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Listeria monocytogenes skin infection with cerebritis and haemophagocytosis syndrome in a bone marrow transplant recipient
Journal of Infection (2005) 50, 356–358
www.elsevierhealth.com/journals/jinf
CASE REPORT
Listeria monocytogenes skin infection with cerebritis and haemophagocytosis syndrome in a bone marrow transplant recipient O. Lambottea,*, V. Fihmanb, C. Poyartb, A. Buzyna, P. Bercheb, V. Soumelisa a
Department of Haematology, Necker Hospital, Paris, France Department of Microbiology, Necker Hospital, Paris, France
b
Accepted 30 March 2004 Available online 8 May 2004
KEYWORDS Listeria monocytogenes; Cerebritis; Haemophagocytosis syndrome; Cutaneous infection; Bone marrow transplantation
Summary In this report, we describe unusual and unreported manifestations of Listeria monocytogenes infection in a bone marrow transplant recipient, including cutaneous infection with an hamophagocytosis syndrome and cerebritis. L. monocytogenes occurred despite a broad spectrum antibiotherapy. L. monocytogenes was isolated from a skin biopsy. Outcome was favorable with amoxicillin and gentamicin therapy. L. monocytogenes infection should be suspected in patients with cerebritis despite large spectrum antibiotherapy and this report underscores the usefulness of skin biopsies in febrile immunocompromised patients. Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
Listeria monocytogenes is a Gram-positive rod known as an agent of meningo-encephalitis, especially in immunocompromised patients.1 Host factors that increase the risk of listerial infection include pregnancy, acquired immunosuppression associated with solid organ transplantation, cytotoxic chemotherapy, hemochromatosis, diabetes mellitus and renal failure.1 The spectrum of L. monocytogenes infections is wide1 with mild gastroenteritis in immunocompetent subjects, *Corresponding author. Address: Department of Infectious Diseases, CHU de Bice ˆtre, 78 rue du Ge ´ne ´ral Leclerc 94275 le Kremlin Bice ´tre, France. Tel.: þ 33-1-45-21-25-33; fax: þ 33-145-21-26-32. E-mail address: [email protected]
bacteraemia and meningo-encephalitis in neonates, immunocompetent or immunocompromised patients, but also rare manifestations such as pneumonias and endocarditis. Cutaneous infections are rare1,2 and occur in veterinarians or farmers from infected animals.2 In bone marrow transplantation, L. monocytogenes infection have been seldon reported consist of bacteraemia or meningitis.3 Here, we report an unusual case of cutaneous L. monocytogenes infection with cerebritis and haemophagocytosis syndrome in a bone marrow transplant (BMT) recipient. This is also the first published case of haemophagocytosis syndrome associated with L. monocytogenes infection.
0163-4453/$30.00 Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2004.03.016
Cutaneous Listeria monocytogenes in BMT
Case report A 36-year-old man was admitted in BMT unit for an allograft for the treatment of a non-Hodgkin malignant lymphoma (NHML). His medical history was unremarkable until March 2002 when he was admitted in the intensive care unit (ICU) for an acute respiratory distress syndrome with fever, diffuse lymphadenopathy and enlarged liver and spleen. Haemophagocytosis syndrome was present. Anaplastic T NHML was diagnosed. Remission was obtained with difficulty after several lines of cytotoxic chemotherapy and BMT was planned. Conditioning regimen was total body irradiation and cyclophosphamide. Blood neutrophils count was less than 500/mm3 on 12th December. The patient received an unrelated bone marrow transplant on the 13th (day 0). The clinical status rapidly deteriorated with an episode of pericarditis and interstitial pneumonia on day 3. Piperacillin-tazobactam (12 g/d), ciprofloxacin (800 mg/d), vancomycin (2 g/d), and acyclovir were started the same day. As no infectious cause was found despite extensive microbiological investigations, conditioning regimen toxicity was suspected and progressive improvement was observed. As low-grade fever persisted, piperacillin-tazobactam and ciprofloxacin were changed on day 11 for ceftazidime (4 g/d) and amikacin (900 mg/d), and amphotericin B was added two days later. However, fever increased (39 8C) and the patient became progressively obtunded. Ceftazidime was replaced by imipenem (3 g/d). Neurologic examination did not show any focal sign. On day 22, a brain CT scanning showed two spotted hyperdensities in the right temporal lobe, enhancing after contrast medium injection. A purple papule on the thigh was biopsied on day 24. Histology showed an inflammatory trichilemmal cyst. Direct bacterial examination of the biopsy was negative. However, within 48 h, aerobic and anaerobic cultures on horse blood Columbia agar yielded pure growth of regular and small Gram-positive rods. Identification of L. monocytogenes was performed by a positive camp-test and an API listeria system (BioMerieux). The strain was susceptible to penicillin, amoxicillin, gentamicin, vancomycin, rifampicin and trimethoprime-sulfamethoxazole (TMP-SXT). Cerebrospinal fluid (CSF) collected on day 26 showed 1 leucocyte and 303 erythrocytes/mm3, 0.54 g/l proteinorachia, and normal glycorachia. Direct examination and the culture were negative as well as a PCR reaction enabling the amplification of a fragment of the L. monocytogenes hemolysin gene. Antibiotic therapy was changed on day 26 with the
357
addition of amoxicillin (20 mg/kg/d) and TMP-SXT (480 mg/2400 mg/d). Repeated blood cultures remained negative. Between day 21 and day 28, twice daily platelets transfusions were required to maintain a platelet count above 20 000/mm3 . High ferritinemia (6700 mg/ml), triglyceride blood levels (4 mmol/l) and cytolysis were observed. On the basis of a possible graft failure and lymphoma evolution with haemophagocytosis, a bone marrow cytology was obtained on day 27, showing pictures of haemophagocytosis but without abnormal cells. All virologic investigations were negative. In the 48 h after the antibiotic therapy change, the clinical status significantly improved with a normal consciousness and apyrexia. On day 28, the blood leukocyte count was 400/mm3. The lap between platelet transfusions increased, blood count markedly improved as cytolysis and triglycerid level in the following days. TMP-SXT was changed for gentamicin after 4 days because of haematologic toxicity. Bitherapy was prolonged during 15 days and amoxicillin alone for one additional week. On day 39, a magnetic brain imaging was normal. One year after the graft, the patient was asymptomatic with normal bone marrow cytology.
Discussion L. monocytogenes infection in the setting of BMT is a rare event with an estimated incidence of 0.47%.3 A rather preserved cellular immunity4 and the broad spectrum antibiotherapy started at fever onset may explain this low rate. The gastrointestinal tract is thought to be the primary site of entry into human host.1 A prolonged gastro-intestinal carriage has been described5 which was probably the case in our observation as no recent, prior-BMT, episode of febrile gastroenteritis was reported. Direct skin infection is unlikely because direct contact with contaminated animals was absent in this case. In addition, no nosocomial L. monocytogenes infections have been reported before or after this case in our hospital. It is difficult to define the onset of L. monocytogenes infection in our patient. The bacteria could have been involved in the pneumonia that occurred right after the graft.1 The initial prescription of piperacillin-tazobactam was efficient but was rapidly stopped and changed first for ceftazidime and ciprofloxacin, then for imipenem, amikacin, and vancomycin. These three last antibiotics
358 were shown to be active in vitro6 and probably in blood where efficient concentrations can be reached. However, their biodisponibilities were likely lower in the two organs involved, skin and brain, which can become sanctuaries for the bacteria. Moreover, L. monocytogenes infection in a patient treated by vancomycin has already been reported.7 L. monocytogenes infection is known as one of the main central nervous system (CNS) infection in the immunocompromised patient. In our case, the regression of the spotted hyperdensities under antibiotic treatment supported a bacterial aetiology. In contrast with the other cases of L. monocytogenes infections in BMT recipients3,8 in whom blood and/or CSF cultures were positive, L. moncytogenes infection evidence was obtained by the culture of a skin biopsy of an unrelated lesion. These data demonstrate the benefit of biopsy of any skin lesion in the setting of a seriously ill immunocompromised patient. Haemophagocytosis syndrome has not been reported in association with L. monocytogenes infection9 but L. monocytogenes may activate macrophages,10 providing a potential mechanism. This observation has several clinical implications. First, an empiric antibiotherapy without penicillin in neutropenic patients may miss listeria. Second, L. monocytogenes can be isolated from skin biopsy and should be added to the list of microorganisms responsible for haemophagocytosis syndrome. Third, BMT recipients should be screened for intestinal carriage of L. monocytogenes.
O. Lambotte et al.
References 1. Schlech III WF. Foodborne listeriosis. Clin Infect Dis 2000;31: 770—775. 2. McLauchlin J, Low JC. Primary cutaneous listeriosis in adults: an occupational disease of veterinarians and farmers. Vet Rec 1994;135:615—617. 3. Safdar A, Papadopoulous EB, Armstrong D. Listeriosis in recipients of allogeneic blood and marrow transplantation: thirteen year review of disease characteristics, treatment outcomes and a new association with human cytomegalovirus infection. Bone Marrow Transplant 2002;29:913—916. 4. Roesler J, Grottrup E, Baccarini M, Lohmann-Mattes ML. Efficient natural defence mechanisms against Listeria monocytogenes in T and B cell-deficient allogeneic bone marrow radiation chimeras. Preactivated macrophages are the main effector cells in an early phase after bone marrow transfer. J Immunol 1989;143:1710—1715. 5. Schuchat A, Deaver K, Hayes PS, Graves L, Mascola L, Wenger JD. Gastrointestinal carriage of Listeria monocytogenes in household contacts of patients with listeriosis. J Infect Dis 1993;167:1261—1262. 6. Safdar A, Armstrong D. Antimicrobial activities against 84 Listeria monocytogenes isolates from patients with systemic listeriosis at a comprehensive cancer center (1955—1997). J Clin Microbiol 2003;41:483—485. 7. Arsene O, Linassier C, Quentin R, Legras A, Colombat P. Development of listeriosis during vancomycin therapy in a neutropenic patient. Scand J Infect Dis 1996;28:415—416. 8. Chang J, Powles R, Mehta J, Paton N, Treleaven J, Jameson B. Listeriosis in bone marrow transplant recipients: incidence, clinical features, and treatment. Clin Infect Dis 1995; 21:1289—1290. 9. Fisman DN. Hemophagocytic syndromes and infection. Emerg Infect Dis 2000;6:601—608. 10. Stoiber D, Stockinger S, Steinlein P, Kovarik J, Decker T. Listeria monocytogenes modulates macrophage cytokine responses through STAT serine phosphorylation and the induction of suppressor of cytokine signaling 3. J Immunol 2001;166:466—472.
www.elsevierhealth.com/journals/jinf
CASE REPORT
Listeria monocytogenes skin infection with cerebritis and haemophagocytosis syndrome in a bone marrow transplant recipient O. Lambottea,*, V. Fihmanb, C. Poyartb, A. Buzyna, P. Bercheb, V. Soumelisa a
Department of Haematology, Necker Hospital, Paris, France Department of Microbiology, Necker Hospital, Paris, France
b
Accepted 30 March 2004 Available online 8 May 2004
KEYWORDS Listeria monocytogenes; Cerebritis; Haemophagocytosis syndrome; Cutaneous infection; Bone marrow transplantation
Summary In this report, we describe unusual and unreported manifestations of Listeria monocytogenes infection in a bone marrow transplant recipient, including cutaneous infection with an hamophagocytosis syndrome and cerebritis. L. monocytogenes occurred despite a broad spectrum antibiotherapy. L. monocytogenes was isolated from a skin biopsy. Outcome was favorable with amoxicillin and gentamicin therapy. L. monocytogenes infection should be suspected in patients with cerebritis despite large spectrum antibiotherapy and this report underscores the usefulness of skin biopsies in febrile immunocompromised patients. Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
Listeria monocytogenes is a Gram-positive rod known as an agent of meningo-encephalitis, especially in immunocompromised patients.1 Host factors that increase the risk of listerial infection include pregnancy, acquired immunosuppression associated with solid organ transplantation, cytotoxic chemotherapy, hemochromatosis, diabetes mellitus and renal failure.1 The spectrum of L. monocytogenes infections is wide1 with mild gastroenteritis in immunocompetent subjects, *Corresponding author. Address: Department of Infectious Diseases, CHU de Bice ˆtre, 78 rue du Ge ´ne ´ral Leclerc 94275 le Kremlin Bice ´tre, France. Tel.: þ 33-1-45-21-25-33; fax: þ 33-145-21-26-32. E-mail address: [email protected]
bacteraemia and meningo-encephalitis in neonates, immunocompetent or immunocompromised patients, but also rare manifestations such as pneumonias and endocarditis. Cutaneous infections are rare1,2 and occur in veterinarians or farmers from infected animals.2 In bone marrow transplantation, L. monocytogenes infection have been seldon reported consist of bacteraemia or meningitis.3 Here, we report an unusual case of cutaneous L. monocytogenes infection with cerebritis and haemophagocytosis syndrome in a bone marrow transplant (BMT) recipient. This is also the first published case of haemophagocytosis syndrome associated with L. monocytogenes infection.
0163-4453/$30.00 Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2004.03.016
Cutaneous Listeria monocytogenes in BMT
Case report A 36-year-old man was admitted in BMT unit for an allograft for the treatment of a non-Hodgkin malignant lymphoma (NHML). His medical history was unremarkable until March 2002 when he was admitted in the intensive care unit (ICU) for an acute respiratory distress syndrome with fever, diffuse lymphadenopathy and enlarged liver and spleen. Haemophagocytosis syndrome was present. Anaplastic T NHML was diagnosed. Remission was obtained with difficulty after several lines of cytotoxic chemotherapy and BMT was planned. Conditioning regimen was total body irradiation and cyclophosphamide. Blood neutrophils count was less than 500/mm3 on 12th December. The patient received an unrelated bone marrow transplant on the 13th (day 0). The clinical status rapidly deteriorated with an episode of pericarditis and interstitial pneumonia on day 3. Piperacillin-tazobactam (12 g/d), ciprofloxacin (800 mg/d), vancomycin (2 g/d), and acyclovir were started the same day. As no infectious cause was found despite extensive microbiological investigations, conditioning regimen toxicity was suspected and progressive improvement was observed. As low-grade fever persisted, piperacillin-tazobactam and ciprofloxacin were changed on day 11 for ceftazidime (4 g/d) and amikacin (900 mg/d), and amphotericin B was added two days later. However, fever increased (39 8C) and the patient became progressively obtunded. Ceftazidime was replaced by imipenem (3 g/d). Neurologic examination did not show any focal sign. On day 22, a brain CT scanning showed two spotted hyperdensities in the right temporal lobe, enhancing after contrast medium injection. A purple papule on the thigh was biopsied on day 24. Histology showed an inflammatory trichilemmal cyst. Direct bacterial examination of the biopsy was negative. However, within 48 h, aerobic and anaerobic cultures on horse blood Columbia agar yielded pure growth of regular and small Gram-positive rods. Identification of L. monocytogenes was performed by a positive camp-test and an API listeria system (BioMerieux). The strain was susceptible to penicillin, amoxicillin, gentamicin, vancomycin, rifampicin and trimethoprime-sulfamethoxazole (TMP-SXT). Cerebrospinal fluid (CSF) collected on day 26 showed 1 leucocyte and 303 erythrocytes/mm3, 0.54 g/l proteinorachia, and normal glycorachia. Direct examination and the culture were negative as well as a PCR reaction enabling the amplification of a fragment of the L. monocytogenes hemolysin gene. Antibiotic therapy was changed on day 26 with the
357
addition of amoxicillin (20 mg/kg/d) and TMP-SXT (480 mg/2400 mg/d). Repeated blood cultures remained negative. Between day 21 and day 28, twice daily platelets transfusions were required to maintain a platelet count above 20 000/mm3 . High ferritinemia (6700 mg/ml), triglyceride blood levels (4 mmol/l) and cytolysis were observed. On the basis of a possible graft failure and lymphoma evolution with haemophagocytosis, a bone marrow cytology was obtained on day 27, showing pictures of haemophagocytosis but without abnormal cells. All virologic investigations were negative. In the 48 h after the antibiotic therapy change, the clinical status significantly improved with a normal consciousness and apyrexia. On day 28, the blood leukocyte count was 400/mm3. The lap between platelet transfusions increased, blood count markedly improved as cytolysis and triglycerid level in the following days. TMP-SXT was changed for gentamicin after 4 days because of haematologic toxicity. Bitherapy was prolonged during 15 days and amoxicillin alone for one additional week. On day 39, a magnetic brain imaging was normal. One year after the graft, the patient was asymptomatic with normal bone marrow cytology.
Discussion L. monocytogenes infection in the setting of BMT is a rare event with an estimated incidence of 0.47%.3 A rather preserved cellular immunity4 and the broad spectrum antibiotherapy started at fever onset may explain this low rate. The gastrointestinal tract is thought to be the primary site of entry into human host.1 A prolonged gastro-intestinal carriage has been described5 which was probably the case in our observation as no recent, prior-BMT, episode of febrile gastroenteritis was reported. Direct skin infection is unlikely because direct contact with contaminated animals was absent in this case. In addition, no nosocomial L. monocytogenes infections have been reported before or after this case in our hospital. It is difficult to define the onset of L. monocytogenes infection in our patient. The bacteria could have been involved in the pneumonia that occurred right after the graft.1 The initial prescription of piperacillin-tazobactam was efficient but was rapidly stopped and changed first for ceftazidime and ciprofloxacin, then for imipenem, amikacin, and vancomycin. These three last antibiotics
358 were shown to be active in vitro6 and probably in blood where efficient concentrations can be reached. However, their biodisponibilities were likely lower in the two organs involved, skin and brain, which can become sanctuaries for the bacteria. Moreover, L. monocytogenes infection in a patient treated by vancomycin has already been reported.7 L. monocytogenes infection is known as one of the main central nervous system (CNS) infection in the immunocompromised patient. In our case, the regression of the spotted hyperdensities under antibiotic treatment supported a bacterial aetiology. In contrast with the other cases of L. monocytogenes infections in BMT recipients3,8 in whom blood and/or CSF cultures were positive, L. moncytogenes infection evidence was obtained by the culture of a skin biopsy of an unrelated lesion. These data demonstrate the benefit of biopsy of any skin lesion in the setting of a seriously ill immunocompromised patient. Haemophagocytosis syndrome has not been reported in association with L. monocytogenes infection9 but L. monocytogenes may activate macrophages,10 providing a potential mechanism. This observation has several clinical implications. First, an empiric antibiotherapy without penicillin in neutropenic patients may miss listeria. Second, L. monocytogenes can be isolated from skin biopsy and should be added to the list of microorganisms responsible for haemophagocytosis syndrome. Third, BMT recipients should be screened for intestinal carriage of L. monocytogenes.
O. Lambotte et al.
References 1. Schlech III WF. Foodborne listeriosis. Clin Infect Dis 2000;31: 770—775. 2. McLauchlin J, Low JC. Primary cutaneous listeriosis in adults: an occupational disease of veterinarians and farmers. Vet Rec 1994;135:615—617. 3. Safdar A, Papadopoulous EB, Armstrong D. Listeriosis in recipients of allogeneic blood and marrow transplantation: thirteen year review of disease characteristics, treatment outcomes and a new association with human cytomegalovirus infection. Bone Marrow Transplant 2002;29:913—916. 4. Roesler J, Grottrup E, Baccarini M, Lohmann-Mattes ML. Efficient natural defence mechanisms against Listeria monocytogenes in T and B cell-deficient allogeneic bone marrow radiation chimeras. Preactivated macrophages are the main effector cells in an early phase after bone marrow transfer. J Immunol 1989;143:1710—1715. 5. Schuchat A, Deaver K, Hayes PS, Graves L, Mascola L, Wenger JD. Gastrointestinal carriage of Listeria monocytogenes in household contacts of patients with listeriosis. J Infect Dis 1993;167:1261—1262. 6. Safdar A, Armstrong D. Antimicrobial activities against 84 Listeria monocytogenes isolates from patients with systemic listeriosis at a comprehensive cancer center (1955—1997). J Clin Microbiol 2003;41:483—485. 7. Arsene O, Linassier C, Quentin R, Legras A, Colombat P. Development of listeriosis during vancomycin therapy in a neutropenic patient. Scand J Infect Dis 1996;28:415—416. 8. Chang J, Powles R, Mehta J, Paton N, Treleaven J, Jameson B. Listeriosis in bone marrow transplant recipients: incidence, clinical features, and treatment. Clin Infect Dis 1995; 21:1289—1290. 9. Fisman DN. Hemophagocytic syndromes and infection. Emerg Infect Dis 2000;6:601—608. 10. Stoiber D, Stockinger S, Steinlein P, Kovarik J, Decker T. Listeria monocytogenes modulates macrophage cytokine responses through STAT serine phosphorylation and the induction of suppressor of cytokine signaling 3. J Immunol 2001;166:466—472.