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Hemolytic uremic syndrome due to Capnocytophaga canimorsus bacteremia after a dog bite
CASE REPORT
Hemolytic Uremic Syndrome Due to Capnocytophaga canimorsus Bacteremia After a Dog Bite Tom J.M. Tobe´, MD, Casper F.M. Franssen, MD, Jan G. Zijlstra, MD, Paul E. de Jong, MD, and Coen A. Stegeman, MD ● The hemolytic uremic syndrome (HUS) is known to have several causes, including infectious diseases, drugs, pregnancy, and malignant disease. We report a patient who developed acute renal failure attributable to HUS in the course of Capnocytophaga canimorsus bacteremia. Acute tubular necrosis as well as HUS should be considered as a cause of acute renal failure in the setting of Capnocytophaga canimorsus bacteremia. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Hemolytic uremic syndrome; Capnocytophaga canimorsus bacteremia; acute renal failure.
T
HE HEMOLYTIC uremic syndrome (HUS) is characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenia, fever, and acute renal failure. It can be caused by various underlying infectious and noninfectious factors.1 If an underlying factor can be identified, then treatment aiming at the correction of that factor may improve outcome in addition to therapy directed toward HUS itself (eg, plasma exchange).2-4 In this report, we describe an adult patient who developed HUS after Capnocytophaga canimorsus bacteremia. CASE REPORT A 50-year-old man presented elsewhere with fever and arthralgias. He had been bitten by his pet dog 1 day before presentation. His blood pressure was 130/80 mm Hg, his heart rate was 100 beats/min, and his temperature was 39°C. He had a small puncture on his left hand, without signs of active infection or lymphangitis. No purpura, rash, gangrene, or lymphadenopathy was found. Results of neurological examination were unremarkable. Initial hematology tests included the following: hematocrit, 45%; platelet count, 77,000/µL; white cell count, 3,700/µL; 80% neutrophils; 1% band forms. Serum creatinine was 1.5 mg/dL; lactate dehydrogenase (LDH) was 514 U/L. Despite the absence of circulatory problems or documented hypotension, the patient remained oliguric and was transferred to our hospital because of progressive renal failure requiring dialysis (urinary output, 150 mL/24 hours). On admission (3 days after the initial presentation), his blood pressure was 145/60 mm Hg, his heart rate was 60 beats/min, and his temperature was 37°C. Hematology tests showed a hematocrit of 30%; reticulocytes, 0.6%; white blood cell count, 15,900 cells/µL; and progressive thrombocytopenia with a platelet count of 9,000 cells/µL. Microangiopathic hemolysis was documented by schistocytes (13%), increased lactate dehydrogenase (LDH) (3,102 U/L), increased bilirubin (total and conjugated, 3.2 and 1.3 mg/dL, respectively). Alkaline phosphatase was 102 U/L (normal, 13 to 120), alanine transaminase, 83 U/L (normal, ⬍40);
aspartate transaminase, 91 U/L (normal, ⬍30). The prothrombin time was 12.4 seconds (normal value, 11 to 16 seconds), activated partial thromboplastin time was 19.3 seconds (normal, 26 to 36 seconds), antithrombin III was 71% (normal, 80% to 120%), fibrinogen was 468 mg/dL (normal, 170 to 350 mg/dL), and fibrinogen-fibrin degradation products were 8 to 16 mg/L (normal, ⬍0.01 mg/L). Serum creatinine was 10.9 mg/dL, and urea was 143 mg/dL. Urinalysis showed 15 to 20 leukocytes and 15 to 20 erythrocytes per high-power field, but no casts. Proteinuria was 2.3 g/24 hours. Blood culture grew Capnocytophaga canimorsus, and treatment with amoxycillin/potassium clavulanate was started. Inotropic support was never necessary. Urine and stool culture were negative (including verocytotoxin producing Escherichia coli strains). A diagnosis of HUS was made on the basis of microangiopathic hemolytic anemia, normal clotting times, thrombocytopenia, and acute oliguric renal failure. Two days after the start of antibiotic therapy (platelets at that time were 24,000/ µL, LDH was 1,386 U/L), plasma exchange using fresh frozen plasma was added to the therapeutic regimen.2-4 The serum LDH level started to decrease after the start of antibiotic therapy (before plasma exchange was started) (Fig 1). Because renal function showed no tendency to improve notwithstanding full normalization of the hematologic parameters characteristic for HUS, a renal biopsy was performed on day 13. It showed mesangiolysis, tubular necrosis, and interstitial inflammation, but no thrombotic microangiopathic changes nor vasculitis. However, at day 14, an increase in urinary output occurred (300 mL/24 hours), and after a phase of polyuria, recovery of renal function was
From the Department of Nephrology and Intensive and Respiratory Care Unit, University Hospital Groningen, Groningen, The Netherlands. Received October 26, 1998; accepted in revised form February 26, 1999. Address reprint requests to Tom J.M. Tobe´, MD, Department of Intensive Care I, University Hospital Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. E-mail: [email protected]
娀 1999 by the National Kidney Foundation, Inc. 1523-6838/99/3306-0037$3.00/0
American Journal of Kidney Diseases, Vol 33, No 6 (June), 1999: E5
1
TOBE´ ET AL
2
Fig 1. Time course of the platelet count (䊊——䊊), LDH (䊉 - - 䊉), serum creatinin (䉬 - - 䉬), and diuresis (bars) in the patient. Days on which hemodialysis or plasmaferesis were performed are indicated by an arrow. Day 0 is the moment of the dog bite.
documented. Dialysis treatment was no longer necessary after day 16. After 6 months, the patient was well, with a blood pressure of 138/88 mm Hg, serum creatinine was 1.2 mg/dL, creatinine clearance was 100 mL/min, protein excretion was 0.1 g/24 hours, and the urinary sediment showed no abnormalities.
DISCUSSION
The relation in time between the septicemia and the development of HUS argues for a causative role of Capnocytophaga canimorsus bacteremia. Second, other factors known to cause HUS such as infectious diseases caused by verocytotoxin producing E coli or Shigella strains, tumors, systemic lupus erythematosus, scleroderma, or drugs were absent. Third, microangiopathic hemolytic anemia was not caused by disseminated intravascular coagulation due to the septicemia itself, because clotting times were normal and fibrinogen was increased.1 Fourth, renal biopsy failed to show intravascular micro-
thrombi but did show mesangiolysis, a finding at least compatible with HUS. Biopsy also showed tubular necrosis; however, the patient had not been in shock during the course of the septicemia. It is known, however, that tubular necrosis is the only lesion found in 10% of adult cases of HUS.5 Finally, recovery of renal function occurred after hematologic recovery, a course that is suggestive of HUS. To our knowledge, three cases of HUS in the course of Capnocytophaga canimorsus septicemia have been reported.6,7 As in the current case, there was evidence of microangiopathic hemolytic anemia with normal clotting times. Neurological features and renal involvement were present in varying degrees. However, in contrast to the current case, confirmation of HUS by renal biopsy findings was not obtained in those reports. Treatment consisted of antibiotics in all cases and plasma exchange in two. In the current case,
HUS AND CAPNOCYTOPHAGA CANIMORSUS INFECTION
antibiotic treatment was started 2 days before the start of plasma exchange. Before plasma exchange was started, LDH decreased. Therefore, the improvement may have been caused by the antibiotic treatment itself; nonetheless, it was decided to add plasma exchange to the regimen. The same dilemma was present in the case described by Finn et al,7 and they resolved it in a similar manner. Capnocytophaga canimorsus (Latin for dog bite), formerly called dysgonic fermenter 2 (DF2), is a slowly growing gram-negative rod.8 Most of the isolates are associated with infections following dog bites or exposure to dogs. Exposure to cats and rabbits has also been described.9 Capnocytophaga canimorsus sepsis predominantly occurs and progresses more severely in asplenic patients, in those with a history of alcohol abuse, and in those receiving corticosteroid therapy. Capnocytophaga canimorsus is usually susceptible to penicillins. On the basis of this case report and those by Scarlett et al6 and Finn et al,7 we think it is justified to recognize Capnocytophaga canimorsus septicemia as a cause of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura.6,7 Conversely, Capnocytophaga canimorsus septicemia also can lead to acute renal failure due to acute tubular necrosis without evidence of HUS.10 Therefore, in case of acute renal failure in the setting of Capnocytophaga canimorsus septicemia, the possibility of an underlying HUS should be considered.
3
REFERENCES 1. Nield GH: Haemolytic-uraemic syndrome in practice. Lancet 343:398-401, 1994 2. Conlon PJ, Howell DN, Macik G, Kovalik EC, Smith SR: The renal manifestations and outcome of thrombocytopenic purpura/hemolytic uremic syndrome in adults. Nephrol Dial Transplant 10:1189-1193, 1995 3. Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, Spasoff RA, and the Canadian Apheresis Study Group: Comparison of plasma exchange with plasma infusion in the treatment of thrombocytopenic purpura. N Engl J Med 325:393-397, 1991 4. Bell WR, Braine HG, Ness PM, Kickler TS: Improved survival in thrombocytopenic purpura-hemolytic uremic syndrome. N Engl J Med 325:398-403, 1991 5. Inniger R, de Oliveira VC, Bohle A: Correlation of structure and function in haemolytic uraemic syndrome. Xth International Congress of Nephrology; July 26-31, 1987, London, Oxford, England, Alden Press, 1987, p 17 6. Scarlett JD, Williamson HG, Dadson PJ, Fassett R, Peel MM: A syndrome resembling thrombotic thrombocytopenic purpura associated with Capnocytophaga canimorsus septicemia. Am J Med 90:127-128, 1991 7. Finn M, Dale B, Isles C: Beware of the dog! A syndrome resembling thrombotic thrombocytopenic purpura associated with Capnocytophaga canimorsis septicaemia. Nephrol Dial Transplant 11:1839-1840, 1996 8. Gill VJ: Capnocytophaga, in Mandell GL, Bennett JE, Dolin R (eds): Principles and Practice of Infectious Diseases, chap 213. New York, NY, United States, Churchill Livingstone, 1995, pp 2103-2106 9. Talan DA, Citron DM, Abrahamian FM, Moran GJ, Goldstein EJC, for the Emergency Medicine Animal Bite Infection Study Group: Bacteriologic analysis of infected dog and cat bites. N Engl J Med 340:85-92, 1999 10. Hovenga S, Tulleken JE, Moeller LVM, Jackson SA, v.d. Werf TS, Zijlstra JG: Dog-bite induced sepsis: A report of four cases. Intensive Care Med 23:1179-1180, 1997
Hemolytic Uremic Syndrome Due to Capnocytophaga canimorsus Bacteremia After a Dog Bite Tom J.M. Tobe´, MD, Casper F.M. Franssen, MD, Jan G. Zijlstra, MD, Paul E. de Jong, MD, and Coen A. Stegeman, MD ● The hemolytic uremic syndrome (HUS) is known to have several causes, including infectious diseases, drugs, pregnancy, and malignant disease. We report a patient who developed acute renal failure attributable to HUS in the course of Capnocytophaga canimorsus bacteremia. Acute tubular necrosis as well as HUS should be considered as a cause of acute renal failure in the setting of Capnocytophaga canimorsus bacteremia. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Hemolytic uremic syndrome; Capnocytophaga canimorsus bacteremia; acute renal failure.
T
HE HEMOLYTIC uremic syndrome (HUS) is characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenia, fever, and acute renal failure. It can be caused by various underlying infectious and noninfectious factors.1 If an underlying factor can be identified, then treatment aiming at the correction of that factor may improve outcome in addition to therapy directed toward HUS itself (eg, plasma exchange).2-4 In this report, we describe an adult patient who developed HUS after Capnocytophaga canimorsus bacteremia. CASE REPORT A 50-year-old man presented elsewhere with fever and arthralgias. He had been bitten by his pet dog 1 day before presentation. His blood pressure was 130/80 mm Hg, his heart rate was 100 beats/min, and his temperature was 39°C. He had a small puncture on his left hand, without signs of active infection or lymphangitis. No purpura, rash, gangrene, or lymphadenopathy was found. Results of neurological examination were unremarkable. Initial hematology tests included the following: hematocrit, 45%; platelet count, 77,000/µL; white cell count, 3,700/µL; 80% neutrophils; 1% band forms. Serum creatinine was 1.5 mg/dL; lactate dehydrogenase (LDH) was 514 U/L. Despite the absence of circulatory problems or documented hypotension, the patient remained oliguric and was transferred to our hospital because of progressive renal failure requiring dialysis (urinary output, 150 mL/24 hours). On admission (3 days after the initial presentation), his blood pressure was 145/60 mm Hg, his heart rate was 60 beats/min, and his temperature was 37°C. Hematology tests showed a hematocrit of 30%; reticulocytes, 0.6%; white blood cell count, 15,900 cells/µL; and progressive thrombocytopenia with a platelet count of 9,000 cells/µL. Microangiopathic hemolysis was documented by schistocytes (13%), increased lactate dehydrogenase (LDH) (3,102 U/L), increased bilirubin (total and conjugated, 3.2 and 1.3 mg/dL, respectively). Alkaline phosphatase was 102 U/L (normal, 13 to 120), alanine transaminase, 83 U/L (normal, ⬍40);
aspartate transaminase, 91 U/L (normal, ⬍30). The prothrombin time was 12.4 seconds (normal value, 11 to 16 seconds), activated partial thromboplastin time was 19.3 seconds (normal, 26 to 36 seconds), antithrombin III was 71% (normal, 80% to 120%), fibrinogen was 468 mg/dL (normal, 170 to 350 mg/dL), and fibrinogen-fibrin degradation products were 8 to 16 mg/L (normal, ⬍0.01 mg/L). Serum creatinine was 10.9 mg/dL, and urea was 143 mg/dL. Urinalysis showed 15 to 20 leukocytes and 15 to 20 erythrocytes per high-power field, but no casts. Proteinuria was 2.3 g/24 hours. Blood culture grew Capnocytophaga canimorsus, and treatment with amoxycillin/potassium clavulanate was started. Inotropic support was never necessary. Urine and stool culture were negative (including verocytotoxin producing Escherichia coli strains). A diagnosis of HUS was made on the basis of microangiopathic hemolytic anemia, normal clotting times, thrombocytopenia, and acute oliguric renal failure. Two days after the start of antibiotic therapy (platelets at that time were 24,000/ µL, LDH was 1,386 U/L), plasma exchange using fresh frozen plasma was added to the therapeutic regimen.2-4 The serum LDH level started to decrease after the start of antibiotic therapy (before plasma exchange was started) (Fig 1). Because renal function showed no tendency to improve notwithstanding full normalization of the hematologic parameters characteristic for HUS, a renal biopsy was performed on day 13. It showed mesangiolysis, tubular necrosis, and interstitial inflammation, but no thrombotic microangiopathic changes nor vasculitis. However, at day 14, an increase in urinary output occurred (300 mL/24 hours), and after a phase of polyuria, recovery of renal function was
From the Department of Nephrology and Intensive and Respiratory Care Unit, University Hospital Groningen, Groningen, The Netherlands. Received October 26, 1998; accepted in revised form February 26, 1999. Address reprint requests to Tom J.M. Tobe´, MD, Department of Intensive Care I, University Hospital Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. E-mail: [email protected]
娀 1999 by the National Kidney Foundation, Inc. 1523-6838/99/3306-0037$3.00/0
American Journal of Kidney Diseases, Vol 33, No 6 (June), 1999: E5
1
TOBE´ ET AL
2
Fig 1. Time course of the platelet count (䊊——䊊), LDH (䊉 - - 䊉), serum creatinin (䉬 - - 䉬), and diuresis (bars) in the patient. Days on which hemodialysis or plasmaferesis were performed are indicated by an arrow. Day 0 is the moment of the dog bite.
documented. Dialysis treatment was no longer necessary after day 16. After 6 months, the patient was well, with a blood pressure of 138/88 mm Hg, serum creatinine was 1.2 mg/dL, creatinine clearance was 100 mL/min, protein excretion was 0.1 g/24 hours, and the urinary sediment showed no abnormalities.
DISCUSSION
The relation in time between the septicemia and the development of HUS argues for a causative role of Capnocytophaga canimorsus bacteremia. Second, other factors known to cause HUS such as infectious diseases caused by verocytotoxin producing E coli or Shigella strains, tumors, systemic lupus erythematosus, scleroderma, or drugs were absent. Third, microangiopathic hemolytic anemia was not caused by disseminated intravascular coagulation due to the septicemia itself, because clotting times were normal and fibrinogen was increased.1 Fourth, renal biopsy failed to show intravascular micro-
thrombi but did show mesangiolysis, a finding at least compatible with HUS. Biopsy also showed tubular necrosis; however, the patient had not been in shock during the course of the septicemia. It is known, however, that tubular necrosis is the only lesion found in 10% of adult cases of HUS.5 Finally, recovery of renal function occurred after hematologic recovery, a course that is suggestive of HUS. To our knowledge, three cases of HUS in the course of Capnocytophaga canimorsus septicemia have been reported.6,7 As in the current case, there was evidence of microangiopathic hemolytic anemia with normal clotting times. Neurological features and renal involvement were present in varying degrees. However, in contrast to the current case, confirmation of HUS by renal biopsy findings was not obtained in those reports. Treatment consisted of antibiotics in all cases and plasma exchange in two. In the current case,
HUS AND CAPNOCYTOPHAGA CANIMORSUS INFECTION
antibiotic treatment was started 2 days before the start of plasma exchange. Before plasma exchange was started, LDH decreased. Therefore, the improvement may have been caused by the antibiotic treatment itself; nonetheless, it was decided to add plasma exchange to the regimen. The same dilemma was present in the case described by Finn et al,7 and they resolved it in a similar manner. Capnocytophaga canimorsus (Latin for dog bite), formerly called dysgonic fermenter 2 (DF2), is a slowly growing gram-negative rod.8 Most of the isolates are associated with infections following dog bites or exposure to dogs. Exposure to cats and rabbits has also been described.9 Capnocytophaga canimorsus sepsis predominantly occurs and progresses more severely in asplenic patients, in those with a history of alcohol abuse, and in those receiving corticosteroid therapy. Capnocytophaga canimorsus is usually susceptible to penicillins. On the basis of this case report and those by Scarlett et al6 and Finn et al,7 we think it is justified to recognize Capnocytophaga canimorsus septicemia as a cause of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura.6,7 Conversely, Capnocytophaga canimorsus septicemia also can lead to acute renal failure due to acute tubular necrosis without evidence of HUS.10 Therefore, in case of acute renal failure in the setting of Capnocytophaga canimorsus septicemia, the possibility of an underlying HUS should be considered.
3
REFERENCES 1. Nield GH: Haemolytic-uraemic syndrome in practice. Lancet 343:398-401, 1994 2. Conlon PJ, Howell DN, Macik G, Kovalik EC, Smith SR: The renal manifestations and outcome of thrombocytopenic purpura/hemolytic uremic syndrome in adults. Nephrol Dial Transplant 10:1189-1193, 1995 3. Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, Spasoff RA, and the Canadian Apheresis Study Group: Comparison of plasma exchange with plasma infusion in the treatment of thrombocytopenic purpura. N Engl J Med 325:393-397, 1991 4. Bell WR, Braine HG, Ness PM, Kickler TS: Improved survival in thrombocytopenic purpura-hemolytic uremic syndrome. N Engl J Med 325:398-403, 1991 5. Inniger R, de Oliveira VC, Bohle A: Correlation of structure and function in haemolytic uraemic syndrome. Xth International Congress of Nephrology; July 26-31, 1987, London, Oxford, England, Alden Press, 1987, p 17 6. Scarlett JD, Williamson HG, Dadson PJ, Fassett R, Peel MM: A syndrome resembling thrombotic thrombocytopenic purpura associated with Capnocytophaga canimorsus septicemia. Am J Med 90:127-128, 1991 7. Finn M, Dale B, Isles C: Beware of the dog! A syndrome resembling thrombotic thrombocytopenic purpura associated with Capnocytophaga canimorsis septicaemia. Nephrol Dial Transplant 11:1839-1840, 1996 8. Gill VJ: Capnocytophaga, in Mandell GL, Bennett JE, Dolin R (eds): Principles and Practice of Infectious Diseases, chap 213. New York, NY, United States, Churchill Livingstone, 1995, pp 2103-2106 9. Talan DA, Citron DM, Abrahamian FM, Moran GJ, Goldstein EJC, for the Emergency Medicine Animal Bite Infection Study Group: Bacteriologic analysis of infected dog and cat bites. N Engl J Med 340:85-92, 1999 10. Hovenga S, Tulleken JE, Moeller LVM, Jackson SA, v.d. Werf TS, Zijlstra JG: Dog-bite induced sepsis: A report of four cases. Intensive Care Med 23:1179-1180, 1997