood gas analysis showed a Peo, of 107mm Hg on 0.8 F102. Right heart catheterization showed a right atrial pressure of 4 mm Hg, right ventricular pressures of 24/3 mm Hg, pulmonary artery pressures of 24/10 mm Hg, pulmonary capillary wedge pressure of 9 mm Hg, cardiac output of 9.1 Umin/m 2, and systemic vascular resistance of 624 dyn-s/crn". His oxygenation improved dramatically with drug therapy over the next 48 h, with resolution of all infiltrates on repeat chest X-ray. He was discharged from the hospital 3 d later.
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Patient 3 A 74-yr-old man with a history of Lyme disease complained of severe headaches and fever. His peripheral blood smear revealed intraerythrocytic parasites consistent with Babesia. The patient was given doxycycline, clindamycin, and quinine. He became afebrile, but his platelet count decreased, reaching a nadir of 55 x 103/mm3 , with a hematocrit of 32%. His chest X-ray revealed bilateral interstitial infiltrates. He was dyspneic with minimal exertion. The Babesia count then was 0.1% of his total erythrocyte count. On arrival, his temperature was 38.6° C and his respiratory rate was 24 breaths/min. Lung examination revealed diffuse wheezing. Laboratory values showed a normal white blood cell count and sodium concentration of 122 mEq/L. Arterial blood gases on 50% O2 face mask showed a Pa02 of 67 mm Hg. A right-heart catherization demonstrated a right atrial pressure of 9 mm Hg, pulmonary artery pressures of 30116 mm Hg, pulmonary capillary wedge pressure of 15 mm Hg, cardiac output of 6.6 L1min/m2, and systemic vascular resistance of 920 dyn·s/cm 5 • The patient was continued on clindamycin and quinine and did not require mechanical ventilation. His hypoxia, thrombocytopenia, and hyponatremia resolved, and he was discharged 6 d later.
DISCUSSION Human babesiosis is a tick-borne protozoal disease. It was first described in the United States in 1966 in a splenectomized man from California (9). In North America, most infections are caused by the species Babesia microti, which is transmitted to the human host by the deer tick Ixodes dammini. In Europe, the predominant pathogens are Babesia bovis and Babesia divergens. Most cases in the United States are clustered in the northeastern coastal region, where I. dammini completes its life cycle using the white-footed mouse, Peromyscus leucopus, as host for its nymphal and larval stage and the white-tailed deer, Odocoileus virginianus for its adult stage (5). This clustering is thought to result from the geographic proximity of all four species. Disease transmission to humans occurs most commonly during the nymphal stage through tick bites between the months of May and July (5). It has also been reported to occur through blood transfusions from asymptomatic carriers (6, 10).The onset of symptoms occurs 1 to 4 wk after the tick bites. Individuals at risk for the disease are usually more than 50 yr of age or have had a splenectomy (11), although babesiosis has also been recently described in the pediatric age group (12). The clinical presentation varies widely, from no symptoms to chills, fatigue, anorexia, myalgia, arthralgia, nausea, and headache (11, 13). The occurrence and the severity of symptoms are not dependent on the level of parasitemia (14).The signs of infection are nonspecific and may include fever, mild hepatomegaly, petechiae, and ecchymosis. The laboratory findings may include a decreased hematocrit and platelet count with a normal or decreased white blood cell count. Lactate dehydrogenase, bilirubin, and transaminases are often increased. Parasitemia of 1 to 20% of red blood cells may persist for weeks to months. The diagnosis is usually made through an inspection of a Giemsa- or Wright-stained peripheral blood smear for intraerythrocytic rings. Babesia is similar in some aspects to the Plasmodium parasite but has several distinguishing features, including "Maltese Cross" formation, a smaller size, and a white vacuole in some of the large Babesia rings-in distinction to a vacuole containing the pink stroma of the erythrocyte seen in the malaria ring-and the absence of the malaria pigment in blood culture or in advanced stages of malaria (15).Babesiosis can be diagnosed with greatest sensitivity by indirect immunofluorescent antibody for B. microti, (16, 17). The treatment of patients with serious disease involves a combination of clindamycin and oral quinine (1, 18).Although this regi-
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men is effective in experimentally infected hamsters, its efficacy in humans has not been established (5, 19). Exchange transfusion is reserved for extremely ill individuals with a high level (> 10%) of parasitemia and hemolysis, and perhaps should be considered for patients with acute respiratory failure. The clinical course of babesiosis in Europe is generally more severe than in North America, but all of the patients reported had previous splenectomies. There have been four reported cases of adult respiratory distress syndrome or pulmonary edema associated with B. microti (5-8). Interestingly, in all cases reported, the pulmonary edema occurred after a few days of therapy, when the parasite load had presumably decreased. Such a temporal association has been described in the pulmonary edema associated with Plasmodium falciparum (20), a parasite that also invades red blood cells and that shares antigenic determinants with B. bovis (21). It is unlikely that the drugs themselves caused pulmonary edema, as a different drug, chloroquine phosphate, was used in an earlier case report (6). Moreover, our patients recovered from noncardiogenic pulmonary edema despite continuation of the drugs. The mechanism of pulmonary edema associated with babesiosis is still speculative. It is probably caused by a combination of mechanisms: decreased deformability, cytoadherence, and an excess production of inflammatory response mediators. The invasion of erythrocytes by B. microti leads to deformities of the cell membrane in the form of pits and protrusions. These protrusions correspond to parasites, as demonstrated by electron microscopy (15). Infected erythrocytes have reduced deformability (22), possibly secondary to increased plasma lipid peroxidation. Bovine erythrocytes infected with B. bovis have increased levels of malonyldialdehyde, a sensitive indicator of lipid peroxidation, and decreases in the antioxidant vitamin E and in sialic acid (23). The decreased deformability of erythrocytes along with an intimate apposition of endothelial and infected erythrocyte membranes, Le., cytoadherence, may cause the red blood cells to sequester in capillaries and venules (24). In human falciparum malaria with respiratory distress, cytoadherence of parasitized erythrocytes appears to be responsible for septal pulmonary changes (25). Cytoadherence has also been demonstrated to occur with erythrocytes infected with B. bovis (26). Red blood cell sequestration in lung capillaries may cause capillary leakage and pulmonary edema. In addition, the presence in lung biopsies of large numbers of neutrophils lining the walls of small vessels of patients with pulmonary edema associated with malaria raises the question of the effect of cytokines, such as tumor necrosis factor and interleukin-1, in its pathophysiology. All of our patients had intact spleens and a history of being treated for Lyme disease. In the previously reported cases, Lyme disease titers were documented in only two and were positive. B. microti and Borrelia burgdorferi, the spirochetal agent of Lyme disease, are both transmitted by the tick I. dammini, and the simultaneous occurrence of Lyme disease and babesiosis by serology has previously been suggested by Benach and coworkers (27). Whether prior exposure to Lyme disease is risk factor for the development of pulmonary edema with babesiosis is unclear. The population of I. dammini is expanding on the North American mainland, consequent to the recent proliferation of deer in the United States (4). The prevalence of Lyme disease spirochetes in populations of I. dammini appears to be double that of B. microti, which explains the discrepancy between the incidence of Lyme disease and that of babesiosis (28). Despite underreporting of babesiosis due to the subclinical presentation of most cases, there is evidence that the frequency of babesiosis has increased. A sera-
Case Report
logic survey for babesial infections in Connecticut, where human babesiosis was first diagnosed in 1989, demonstrated that 2 to 4% of the population in some parts of the state have been exposed to B. microti. The prevalence of serologic reactivity appears to have increased over the past 30 yr and to have remained stable over the past 4 yr (2). Whether the unusual presentation of pulmonary edema in babesiosis seen in our patients over the past 14 mo reflects an increased incidence of the disease, the emergence of a more virulent strain on Nantucket Island, or other causes remains to be defined. Clinicians should be alerted to the potential development of noncardiogenic pulmonary edema in patients receiving treatment for babesiosis, an infection that is no longer a rarity in the coastal areas of Massachusetts, Rhode Island, New York (3), and Connecticut (2). References 1. Gelfand JA. Babesia. In: Mandell GL, Douglas RG, Bennett JE, eds. Principles and practice of infectious diseases. 3rd ed. New York: Churchill Livingstone, 1990;2119-22. 2. Krause PJ, Telford SR III, Ryan R, HurtaAB, Kwasnik I, Luger S, Niederman J, Gerber M, Speilman A. Geographical and temporal distribution of babesial infection in Connecticut. J elin Microb 1991;29:1-4. 3. Meldrum SC, Birkhead GS, White DJ, Benach JL, Morse DL. Human babesiosis in New York state: an epidemiological description of 136 cases. elin Infect Dis 1992;15:1019-23. 4. Spielman A, Wilson ML, Levine JF, Piesman J. Ecology of Ixodes daminiiborne human babesiosis and Lyme disease. Annu Rev Entomol 1985;30:439-60. 5. Golighlty LM, Hirschhorn LR, Weller PF. Fever and headache in a splenectomized woman. Rev Infect Dis 1989;11:629-37. 6. Gordon S, Cordon R, Mazdzer E, Valigorsky JM, Blagg NA, Barnes SJ. Adult respiratory distress syndrome in babesiosis. Chest 1984;84:633-4. 7. lacopino V, Earnhart T. Life-threatening Babesiosis in a woman from Wisconsin. Arch Intern Med 1990;150:1527-8. 8. Rowin KS, Tanowitz H, Rubinstein A, Kunkel M, Wittner M. Babesiosis in asplenic hosts. Trans R Soc Trop Med Hyg 1984;78:442-4. 9. Scholtens RG, Braff EH, Healy GR, Gleason N. A case of babesiosis in man in the United States. Am J Trop Med Hyg 1968;17:810-3. 10. Healy GR, Walzer PD, Sulzer AJ. A case of asymptomatic babesiosis in Georgia. Am J Trop Med Hyg 1976;25:376-8. 11. Gombert ME, Goldstein EJC, Benach JL, Tenenbaum MJ, Grunwaldt E, Kaplan MH, Eveland LK. Human babesiosis, clinical and therapeutic considerations. JAMA 1982;248:3005-7.
1691 12. Krause PJ, Telford SR III, Pollack RJ, Ryan R, Brassard P, Zemel L, Spielman A. Babesiosis: an underdiagnosed disease in children. Pediatrics 1992;89:1045-8. 13. Ruebush TK II. Human babesiosis in North America. Trans R Soc Trop Med Hyg 1980;74:149-52. 14. Sun T, Tenenbaum MJ, Greenspan J, Teichberg S, Wang R-T, Degnan T, Kaplan MH. Morphologic and clinical observations in human infection with Babesia microti. J Infect Dis 1983;148:239-48. 15. Garnham PCC. Human babesiosis: European aspects. Trans R Soc Trop Med Hyg 1980;74:153-5. 16. Chisolm ES, Sulzer AJ, Ruebush TK II. Indirect immunofluorescence test for human Babesia microti infection: antigenic specificity. Am J Trop Med Hyg 1986;35:921-5. 17. Ruebush TK II, Juranek DD, Chisolm ES, Snow PC, Healy GR, Sulzer A. Human babesiosis on Nantucket Island, evidence for a self-limited and subclinical infection. N Engl J Med 1977;297:825-7. 18. Wittner M, Rowin K, Tanowitz H, Hobbs J, Saltzman S, Wenz B, Hirsh R, Chisolm E, Healy G. Successful chemotherapy of transfusion babesiosis. Ann Intern Med 1982;96:601-4. 19. Rowin KS, Tanowitz HB, Wittner M. Therapy of experimental babesiosis. Ann Intern Med 1982;97:556-8. 20. Feldman RM, Singer C. Noncardiogenic pulmonary edema and pulmonary fibrosis in falciparum malaria. Rev Infect Dis 1987;9:134-9. 21. James MA, Montenegro-James S, Fajfar-Whetstone C, Montealegre F, Erickson J, Ristic M. Antigenic relationship between Plasmodium f1aciparum and Babesia bovis: reactivity with antibodies to culture-derived soluble exoantigens. J Protozool 1987;34:328-32. 22. Krogstad D, Sutera S, Boyland C, Gluzman I, Qian Z-F, Rao PRo Intraerythrocytic parasites and red cell deformability: Plasmodium berghei and Babesia microti. Blood Cells 1991;17:209-21. 23. Commins MA, Goodger BV, Waltisbuhl DJ, Wright IG. Babesia bovis: studies of the parameters influencing microvascular stasis of infected erythrocytes. Res Vet Sci 1988;44:226-8. 24. Barwell J. Cytoadherence and sequestration in falciparum malaria. Exp Parasitol 1989;69:407-12. 25. Corbett CEP, Duarte MIS, Lancellotti CLP, Silva MALG, Andrade HF Jr. Cytoadherence in human falciparum malaria as a cause of respiratory distress. J Trop Med Hyg 1989;92:112-20. 26. Wright IG, Goodger BV, Buffington GD, Clark lA, Parrodi F, Waltisbuhl DJ. Immunopathophysiology of babesial infections. Trans R Soc Trop Med Hyg 1989;83:S11-3. 27. Benach J, Coleman J, Habicht G, MacDonald A, Grunwaldt E, Giron J. Serological evidence for simultaneous occurrences of Lyme disease and Babesiosis. J Infect Dis 1985;152:473-7. 28. Mather TN, Telford SR III, Moore SI, Spielman A. Borrelia burgdorferi and Babesia microti: efficiency of transmission from reservoirs to vector ticks (Ixodes dammint). Exp Parasitol 1990;70:55-61.
