- Email: [email protected]
Ruxolitinib can mask symptoms and signs of necrotizing fasciitis
296
Letters to the Editor
Ec/Kp bacteraemia only to assess the effect of treatment and outcome. Further study with larger number of patients and prospective follow-up should be done. In conclusions, meropenem is an independent risk factor for ENS-Ec/Kp bacteraemia. Ertapenem non-susceptibility in our Ec/Kp bacteraemia cases was due to a combination of ESBL and ampC enzymes. Meropenem or imipenem monotherapy was effective for treating susceptible ENSEc/Kp bacteraemia.
References 1. Chen YH, Hsueh PR, Badal RE, Hawser SP, Hoban DJ, Bouchillon SK, et al. Antimicrobial susceptibility profiles of aerobic and facultative gram-negative bacilli isolated from patients with intra-abdominal infections in the Asia-Pacific region according to currently established susceptibility interpretive criteria. J Infect 2011;62(4):280e91. 2. Ong DC, Koh TH, Syahidah N, Krishnan P, Tan TY. Rapid detection of the blaNDM-1 gene by real-time PCR. J Antimicrob Chemother 2011;66(7):1647e9. 3. Orsi GB, Garcia-Fernandez A, Giordano A, Venditti C, Bencardino A, Gianfreda R, et al. Risk factors and clinical significance of ertapenem-resistant Klebsiella pneumoniae in hospitalised patients. J Hosp Infect 2011;78(1):54e8. 4. Falagas ME, Rafailidis PI, Kofteridis D, Virtzili S, Chelvatzoglou FC, Papaioannou V, et al. Risk factors of carbapenem-resistant Klebsiella pneumoniae infections: a matched case control study. J Antimicrob Chemother 2007;60(5):1124e30. 5. Findlay J, Hamouda A, Dancer SJ, Amyes SG. Rapid acquisition of decreased carbapenem susceptibility in a strain of Klebsiella pneumoniae arising during meropenem therapy. Clin Microbiol Infect 2012;18(2):140e6. 6. Balm MN, Ngan G, Jureen R, Lin RT, Teo J. Molecular characterization of newly emerged blaKPC-2-producing Klebsiella pneumoniae in Singapore. J Clin Microbiol 2012;50(2):475e6.
Kalisvar Marimuthu* Tat Ming Ng Christine Teng Tan Tock Seng Hospital, Singapore E-mail address: [email protected] (K. Marimuthu) Tse Peng Lim Tse Hsien Koh Singapore General Hospital, Singapore Thean Yen Tan Changi General Hospital, Singapore Prabha Unny Krishnan David Lye Tan Tock Seng Hospital, Singapore *Corresponding author. Tel.: þ65 96451789. Accepted 24 November 2012 ª 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jinf.2012.11.010
Ruxolitinib can mask symptoms and signs of necrotizing fasciitis
An increasing arsenal of drugs together referred to as ‘biologicals’ are under study for a wide range of diseases. These biologicals interfere with the host immune response and a high awareness of infectious complications is warranted. This was exemplified by reactivation tuberculosis during use of tumor necrosis factor antagonists, recognized first after these agents were marketed. A recent report in this journal showed that there is evidence for an increased incidence of necrotizing fasciitis.1 It remains unclear what caused this increased incidence of necrotizing fasciitis, one possibility could be the increased use of immune modulators. We report a patient with myelofibrosis who used ruxolitinib, a JAK1/2 inhibitor, and developed necrotizing fasciitis. His clinical presentation was remarkable, with minor local signs and normal inflammatory parameters. Based on the mechanism of action, a relationship between ruxolitinib use and the masked clinical presentation seems plausible. In myelofibrosis, constitutional symptoms are secondary to an inflammatory state. Ruxolitinib, an inhibitor of Janus kinase (JAK)-1 and JAK-2, reduces spleen size and constitutional symptoms in patients with myelofibrosis. Ruxolitinib leads to a rapid decrease of pro-inflammatory cytokines, tumor necrosis factor a, interleukin-6 (IL-6) and C-reactive protein (CRP) levels.2,3 Although there are as of yet no indications that ruxulitinib increases the risk of infection, it seems plausible that infection-associated symptoms could be masked. A clinical observation led us to consider a role of ruxolitinib in an unusual clinical presentation and course of a severe infection. August 2012, a 73-year-old man was admitted with fever. He had a 3-year history of myelofibrosis and started ruxolitinib (15 mg bid, compassionate use) 6 weeks prior to admission. On admission he reported an uncomfortable feeling in sitting position in the perianal region since 18 h, followed by high fever and chills several hours later. On examination he had high fever and tachycardia. There was minor perianal swelling without pain or fluctuation during digital rectal examination. Laboratory results on admission are shown in Table 1. The presumptive diagnosis of sepsis was made and empirical treatment with cefuroxim and gentamicin was started. Initially, the consulting surgeon considered necrotizing fasciitis unlikely. During the next hours the scrotum became swollen and the skin necrotic, while the patient still had only moderate pain. Meropenem was started and surgical treatment consisted of extensive debridement of necrotic skin, fascia of the scrotum and penis up to the femoral region while the testes could be spared. There was a marked paucity of inflammatory exudate. Microscopy of the debris showed Gram-negative bacteria, tissue and blood cultures yielded Escherichia coli. The postoperative course was favorable; he needed inotropic support for less than 24 h and his creatinine clearance normalized. Unusual characteristics in this case were the mild pain, virtual lack of local signs and normal inflammatory parameters with low CRP level on admission, which did not suggest fasciitis necroticans. The low CRP level could be
Letters to the Editor Table 1
297
Laboratory data on admission. Reference On value admission
4.4e11 Leucocytes (109/mm3) Neutrophils (%) 40e70 C-reactive protein (mg/L) <10 Erythrocyte sedimentation rate (mm) 0e17 Creatinine (mmol/L) <1.2 Arterial lactate (mmol/L) <2.0 a
6 50 13 15 1.4a 4.2
The patient’s pre-admission creatitine value was 0.9 mmol/L.
the result of a blunted IL-6 response, as IL-6 normally induces an acute phase response resulting in production of CRP. Interestingly, tocilizumab, an IL-6 receptor-antagonist, has been associated with a lack of diagnostic value of physical signs and CRP in patients with infections including a case with necrotizing fasciitis.4e6 Criteria used to detect a severe fasciitis are thus unreliable in this setting.7 By a similar mechanism of ruxolitinib, the relative lack of pain and initial limited local signs of infection could possibly have resulted from low prostaglandin and IL-6 responses after release of lipopolysaccharide (LPS).5,8 An inability to respond to LPS might also explain the favorable clinical course and rapid postoperative recovery. This assumption is supported by animal data showing that JAK-2 deficient mice could tolerate lethal doses of LPS via reduced activation of innate immune responses.9,10 We hypothesize that JAK1/2 inhibitors can blunt the acute phase response in patients with infection, which can mask serious infection, while hemodynamic consequences of LPS release are mitigated. This case illustrates that a lack of local symptoms and signs and a normal CRP level do not exclude the presence of severe infection in a patient using JAK inhibitors. The case underscores, yet again, that physicians should be aware that novel biologicals could affect the clinical manifestations and course of infections.
Conflicts of interest
2. Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. New Engl J Med 2012;366(9):787e98. Epub 2012/03/02. 3. Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. New Engl J Med 2012;366(9):799e807. Epub 2012/03/02. 4. Hirao M, Nampei A, Shi K, Yoshikawa H, Nishimoto N, Hashimoto J. Diagnostic features of mild cellulitis phlegmon in patients with rheumatoid arthritis treated with tocilizumab: a report of two cases. Mod Rheumatol 2011;21(6):673e7. Epub 2011/05/03. 5. van de Sande MG, van Slobbe-Bijlsma ER. Necrotizing fasciitis in a rheumatoid arthritis patient treated with tocilizumab. Rheumatology (Oxford) 2012;51(3):577e8. Epub 2011/11/19. 6. Yoshida A, Ota T, Sasaoka S, Matsuura H, Fujimoto W, Morita Y. Necrotizing fasciitis in a patient with rheumatoid arthritis treated with tocilizumab. Mod Rheumatol 2012;22(2):317e8. Epub 2011/08/11. 7. Wong CH, Khin LW. Clinical relevance of the LRINEC (laboratory risk indicator for necrotizing fasciitis) score for assessment of early necrotizing fasciitis. Crit Care Med 2005;33(7):1677. Epub 2005/07/09. 8. Trebino CE, Stock JL, Gibbons CP, Naiman BM, Wachtmann TS, Umland JP, et al. Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proc Natl Acad Sci U S A 2003;100(15):9044e9. Epub 2003/07/02. 9. Pena G, Cai B, Deitch EA, Ulloa L. JAK2 inhibition prevents innate immune responses and rescues animals from sepsis. J Mol Med (Berl) 2010;88(8):851e9. Epub 2010/04/16. 10. Zhong J, Yang P, Muta K, Dong R, Marrero M, Gong F, et al. Loss of Jak2 selectively suppresses DC-mediated innate immune response and protects mice from lethal dose of LPS-induced septic shock. PLoS One 2010;5(3):e9593. Epub 2010/03/17.
G.W.D. Landman* S.M. Arend J.T. van Dissel Leiden University Medical Centre, Department of Infectious Diseases, The Netherlands E-mail address: [email protected] (G.W.D. Landman) *Corresponding author.
All authors declare that they have no conflicts of interest. Accepted 24 November 2012
References 1. Das DK, Baker MG, Venugopal K. Increasing incidence of necrotizing fasciitis in New Zealand: a nationwide study over the period 1990 to 2006. J Infect 2011;63(6):429e33. Epub 2011/08/26.
ª 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jinf.2012.11.011
Letters to the Editor
Ec/Kp bacteraemia only to assess the effect of treatment and outcome. Further study with larger number of patients and prospective follow-up should be done. In conclusions, meropenem is an independent risk factor for ENS-Ec/Kp bacteraemia. Ertapenem non-susceptibility in our Ec/Kp bacteraemia cases was due to a combination of ESBL and ampC enzymes. Meropenem or imipenem monotherapy was effective for treating susceptible ENSEc/Kp bacteraemia.
References 1. Chen YH, Hsueh PR, Badal RE, Hawser SP, Hoban DJ, Bouchillon SK, et al. Antimicrobial susceptibility profiles of aerobic and facultative gram-negative bacilli isolated from patients with intra-abdominal infections in the Asia-Pacific region according to currently established susceptibility interpretive criteria. J Infect 2011;62(4):280e91. 2. Ong DC, Koh TH, Syahidah N, Krishnan P, Tan TY. Rapid detection of the blaNDM-1 gene by real-time PCR. J Antimicrob Chemother 2011;66(7):1647e9. 3. Orsi GB, Garcia-Fernandez A, Giordano A, Venditti C, Bencardino A, Gianfreda R, et al. Risk factors and clinical significance of ertapenem-resistant Klebsiella pneumoniae in hospitalised patients. J Hosp Infect 2011;78(1):54e8. 4. Falagas ME, Rafailidis PI, Kofteridis D, Virtzili S, Chelvatzoglou FC, Papaioannou V, et al. Risk factors of carbapenem-resistant Klebsiella pneumoniae infections: a matched case control study. J Antimicrob Chemother 2007;60(5):1124e30. 5. Findlay J, Hamouda A, Dancer SJ, Amyes SG. Rapid acquisition of decreased carbapenem susceptibility in a strain of Klebsiella pneumoniae arising during meropenem therapy. Clin Microbiol Infect 2012;18(2):140e6. 6. Balm MN, Ngan G, Jureen R, Lin RT, Teo J. Molecular characterization of newly emerged blaKPC-2-producing Klebsiella pneumoniae in Singapore. J Clin Microbiol 2012;50(2):475e6.
Kalisvar Marimuthu* Tat Ming Ng Christine Teng Tan Tock Seng Hospital, Singapore E-mail address: [email protected] (K. Marimuthu) Tse Peng Lim Tse Hsien Koh Singapore General Hospital, Singapore Thean Yen Tan Changi General Hospital, Singapore Prabha Unny Krishnan David Lye Tan Tock Seng Hospital, Singapore *Corresponding author. Tel.: þ65 96451789. Accepted 24 November 2012 ª 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jinf.2012.11.010
Ruxolitinib can mask symptoms and signs of necrotizing fasciitis
An increasing arsenal of drugs together referred to as ‘biologicals’ are under study for a wide range of diseases. These biologicals interfere with the host immune response and a high awareness of infectious complications is warranted. This was exemplified by reactivation tuberculosis during use of tumor necrosis factor antagonists, recognized first after these agents were marketed. A recent report in this journal showed that there is evidence for an increased incidence of necrotizing fasciitis.1 It remains unclear what caused this increased incidence of necrotizing fasciitis, one possibility could be the increased use of immune modulators. We report a patient with myelofibrosis who used ruxolitinib, a JAK1/2 inhibitor, and developed necrotizing fasciitis. His clinical presentation was remarkable, with minor local signs and normal inflammatory parameters. Based on the mechanism of action, a relationship between ruxolitinib use and the masked clinical presentation seems plausible. In myelofibrosis, constitutional symptoms are secondary to an inflammatory state. Ruxolitinib, an inhibitor of Janus kinase (JAK)-1 and JAK-2, reduces spleen size and constitutional symptoms in patients with myelofibrosis. Ruxolitinib leads to a rapid decrease of pro-inflammatory cytokines, tumor necrosis factor a, interleukin-6 (IL-6) and C-reactive protein (CRP) levels.2,3 Although there are as of yet no indications that ruxulitinib increases the risk of infection, it seems plausible that infection-associated symptoms could be masked. A clinical observation led us to consider a role of ruxolitinib in an unusual clinical presentation and course of a severe infection. August 2012, a 73-year-old man was admitted with fever. He had a 3-year history of myelofibrosis and started ruxolitinib (15 mg bid, compassionate use) 6 weeks prior to admission. On admission he reported an uncomfortable feeling in sitting position in the perianal region since 18 h, followed by high fever and chills several hours later. On examination he had high fever and tachycardia. There was minor perianal swelling without pain or fluctuation during digital rectal examination. Laboratory results on admission are shown in Table 1. The presumptive diagnosis of sepsis was made and empirical treatment with cefuroxim and gentamicin was started. Initially, the consulting surgeon considered necrotizing fasciitis unlikely. During the next hours the scrotum became swollen and the skin necrotic, while the patient still had only moderate pain. Meropenem was started and surgical treatment consisted of extensive debridement of necrotic skin, fascia of the scrotum and penis up to the femoral region while the testes could be spared. There was a marked paucity of inflammatory exudate. Microscopy of the debris showed Gram-negative bacteria, tissue and blood cultures yielded Escherichia coli. The postoperative course was favorable; he needed inotropic support for less than 24 h and his creatinine clearance normalized. Unusual characteristics in this case were the mild pain, virtual lack of local signs and normal inflammatory parameters with low CRP level on admission, which did not suggest fasciitis necroticans. The low CRP level could be
Letters to the Editor Table 1
297
Laboratory data on admission. Reference On value admission
4.4e11 Leucocytes (109/mm3) Neutrophils (%) 40e70 C-reactive protein (mg/L) <10 Erythrocyte sedimentation rate (mm) 0e17 Creatinine (mmol/L) <1.2 Arterial lactate (mmol/L) <2.0 a
6 50 13 15 1.4a 4.2
The patient’s pre-admission creatitine value was 0.9 mmol/L.
the result of a blunted IL-6 response, as IL-6 normally induces an acute phase response resulting in production of CRP. Interestingly, tocilizumab, an IL-6 receptor-antagonist, has been associated with a lack of diagnostic value of physical signs and CRP in patients with infections including a case with necrotizing fasciitis.4e6 Criteria used to detect a severe fasciitis are thus unreliable in this setting.7 By a similar mechanism of ruxolitinib, the relative lack of pain and initial limited local signs of infection could possibly have resulted from low prostaglandin and IL-6 responses after release of lipopolysaccharide (LPS).5,8 An inability to respond to LPS might also explain the favorable clinical course and rapid postoperative recovery. This assumption is supported by animal data showing that JAK-2 deficient mice could tolerate lethal doses of LPS via reduced activation of innate immune responses.9,10 We hypothesize that JAK1/2 inhibitors can blunt the acute phase response in patients with infection, which can mask serious infection, while hemodynamic consequences of LPS release are mitigated. This case illustrates that a lack of local symptoms and signs and a normal CRP level do not exclude the presence of severe infection in a patient using JAK inhibitors. The case underscores, yet again, that physicians should be aware that novel biologicals could affect the clinical manifestations and course of infections.
Conflicts of interest
2. Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. New Engl J Med 2012;366(9):787e98. Epub 2012/03/02. 3. Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. New Engl J Med 2012;366(9):799e807. Epub 2012/03/02. 4. Hirao M, Nampei A, Shi K, Yoshikawa H, Nishimoto N, Hashimoto J. Diagnostic features of mild cellulitis phlegmon in patients with rheumatoid arthritis treated with tocilizumab: a report of two cases. Mod Rheumatol 2011;21(6):673e7. Epub 2011/05/03. 5. van de Sande MG, van Slobbe-Bijlsma ER. Necrotizing fasciitis in a rheumatoid arthritis patient treated with tocilizumab. Rheumatology (Oxford) 2012;51(3):577e8. Epub 2011/11/19. 6. Yoshida A, Ota T, Sasaoka S, Matsuura H, Fujimoto W, Morita Y. Necrotizing fasciitis in a patient with rheumatoid arthritis treated with tocilizumab. Mod Rheumatol 2012;22(2):317e8. Epub 2011/08/11. 7. Wong CH, Khin LW. Clinical relevance of the LRINEC (laboratory risk indicator for necrotizing fasciitis) score for assessment of early necrotizing fasciitis. Crit Care Med 2005;33(7):1677. Epub 2005/07/09. 8. Trebino CE, Stock JL, Gibbons CP, Naiman BM, Wachtmann TS, Umland JP, et al. Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proc Natl Acad Sci U S A 2003;100(15):9044e9. Epub 2003/07/02. 9. Pena G, Cai B, Deitch EA, Ulloa L. JAK2 inhibition prevents innate immune responses and rescues animals from sepsis. J Mol Med (Berl) 2010;88(8):851e9. Epub 2010/04/16. 10. Zhong J, Yang P, Muta K, Dong R, Marrero M, Gong F, et al. Loss of Jak2 selectively suppresses DC-mediated innate immune response and protects mice from lethal dose of LPS-induced septic shock. PLoS One 2010;5(3):e9593. Epub 2010/03/17.
G.W.D. Landman* S.M. Arend J.T. van Dissel Leiden University Medical Centre, Department of Infectious Diseases, The Netherlands E-mail address: [email protected] (G.W.D. Landman) *Corresponding author.
All authors declare that they have no conflicts of interest. Accepted 24 November 2012
References 1. Das DK, Baker MG, Venugopal K. Increasing incidence of necrotizing fasciitis in New Zealand: a nationwide study over the period 1990 to 2006. J Infect 2011;63(6):429e33. Epub 2011/08/26.
ª 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jinf.2012.11.011