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An Unsuspected Zoonotic Infection Presenting as Sepsis
Accepted Manuscript Title: An Unsuspected Zoonotic Infection Presenting as Sepsis Author: Epstein R., Ristau J., Ellner J.J. PII: DOI: Reference:
S0002-9343(17)30843-4 http://dx.doi.org/doi: 10.1016/j.amjmed.2017.07.040 AJM 14248
To appear in:
The American Journal of Medicine
Please cite this article as: Epstein R., Ristau J., Ellner J.J., An Unsuspected Zoonotic Infection Presenting as Sepsis, The American Journal of Medicine (2017), http://dx.doi.org/doi: 10.1016/j.amjmed.2017.07.040. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
An Unsuspected Zoonotic Infection Presenting as Sepsis Epstein, R. M.D., M.A.a, Ristau, J., M.D.b, 1, Ellner, J.J., M.D. c a
Department of Pediatric Infectious Diseases, Department of Infectious Diseases, Boston University School of Medicine (BUSM), Boston Medical Center 670 Albany St., 6th Floor, Pediatric Infectious Diseases, Boston, MA, 02118, USA [email protected] b
Boston University School of Medicine, 72 East Concord St., Boston Medical Center, Boston, MA, 02118, USA c
Department of Infectious Diseases, Boston University School of Medicine, Boston Medical Center 801 Massachusetts Avenue, 2nd Floor, Boston, MA 02118, USA [email protected]
Author Contributions: Both first and second authors had equal contributions to this article. Conception, design, drafting and revision: J. Ristau, R. Epstein, J.J. Ellner. Manuscript Type: Clinical Communication to the Editor Keywords: Anaplasmosis, Sepsis, Tick-borne Diseases Conflicts of interest: none Funding sources: none Word Count: 653 Corresponding Author: Rachel Epstein 670 Albany St., 6th Floor Pediatric Infectious Diseases Boston, MA 02118 [email protected] Telephone 617-414-6395 / Fax 617-414-7230 1
Present Address for Dr. Ristau: Department of Medicine, University of California San Francisco, 505 Parnassus Avenue, Room M-987 San Francisco, CA 94143-0119, USA [email protected]
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To the Editor:
We describe two patients from an urban center in New England with undifferentiated sepsis. Patient 1, a 65-year-old male with hypertension and diabetes, presented with three days of fevers and malaise. He denied tick bites, exposure to forested areas, animals, or blood transfusion, but had returned from Bangladesh three weeks previously. Physical examination revealed temperature of 38.8 C, heart rate 93, and tenderness to palpation of large muscle groups; blood lactate was 5mM. Despite antibiotic coverage with ceftriaxone, azithromycin and vancomycin, he deteriorated over the next three days with “hectic” fevers (Figure 1a), profuse sweats, rigors and confusion. Bacterial cultures, viral serologies and computed tomography (CT) of the chest, abdomen and pelvis were negative. He developed pancytopenia (Figure 1b). A blood smear to rule out malaria revealed intracytoplasmic inclusions in neutrophils (morulae). Human granulocytic anaplasmosis was suspected, and doxycycline therapy initiated. Dramatic clinical improvement followed (defervescence within two hours), and he recovered without sequelae. Serum polymerase chain reaction for Anaplasma phagocytophilum was positive.
Patient 2, a 49-year-old asplenic male, presented with fevers, rigors and cough. Physical examination revealed a temperature of 39.2 C, heart rate 120, respiratory rate 22, oxygen saturation 90% on supplemental oxygen, and rhonchi at the left lung base; chest radiograph demonstrated a left lower lobe opacity. Vancomycin, ceftriaxone, and azithromycin were given for severe community acquired pneumonia with initial improvement. Leukocytosis persisted; on day eight, fevers, rigors, headache, nausea, and diarrhea returned. Blood, urine, and throat cultures, respiratory nasopharyngeal polymerase chain reaction panel, Clostridium difficile stool testing, and CT of chest, abdomen and sinuses were normal. Tick-borne illnesses were
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considered in the setting of asplenia with worsening anemia, thrombocytopenia, and elevated liver enzymes (Figure 1b). Doxycycline was initiated; fevers and leukocytosis resolved within 24 hours. Blood smear was negative, but serum polymerase chain reaction for A. phagocytophilum was positive.
Human granulocytic anaplasmosis is prevalent in Massachusetts, with 828 confirmed cases in 2016, increased 152% from 329 in 20131; similar trends have occurred elsewhere in the US2. Tick bites were reported by only 38% of patients with anaplasmosis in Massachusetts1. Spontaneous resolution with mild disease is typical2, although potential complications include renal failure, acute respiratory distress syndrome, disseminated intravascular coagulopathy, and central nervous system involvement3. Mortality is 0.5-1%3, but this may be an underestimate due to lack of pathognomonic findings and missed diagnoses. Elderly and immunocompromised persons are at risk of poor outcomes; cases of severe and prolonged anaplasmosis in splenectomized individuals have been reported3, 4.
Rapid to perform and interpret, blood smear sensitivity for detecting morulae characteristic of human granulocytic anaplasmosis is 20-80%3. Comparison of acute and convalescent titers by immunofluorescence antibody assay is very sensitive (94-100% after 14 days of illness3), but takes weeks. Polymerase chain reaction testing is widely available, with fast turn-around times, and a sensitivity of 60-70%3.
These cases illustrate the nonspecific nature and severity of human granulocytic anaplasmosis and the rapid response to treatment. Doxycycline should be considered in appropriate geographic
3
Page 3 of 6
areas for patients with sepsis syndromes or cytopenias who do not respond to broad spectrum antibiotics. Delays in treatment due to lack of consideration of anaplasmosis or ehrlichiosis may increase morbidity and mortality in an otherwise easily treatable disease.
4
Page 4 of 6
Acknowledgements:
Anas Sarhan, MD, BUSM, contributed to conception, design and initial drafting. Alfred DeMaria, Jr., MD, Massachusetts DPH, and Deborah Cotton, MD, MPH, BUSM, contributed to revision and intellectual content.
References: 1. Massachusetts Department of Public Health. Human Granulocytic Anaplasmosis Surveillance in Massachusetts, 2016. Available at: http://www.mass.gov/eohhs/gov/departments/dph/programs/id/epidemiology/ticks/surveillan ce-summaries-data.html. Accessed 17 July 2017. 2. Bakken JS, Dumler JS. Human granulocytic anaplasmosis. Infect Dis Clin North Am. 2015 Jun;29(2):341-55. https://doi.org/10.1016/j.idc.2015.02.007. 3. Chapman AS, Bakken JS, Folk SM, et al. Tickborne Rickettsial Diseases Working Group; CDC. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and anaplasmosis. MMWR 2006;55(RR-4):1-27. 4. Rabinstein A, Tikhomirov V, Kaluta A, et al. Recurrent and prolonged fever in asplenic patients with human granulocytic ehrlichiosis. QJM. 2000 Mar;93(3):198-201.
Figure 1: Fever Curve and Laboratory Values 1a:
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Page 5 of 6
Fever Curve, Patient 1
Temperature (C)
40
39
38
37
36 0
24
48
72
96
Hours after Presentation
1b: Laboratory Measure Admission Patient 1: White Blood Cells (K/UL) 4.9 Hemoglobin (G/DL) 11.2 Platelets (K/UL) 96 AST/ALT (K/UL) 20/20 Patient 2: White Blood Cells (K/UL) 8.0 Hemoglobin (G/DL) 13.9 Platelets (K/UL) 219 AST/ALT (K/UL) 172/171
Nadir/ Peak
Post Treatment
3.1 9.7 34 -
4.4 9.5 46 -
4.4/18.9 7.7 73 172/171
10.1 9.5 594 30/19
Figure 1 Legend: Figure 1a demonstrates the fever curve for patient one, with star indicating the initiation of doxycycline. Figure 1b displays laboratory values during acute illness and after treatment for both patients. Abbreviations: AST aspartate aminotransferase ALT alanine transaminase.
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S0002-9343(17)30843-4 http://dx.doi.org/doi: 10.1016/j.amjmed.2017.07.040 AJM 14248
To appear in:
The American Journal of Medicine
Please cite this article as: Epstein R., Ristau J., Ellner J.J., An Unsuspected Zoonotic Infection Presenting as Sepsis, The American Journal of Medicine (2017), http://dx.doi.org/doi: 10.1016/j.amjmed.2017.07.040. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
An Unsuspected Zoonotic Infection Presenting as Sepsis Epstein, R. M.D., M.A.a, Ristau, J., M.D.b, 1, Ellner, J.J., M.D. c a
Department of Pediatric Infectious Diseases, Department of Infectious Diseases, Boston University School of Medicine (BUSM), Boston Medical Center 670 Albany St., 6th Floor, Pediatric Infectious Diseases, Boston, MA, 02118, USA [email protected] b
Boston University School of Medicine, 72 East Concord St., Boston Medical Center, Boston, MA, 02118, USA c
Department of Infectious Diseases, Boston University School of Medicine, Boston Medical Center 801 Massachusetts Avenue, 2nd Floor, Boston, MA 02118, USA [email protected]
Author Contributions: Both first and second authors had equal contributions to this article. Conception, design, drafting and revision: J. Ristau, R. Epstein, J.J. Ellner. Manuscript Type: Clinical Communication to the Editor Keywords: Anaplasmosis, Sepsis, Tick-borne Diseases Conflicts of interest: none Funding sources: none Word Count: 653 Corresponding Author: Rachel Epstein 670 Albany St., 6th Floor Pediatric Infectious Diseases Boston, MA 02118 [email protected] Telephone 617-414-6395 / Fax 617-414-7230 1
Present Address for Dr. Ristau: Department of Medicine, University of California San Francisco, 505 Parnassus Avenue, Room M-987 San Francisco, CA 94143-0119, USA [email protected]
1
Page 1 of 6
To the Editor:
We describe two patients from an urban center in New England with undifferentiated sepsis. Patient 1, a 65-year-old male with hypertension and diabetes, presented with three days of fevers and malaise. He denied tick bites, exposure to forested areas, animals, or blood transfusion, but had returned from Bangladesh three weeks previously. Physical examination revealed temperature of 38.8 C, heart rate 93, and tenderness to palpation of large muscle groups; blood lactate was 5mM. Despite antibiotic coverage with ceftriaxone, azithromycin and vancomycin, he deteriorated over the next three days with “hectic” fevers (Figure 1a), profuse sweats, rigors and confusion. Bacterial cultures, viral serologies and computed tomography (CT) of the chest, abdomen and pelvis were negative. He developed pancytopenia (Figure 1b). A blood smear to rule out malaria revealed intracytoplasmic inclusions in neutrophils (morulae). Human granulocytic anaplasmosis was suspected, and doxycycline therapy initiated. Dramatic clinical improvement followed (defervescence within two hours), and he recovered without sequelae. Serum polymerase chain reaction for Anaplasma phagocytophilum was positive.
Patient 2, a 49-year-old asplenic male, presented with fevers, rigors and cough. Physical examination revealed a temperature of 39.2 C, heart rate 120, respiratory rate 22, oxygen saturation 90% on supplemental oxygen, and rhonchi at the left lung base; chest radiograph demonstrated a left lower lobe opacity. Vancomycin, ceftriaxone, and azithromycin were given for severe community acquired pneumonia with initial improvement. Leukocytosis persisted; on day eight, fevers, rigors, headache, nausea, and diarrhea returned. Blood, urine, and throat cultures, respiratory nasopharyngeal polymerase chain reaction panel, Clostridium difficile stool testing, and CT of chest, abdomen and sinuses were normal. Tick-borne illnesses were
2
Page 2 of 6
considered in the setting of asplenia with worsening anemia, thrombocytopenia, and elevated liver enzymes (Figure 1b). Doxycycline was initiated; fevers and leukocytosis resolved within 24 hours. Blood smear was negative, but serum polymerase chain reaction for A. phagocytophilum was positive.
Human granulocytic anaplasmosis is prevalent in Massachusetts, with 828 confirmed cases in 2016, increased 152% from 329 in 20131; similar trends have occurred elsewhere in the US2. Tick bites were reported by only 38% of patients with anaplasmosis in Massachusetts1. Spontaneous resolution with mild disease is typical2, although potential complications include renal failure, acute respiratory distress syndrome, disseminated intravascular coagulopathy, and central nervous system involvement3. Mortality is 0.5-1%3, but this may be an underestimate due to lack of pathognomonic findings and missed diagnoses. Elderly and immunocompromised persons are at risk of poor outcomes; cases of severe and prolonged anaplasmosis in splenectomized individuals have been reported3, 4.
Rapid to perform and interpret, blood smear sensitivity for detecting morulae characteristic of human granulocytic anaplasmosis is 20-80%3. Comparison of acute and convalescent titers by immunofluorescence antibody assay is very sensitive (94-100% after 14 days of illness3), but takes weeks. Polymerase chain reaction testing is widely available, with fast turn-around times, and a sensitivity of 60-70%3.
These cases illustrate the nonspecific nature and severity of human granulocytic anaplasmosis and the rapid response to treatment. Doxycycline should be considered in appropriate geographic
3
Page 3 of 6
areas for patients with sepsis syndromes or cytopenias who do not respond to broad spectrum antibiotics. Delays in treatment due to lack of consideration of anaplasmosis or ehrlichiosis may increase morbidity and mortality in an otherwise easily treatable disease.
4
Page 4 of 6
Acknowledgements:
Anas Sarhan, MD, BUSM, contributed to conception, design and initial drafting. Alfred DeMaria, Jr., MD, Massachusetts DPH, and Deborah Cotton, MD, MPH, BUSM, contributed to revision and intellectual content.
References: 1. Massachusetts Department of Public Health. Human Granulocytic Anaplasmosis Surveillance in Massachusetts, 2016. Available at: http://www.mass.gov/eohhs/gov/departments/dph/programs/id/epidemiology/ticks/surveillan ce-summaries-data.html. Accessed 17 July 2017. 2. Bakken JS, Dumler JS. Human granulocytic anaplasmosis. Infect Dis Clin North Am. 2015 Jun;29(2):341-55. https://doi.org/10.1016/j.idc.2015.02.007. 3. Chapman AS, Bakken JS, Folk SM, et al. Tickborne Rickettsial Diseases Working Group; CDC. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and anaplasmosis. MMWR 2006;55(RR-4):1-27. 4. Rabinstein A, Tikhomirov V, Kaluta A, et al. Recurrent and prolonged fever in asplenic patients with human granulocytic ehrlichiosis. QJM. 2000 Mar;93(3):198-201.
Figure 1: Fever Curve and Laboratory Values 1a:
5
Page 5 of 6
Fever Curve, Patient 1
Temperature (C)
40
39
38
37
36 0
24
48
72
96
Hours after Presentation
1b: Laboratory Measure Admission Patient 1: White Blood Cells (K/UL) 4.9 Hemoglobin (G/DL) 11.2 Platelets (K/UL) 96 AST/ALT (K/UL) 20/20 Patient 2: White Blood Cells (K/UL) 8.0 Hemoglobin (G/DL) 13.9 Platelets (K/UL) 219 AST/ALT (K/UL) 172/171
Nadir/ Peak
Post Treatment
3.1 9.7 34 -
4.4 9.5 46 -
4.4/18.9 7.7 73 172/171
10.1 9.5 594 30/19
Figure 1 Legend: Figure 1a demonstrates the fever curve for patient one, with star indicating the initiation of doxycycline. Figure 1b displays laboratory values during acute illness and after treatment for both patients. Abbreviations: AST aspartate aminotransferase ALT alanine transaminase.
6
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