- Email: [email protected]
Hepatitis E virus in hematopoietic stem cell donors: Towards a systematic HEV screening of donors?
Letters to the Editor to be aware of increasing frequencies in the current era of globalisation and widespread travel.1 The demonstration of amastigotes in Giemsa stained smears taken from the lesion is a typical first approach to diagnose cutaneous leishmaniasis.7 Amastigotes can also often be found on histopathological examination of biopsies8 and are easy to visualize on routine H&E stained sections during early disease, but may be difficult to find in later stages. The growth and expansion of parasites in cultures (Novy-, McNeal- or Nicolle-Agar or liquid media) has been considered as a diagnostic gold standard, however, the sensitivity of the method is only 50e70% for the detection of Old World and 15e30% for New World species.9 In earlier cases of penile leishmaniasis parasites were easily identified by the classical diagnostic tools.10 These tools all failed in the present case, probably due to a low number of viable parasites at this disease stage and following multiple topical therapies. Evidence of leishmaniasis was exclusively produced by means of real-time pan-Leishmania PCR amplifying a short fragment of the ssrRNA gene. Species identification, here done via cytochrome b sequencing, is a prerequisite for the selection of the appropriate treatment regime. In conclusion, cutaneous leishmaniasis should be considered in patients with refractory chronic granulomatous ulcerative lesions who are travellers to or residents of endemic regions, even if the lesions occur at unusual sites. The definite diagnosis requires demonstration of the parasite by microscopy, culture, and/or molecular analysis. PCR and species identification by cytochrome b sequencing performed on formalin-fixed, paraffin-embedded tissue proved to be a fast and sensitive diagnostic tool in our patient.
Funding sources
141 9. Goto H, Lindoso JA. Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis. Expert Rev Anti Infect Ther 2010 Apr;8:419e33. 10. Grunwald MH, Amichai B, Trau H. Cutaneous leishmaniasis on an unusual site: the glans penis. Br J Urol 1998;82:928.
V.G. Herbert* €er-Auer A. Bo A. Brandenburg T.M. Falk Dermatologikum Hamburg, Germany I. Reiter-Owona Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Germany J.K. Rockstroh Department of Internal Medicine I, University Hospital Bonn, Germany K. Reich Dermatologikum Hamburg, Germany *Corresponding author. Dermatologikum Hamburg, Stephansplatz 5, 20354 Hamburg, Germany. Tel.: þ49 40 351075 0; fax: þ49 40 351075 10.
E-mail address: [email protected] (V.G. Herbert) Accepted 20 February 2015 http://dx.doi.org/10.1016/j.jinf.2015.02.009 ª 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
None.
Conflict of interest disclosures None disclosed.
Hepatitis E virus in hematopoietic stem cell donors: Towards a systematic HEV screening of donors?
References 1. Pace D. Leishmaniasis. J Infect 2014;1(Suppl. 69):S10e8. 2. AWMF Leitlinie “Kutane und mukokutane Leishmaniasis, Diagnostik und Therapie”. http://www.awmf.org/leitlinien/ detail/ll/042-007.html. €ussinger D, Lo €scher T, Harms G. Mucosal 3. Richter J, Hanus I, Ha Leishmania infantum infection. Parasitol Res 2011;109:959e62. 4. Pearson RD, Sousa AQ. Clinical spectrum of Leishmaniasis. Clin Infect Dis 1996 Jan;22:1e13. 5. Gurel MS, Ulukanligil M, Ozbilge H. Cutaneous leishmaniasis in Sanliurfa: epidemiologic and clinical features of the last four years (1997e2000). Int J Dermatol 2002;41:32e7. 6. Schubach A, Cuzzi-Maya T, Gonalves-Costa SC, Pirmez C, OliveiraNeto MP. Leishmaniasis of glans penis. JEADV 1998;10:226e8. 7. Kocarslan S, Turan E, Ekinci T, Yesilova Y, Apari R. Clinical and histopathological characteristics of cutaneous Leishmaniasis in Sanliurfa city of Turkey including Syrian refugees. Indian J Pathol Microbiol 2013;56:211e5. 8. Pehoushek JF, Quinn DM, Crum WP. Cutaneous leishmaniasis in soldiers returning from deployment to Iraq. J Am Acad Dermatol 2004;51:S197e200.
KEYWORDS Hepatitis E virus; Hematopoietic stem cell transplantation; Bone marrow transplantation; France; Donors
In this Journal, Tan and colleagues showed in a welldefined cohort the increasing prevalence of acute hepatitis E virus (HEV) infection in Singapore.1 Cases of HEV transmission by transfusion have been reported in several countries over the world through labile blood products.2 In severely immunocompromised patients (such as recipients of
142
Letters to the Editor
allogeneic hematopoietic stem cell (HSC) transplantation), HEV clearance can be inefficient, potentially leading to chronic liver disease and cirrhosis.3 These severe consequences have prompted some practitioners to advocate a systematic screening of blood donations for HEV RNA in countries where HEV is endemic.4 Similarly, HEV could be theoretically transmitted through HSC therapy products,5 although no case of HSC transplantation-related HEV transmission has been reported to date. Because some characteristics could differ between blood and HSC donors, previous results about HEV seroprevalence in blood donors may not been extrapolated to HSC donors. We herein report the first epidemiological study about HEV prevalence among HSC donors, in order to discuss the need for implementation of a systematic screening for HEV before HSC collection. Serum samples collected in 89 donors, who provided HSC for children undergoing HSC transplantation at Necker Hospital (Paris, France) between 2009 and 2013, were retrospectively screened for anti-HEV IgG and IgM and for HEV RNA, using previously reported virological methods.6 Characteristics of donors are shown in Table 1. Overall, 8/89 donors (9%) were positive for anti-HEV IgG. Anti-HEV IgM and HEV RNA were not detected in any donor. The rate of HEV seroprevalence in HSC donors is thus lower than the one reported in previous studies in French blood donors using the same HEV IgG assay (22.5%).7 This could be explained by three characteristics of the HSC donors included in the present report. First, our study included a high proportion of HSC donors, whose young age does not allow them to be blood donors. Restricting the analysis to the 60 HSC donors older than 18 years, the rate of HEV seroprevalence increased to 13%, confirming previous descriptions that HEV seroprevalence is increasing with age.8 Second, our study included a high proportion of related HSC donors who spontaneously declared to avoid
any wild-boar/pork consumption for religious reasons (40%). Because HEV cases in developed countries are often linked to zoonotic transmission through consumption of undercooked pork, wild-boar and game meat, the HEV seroprevalence among HSC donors could be higher in transplant centers with less frequent donors avoiding wild-boar/pork consumption. Third, the proportion of French HSC donors originating from Southern France could impact the rate of HEV seroprevalence. Indeed, HEV is hyperendemic in Southwest France, where 52% of blood donors carry anti-HEV IgG.8 We herein confirm that HEV seroprevalence was more than 2-fold greater in HSC donors living in Southern versus Northern France (18% versus 7%). Our results suggest that anti-HEV IgG could be more frequently isolated in other HSC transplantation centers using a higher proportion of HSC donors living in Southwest France. We did not find any case of HEV viremic donors, probably because of the small size of our study. Indeed, the frequency of HEV infection in blood donations varies from 1/14,520 in Scotland 9 to 1/2218 in France.10 Because of these high geographical disparities, further and larger studies are needed to estimate the rates of HEV seroprevalence and HEV infection in HSC donations in developed countries. Such studies could be useful for determining the best safety measures to prevent HEV transmission through HSC transplantation. Indeed, because (i) the rate of HEV transmission through infected blood transfusion is high and (ii) HEV infection can be life-threatening in immunocompromised patients or can worsen the post-transplant course, we suggest that a systematic HEV screening of HSC donors should be considered in areas where HEV is endemic (i.e., the European countries). This question is of special importance in France, because HEV is hyperendemic in the Southwest. Moreover, ribavirin administration, which may be effective in the treatment of chronic HEV infection in patients with solid organ transplant,
Table 1 Characteristics of hematopoietic stem cells donors according to the results of the hepatitis E virus serological screening. Characteristics
Total (n Z 89)
Donors with negative HEV serology (n Z 81)
Donors with anti-HEV IgG (n Z 8)
Male (n, %) Age (years) (median, range) 0e17 years (n, %) 18e35 years (n, %) >35 years (n, %) Relationships to the HSC recipient Brother/sister (n, %) Father/mother (n, %) Unrelated donor (n, %) Living place France (n, %) North Franceb (n, %) South Franceb (n, %) Other countriesa (n, %) Absence of wild-boar/pork consumptionb (n, %)
56 28 29 43 17
50 27 29 37 15
6 (75) 34 [23e51] 0 (0) 6 (75) 2 (25)
(63) [1e51] (33) (48) (19)
(62) [1e51] (36) (46) (18)
31 (35) 31 (35) 27 (30)
31 (38) 25 (31) 24 (31)
0 (0) 5 (63) 3 (37)
63 44 11 26 25
56 (69) 41 (73) 9 (16) 25 (31) 24 (42)
7 3 2 1 1
(71) (49) (12) (29) (40)
(88) (42) (29) (13) (20)
HEV Z hepatitis E virus; HSC Z hematopoietic stem cell. a Germany (n Z 9), USA (n Z 5); Algeria (n Z 2); Belgium (n Z 2), Portugal (n Z 2), Brazil (n Z 1), Greece (n Z 1), Israel (n Z 1), Luxembourg (n Z 1), Marocco (n Z 1), United Kingdom (n Z 1). b The total of patients for each variable does not always equal the total sample due to some missing values for unrelated donors.
Letters to the Editor may not been applicable in HSC recipients, especially because of the high risk of hematological toxicity. In line with previous studies in blood donors showing that most of the HEV viremic individuals were seronegative at the time of donation,10 implementation of a systematic HEV screening in HSC donors should also be based on HEV RNA detection. Further large prospective studies are needed to evaluate if patients receiving HSC products from HEV-viremic donors are at higher risk of mortality, liver disease and/or graftversus-host disease.
Conflict of interest statement Neither authors nor their institutions have received payments or services from a third party for any aspect of the submitted work at any time.
Financial support None.
Author contribution PF designed the study, collected the data and drafted the manuscript. A-MR-A and M-LV performed the virological analyses. PF, BN, DM, FT, MC, AF and SB contributed in study design and participated in patient follow-up. All authors read and commented the manuscript and approved the final version.
References 1. Tan LT, Tan J, Ang LW, Chan KP, Chiew KT, Cutter J, et al. Epidemiology of acute hepatitis E in Singapore. J Infect 2013;66:453e9. 2. Boxall E, Herborn A, Kochethu G, Pratt G, Adams D, Ljiaz S, et al. Transfusion-transmitted hepatitis E in a ‘nonhyperendemic’ country. Transfus Med 2006;16:79e83. 3. Versluis J, Pas SD, Agteresch HJ, de Man RA, Maaskant J, Schipper ME, et al. Hepatitis E virus: an underestimated opportunistic pathogen in recipients of allogeneic hematopoietic stem cell transplantation. Blood 2013;122:1079e86. ray C, Pawlotsky JM, Roque-Afonso AM, Samuel D, 4. Fe Dhumeaux D. Should we screen blood products for hepatitis E virus RNA? Lancet 2014;383:218. 5. Koenecke C, Pischke S, Beutel G, Ritter U, Ganser A, Wedemeyer H, et al. Hepatitis E virus infection in a hematopoietic stem cell donor. Bone Marrow Transplant 2014;49:159e60. 6. Renou C, Gobert V, Locher C, Moumen A, Timbely O, Savary J, et al. Prospective study of hepatitis E virus infection among pregnant women in France. Virol J 2014;11:68. 7. Gallian P, Piquet Y, Assal A, Djoudi R, Chiaroni J, Izopet J, et al. Hepatitis E virus: blood transfusion implications. Transfus Clin Biol 2014;21:173e7. K, 8. Mansuy JM, Bendall R, Legrand-Abravanel F, Saune douge M, Ellis V, et al. Hepatitis E virus antibodies in blood Mie donors, France. Emerg Infect Dis 2011;17:2309e12. 9. Cleland A, Smith L, Crossan C, Blatchford O, Dalton HR, Scobie L, et al. Hepatitis E virus in Scottish blood donors. Vox Sang 2013;105:283e9. K, Abravanel F, Assal A, 10. Gallian P, Lhomme S, Piquet Y, Saune et al. Hepatitis E virus infections in blood donors, France. Emerg Infect Dis 2014;20:1914e7.
143 Pierre Frange* Laboratoire de Microbiologie clinique, Assistance Publique e Ho^pitaux de Paris (AP-HP), Ho^pital Necker e Enfants malades, Paris, France Unite d’Immunologie, Hematologie et Rhumatologie pediatriques, AP-HP, Ho^pital Necker e Enfants malades, Paris, France EA 7327, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France Anne-Marie Roque-Afonso Laboratoire de Virologie, AP-HP, Ho^pital Paul Brousse, Villejuif, 94804, France Univ. Paris Sud, UMR-S 1193, Villejuif, 94804, France INSERM U1193, Villejuif, 94804, France ne dicte Neven Be Despina Moshous Unite d’Immunologie, Hematologie et Rhumatologie pediatriques, AP-HP, Ho^pital Necker e Enfants malades, Paris, France Institut Imagine, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France INSERM UMR 1163, Paris, France Fabien Touzot Marina Cavazzana Institut Imagine, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France INSERM UMR 1163, Paris, France Departement de Biotherapie, Centre d’Investigation Clinique integre en Biotherapies, AP-HP, Ho^pital Necker e Enfants malades, Paris, France Alain Fischer Unite d’Immunologie, Hematologie et Rhumatologie pediatriques, AP-HP, Ho^pital Necker e Enfants malades, Paris, France Institut Imagine, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France INSERM UMR 1163, Paris, France College de France, Paris, France Marianne Leruez-Ville Laboratoire de Microbiologie clinique, Assistance Publique e Ho^pitaux de Paris (AP-HP), Ho^pital Necker e Enfants malades, Paris, France EA 7328, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France phane Blanche Ste Unite d’Immunologie, Hematologie et Rhumatologie pediatriques, AP-HP, Ho^pital Necker e Enfants malades, Paris, France
144
Letters to the Editor
Institut Imagine, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France EA08, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France ^pital *Corresponding author. Laboratoire de Microbiologie, Ho vres, 75015 Paris, France. Necker e Enfants malades, 149 rue de Se Tel.: þ33 1 44 49 49 61; fax: þ33 1 44 49 49 60.
E-mail address: [email protected] Accepted 20 February 2015 http://dx.doi.org/10.1016/j.jinf.2015.02.008 ª 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Letter to the Editor concerning the review of Prof. Sheldon L. Kaplan “Recent lessons for the management of bone and joint infections” e Bacteriostatic or bactericidal agents in osteoarticular infections?
KEYWORDS Osteoarticular infections; infection remission; bacteriostatic; bactericidal; antibiotic therapy
Sir, We read with great interest the recent review of Prof. Kaplan regarding the management of bone and joint infections.1 We congratulate the author for his excellent and short review and have nothing to correct. We however think that there is one important aspect missing, which can be summarized in one single question we encounter when treating these infections: “Should we rather use a bacteriostatic or a bactericidal agent” (if we have a choice)? Antibiotics are often divided into those that kill bacteria, i.e., are bactericidal, and those that inhibit growth, i.e., are bacteriostatic.2e5 Clinicians are told to consider this for treating difficult-to-cure or potentially fatal infections, such as endocarditis, meningitis, neutropenia-associated sepsis or osteoarticular infections.2e4 Microbiologists define criteria for a bactericidal agent requiring either a 3 log10reduction in the number of surviving bacteria within
18e24 h under laboratory conditions or a ratio of minimal bactericidal concentrations to minimal inhibitory concentrations of >4.2 While bactericidal agents have shown superior results compared with bacteriostatic agents in some animal and in vitro studies,3 there is no high quality of evidence favoring their use in clinical situations.2e8 We thus used our prospective single-centre cohort study to investigate the association of type of antibiotic (bacteriostatic vs. bactericidal) used and the infection remission rates among adult patients hospitalized for an osteoarticular infection. We included all episodes 2000e2014 for which the antibiotic treatment prescribed was either a bactericidal or bacteriostatic agent during >75% of their total antibiotic course. To confirm infection we required that the same pathogen be isolated on culture from at least two intraoperative samples, together with clinical signs of infection (new pain, fever, wound discharge or implant loosening). Remission was defined as the resolution of any signs of infection, with no recurrence during a minimum follow-up of 1 year. To avoid data clustering, we included only the first episode of each infection and eliminated recurrent episodes from further analysis. Other exclusion criteria were absence of surgical debridement, limb amputation, pediatric patient (<17 years), soft tissue infections, and infections due to mycobacteria, virus, fungi or Nocardia spp. We classified antibiotics as either bacteriostatic or bactericidal according to international publications and Swiss national drug recommendations.2,3 Antibiotics generally considered bacteriostatic were macrolides; clindamycin; co-trimoxazole; tetracyclines; tigecycline; and, linezolid. Those considered bactericidal agents were b-lactam antibiotics, aminoglycosides; daptomycin; rifampicin; and, quinolones. We classified a regimen as bactericidal if it was combination therapy of any bacteriostatic agent with rifampicin for a staphylococcal implant infection, or involved the use of local gentamicin beads. Overall, 612 episodes of osteoarticular infection met our enrollment criteria (Table 1). In total, 511 episodes maintained a remission of infection (84%) after a median followup time of 2.6 years (range, 1e16 years). The 101 recurrences (16%) occurred at the same anatomic site with the same pathogen as the original infection. The median number of surgical interventions was two (range, 1e17 interventions). Bactericidal agents were used in 471 cases (77%), including rifampin in 210 episodes. Among the bacteriostatic agents, the most frequent single regimen was clindamycin (n Z 70). The median duration of antibiotic therapy was 51 days (interquartile range, 42e90 d), with a median of 14 days being given intravenously. Total antibiotic duration was similar for the bacteriostatic and bactericidal regimens (median 49 vs. 56 days, respectively; p Z 0.502), as was the median number of surgical interventions (2 vs. 2; p Z 0.929). Overall, there was no difference in the rate of remission of infection between populations receiving bactericidal vs. bacteriostatic agents (85% vs. 80%, p Z 0.221). In multivariate analysis, the use of bactericidal agents was unrelated to remission (odds ratio 1.2, 95% CI 0.7e2.1) (Table 2). Likewise, in stratified multivariate analyses, there was no advantage of bactericidal drugs in increasing remission rates for chronic osteomyelitis (OR 3.8, 95% CI 0.7e20.7), implant-associated infections (OR 0.4, 0.3e1.4), prosthetic
Funding sources
141 9. Goto H, Lindoso JA. Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis. Expert Rev Anti Infect Ther 2010 Apr;8:419e33. 10. Grunwald MH, Amichai B, Trau H. Cutaneous leishmaniasis on an unusual site: the glans penis. Br J Urol 1998;82:928.
V.G. Herbert* €er-Auer A. Bo A. Brandenburg T.M. Falk Dermatologikum Hamburg, Germany I. Reiter-Owona Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Germany J.K. Rockstroh Department of Internal Medicine I, University Hospital Bonn, Germany K. Reich Dermatologikum Hamburg, Germany *Corresponding author. Dermatologikum Hamburg, Stephansplatz 5, 20354 Hamburg, Germany. Tel.: þ49 40 351075 0; fax: þ49 40 351075 10.
E-mail address: [email protected] (V.G. Herbert) Accepted 20 February 2015 http://dx.doi.org/10.1016/j.jinf.2015.02.009 ª 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
None.
Conflict of interest disclosures None disclosed.
Hepatitis E virus in hematopoietic stem cell donors: Towards a systematic HEV screening of donors?
References 1. Pace D. Leishmaniasis. J Infect 2014;1(Suppl. 69):S10e8. 2. AWMF Leitlinie “Kutane und mukokutane Leishmaniasis, Diagnostik und Therapie”. http://www.awmf.org/leitlinien/ detail/ll/042-007.html. €ussinger D, Lo €scher T, Harms G. Mucosal 3. Richter J, Hanus I, Ha Leishmania infantum infection. Parasitol Res 2011;109:959e62. 4. Pearson RD, Sousa AQ. Clinical spectrum of Leishmaniasis. Clin Infect Dis 1996 Jan;22:1e13. 5. Gurel MS, Ulukanligil M, Ozbilge H. Cutaneous leishmaniasis in Sanliurfa: epidemiologic and clinical features of the last four years (1997e2000). Int J Dermatol 2002;41:32e7. 6. Schubach A, Cuzzi-Maya T, Gonalves-Costa SC, Pirmez C, OliveiraNeto MP. Leishmaniasis of glans penis. JEADV 1998;10:226e8. 7. Kocarslan S, Turan E, Ekinci T, Yesilova Y, Apari R. Clinical and histopathological characteristics of cutaneous Leishmaniasis in Sanliurfa city of Turkey including Syrian refugees. Indian J Pathol Microbiol 2013;56:211e5. 8. Pehoushek JF, Quinn DM, Crum WP. Cutaneous leishmaniasis in soldiers returning from deployment to Iraq. J Am Acad Dermatol 2004;51:S197e200.
KEYWORDS Hepatitis E virus; Hematopoietic stem cell transplantation; Bone marrow transplantation; France; Donors
In this Journal, Tan and colleagues showed in a welldefined cohort the increasing prevalence of acute hepatitis E virus (HEV) infection in Singapore.1 Cases of HEV transmission by transfusion have been reported in several countries over the world through labile blood products.2 In severely immunocompromised patients (such as recipients of
142
Letters to the Editor
allogeneic hematopoietic stem cell (HSC) transplantation), HEV clearance can be inefficient, potentially leading to chronic liver disease and cirrhosis.3 These severe consequences have prompted some practitioners to advocate a systematic screening of blood donations for HEV RNA in countries where HEV is endemic.4 Similarly, HEV could be theoretically transmitted through HSC therapy products,5 although no case of HSC transplantation-related HEV transmission has been reported to date. Because some characteristics could differ between blood and HSC donors, previous results about HEV seroprevalence in blood donors may not been extrapolated to HSC donors. We herein report the first epidemiological study about HEV prevalence among HSC donors, in order to discuss the need for implementation of a systematic screening for HEV before HSC collection. Serum samples collected in 89 donors, who provided HSC for children undergoing HSC transplantation at Necker Hospital (Paris, France) between 2009 and 2013, were retrospectively screened for anti-HEV IgG and IgM and for HEV RNA, using previously reported virological methods.6 Characteristics of donors are shown in Table 1. Overall, 8/89 donors (9%) were positive for anti-HEV IgG. Anti-HEV IgM and HEV RNA were not detected in any donor. The rate of HEV seroprevalence in HSC donors is thus lower than the one reported in previous studies in French blood donors using the same HEV IgG assay (22.5%).7 This could be explained by three characteristics of the HSC donors included in the present report. First, our study included a high proportion of HSC donors, whose young age does not allow them to be blood donors. Restricting the analysis to the 60 HSC donors older than 18 years, the rate of HEV seroprevalence increased to 13%, confirming previous descriptions that HEV seroprevalence is increasing with age.8 Second, our study included a high proportion of related HSC donors who spontaneously declared to avoid
any wild-boar/pork consumption for religious reasons (40%). Because HEV cases in developed countries are often linked to zoonotic transmission through consumption of undercooked pork, wild-boar and game meat, the HEV seroprevalence among HSC donors could be higher in transplant centers with less frequent donors avoiding wild-boar/pork consumption. Third, the proportion of French HSC donors originating from Southern France could impact the rate of HEV seroprevalence. Indeed, HEV is hyperendemic in Southwest France, where 52% of blood donors carry anti-HEV IgG.8 We herein confirm that HEV seroprevalence was more than 2-fold greater in HSC donors living in Southern versus Northern France (18% versus 7%). Our results suggest that anti-HEV IgG could be more frequently isolated in other HSC transplantation centers using a higher proportion of HSC donors living in Southwest France. We did not find any case of HEV viremic donors, probably because of the small size of our study. Indeed, the frequency of HEV infection in blood donations varies from 1/14,520 in Scotland 9 to 1/2218 in France.10 Because of these high geographical disparities, further and larger studies are needed to estimate the rates of HEV seroprevalence and HEV infection in HSC donations in developed countries. Such studies could be useful for determining the best safety measures to prevent HEV transmission through HSC transplantation. Indeed, because (i) the rate of HEV transmission through infected blood transfusion is high and (ii) HEV infection can be life-threatening in immunocompromised patients or can worsen the post-transplant course, we suggest that a systematic HEV screening of HSC donors should be considered in areas where HEV is endemic (i.e., the European countries). This question is of special importance in France, because HEV is hyperendemic in the Southwest. Moreover, ribavirin administration, which may be effective in the treatment of chronic HEV infection in patients with solid organ transplant,
Table 1 Characteristics of hematopoietic stem cells donors according to the results of the hepatitis E virus serological screening. Characteristics
Total (n Z 89)
Donors with negative HEV serology (n Z 81)
Donors with anti-HEV IgG (n Z 8)
Male (n, %) Age (years) (median, range) 0e17 years (n, %) 18e35 years (n, %) >35 years (n, %) Relationships to the HSC recipient Brother/sister (n, %) Father/mother (n, %) Unrelated donor (n, %) Living place France (n, %) North Franceb (n, %) South Franceb (n, %) Other countriesa (n, %) Absence of wild-boar/pork consumptionb (n, %)
56 28 29 43 17
50 27 29 37 15
6 (75) 34 [23e51] 0 (0) 6 (75) 2 (25)
(63) [1e51] (33) (48) (19)
(62) [1e51] (36) (46) (18)
31 (35) 31 (35) 27 (30)
31 (38) 25 (31) 24 (31)
0 (0) 5 (63) 3 (37)
63 44 11 26 25
56 (69) 41 (73) 9 (16) 25 (31) 24 (42)
7 3 2 1 1
(71) (49) (12) (29) (40)
(88) (42) (29) (13) (20)
HEV Z hepatitis E virus; HSC Z hematopoietic stem cell. a Germany (n Z 9), USA (n Z 5); Algeria (n Z 2); Belgium (n Z 2), Portugal (n Z 2), Brazil (n Z 1), Greece (n Z 1), Israel (n Z 1), Luxembourg (n Z 1), Marocco (n Z 1), United Kingdom (n Z 1). b The total of patients for each variable does not always equal the total sample due to some missing values for unrelated donors.
Letters to the Editor may not been applicable in HSC recipients, especially because of the high risk of hematological toxicity. In line with previous studies in blood donors showing that most of the HEV viremic individuals were seronegative at the time of donation,10 implementation of a systematic HEV screening in HSC donors should also be based on HEV RNA detection. Further large prospective studies are needed to evaluate if patients receiving HSC products from HEV-viremic donors are at higher risk of mortality, liver disease and/or graftversus-host disease.
Conflict of interest statement Neither authors nor their institutions have received payments or services from a third party for any aspect of the submitted work at any time.
Financial support None.
Author contribution PF designed the study, collected the data and drafted the manuscript. A-MR-A and M-LV performed the virological analyses. PF, BN, DM, FT, MC, AF and SB contributed in study design and participated in patient follow-up. All authors read and commented the manuscript and approved the final version.
References 1. Tan LT, Tan J, Ang LW, Chan KP, Chiew KT, Cutter J, et al. Epidemiology of acute hepatitis E in Singapore. J Infect 2013;66:453e9. 2. Boxall E, Herborn A, Kochethu G, Pratt G, Adams D, Ljiaz S, et al. Transfusion-transmitted hepatitis E in a ‘nonhyperendemic’ country. Transfus Med 2006;16:79e83. 3. Versluis J, Pas SD, Agteresch HJ, de Man RA, Maaskant J, Schipper ME, et al. Hepatitis E virus: an underestimated opportunistic pathogen in recipients of allogeneic hematopoietic stem cell transplantation. Blood 2013;122:1079e86. ray C, Pawlotsky JM, Roque-Afonso AM, Samuel D, 4. Fe Dhumeaux D. Should we screen blood products for hepatitis E virus RNA? Lancet 2014;383:218. 5. Koenecke C, Pischke S, Beutel G, Ritter U, Ganser A, Wedemeyer H, et al. Hepatitis E virus infection in a hematopoietic stem cell donor. Bone Marrow Transplant 2014;49:159e60. 6. Renou C, Gobert V, Locher C, Moumen A, Timbely O, Savary J, et al. Prospective study of hepatitis E virus infection among pregnant women in France. Virol J 2014;11:68. 7. Gallian P, Piquet Y, Assal A, Djoudi R, Chiaroni J, Izopet J, et al. Hepatitis E virus: blood transfusion implications. Transfus Clin Biol 2014;21:173e7. K, 8. Mansuy JM, Bendall R, Legrand-Abravanel F, Saune douge M, Ellis V, et al. Hepatitis E virus antibodies in blood Mie donors, France. Emerg Infect Dis 2011;17:2309e12. 9. Cleland A, Smith L, Crossan C, Blatchford O, Dalton HR, Scobie L, et al. Hepatitis E virus in Scottish blood donors. Vox Sang 2013;105:283e9. K, Abravanel F, Assal A, 10. Gallian P, Lhomme S, Piquet Y, Saune et al. Hepatitis E virus infections in blood donors, France. Emerg Infect Dis 2014;20:1914e7.
143 Pierre Frange* Laboratoire de Microbiologie clinique, Assistance Publique e Ho^pitaux de Paris (AP-HP), Ho^pital Necker e Enfants malades, Paris, France Unite d’Immunologie, Hematologie et Rhumatologie pediatriques, AP-HP, Ho^pital Necker e Enfants malades, Paris, France EA 7327, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France Anne-Marie Roque-Afonso Laboratoire de Virologie, AP-HP, Ho^pital Paul Brousse, Villejuif, 94804, France Univ. Paris Sud, UMR-S 1193, Villejuif, 94804, France INSERM U1193, Villejuif, 94804, France ne dicte Neven Be Despina Moshous Unite d’Immunologie, Hematologie et Rhumatologie pediatriques, AP-HP, Ho^pital Necker e Enfants malades, Paris, France Institut Imagine, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France INSERM UMR 1163, Paris, France Fabien Touzot Marina Cavazzana Institut Imagine, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France INSERM UMR 1163, Paris, France Departement de Biotherapie, Centre d’Investigation Clinique integre en Biotherapies, AP-HP, Ho^pital Necker e Enfants malades, Paris, France Alain Fischer Unite d’Immunologie, Hematologie et Rhumatologie pediatriques, AP-HP, Ho^pital Necker e Enfants malades, Paris, France Institut Imagine, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France INSERM UMR 1163, Paris, France College de France, Paris, France Marianne Leruez-Ville Laboratoire de Microbiologie clinique, Assistance Publique e Ho^pitaux de Paris (AP-HP), Ho^pital Necker e Enfants malades, Paris, France EA 7328, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France phane Blanche Ste Unite d’Immunologie, Hematologie et Rhumatologie pediatriques, AP-HP, Ho^pital Necker e Enfants malades, Paris, France
144
Letters to the Editor
Institut Imagine, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France EA08, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France ^pital *Corresponding author. Laboratoire de Microbiologie, Ho vres, 75015 Paris, France. Necker e Enfants malades, 149 rue de Se Tel.: þ33 1 44 49 49 61; fax: þ33 1 44 49 49 60.
E-mail address: [email protected] Accepted 20 February 2015 http://dx.doi.org/10.1016/j.jinf.2015.02.008 ª 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Letter to the Editor concerning the review of Prof. Sheldon L. Kaplan “Recent lessons for the management of bone and joint infections” e Bacteriostatic or bactericidal agents in osteoarticular infections?
KEYWORDS Osteoarticular infections; infection remission; bacteriostatic; bactericidal; antibiotic therapy
Sir, We read with great interest the recent review of Prof. Kaplan regarding the management of bone and joint infections.1 We congratulate the author for his excellent and short review and have nothing to correct. We however think that there is one important aspect missing, which can be summarized in one single question we encounter when treating these infections: “Should we rather use a bacteriostatic or a bactericidal agent” (if we have a choice)? Antibiotics are often divided into those that kill bacteria, i.e., are bactericidal, and those that inhibit growth, i.e., are bacteriostatic.2e5 Clinicians are told to consider this for treating difficult-to-cure or potentially fatal infections, such as endocarditis, meningitis, neutropenia-associated sepsis or osteoarticular infections.2e4 Microbiologists define criteria for a bactericidal agent requiring either a 3 log10reduction in the number of surviving bacteria within
18e24 h under laboratory conditions or a ratio of minimal bactericidal concentrations to minimal inhibitory concentrations of >4.2 While bactericidal agents have shown superior results compared with bacteriostatic agents in some animal and in vitro studies,3 there is no high quality of evidence favoring their use in clinical situations.2e8 We thus used our prospective single-centre cohort study to investigate the association of type of antibiotic (bacteriostatic vs. bactericidal) used and the infection remission rates among adult patients hospitalized for an osteoarticular infection. We included all episodes 2000e2014 for which the antibiotic treatment prescribed was either a bactericidal or bacteriostatic agent during >75% of their total antibiotic course. To confirm infection we required that the same pathogen be isolated on culture from at least two intraoperative samples, together with clinical signs of infection (new pain, fever, wound discharge or implant loosening). Remission was defined as the resolution of any signs of infection, with no recurrence during a minimum follow-up of 1 year. To avoid data clustering, we included only the first episode of each infection and eliminated recurrent episodes from further analysis. Other exclusion criteria were absence of surgical debridement, limb amputation, pediatric patient (<17 years), soft tissue infections, and infections due to mycobacteria, virus, fungi or Nocardia spp. We classified antibiotics as either bacteriostatic or bactericidal according to international publications and Swiss national drug recommendations.2,3 Antibiotics generally considered bacteriostatic were macrolides; clindamycin; co-trimoxazole; tetracyclines; tigecycline; and, linezolid. Those considered bactericidal agents were b-lactam antibiotics, aminoglycosides; daptomycin; rifampicin; and, quinolones. We classified a regimen as bactericidal if it was combination therapy of any bacteriostatic agent with rifampicin for a staphylococcal implant infection, or involved the use of local gentamicin beads. Overall, 612 episodes of osteoarticular infection met our enrollment criteria (Table 1). In total, 511 episodes maintained a remission of infection (84%) after a median followup time of 2.6 years (range, 1e16 years). The 101 recurrences (16%) occurred at the same anatomic site with the same pathogen as the original infection. The median number of surgical interventions was two (range, 1e17 interventions). Bactericidal agents were used in 471 cases (77%), including rifampin in 210 episodes. Among the bacteriostatic agents, the most frequent single regimen was clindamycin (n Z 70). The median duration of antibiotic therapy was 51 days (interquartile range, 42e90 d), with a median of 14 days being given intravenously. Total antibiotic duration was similar for the bacteriostatic and bactericidal regimens (median 49 vs. 56 days, respectively; p Z 0.502), as was the median number of surgical interventions (2 vs. 2; p Z 0.929). Overall, there was no difference in the rate of remission of infection between populations receiving bactericidal vs. bacteriostatic agents (85% vs. 80%, p Z 0.221). In multivariate analysis, the use of bactericidal agents was unrelated to remission (odds ratio 1.2, 95% CI 0.7e2.1) (Table 2). Likewise, in stratified multivariate analyses, there was no advantage of bactericidal drugs in increasing remission rates for chronic osteomyelitis (OR 3.8, 95% CI 0.7e20.7), implant-associated infections (OR 0.4, 0.3e1.4), prosthetic