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A Gardener with a Fever for 2 Weeks
The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–4, 2015 Copyright Ó 2015 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter
Case Presentations of the Harvard Emergency Medicine Residencies
A GARDENER WITH A FEVER FOR 2 WEEKS William Binder, MD,* Nicholas G. Maldonado, MD,† David F. M. Brown, MD,‡ and Emily S. Miller, MD‡ *Department of Emergency Medicine, Alpert School of Medicine, Brown University, Rhode Island Hospital/Miriam Hospital, Providence, Rhode Island, †Department of Emergency Medicine, University of Florida College of Medicine, University of Florida Health Shands Hospital, Gainesville, Florida, and ‡Department of Emergency Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts Reprint Address: Emily S. Miller, MD, Department of Emergency Medicine, Harvard Medical School, Massachusetts General Hospital, Zero Emerson Place, Suite 3B, Boston, MA 02114
procedures. He reported a mild headache but had not had stiff neck, rash, nausea, vomiting, diarrhea, or dysuria. He had not received any blood transfusions, and drank well water. Dr. Andrew Liteplo: Could you describe the physical exam? Dr. Greenwood-Erickson: The patient had a temperature of 100.9 F, pulse was 92 beats/min, and blood pressure was 101/57 mm Hg. The oxygen saturation was 94% on room air. He was awake, alert, and oriented but appeared tired. The sclera were anicteric and pupils were symmetric. The neck was supple and without adenopathy or meningismus. The lungs were clear to auscultation and respiratory effort was normal. Cardiac examination revealed a normal regular S1 and S2 without murmur. The abdomen was soft and nontender; there was no hepatosplenomegaly. There was no costovertebral angle tenderness. The skin was without rash, nail beds showed no splinter hemorrhages, and there was no significant lymphadenopathy. Neurologically, he was nonfocal and intact. Dr. Michael Billington: What did you consider in your differential and how did you proceed with the initial evaluation in the ED? Dr. William Binder: The differential diagnosis was vast, but certain clues helped narrow down the possible causes of this patient’s illness. The patient’s symptoms
Dr. Margaret Greenwood-Erickson: Today’s case is that of a 58-year-old man who was sent to the emergency department (ED) by his primary care physician (PCP) for evaluation of fevers and lightheadedness. He had been well until 2 weeks before ED presentation when he developed nonproductive cough, malaise, weakness, and daily subjective fevers. He was seen by his PCP 2 days before presentation and started on doxycycline for treatment of presumptive Lyme disease. Laboratory tests, including a Lyme titer, were sent. Symptoms did not improve, however, and he returned to his PCP, where he had an episode of near syncope. The patient was noted in the office to have a blood pressure of 90/50 mm Hg and a temperature of 101.2 F. Based on the ongoing symptoms and abnormal vital signs, he was referred to the ED. The patient’s medical history was significant for hypertension, hyperlipidemia, and allergic rhinitis. His daily medications were amlodipine, doxazosin, triamterene/hydrochlorothiazide, and atorvastatin. He was allergic to penicillin. He had a family history significant for coronary artery disease in his father. He did not smoke or use illicit drugs and drank alcohol only occasionally. The patient had not traveled recently, but was an avid gardener at his home in Massachusetts. He denied tick bites, reported no mosquito bites, and no exposure to bats. He reported no ill contacts. He denied recent dental
1
2
could have stemmed from an oncologic process, such as leukemia or lymphoma. Daily cyclical fevers with weight loss and fatigue were all consistent with such a process. However, an infectious etiology seemed more likely to us. The possibilities included bacterial, parasitic, or viral etiologies. Common infections such as pneumonia or bronchitis were considered, and the complaint of cough raised suspicion for a respiratory infection. Urinary tract infection, pyelonephritis, or prostatitis could have caused persistent fever and malaise. However, the patient did not have genitourinary symptoms, which made these diagnoses less likely. While endocarditis could have caused the fevers and constitutional symptoms, he did not have a murmur or obvious risk factors. Less common infectious etiologies were also considered. Although this case did occur in early summer, it was unlikely that the cause of the fever was an arbovirus. First, the patient had not traveled to the southern United States or Caribbean, and thus Dengue fever was unlikely. Further, West Nile virus usually occurs in late summer and does not last for longer than 2 weeks, as had this patient’s symptoms. Other viral illnesses such as Epstein-Barr virus, cytomegalovirus, and acute human immunodeficiency virus (HIV) could have caused persistent fever without focal findings, although one would have expected a higher degree of lymphadenopathy. Importantly, the patient had not had transfusions and had no risk factors for HIV. Autochthonous malaria is quite unusual in the United States and has not been noted in Massachusetts in the past 70 years (1). Tick-borne diseases, including Lyme, Ehrlichia, Anaplasma, and Babesia, were within the differential and strongly considered, especially as the patient lived in an endemic area for these tick-borne illnesses. Each of these diseases can cause a nondescript illness consistent with this patient’s presentation. Dr. Greenwood-Erickson: Initial laboratory analysis was revealing. The patient had a Lyme titer performed at his PCP’s office 2 days before his visit, and the IgM/IgG antibody was negative. In the ED, a complete blood count demonstrated pancytopenia; the white blood cell count was 2,900 cells/mm3, hemoglobin was 10.2 g/dL, hematocrit was 31%, and platelets were 33,000/mm3. The differential revealed 47% neutrophils, 34% lymphocytes, 15% monocytes, and 3% atypical lymphocytes. Chemistries revealed a sodium of 131 mEq/L, potassium of 2.9 mEq/L, chloride of 94 mmol/L, and creatinine of 1.38 mg/dL. The aspartate aminotransferase and alanine aminotransferase were 61 and 96 U/L, respectively, and direct and total bilirubin were 0.6 mg/dL and 1.7 mg/ dL, respectively. Ehrlichia and Anaplasma titers were sent off and were pending. A monospot was performed and was positive. A thick and thin smear was sent for Babesia and was reported as positive, with an estimated 1.5% parisitemia.
W. Binder et al.
Dr. John Eicken: How common is babesiosis? Is this a disease primarily seen in New England? Dr. William Binder: Babesiosis is caused by protozoal parasites of the genus Babesia and they infect red blood cells. The disease shares a niche in the red cell similar to malaria, although there are significant differences in its development within the host (2). Babesiosis was first identified by Victor Babes in 1888 in an article describing the cause of hemoglobinuria in Romanian cattle. However, it was not reported in humans until the 1950s, when it was noted in a splenectomized Croatian herdsman who quickly succumbed to the disease (3). The first immunocompetent individual reported to have babesiosis occurred on Nantucket in 1969 (3). The number of cases in the United States has increased steadily over the past 2 decades and, in 2012, there were almost 1,000 cases reported in the United States (4). Although Babesia was originally known in the United States as Nantucket fever, the disease has a worldwide spectrum. There are > 100 babesia species, but the primary cause of illness in the United States is Babesia microti. Babesia divergens (the same organism responsible for the death of the Croation herdsman) is seen sporadically in the United States and has been reported in Washington State, Kentucky, and Missouri, as well as throughout Europe. Babesia duncani has been reported in California (5). Dr. Susan Wilcox: Why are we seeing an increase in Babesia? What are the modes of transmission for this disease? Dr. William Binder: Babesia is a tick-borne illness. In the United States, it is carried primarily by Ixodes scapularis, the same vector that transmits Lyme disease as well as anaplasmosis. The primary reservoir for the disease is the white-footed mouse. In the northeastern United States, where Ixodes ticks are prevalent and Lyme disease is endemic, dual infection with the organisms responsible for either Lyme disease, babesiosis, or human anaplasmosis are seen in up to 28% of ticks, although, interestingly, it is rare to find all 3 together in one tick (5,6). Although adult ticks carry B. microti, nymphal ticks are responsible for most cases of babesiosis in the United States. Humans are accidental hosts for the disease. White tail deer are not reservoirs, and do not become infected, but serve to amplify the tick population by providing a blood meal for adult ticks. In addition, Babesia can also be transmitted vertically through the placenta and through blood and blood products (7). The increase in babesiosis cases in the United States is mirrored by an increase in tick-borne illnesses seen worldwide. Better detection methods, climate change, evolving land use patterns, and widespread travel have led to an unprecedented surge in tick-borne illnesses in every continent except Antarctica. In North America,
the preceding factors, as well as an increase in the deer population and a decrease in land-based mammals feeding on mice, have all led to an increase in tick–human interaction, leading to the increase in tick-borne illnesses (8–11). Dr. Katie Golden: This patient presented with fever, malaise, and lightheadedness, which are all nonspecific constitutional symptoms. What was it about this patient that led you to consider tick-borne illnesses such as babesiosis in the differential? Dr. Nicholas Maldonado: Babesiosis can range from an asymptomatic disease to a severe and fatal illness. In one study of residents of an endemic area in Rhode Island about 33% of all babesial infections were asymptomatic; 19% of adults and 40% of children of this group seroconverted despite no report of symptoms (12). Symptomatic disease usually occurs within 1 to 6 weeks after a tick feeding. The majority of patients who are admitted to the hospital for babesiosis experience a range of nonspecific constitutional symptoms, including fatigue, weakness, and malaise. These symptoms can progress to chills, sweats, headache, arthralgias, anorexia, and cough. Photophobia is rare and a rash is seldom seen (5,13). The symptoms noted in mild babesiosis are commonly associated with less emergent diagnoses, such as viral syndromes, and no studies have specifically sought to determine the diagnostic accuracy of particular signs and symptoms of babesiosis that would help discern its clinical probability. In a patient with an unexplained febrile illness or a febrile illness that is not following the typical course of a viral syndrome, and in the proper setting, babesiosis should be considered in the differential. This is particularly true if the patient resides in an endemic region of the country, has outdoor exposures, and presents in the late spring and summer. Although this patient had no recollection of sustaining a tick bite, his regular work outdoors in the garden heightened his risk for tick-borne illness. Babesiosis should also be suspected in patients who have received a blood transfusion weeks to months before clinical presentation (14,15). Dyspnea and abdominal pain signify more advanced disease, while fulminant babesiosis is marked by respiratory failure, disseminated intravascular coagulation, liver and renal infection, and splenic infarcts. Patients aged older than 50 years are more likely to be symptomatic and to suffer severe disease. Additionally, patients with an underlying immunosuppressive condition, such as HIV, malignancy, and splenectomy, or are on chronic therapy with immunomodulators, are more likely to suffer severe complications of babesiosis and can have a 20% mortality rate (5). Host immune factors lead to an inflammatory reaction—cytokine and nitric oxide production—which can result in the systemic inflammatory
3
response syndrome, sepsis, and adult respiratory distress syndrome (16). Dr. Eric Nadel: How was this patient diagnosed? Are there tests other than a thick and thin smear for babesiosis? Also, this patient had a positive monospot. Did he have both babesiosis and Epstein-Barr virus? Dr. Nicholas Maldonado: The diagnosis of babesiosis is often made by reviewing a thin and thick Giemsaor Wright-stained blood smear and identifying B. microti ring forms within the erythrocyte. The trophozoites appear as pleomorphic ring forms, which may be both intraerythrocytic and extraerythrocytic. Babesia divide by fission, so one organism becomes two, and subsequently four organisms. Tetrads of babesia may be seen intracellularly (Figure 1), and rarely are arranged in a cross-like pattern (i.e., the Maltese cross) (17). The ring forms can resemble those of Plasmodium falciparum, but malaria should be able to be eliminated from consideration through a careful travel history. Likewise, a tetrad of malaria would be highly unusual, as it would only occur if an erythrocyte were invaded by four separate malaria merozoites. Parasitemia is often <1% early in babesiosis and so, if suspected, repeat blood smears and review of multiple microscopic fields should be requested (18). Polymerase chain reaction assay is available for the detection of babesia DNA in blood, but is not available in all laboratories. Indirect immunofluorescence assays are the standard assay for the detection of babesia antibody. IgM antibody is usually noted in the first 2 weeks after the onset of illness, and IgG titers rise and remain elevated for up to 1 year. If laboratory tests are inconclusive and babesiosis remains high on the differential, blood from the patient can be injected into a hamster, and B. microti organisms will appear in the inoculated animal within 2 to 4 weeks (3,5). Of note, the positive monospot test in our patient was a false positive. There are many causes of false-positive monospot test, such as
web 4C/FPO
Diagnosing Fever Lasting 2 Weeks
Figure 1. Thin preparation peripheral blood smear demonstrating an intraerythrocytic tetrad of babesia (circle).
4
W. Binder et al.
systemic lupus erythematosus and rheumatoid arthritis, as well as viral causes, such as influenza, cytomegalovirus, and hepatitis. Malaria and Babesia can both cause false-positive monospot tests, as well (19). Dr. Henry Epino: How was this patient treated, and what was his eventual outcome? Does the degree of parasitemia correlate to symptoms? Dr. Binder: Patients who are symptomatic and have a diagnosis confirmed by a positive blood smear or polymerase chain reaction should be treated with antibiotics. Mild to moderate illness is treated with atovoquone and azithromycin for 7 to 10 days. Clindamycin and quinine can be used, but this combination is associated with a high frequency of adverse reactions (72%) (20). This latter combination is used in severe disease and in cases of B. divergens, which is associated with higher morbidity. Patients with parasitemia of <1% are usually only mildly ill. Our patient had a parasitemia of 1.5%, but appeared to be more symptomatic, probably due to his age. In cases where the parasitemia is >10% and in which the patient is ill, exchange transfusions can be undertaken (5). The patient was hospitalized for 5 days, and he briefly developed pulmonary edema and dyspnea during his hospitalization. He was diuresed and improved, but continued to complain of fatigue and malaise for several weeks after his initial presentation. He had a negative babesia smear 6 weeks after initiation of treatment and slowly returned to his baseline. REFERENCES 1. Zucker JR. Changing patterns of autochthonous malarial transmission in the United States: a review of recent outbreaks. Emerg Infect Dis 1996;2:37–43. 2. Schuster FL. Cultivation of Babesia and Babesia-like blood parasites: agents of an emerging zoonotic disease. Clin Microbiol Rev 2002;15:365–73.
3. Vannier E, Krause PJ. Human babesiosis. N Engl J Med 2012;366: 2397–407. 4. Centers for Disease Control and Prevention. Parasites–babesiosis. Available at: www.CDC.gov/parasites/babesiosis/data-statistics. html. Accessed July 12, 2014. 5. Vanner E, Gewurz BE, Krause PJ. Human babesiosis. Infect Dis Clin North Am 2008;22:469–88. 6. Swanson SJ, Neitzel D, Reed KD, et al. Coinfections acquired from Ixodes ticks. Clin Microbiol Rev 2006;19:708–27. 7. Abramowsky C, Aguero-Rosenfeld ME, Horowitz HW, et al. Vertical transmission of Babesia microti, United States. Emerg Infect Dis 2012;18:1318–25. 8. Pfaffle M, Littwin N, Muders SV, et al. The ecology of tick-borne diseases. Int J Parasitol 2013;43:1059–77. 9. Dumler JS. Fitness and freezing: vector biology and human health. J Clin Invest 2010;120:3087–90. 10. Patz JA, Campbell-Lendrum D, Holloway T, et al. Impact of regional climate change on human health. Nature 2005; 438:310–7. 11. Gubler DJ, Reiter P, Ebi KL, et al. Climate variability and change in the United States: potential impacts on vector- and rodentborne diseases. Environ Health Perspect 2001;109(Suppl 2): 223–33. 12. Krause PJ, McKay K, Garbaw J. Increasing health burden of human babesiosis in endemic sites. Am J Trop Med Hyg 2003;68: 431–6. 13. White DJ, Talarico J, Chang HG. Human babesiosis in New York state: review of 139 hospitalized cases and analysis of prognostic factors. Arch Intern Med 1998;158:2149–54. 14. Gubernot DM, Lucey CT, Lee KC. Babesia infection through blood transfusion: reports received by the US Food and Drug Administration 1997–2007. Clin Infect Dis 2009;48:25–30. 15. Johnson ST, Cable RG, Tonnetti L. Seroprevalence of Babesia microti in blood donors from Babesia-endemic areas of the northeastern United States: 2000–2007. Transfusion 2009;29:2574–82. 16. Shoda LK, Palmer GH, Florin-Christensen J. Babesia bovisstimulated macrophages express interleukin-1B, interleukin-12, tumor necrosis factor alpha, and nitric oxide and inhibit parasite replication in vitro. Infect Immun 2000;68:5139–45. 17. Filbin MR, Mylonakis EE, Callegan L, et al. Babesiosis. J Emerg Med 2001;20:21–4. 18. Mylonakis E. When to suspect and how to monitor babesiosis. Am Fam Physician 2001;15:1969–75. 19. Cunha BA, Mickail N, Laguerre M. Babesiosis mimicking Epstein Barr virus (EBV) infectious mononucleosis: another cause of a false positive monospot test. J Infect 2012;64:531–2. 20. Krause PJ, Lepore T, Sikand VK. Atovaquone and azithromycin for the treatment of babesisosis. N Engl J Med 2000;343:1454–8.
Case Presentations of the Harvard Emergency Medicine Residencies
A GARDENER WITH A FEVER FOR 2 WEEKS William Binder, MD,* Nicholas G. Maldonado, MD,† David F. M. Brown, MD,‡ and Emily S. Miller, MD‡ *Department of Emergency Medicine, Alpert School of Medicine, Brown University, Rhode Island Hospital/Miriam Hospital, Providence, Rhode Island, †Department of Emergency Medicine, University of Florida College of Medicine, University of Florida Health Shands Hospital, Gainesville, Florida, and ‡Department of Emergency Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts Reprint Address: Emily S. Miller, MD, Department of Emergency Medicine, Harvard Medical School, Massachusetts General Hospital, Zero Emerson Place, Suite 3B, Boston, MA 02114
procedures. He reported a mild headache but had not had stiff neck, rash, nausea, vomiting, diarrhea, or dysuria. He had not received any blood transfusions, and drank well water. Dr. Andrew Liteplo: Could you describe the physical exam? Dr. Greenwood-Erickson: The patient had a temperature of 100.9 F, pulse was 92 beats/min, and blood pressure was 101/57 mm Hg. The oxygen saturation was 94% on room air. He was awake, alert, and oriented but appeared tired. The sclera were anicteric and pupils were symmetric. The neck was supple and without adenopathy or meningismus. The lungs were clear to auscultation and respiratory effort was normal. Cardiac examination revealed a normal regular S1 and S2 without murmur. The abdomen was soft and nontender; there was no hepatosplenomegaly. There was no costovertebral angle tenderness. The skin was without rash, nail beds showed no splinter hemorrhages, and there was no significant lymphadenopathy. Neurologically, he was nonfocal and intact. Dr. Michael Billington: What did you consider in your differential and how did you proceed with the initial evaluation in the ED? Dr. William Binder: The differential diagnosis was vast, but certain clues helped narrow down the possible causes of this patient’s illness. The patient’s symptoms
Dr. Margaret Greenwood-Erickson: Today’s case is that of a 58-year-old man who was sent to the emergency department (ED) by his primary care physician (PCP) for evaluation of fevers and lightheadedness. He had been well until 2 weeks before ED presentation when he developed nonproductive cough, malaise, weakness, and daily subjective fevers. He was seen by his PCP 2 days before presentation and started on doxycycline for treatment of presumptive Lyme disease. Laboratory tests, including a Lyme titer, were sent. Symptoms did not improve, however, and he returned to his PCP, where he had an episode of near syncope. The patient was noted in the office to have a blood pressure of 90/50 mm Hg and a temperature of 101.2 F. Based on the ongoing symptoms and abnormal vital signs, he was referred to the ED. The patient’s medical history was significant for hypertension, hyperlipidemia, and allergic rhinitis. His daily medications were amlodipine, doxazosin, triamterene/hydrochlorothiazide, and atorvastatin. He was allergic to penicillin. He had a family history significant for coronary artery disease in his father. He did not smoke or use illicit drugs and drank alcohol only occasionally. The patient had not traveled recently, but was an avid gardener at his home in Massachusetts. He denied tick bites, reported no mosquito bites, and no exposure to bats. He reported no ill contacts. He denied recent dental
1
2
could have stemmed from an oncologic process, such as leukemia or lymphoma. Daily cyclical fevers with weight loss and fatigue were all consistent with such a process. However, an infectious etiology seemed more likely to us. The possibilities included bacterial, parasitic, or viral etiologies. Common infections such as pneumonia or bronchitis were considered, and the complaint of cough raised suspicion for a respiratory infection. Urinary tract infection, pyelonephritis, or prostatitis could have caused persistent fever and malaise. However, the patient did not have genitourinary symptoms, which made these diagnoses less likely. While endocarditis could have caused the fevers and constitutional symptoms, he did not have a murmur or obvious risk factors. Less common infectious etiologies were also considered. Although this case did occur in early summer, it was unlikely that the cause of the fever was an arbovirus. First, the patient had not traveled to the southern United States or Caribbean, and thus Dengue fever was unlikely. Further, West Nile virus usually occurs in late summer and does not last for longer than 2 weeks, as had this patient’s symptoms. Other viral illnesses such as Epstein-Barr virus, cytomegalovirus, and acute human immunodeficiency virus (HIV) could have caused persistent fever without focal findings, although one would have expected a higher degree of lymphadenopathy. Importantly, the patient had not had transfusions and had no risk factors for HIV. Autochthonous malaria is quite unusual in the United States and has not been noted in Massachusetts in the past 70 years (1). Tick-borne diseases, including Lyme, Ehrlichia, Anaplasma, and Babesia, were within the differential and strongly considered, especially as the patient lived in an endemic area for these tick-borne illnesses. Each of these diseases can cause a nondescript illness consistent with this patient’s presentation. Dr. Greenwood-Erickson: Initial laboratory analysis was revealing. The patient had a Lyme titer performed at his PCP’s office 2 days before his visit, and the IgM/IgG antibody was negative. In the ED, a complete blood count demonstrated pancytopenia; the white blood cell count was 2,900 cells/mm3, hemoglobin was 10.2 g/dL, hematocrit was 31%, and platelets were 33,000/mm3. The differential revealed 47% neutrophils, 34% lymphocytes, 15% monocytes, and 3% atypical lymphocytes. Chemistries revealed a sodium of 131 mEq/L, potassium of 2.9 mEq/L, chloride of 94 mmol/L, and creatinine of 1.38 mg/dL. The aspartate aminotransferase and alanine aminotransferase were 61 and 96 U/L, respectively, and direct and total bilirubin were 0.6 mg/dL and 1.7 mg/ dL, respectively. Ehrlichia and Anaplasma titers were sent off and were pending. A monospot was performed and was positive. A thick and thin smear was sent for Babesia and was reported as positive, with an estimated 1.5% parisitemia.
W. Binder et al.
Dr. John Eicken: How common is babesiosis? Is this a disease primarily seen in New England? Dr. William Binder: Babesiosis is caused by protozoal parasites of the genus Babesia and they infect red blood cells. The disease shares a niche in the red cell similar to malaria, although there are significant differences in its development within the host (2). Babesiosis was first identified by Victor Babes in 1888 in an article describing the cause of hemoglobinuria in Romanian cattle. However, it was not reported in humans until the 1950s, when it was noted in a splenectomized Croatian herdsman who quickly succumbed to the disease (3). The first immunocompetent individual reported to have babesiosis occurred on Nantucket in 1969 (3). The number of cases in the United States has increased steadily over the past 2 decades and, in 2012, there were almost 1,000 cases reported in the United States (4). Although Babesia was originally known in the United States as Nantucket fever, the disease has a worldwide spectrum. There are > 100 babesia species, but the primary cause of illness in the United States is Babesia microti. Babesia divergens (the same organism responsible for the death of the Croation herdsman) is seen sporadically in the United States and has been reported in Washington State, Kentucky, and Missouri, as well as throughout Europe. Babesia duncani has been reported in California (5). Dr. Susan Wilcox: Why are we seeing an increase in Babesia? What are the modes of transmission for this disease? Dr. William Binder: Babesia is a tick-borne illness. In the United States, it is carried primarily by Ixodes scapularis, the same vector that transmits Lyme disease as well as anaplasmosis. The primary reservoir for the disease is the white-footed mouse. In the northeastern United States, where Ixodes ticks are prevalent and Lyme disease is endemic, dual infection with the organisms responsible for either Lyme disease, babesiosis, or human anaplasmosis are seen in up to 28% of ticks, although, interestingly, it is rare to find all 3 together in one tick (5,6). Although adult ticks carry B. microti, nymphal ticks are responsible for most cases of babesiosis in the United States. Humans are accidental hosts for the disease. White tail deer are not reservoirs, and do not become infected, but serve to amplify the tick population by providing a blood meal for adult ticks. In addition, Babesia can also be transmitted vertically through the placenta and through blood and blood products (7). The increase in babesiosis cases in the United States is mirrored by an increase in tick-borne illnesses seen worldwide. Better detection methods, climate change, evolving land use patterns, and widespread travel have led to an unprecedented surge in tick-borne illnesses in every continent except Antarctica. In North America,
the preceding factors, as well as an increase in the deer population and a decrease in land-based mammals feeding on mice, have all led to an increase in tick–human interaction, leading to the increase in tick-borne illnesses (8–11). Dr. Katie Golden: This patient presented with fever, malaise, and lightheadedness, which are all nonspecific constitutional symptoms. What was it about this patient that led you to consider tick-borne illnesses such as babesiosis in the differential? Dr. Nicholas Maldonado: Babesiosis can range from an asymptomatic disease to a severe and fatal illness. In one study of residents of an endemic area in Rhode Island about 33% of all babesial infections were asymptomatic; 19% of adults and 40% of children of this group seroconverted despite no report of symptoms (12). Symptomatic disease usually occurs within 1 to 6 weeks after a tick feeding. The majority of patients who are admitted to the hospital for babesiosis experience a range of nonspecific constitutional symptoms, including fatigue, weakness, and malaise. These symptoms can progress to chills, sweats, headache, arthralgias, anorexia, and cough. Photophobia is rare and a rash is seldom seen (5,13). The symptoms noted in mild babesiosis are commonly associated with less emergent diagnoses, such as viral syndromes, and no studies have specifically sought to determine the diagnostic accuracy of particular signs and symptoms of babesiosis that would help discern its clinical probability. In a patient with an unexplained febrile illness or a febrile illness that is not following the typical course of a viral syndrome, and in the proper setting, babesiosis should be considered in the differential. This is particularly true if the patient resides in an endemic region of the country, has outdoor exposures, and presents in the late spring and summer. Although this patient had no recollection of sustaining a tick bite, his regular work outdoors in the garden heightened his risk for tick-borne illness. Babesiosis should also be suspected in patients who have received a blood transfusion weeks to months before clinical presentation (14,15). Dyspnea and abdominal pain signify more advanced disease, while fulminant babesiosis is marked by respiratory failure, disseminated intravascular coagulation, liver and renal infection, and splenic infarcts. Patients aged older than 50 years are more likely to be symptomatic and to suffer severe disease. Additionally, patients with an underlying immunosuppressive condition, such as HIV, malignancy, and splenectomy, or are on chronic therapy with immunomodulators, are more likely to suffer severe complications of babesiosis and can have a 20% mortality rate (5). Host immune factors lead to an inflammatory reaction—cytokine and nitric oxide production—which can result in the systemic inflammatory
3
response syndrome, sepsis, and adult respiratory distress syndrome (16). Dr. Eric Nadel: How was this patient diagnosed? Are there tests other than a thick and thin smear for babesiosis? Also, this patient had a positive monospot. Did he have both babesiosis and Epstein-Barr virus? Dr. Nicholas Maldonado: The diagnosis of babesiosis is often made by reviewing a thin and thick Giemsaor Wright-stained blood smear and identifying B. microti ring forms within the erythrocyte. The trophozoites appear as pleomorphic ring forms, which may be both intraerythrocytic and extraerythrocytic. Babesia divide by fission, so one organism becomes two, and subsequently four organisms. Tetrads of babesia may be seen intracellularly (Figure 1), and rarely are arranged in a cross-like pattern (i.e., the Maltese cross) (17). The ring forms can resemble those of Plasmodium falciparum, but malaria should be able to be eliminated from consideration through a careful travel history. Likewise, a tetrad of malaria would be highly unusual, as it would only occur if an erythrocyte were invaded by four separate malaria merozoites. Parasitemia is often <1% early in babesiosis and so, if suspected, repeat blood smears and review of multiple microscopic fields should be requested (18). Polymerase chain reaction assay is available for the detection of babesia DNA in blood, but is not available in all laboratories. Indirect immunofluorescence assays are the standard assay for the detection of babesia antibody. IgM antibody is usually noted in the first 2 weeks after the onset of illness, and IgG titers rise and remain elevated for up to 1 year. If laboratory tests are inconclusive and babesiosis remains high on the differential, blood from the patient can be injected into a hamster, and B. microti organisms will appear in the inoculated animal within 2 to 4 weeks (3,5). Of note, the positive monospot test in our patient was a false positive. There are many causes of false-positive monospot test, such as
web 4C/FPO
Diagnosing Fever Lasting 2 Weeks
Figure 1. Thin preparation peripheral blood smear demonstrating an intraerythrocytic tetrad of babesia (circle).
4
W. Binder et al.
systemic lupus erythematosus and rheumatoid arthritis, as well as viral causes, such as influenza, cytomegalovirus, and hepatitis. Malaria and Babesia can both cause false-positive monospot tests, as well (19). Dr. Henry Epino: How was this patient treated, and what was his eventual outcome? Does the degree of parasitemia correlate to symptoms? Dr. Binder: Patients who are symptomatic and have a diagnosis confirmed by a positive blood smear or polymerase chain reaction should be treated with antibiotics. Mild to moderate illness is treated with atovoquone and azithromycin for 7 to 10 days. Clindamycin and quinine can be used, but this combination is associated with a high frequency of adverse reactions (72%) (20). This latter combination is used in severe disease and in cases of B. divergens, which is associated with higher morbidity. Patients with parasitemia of <1% are usually only mildly ill. Our patient had a parasitemia of 1.5%, but appeared to be more symptomatic, probably due to his age. In cases where the parasitemia is >10% and in which the patient is ill, exchange transfusions can be undertaken (5). The patient was hospitalized for 5 days, and he briefly developed pulmonary edema and dyspnea during his hospitalization. He was diuresed and improved, but continued to complain of fatigue and malaise for several weeks after his initial presentation. He had a negative babesia smear 6 weeks after initiation of treatment and slowly returned to his baseline. REFERENCES 1. Zucker JR. Changing patterns of autochthonous malarial transmission in the United States: a review of recent outbreaks. Emerg Infect Dis 1996;2:37–43. 2. Schuster FL. Cultivation of Babesia and Babesia-like blood parasites: agents of an emerging zoonotic disease. Clin Microbiol Rev 2002;15:365–73.
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