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Leukemoid reaction to Clostridium difficile infection
Anaerobe 34 (2015) 158e160
Contents lists available at ScienceDirect
Anaerobe journal homepage: www.elsevier.com/locate/anaerobe
Technical note
Leukemoid reaction to Clostridium difficile infection Ashutossh Naaraayan*, Melissa Aleta, Prasanta Basak, Stephen Jesmajian, Robert Goldstein Department of Internal Medicine, Montefiore New Rochelle Hospital, Albert Einstein College of Medicine, 16 Guion Place, New Rochelle, NY, 10801, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 February 2015 Received in revised form 10 May 2015 Accepted 11 May 2015 Available online 13 May 2015
Clostridium difficile infections (CDI) are increasing in incidence and severity. Leukemoid reaction is rarely seen with CDI, and indicates severe disease with grave prognosis. We present an elderly female who developed leukemoid reaction in response to CDI. The patient died despite early antibiotic therapy with surgical evaluation. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Clostridium difficile Leukemoid reaction Toxic megacolon
1. Introduction Clostridium difficile is a gram positive bacillus, recognized as the primary pathogen responsible for antibiotic-associated colitis and nosocomial antibiotic-associated diarrhea [1]. C. difficile infections (CDI) can lead to diarrhea, sepsis, multi-organ system failure and even death [2]. Leukemoid reaction is a known but rare finding with severe CDI and is associated with an adverse prognosis. 2. Case report A 74 year old female presented to the emergency department (ED) with several days of diarrhea and progressive weakness. Five weeks prior to presentation, she was hospitalized for pneumonia and treated with ceftriaxone, azithromycin and vancomycin. After 6 days in the hospital she was at a rehabilitation facility for two weeks. A week prior to presentation, she began having 8e10 episodes per day of loose, greenish, foul-smelling and explosive bowel movements. Fever, chills, nausea, vomiting and abdominal pain were not reported. Two days prior to presentation, outpatient stool testing for C. difficile toxins with ELISA was positive. The patient received only one oral dose of metronidazole 500 mg prior to admission. On the day of admission, she was lethargic and minimally responsive. She was intubated by emergency response
* Corresponding author. E-mail addresses: [email protected] (A. Naaraayan), melissa.aleta@gmail. com (M. Aleta), pbasak@montefiore.org (P. Basak), sjesmaji@montefiore.org (S. Jesmajian), robgolds@montefiore.org (R. Goldstein). http://dx.doi.org/10.1016/j.anaerobe.2015.05.005 1075-9964/© 2015 Elsevier Ltd. All rights reserved.
personnel en-route to the ED. Her medical history included breast and lung cancer many years ago, hypothyroidism, hypertension, Alzheimer's disease and chronic obstructive pulmonary disease (COPD). Her medications at home included levothyroxine, diltiazem, losartan, atorvastatin, aspirin, donepezil, sertraline, budesonide-formoterol inhaler and pantoprazole. Vitals signs in the ED were: blood pressure 101/64 mm Hg, heart rate 80 per minute, respiratory rate 20 per minute and temperature 97.8 Fahrenheit. Her skin was mottled, cold and cyanotic. Her abdomen was distended and soft with hypoactive bowel sounds. Rectal vault was empty. Mechanical ventilation was continued, and she received intravenous (IV) fluids and vasopressors. Laboratory data revealed a white blood cell count (WBC) of 105,000 cells/ microliter with 73% neutrophils and 7% bands (Figs. 1 and 2). Peripheral blood smear showed several neutrophil precursors including metamyelocytes (4%), myelocytes (6%), and promyelocytes (2%) but no blasts. This extreme leukocytosis was in sharp contrast to her WBC of 12,400 cells/microliter two weeks prior to presentation. Computed tomographic scan (CT) without contrast of the abdomen and pelvis showed extensive colonic wall thickening and colitis (Fig. 3). Other laboratory data revealed a Hemoglobin of 11 g/deciliter, platelet count of 407,000 platelets/microliter, blood urea nitrogen of 59 mg/deciliter, serum creatinine of 3.41 mg/ deciliter and serum albumin of 1.2 g/deciliter. An arterial blood gas showed a pH of 7.079, partial pressure of CO2 28.2 mmHg, partial pressure of O2 549 mmHg, bicarbonate of 8.0 milliequivalents/liter and a lactate level of 5.4 mmol/liter. Chest radiograph showed hyperinflated lungs consistent with COPD and no infiltrates. Urinalysis revealed pyuria with 22 WBCs/high power field (hpf), 47 red
A. Naaraayan et al. / Anaerobe 34 (2015) 158e160
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Fig. 3. CT scan imaging of the abdomen and pelvis, showing significant bowel wall thickening (arrows) consistent with severe colitis.
Fig. 1. Low power microscopic image of peripheral blood smear showing increased neutrophil count.
blood cells/hpf and a positive leukocyte esterase. Urine culture grew Klebsiella pneumonia. Blood cultures were negative. C. difficile polymerase chain reaction (PCR) testing of the stool was positive. She was admitted with septic shock and multi-organ failure from severe CDI, anion-gap metabolic acidosis, acute renal failure and urinary tract infection (UTI). Treatment with metronidazole IV 500 mg every 8 h and vancomycin by nasogastric tube 500 mg every 6 h was started. Intravenous piperacillin-tazobactam 2.25 g IV every 8 h was given for the accompanying UTI. On the second day of hospitalization, bowel sounds were absent. Toxic megacolon was suspected and vancomycin retention enema 500 mg every 6 h was started. The WBC count increased to 127,600 cells/microliter and she died the same day before surgical intervention.
3. Discussion CDI mostly affects people aged 65 years and those in healthcare facilities, such as hospitals and nursing homes. The incidence of CDI for hospitalized people aged 65 years increased 200% from 1996 to 2009 in the United States [3]. CDI is also increasingly severe
and refractory to medical treatment; with increasing incidence of toxic megacolon requiring surgery and Intensive care unit (ICU) admissions [4,5]. Similar increase in disease incidence and virulence has been reported in Europe [6]. The increasing incidence of CDI is attributed to hypervirulent B1/NAP1/027 strain of C. difficile [6]. Antibiotic use is the best known risk factor for CDI [6]. In one study, 96% of patients with symptomatic CDI received antimicrobials within the 14 days before the onset of diarrhea and all patients received antibiotics within 3 months [7]. Other risk factors include advanced age, recent hospitalization, use of gastric acid suppressing agents, enteral feeding, and cancer chemotherapy [2,8e10]. Severe infection and worse outcomes are indicated by pan-colitis on CT, hypoalbuminemia, acute renal failure, leukocytosis, shock, ICU admission, multi-organ failure and age 65 years [11]. Leukocytosis resembling leukemia with WBC counts exceeding 50,000 cells/microliter, in the absence of a primary bone marrow disorder, is referred to as a leukemoid reaction [12]. Leukemoid reactions are commonly associated with hemolysis, burns or tissue necrosis, hemorrhage, infections and non-hematologic malignancies [13]. Leukemoid reaction is a known but rare laboratory finding with severe CDI. It is associated with almost a 100% fatality [14e16]. Marinella et al. observed that the presence of a respiratory tract infection in patients with CDI was an independent predictor for a leukemoid reaction [15]. Here, we describe a case of a UTI with CDI associated leukemoid reaction. Our patient had multiple risk factors for CDI including recent hospital and nursing home stay, recent antibiotic use, age greater than 65 years and use of a proton pump inhibitor. Additionally, our patient had multiple indicators of severe infection including pancolitis on CT, hypoalbuminemia, acute renal failure, leukocytosis, shock, ICU admission, multi-organ failure and age greater than 65 years. 4. Conclusion Leukemoid reaction to CDI should be identified as a worse prognostic factor and should prompt aggressive supportive measures including antibiotic therapy and early surgical evaluation. We believe there may be an increased risk of developing a leukemoid reaction in patients who have a concomitant infection to CDI. Conflicts of interests and funding
Fig. 2. High power microscopy showing immature neutrophils or band forms (arrow) with toxic granulations in the cytoplasm.
The authors have not received any funding or benefits from the industry or elsewhere to conduct this study.
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A. Naaraayan et al. / Anaerobe 34 (2015) 158e160
Acknowledgments None. References [1] J.G. Bartlett, Clinical practice. Antibiotic-associated diarrhea, N. Engl. J. Med. 346 (5) (2002) 334e339. [2] J.G. Bartlett, Narrative review: the new epidemic of Clostridium difficileassociated enteric disease, Ann. Intern Med. 145 (10) (2006) 758e764. [3] CDC, Morbidity and Mortality Weekly Report, vol. 60(34), September 2, 2011, p. 1171. Based on National Hospital Discharge Survey 1996e2009, http:// www.cdc.gov/nchs/nhds.htm. [4] V.G. Loo, L. Poirier, M.A. Miller, M. Oughton, M.D. Libman, S. Michaud, et al., A predominantly clonal multi-institutional outbreak of Clostridium difficileassociated diarrhea with high morbidity and mortality, N. Engl. J. Med. 353 (23) (2005) 2442e2449. pin, L. Valiquette, B. Cossette, Mortality attributable to nosocomial Clos[5] J. Pe tridium difficile-associated disease during an epidemic caused by a hypervirulent strain in Quebec, CMAJ 173 (9) (2005) 1037e1042. [6] F.C. Lessa, C.V. Gould, L.C. McDonald, Current status of Clostridium difficile infection epidemiology, Clin. Infect. Dis. 55 (Suppl. 2) (2012) S65eS70. [7] M.M. Olson, C.J. Shanholtzer, J.T. Lee Jr., D.N. Gerding, Ten years of prospective Clostridium difficileeassociated disease surveillance and treatment at the Minneapolis VA Medical Center, 1982e1991, Infect. Control Hosp. Epidemiol.
15 (6) (1994) 371e381. [8] L. Kyne, S. Sougioultzis, L.V. McFarland, C.P. Kelly, Underlying disease severity as a major risk factor for nosocomial Clostridium difficile diarrhea, Infect. Control Hosp. Epidemiol. 23 (11) (2002) 653e659. [9] A.G. Kamthan, H.W. Bruckner, S.Z. Hirschman, S.G. Agus, Clostridium difficile diarrhea induced by cancer chemotherapy, Arch. Intern Med. 152 (8) (1992) 1715e1717. [10] C.S. Kwok, A.K. Arthur, C.I. Anibueze, S. Singh, R. Cavallazzi, Y.K. Loke, Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis, Am. J. Gastroenterol. 107 (7) (2012) 1011e1019. [11] C.M. Surawicz, L.J. Brandt, D.G. Binion, A.N. Ananthakrishnan, S.R. Curry, P.H. Gilligan, et al., Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections, Am. J. Gastroenterol. 108 (4) (2013) 478e498 quiz 499. [12] W. Huang, F. Wang, Y. Li, F. Duan, Z. Yu, Leukemoid reaction in sarcomatoid renal cell carcinoma: a two-case report, World J. Surg. Oncol. 12 (2014) 100. [13] C.J. Halkes, H.M. Dijstelbloem, S.J. Eelkman Rooda, M.H. Kramer, Extreme leucocytosis: not always leukaemia, Neth J. Med. 65 (7) (2007) 248e251. [14] F.G. De Toledo, S.N. Symes, Leukemoid reaction due to Clostridium difficile infection in acquired immunodeficiency syndrome: two case reports and a review of the literature, South Med. J. 97 (4) (2004) 388e392. [15] M.A. Marinella, S.D. Burdette, R. Bedimo, R.J. Markert, Leukemoid reactions complicating colitis due to Clostridium difficile, South Med. J. 97 (10) (2004) 959e963. [16] C.H. Lin, M.H. Chou, C.T. Liu, Y.C. Tsai, C.H. Chuang, J.C. Yu, Leukemoid reaction in pseudomembranous colitis, Rev. Esp. Enferm. Dig. 99 (5) (2007) 305e306.
Contents lists available at ScienceDirect
Anaerobe journal homepage: www.elsevier.com/locate/anaerobe
Technical note
Leukemoid reaction to Clostridium difficile infection Ashutossh Naaraayan*, Melissa Aleta, Prasanta Basak, Stephen Jesmajian, Robert Goldstein Department of Internal Medicine, Montefiore New Rochelle Hospital, Albert Einstein College of Medicine, 16 Guion Place, New Rochelle, NY, 10801, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 February 2015 Received in revised form 10 May 2015 Accepted 11 May 2015 Available online 13 May 2015
Clostridium difficile infections (CDI) are increasing in incidence and severity. Leukemoid reaction is rarely seen with CDI, and indicates severe disease with grave prognosis. We present an elderly female who developed leukemoid reaction in response to CDI. The patient died despite early antibiotic therapy with surgical evaluation. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Clostridium difficile Leukemoid reaction Toxic megacolon
1. Introduction Clostridium difficile is a gram positive bacillus, recognized as the primary pathogen responsible for antibiotic-associated colitis and nosocomial antibiotic-associated diarrhea [1]. C. difficile infections (CDI) can lead to diarrhea, sepsis, multi-organ system failure and even death [2]. Leukemoid reaction is a known but rare finding with severe CDI and is associated with an adverse prognosis. 2. Case report A 74 year old female presented to the emergency department (ED) with several days of diarrhea and progressive weakness. Five weeks prior to presentation, she was hospitalized for pneumonia and treated with ceftriaxone, azithromycin and vancomycin. After 6 days in the hospital she was at a rehabilitation facility for two weeks. A week prior to presentation, she began having 8e10 episodes per day of loose, greenish, foul-smelling and explosive bowel movements. Fever, chills, nausea, vomiting and abdominal pain were not reported. Two days prior to presentation, outpatient stool testing for C. difficile toxins with ELISA was positive. The patient received only one oral dose of metronidazole 500 mg prior to admission. On the day of admission, she was lethargic and minimally responsive. She was intubated by emergency response
* Corresponding author. E-mail addresses: [email protected] (A. Naaraayan), melissa.aleta@gmail. com (M. Aleta), pbasak@montefiore.org (P. Basak), sjesmaji@montefiore.org (S. Jesmajian), robgolds@montefiore.org (R. Goldstein). http://dx.doi.org/10.1016/j.anaerobe.2015.05.005 1075-9964/© 2015 Elsevier Ltd. All rights reserved.
personnel en-route to the ED. Her medical history included breast and lung cancer many years ago, hypothyroidism, hypertension, Alzheimer's disease and chronic obstructive pulmonary disease (COPD). Her medications at home included levothyroxine, diltiazem, losartan, atorvastatin, aspirin, donepezil, sertraline, budesonide-formoterol inhaler and pantoprazole. Vitals signs in the ED were: blood pressure 101/64 mm Hg, heart rate 80 per minute, respiratory rate 20 per minute and temperature 97.8 Fahrenheit. Her skin was mottled, cold and cyanotic. Her abdomen was distended and soft with hypoactive bowel sounds. Rectal vault was empty. Mechanical ventilation was continued, and she received intravenous (IV) fluids and vasopressors. Laboratory data revealed a white blood cell count (WBC) of 105,000 cells/ microliter with 73% neutrophils and 7% bands (Figs. 1 and 2). Peripheral blood smear showed several neutrophil precursors including metamyelocytes (4%), myelocytes (6%), and promyelocytes (2%) but no blasts. This extreme leukocytosis was in sharp contrast to her WBC of 12,400 cells/microliter two weeks prior to presentation. Computed tomographic scan (CT) without contrast of the abdomen and pelvis showed extensive colonic wall thickening and colitis (Fig. 3). Other laboratory data revealed a Hemoglobin of 11 g/deciliter, platelet count of 407,000 platelets/microliter, blood urea nitrogen of 59 mg/deciliter, serum creatinine of 3.41 mg/ deciliter and serum albumin of 1.2 g/deciliter. An arterial blood gas showed a pH of 7.079, partial pressure of CO2 28.2 mmHg, partial pressure of O2 549 mmHg, bicarbonate of 8.0 milliequivalents/liter and a lactate level of 5.4 mmol/liter. Chest radiograph showed hyperinflated lungs consistent with COPD and no infiltrates. Urinalysis revealed pyuria with 22 WBCs/high power field (hpf), 47 red
A. Naaraayan et al. / Anaerobe 34 (2015) 158e160
159
Fig. 3. CT scan imaging of the abdomen and pelvis, showing significant bowel wall thickening (arrows) consistent with severe colitis.
Fig. 1. Low power microscopic image of peripheral blood smear showing increased neutrophil count.
blood cells/hpf and a positive leukocyte esterase. Urine culture grew Klebsiella pneumonia. Blood cultures were negative. C. difficile polymerase chain reaction (PCR) testing of the stool was positive. She was admitted with septic shock and multi-organ failure from severe CDI, anion-gap metabolic acidosis, acute renal failure and urinary tract infection (UTI). Treatment with metronidazole IV 500 mg every 8 h and vancomycin by nasogastric tube 500 mg every 6 h was started. Intravenous piperacillin-tazobactam 2.25 g IV every 8 h was given for the accompanying UTI. On the second day of hospitalization, bowel sounds were absent. Toxic megacolon was suspected and vancomycin retention enema 500 mg every 6 h was started. The WBC count increased to 127,600 cells/microliter and she died the same day before surgical intervention.
3. Discussion CDI mostly affects people aged 65 years and those in healthcare facilities, such as hospitals and nursing homes. The incidence of CDI for hospitalized people aged 65 years increased 200% from 1996 to 2009 in the United States [3]. CDI is also increasingly severe
and refractory to medical treatment; with increasing incidence of toxic megacolon requiring surgery and Intensive care unit (ICU) admissions [4,5]. Similar increase in disease incidence and virulence has been reported in Europe [6]. The increasing incidence of CDI is attributed to hypervirulent B1/NAP1/027 strain of C. difficile [6]. Antibiotic use is the best known risk factor for CDI [6]. In one study, 96% of patients with symptomatic CDI received antimicrobials within the 14 days before the onset of diarrhea and all patients received antibiotics within 3 months [7]. Other risk factors include advanced age, recent hospitalization, use of gastric acid suppressing agents, enteral feeding, and cancer chemotherapy [2,8e10]. Severe infection and worse outcomes are indicated by pan-colitis on CT, hypoalbuminemia, acute renal failure, leukocytosis, shock, ICU admission, multi-organ failure and age 65 years [11]. Leukocytosis resembling leukemia with WBC counts exceeding 50,000 cells/microliter, in the absence of a primary bone marrow disorder, is referred to as a leukemoid reaction [12]. Leukemoid reactions are commonly associated with hemolysis, burns or tissue necrosis, hemorrhage, infections and non-hematologic malignancies [13]. Leukemoid reaction is a known but rare laboratory finding with severe CDI. It is associated with almost a 100% fatality [14e16]. Marinella et al. observed that the presence of a respiratory tract infection in patients with CDI was an independent predictor for a leukemoid reaction [15]. Here, we describe a case of a UTI with CDI associated leukemoid reaction. Our patient had multiple risk factors for CDI including recent hospital and nursing home stay, recent antibiotic use, age greater than 65 years and use of a proton pump inhibitor. Additionally, our patient had multiple indicators of severe infection including pancolitis on CT, hypoalbuminemia, acute renal failure, leukocytosis, shock, ICU admission, multi-organ failure and age greater than 65 years. 4. Conclusion Leukemoid reaction to CDI should be identified as a worse prognostic factor and should prompt aggressive supportive measures including antibiotic therapy and early surgical evaluation. We believe there may be an increased risk of developing a leukemoid reaction in patients who have a concomitant infection to CDI. Conflicts of interests and funding
Fig. 2. High power microscopy showing immature neutrophils or band forms (arrow) with toxic granulations in the cytoplasm.
The authors have not received any funding or benefits from the industry or elsewhere to conduct this study.
160
A. Naaraayan et al. / Anaerobe 34 (2015) 158e160
Acknowledgments None. References [1] J.G. Bartlett, Clinical practice. Antibiotic-associated diarrhea, N. Engl. J. Med. 346 (5) (2002) 334e339. [2] J.G. Bartlett, Narrative review: the new epidemic of Clostridium difficileassociated enteric disease, Ann. Intern Med. 145 (10) (2006) 758e764. [3] CDC, Morbidity and Mortality Weekly Report, vol. 60(34), September 2, 2011, p. 1171. Based on National Hospital Discharge Survey 1996e2009, http:// www.cdc.gov/nchs/nhds.htm. [4] V.G. Loo, L. Poirier, M.A. Miller, M. Oughton, M.D. Libman, S. Michaud, et al., A predominantly clonal multi-institutional outbreak of Clostridium difficileassociated diarrhea with high morbidity and mortality, N. Engl. J. Med. 353 (23) (2005) 2442e2449. pin, L. Valiquette, B. Cossette, Mortality attributable to nosocomial Clos[5] J. Pe tridium difficile-associated disease during an epidemic caused by a hypervirulent strain in Quebec, CMAJ 173 (9) (2005) 1037e1042. [6] F.C. Lessa, C.V. Gould, L.C. McDonald, Current status of Clostridium difficile infection epidemiology, Clin. Infect. Dis. 55 (Suppl. 2) (2012) S65eS70. [7] M.M. Olson, C.J. Shanholtzer, J.T. Lee Jr., D.N. Gerding, Ten years of prospective Clostridium difficileeassociated disease surveillance and treatment at the Minneapolis VA Medical Center, 1982e1991, Infect. Control Hosp. Epidemiol.
15 (6) (1994) 371e381. [8] L. Kyne, S. Sougioultzis, L.V. McFarland, C.P. Kelly, Underlying disease severity as a major risk factor for nosocomial Clostridium difficile diarrhea, Infect. Control Hosp. Epidemiol. 23 (11) (2002) 653e659. [9] A.G. Kamthan, H.W. Bruckner, S.Z. Hirschman, S.G. Agus, Clostridium difficile diarrhea induced by cancer chemotherapy, Arch. Intern Med. 152 (8) (1992) 1715e1717. [10] C.S. Kwok, A.K. Arthur, C.I. Anibueze, S. Singh, R. Cavallazzi, Y.K. Loke, Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis, Am. J. Gastroenterol. 107 (7) (2012) 1011e1019. [11] C.M. Surawicz, L.J. Brandt, D.G. Binion, A.N. Ananthakrishnan, S.R. Curry, P.H. Gilligan, et al., Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections, Am. J. Gastroenterol. 108 (4) (2013) 478e498 quiz 499. [12] W. Huang, F. Wang, Y. Li, F. Duan, Z. Yu, Leukemoid reaction in sarcomatoid renal cell carcinoma: a two-case report, World J. Surg. Oncol. 12 (2014) 100. [13] C.J. Halkes, H.M. Dijstelbloem, S.J. Eelkman Rooda, M.H. Kramer, Extreme leucocytosis: not always leukaemia, Neth J. Med. 65 (7) (2007) 248e251. [14] F.G. De Toledo, S.N. Symes, Leukemoid reaction due to Clostridium difficile infection in acquired immunodeficiency syndrome: two case reports and a review of the literature, South Med. J. 97 (4) (2004) 388e392. [15] M.A. Marinella, S.D. Burdette, R. Bedimo, R.J. Markert, Leukemoid reactions complicating colitis due to Clostridium difficile, South Med. J. 97 (10) (2004) 959e963. [16] C.H. Lin, M.H. Chou, C.T. Liu, Y.C. Tsai, C.H. Chuang, J.C. Yu, Leukemoid reaction in pseudomembranous colitis, Rev. Esp. Enferm. Dig. 99 (5) (2007) 305e306.