nocardiosis in the south of france during the last ten years

Accepted Manuscript Title: Nocardiosis in south of France during the last ten years Author: Delphine Haussaire Pierre-Edouard Fournier Karamoko Djiguiba Valerie Moal Tristan Legris Rajsingh Purgus Jeremy Bismuth Xavier Elharrar Martine Reynaud-Gaubert Henri Vacher-Coponat PII: DOI: Reference: S1201-9712(17)30008-5 http://dx.doi.org/doi:10.1016/j.ijid.2017.01.005 IJID 2830 To appear in: International Journal of Infectious Diseases Received date: Revised date: Accepted date: 15-9-2016 29-12-2016 5-1-2017 Please cite this article as: Haussaire Delphine, Fournier Pierre-Edouard, Djiguiba Karamoko, Moal Valerie, Legris Tristan, Purgus Rajsingh, Bismuth Jeremy, Elharrar Xavier, Reynaud-Gaubert Martine, Vacher-Coponat Henri.Nocardiosis in south of France during the last ten years.International Journal of Infectious Diseases http://dx.doi.org/10.1016/j.ijid.2017.01.005 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain Nocardiosis in south of France during the last ten years Running head: nocardiosis and clinical forms Delphine Haussaire1*delphaus@aol.com, Pierre-Edouard Fournier2, Karamoko Djiguiba1, Valerie Moal1, Tristan Legris1, Rajsingh Purgus1, Jeremy Bismuth3, Xavier Elharrar4, Martine Reynaud-Gaubert3, Henri Vacher- Coponat1**Henri.VACHERCOPONAT@ap-hm.fr Department of Nephrology, AP-HM, Aix-Marseille University, Hôpital de la Conception 147, boulevard Baille 13385 Marseille cedex 5, France Department of Infectious Diseases, AP-HM, Aix-Marseille University, Hôpital de la Timone, 264 rue Saint-Pierre, 13005 Marseille, France Department of Pneumology and Lung Transplantation, AP-HM, Aix-Marseille University, Hôpital Nord, chemin des Bourrely, 13015 Marseille, France Department of Multidisciplinary Oncology and Therapeutic Innovations - Aix Marseille University, Hôpital Nord, chemin des Bourrely, 13015 Marseille, France * Corresponding autor :Service de Néphrologie, Hôpital de la Conception 147, boulevard Baille 13385 Marseille cedex 5, France, ** Corresponding autor :Service Service de Néphrologie, Hôpital de la Conception 147, boulevard Baille 13385 Marseille cedex 5, France Highlights:  Clinical presentation of nocardiosis depend on immune status and underlying condition  Severe forms in our study all occurring after treatments altering the immune system  In our cohort, 38% of patients required both medical and surgical treatment Abstract Background:Nocardiosisis a raredisease with polymorphic presentations Epidemiology and clinical presentation could change with the increasing number of immunocompromised patients Methods: Medical records and microbiologic data forpatients affected by nocardiosis and treated in the university hospital of Marseille between 2004 and 2014 were retrospectively analyzed Results:We analyzed34 patients infected by Nocardia spp during this period The main underlying conditions were: transplantation (15), malignancy (9), cystic fibrosis (4) and immune disease (3) No immunodeficient condition was observed for patients No AIDS case was observed At diagnosis, 61.8 % had received steroids for over months Four clinical presentations depending on the underlying condition were identified: disseminated forms (50.0%) and visceral isolated forms (26.5%) in severe immunocompromised patients, bonchial forms (14.7%) in patients with chronic lung disease and cutaneous isolated forms (8.8%) in immunocompetent patients N.farcinica was the main observed strain (26.5%) Trimethoprimsulfamethoxazole was prescribed in 68.0% of patients, and 38.0% had surgery.Mortality was 11.7%, concerning patients with disseminated or visceral nocardiosis Conclusion:Clinical presentation and evolution of nocardiosis depend on initial immune status and pulmonary underlying condition Severe forms were all iatrogenic, occurring after treatments altering the immune system Abbreviations AIDS: Acquired Immune Deficiency Syndrome AM: Antimetabolite ANCA: AntiNeutrophil cytoplasmic antibodies AP-HM: Assistance Publique des Hôpitaux de Marseille BAL: Bronchoalveoloar liquid BMT: Bone marrow transplantation CAP CT: Chest, abdomen and pelvis computed tomography CLL: Chronic Lymphocytic Leukemia CNI: Calcineurin Inhibitor CNS: Central Nervous System CRP: C Reactiv Proteine CT: computed tomography GVHD: graft versus host disease HBP: High Blood Pressure HIV: Human Immunodeficiency Virus NHL: Non Hodgkin’s Lymphoma SOT: Solid Organ Transplantation TMP-SFZ: Trimethoprim-Sulfamethoxazole Keywords: nocardiosis, transplantation, cancer, cystic fibrosis, opportunistic infection BACKGROUND Nocardia spp are aerobic actinomycetes distributed worldwide,found in soil, decaying vegetation and water, which may be pathogenic for human beings Their transmission mainly results from inhalation of spores, or direct inoculation Nocardia spp cause localized or invasive infection leading to long-term treatment and surgery and may occasionally be fatal Nocardiosis are usually reported in immunocompromised patients with AIDS, malignancy, solid organ transplantation (SOT), or long-term steroid therapy234.It rarely affects patients without any serious underlying condition56 Nocardia spp can be isolated with standard microbiological culture in various samples like sputum, bronchoalveolar liquid (BAL), abscess, blood culture and then identified by genotypic study Nowadays, up to 80 species of Nocardiasppare known Nocardia asteroides was one of the first predominant strain identified and now corresponds to several complexes: N.abscessus, N.brevicatena/pauciverans, N.cyriacigeorgica, N.farcinica, N.nova, and N.wallacei78 Some series of nocardiosis are described910111213141516but few recent studies investigated nocardiosis epidemiology since improvement in treatment of HIV infection, immune diseases or in the field of transplantation, which could have changed patient characteristics with nocardiosis We reviewed all cases of nocardiosis diagnosed during the past 10 years in Marseille University Hospitals, to study their demographic, clinical, biological and bacteriological characteristics, their treatment and prognosis MATERIALS AND METHODS Retrospectively, we analyzed all cases of nocardiosis identified between 2004 and 2014 in the microbiology laboratory of the university hospital of Marseille (4 hospitals belonging to the Assistance Publique des Hôpitaux de Marseille; AP-HM) Our institution treats more than 120,000 patients per year,for a regional population estimated at 3,398,906 persons in 2014 During this period, 2,229 solid organ transplantations have been performed including 1,144 kidney, 520 liver, 263 adult lung, 236 heart and 11 heart-lung transplantations We collected data from the corresponding medical records using a standardized questionnaire Demographic and underlying conditions analyzed were: gender, date of birth, age at nocardiosis diagnosis, history of cancer, transplantation, immune disease or HIV infection, history of any opportunistic infection (cytomegalovirus disease, aspergillosis, Pneumocystis carinii infection), and history of acute rejection in transplanted patients Treatment at diagnosis was also reported: immunosuppressive drugs, steroids and Trimethoprim-sulfamethoxazole (TMP-SFZ) prophylaxis for Pneumocystis pneumonia Clinical, biological, radiological data at diagnosis and outcomes were recorded: fever, cough, dyspnea, expectoration, pain, confusion, neurological deficit, coma, seizures, C Reactive Protein (CRP) level, complete blood count, T lymphocytes count, source of bacteriological diagnosis, Nocardia spp strain and antibiotics susceptibility, treatment, cure, functional sequellae, recurrence and death Bacteriological study Nocardia spp were cultivated from clinical specimen and all strains were indentified using 16s rRNA by gene polymerase chain reaction The sequences obtained were compared with those stored in GenBank Strains had to have >99% sequence similarity with one species only Sequencing of the Hsp65 gene was also performed to separate similar species, as previously described17 Antibiotic susceptibility was tested by disk diffusion We reported TMP-SFZ and carbapenem susceptibility only, the most commonly used antibiotics when nocardiosis is suspected (7) RESULTS From January 2004 to January 2014, 41 cases were identified in the microbiological laboratory data base Among them, 36 patients had beenhospitalized at AP-HM hospital including 34 patients with available medical records (table 1: general view of the 34 patients with nocardiosis) The data concerning the patients with medical record missing are reported in supplementary material.(TableS1: patients, nocardia strains, source of diagnosis, antibiotic susceptibility) Patient’s characteristics Mean age was 55.4 years (7-94), patients were children aged and years, 70.6 % were males Underlying conditions At diagnosis 61.8% patients were receiving steroids and chemotherapy or calcineurin inhibitor (CNI) or antimetabolite (AM) for over months, 8.8% patients received chemotherapy without other immunosuppressive agent History of allograft was the main underlying condition (44.1%) observed in 14 patients with SOT, mean age 56.1 years (8 kidneys, lungs, liver and heart) and one years old girl with bone marrow transplantation (BMT) performed for an acute lymphocytic leukemia All received an immunosuppressive regimen: 11 triple therapy including a CNI, AM and steroids; regimens with CNI and steroids An episode of acute rejection was reported in 28.0% patients before nocardiosis diagnosis and opportunistic disease in 35.7% No patient had TMP-SFZ prophylaxis at diagnosis.Mean delay between transplantation and nocardiosis diagnosis was 17.5 months (2 to 34 months) with 9.4 months after lung transplantation; 16.5 months after renal transplantation The incidence of nocardiosis was 15.2/1000 lung transplantations (4/263), 7/1000 kidney transplantations (8/1144), 4.2/1000 heart transplantations (1/236), 2/1000 liver transplantations (1/520) (See table S2 in supplementary material) A history of malignancy was observed in patients (mean age 73.7 years): solid cancer in (carcinoma of the ampulla of Vater and anal cancer with surgical treatment, metastatic breast cancer, one patient with solid cancers (glioblastoma and non small cell lung cancer), haemopathy in patients (Waldenstrom disease, non Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia (CLL), dysmyelopoietic syndrome) The last one had a haemopathy and a solid cancer (rectal adenocarcinoma and NHL) At diagnosis patients received chemotherapy, of them with steroids, one only received steroids An immune disease was observed in patients (58, 63, and 71 years old) They had respectively lymphopenia with IgG1 and IgG4 deficit, seborrheic pemphigus treated by steroids, and glomerulonephritis with ANCA treated by AM and steroids Cystic fibrosis without transplantation was observed in patients, mean age 16.5 years Three patients aged 74, 76 and 94 years were immunocompetent All of them had high blood pressure (HBP), one had diabetes Monovisceral form was the second most common clinical presentation in patients Seven of them were immunocompromised: had lung transplantation, haemopathy, one solid cancer and one livertransplantation Cystic fibrosis was observed in one patient, and one was a 76 years old man with HBP only Lung localization was observed in patients, were explored with CAP CT associated with head CT in patients, and one with chest and head CT Localized brain nocardiosis was observed in patients with haemopathy, explored only with head CT and head MRI, without blood culture Mean duration of antibiotic therapy was 13.6 weeks (2-24).Two patients had surgery for brain abscess A cure was obtained in patients without sequellae (77.8%), patients (22.2%) died from sepsis (one liver and one lung transplant from multibacterial pneumoniae with Nocardia spp) A recurrence during the next 24 months was observed in one patient with cystic fibrosis Bronchial form (14.7%) Bronchial form was defined by poor respiratory symptoms, positive sputum for Nocardiaspp, without radiological evidence of pneumonia It was observed in patients All patients had a chronic lung disease: cystic fibrosis (n=3), lung transplantation (n=1), and one BMT complicated with GVHD and bronchiolitis obliterans (n=1) Chest X-ray was performed in patients including one with a chest CT; one patienthad no radiological exploration N.cyriacygeorgica was the main strain (60%).Nocardia spp was always isolated in sputum and was associated with one or more other pathogens for patients; Staphylococcus aureus (n=3), Pseudomonas aeruginosa (n=2), Acromobacter xiloxidans (n=1), and Stenotrophomonas maltophila (n=1) Mean duration of antibiotic therapy was 5.5 weeks (2-12), shorter than in disseminated or monovisceral nocardiosis All were cured, with recurrence in the next 24 months Cutaneous form: (8.8%) An isolated cutaneous localization was observed in patients The mean age was 84.2 years One patient had a history of carcinoma of the ampulla of Vater only treated with surgery, had HBP including one with diabetes CAP CT was performed for patients associated with cervical CT for one, and only arm X-ray for one patient N brasiliensis was isolated from abscess in cases.Mean duration of antibiotic therapy was weeks (2-12), had surgery.All were cured without sequellae DISCUSSION Our study is one of the largest recent series of nocardiosis in a European country, which provides an overview of this infection over the past decade (table 4: review of largest series with more than 30 cases of nocardiosis from 1990 to 2014) Nocardiosis remains a severe disease, with 11.7% of related mortality, less than previously reported in Spain (21.6%)12, in Thailand (20%)10, or in China in a cohort of pulmonary nocardiosis (18.7%)18 Underlying conditions determine bacteriological dissemination Steroid therapy is often regarded as a risk factor for nocardiosis192021 In our study 61.8% patients received a steroid therapy, mainlyfor a cancer or transplantation.The incidence reported in transplant recipients varies between 0.7 and 3.5%2 In our study, transplantationwas the first underlying condition, 41.0% of the cohort, close to the 26.1% observed in occidental countries12 They mainly suffered from disseminated form This high rate of invasive nocardiosis in transplant recipients may be explained by a profound immunodeficiency All patients received steroids and at least CNI, patients were undergoing their 2nd kidney transplantation, 28.6% of patients had been previously treated for acute rejection and 35.7% had already had an opportunistic disease In literature high doses of CNI and a history of cytomegalovirus disease have been described as risk factor for nocardiosis in transplantation22 We identified clinical forms The disseminated form was the first clinical presentation (50%), more than previously reported; 13.5% in Spain12, 11.4% in Thailand10, 6% in Taiwan23, or 36% in Israël13 This difference may be related to the systematic radiological strategy, allowing toidentify more patients with disseminated disease, or related to the high rate of immunocompromised patients in our cohort Disseminated form was always observed in immunocompromised patients, mainly drug related: steroid therapy or anti-rejection therapy for organ transplantation, or after chemotherapy for a solid cancer Most of these patients received an extensive radiological examination compared to the monovisceral form in our study According to the infection pathway, lung was the first localization, then brain, but many other organs could be infected, such as liver or thyroid As recommended, a long-term antibiotherapy was prescribed, withoutrecurrence and a relative low rate of mortality, occurring mainly during the first weeks following the diagnosis Visceral form was the second clinical presentation Lung nocardiosis was observed mainly in patients with chronic lung disease and/or with immunosuppressive condition (lung transplantation recipients and one liver transplantation recipient or cystic fibrosis), and in one elderly patient without any serious underlying condition Most patients with lung infection were explored by CAP and head CT scanner On the contrary, the patients with localized brain infection were not investigated for other visceral localizations, and we cannot exclude a disseminated form Indeed, the other patientswith cerebral localizations were explored by total body scanner and had a disseminated form In the literature, several cases of isolated brain abscess are reported but often with poor information about radiological staging242526.Strategy for radiological staging was unfortunately heterogeneous depending on the medical staff In visceral nocardiosis especially in immunocompromised patient, a systematic examination with blood cultures, CAP and head CT scanner should be performed Isolated cutaneous forms were always observed in elderly patients without serious medical condition, occurring probably after a skin injury and were locally contained This clinical form was mainly reported in Asia, in Thailand10, Taiwan27, and in China19 Isolated bronchial forms, defined by respiratory symptoms without radiologic lesion, were all observed in patients with chronic lung disease, mainly in cystic fibrosis, but also in lung transplantation, or bronchiolitis obliterans Multiple other bacterial species are associated with Nocardiasuch as Pseudomonas aeruginosa or Staphyloccocus aureus In cystic fibrosis patients, the same Nocardia spp strain was found in successive samples, suggesting colonization, and the same happened with the patient with cystic fibrosis who had lung visceral form Nocardia spp pathogenic role in patients with chronic lung disease remains unclear Nocardia spp had already been reported in respiratory tract of patients with chronic lung disease like cystic fibrosis or bronchiectasies, with evidence of infection only in 62.5% of cases28 Actually, in patients colonized by Nocardia spp without pulmonary lesion, there is no evidence of improved outcome with antibiotherapy29 All patients in our study received antibiotics active on Nocardia spp and others pathogens isolated in the sputum Duration of treatment is not codified, and varies from weeks to months, as reported by Veronica Rodriguez-Nava et al with good prognosis30.In bronchial form, in patients with chronic lung disease, chest radiological exams seem sufficient We did not report any case of patient with AIDS, probably because of the improvement in antiretroviral therapy, as observed in a recent study in Israel13 Most species had been identified, thanks to molecular technics being systematically applied N.farcinica, N.abscessus, N.cyriacigeorgica, and N.nova, the first species found in our patients, are known to be responsible for the majority of human nocardia infections They are all part of the old Nocardia asteroids complex 8N.brasiliensis was more represented in isolated cutaneous infections, as previously observed by W.L LIU et al in Taiwan23 In recent studies, between 75% and 89% of Nocardia.spp were sensitive to TMPSFZ111221 In our study 59.25% of Nocardia spp were sensitive to TMP-SFZ and 95.6% to carbapenem Recent studies in the United States reported only 2% of sulfonamide resistance in Nocardia spp, reviewing susceptibilities of large series of Nocardia spp isolates They previously suggested increasing in vitro sulfonamide resistance in Nocardia spp could actually be due to difficulties in laboratory interpretation of TMP-SFZ susceptibility3132.Our high resistance degree to TMP-SFZ can be technique related in part, or may be explained by new found resistance after previous sulfonamide antibiotherapy, as recommended in the first month after transplantation In addition, antibiograms for TMP-SFZ were missing in cases over the 34, which could haveartificially underestimated TMP-SFZ susceptibility None were receiving TMP-SFZ prophylaxis at diagnosis TMP-SFZ had sometimes been considered as a prophylactic treatment for nocardiosis,but since several cases of nocardiosis were reported despiteTMP-SFZ prophylaxis in transplantation,this hypothesis doesn’t hold true912 Combination therapy with carbapenem and TMP-SFZ is recommended if invasive nocardiosis is suspected, as in vitro synergism has been demonstrated between carbapenem and TMP-SFZ Amikacin in addition to carbapenem, and linezolid are also effective and can be used in severe infection313334.Duration of treatment depends on the severity of context, clinical form and immunosuppressive condition For visceral and disseminated forms, a treatment lasting from to 12 months is largely prescribed133536 CONCLUSION Nocardiosis remains a severe infectious disease, occasionally fatal, with risk of functional sequellea, especially after brain involvement Nocardiosis management often requires a medical and surgical treatment and a long term therapy and followup Our study has several limits but reveals the large panel of clinical presentations of nocardiosis in our area, and the impact of the main underlying conditions Transplant recipients, patients with malignancy, with long term steroids therapy, or with chronic lung disease are the first concerned Epidemiology and treatment of nocardiosis are evolving, requiring further studies A systematic radiologic evaluation could improve the description of clinical forms and the adapted treatment Potential conflicts of interest The authors declare that they have no competing interests Acknowledgements The authors gratefully thank L.Boiron and F.Bourriche who provided english medical writing services, Brice Chanez, Maite Meunier for their help in data collection Funding information This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors REFERENCES Provost F, Laurent F, Blanc MV, Boiron P Transmission of nocardiosis and molecular typing of Nocardia species: a short review Eur J Epidemiol 1997;13(2):235–8 Clark NM, Reid GE, AST Infectious Diseases Community of Practice Nocardia infections in solid organ transplantation Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2013;13 Suppl 4:83–92 Doi: 10.1111/ajt.12102 Javaly K, Horowitz HW, Wormser GP Nocardiosis in patients with human immunodeficiency virus infection Report of cases and review of the literature Medicine (Baltimore) 1992;71(3):128–38 Beaman BL, Beaman L Nocardia species: host-parasite relationships Clin Microbiol Rev 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Welsh Oliverio, Said-Fernández Salvador, Lozano-Garza Gerardo, TavarezAlejandro Roman Erick, Vera-Cabrera Lucio In vitro and in vivo activities of antimicrobials against Nocardia brasiliensis Antimicrob Agents Chemother 2004;48(3):832–7 34 Moylett Edina H, Pacheco Susan E, Brown-Elliott Barbara A, Perry Tracy R, Buescher E Stephen, Birmingham Mary C, et al Clinical experience with linezolid for the treatment of nocardia infection Clin Infect Dis Off Publ Infect Dis Soc Am 2003;36(3):313–8 Doi: 10.1086/345907 35 Peraira JR, Segovia J, Fuentes R, Jiménez-Mazuecos J, Arroyo R, Fuertes B, et al Pulmonary nocardiosis in heart transplant recipients: treatment and outcome Transplant Proc 2003;35(5):2006–8 36 Wilson JP, Turner HR, Kirchner KA, Chapman SW Nocardial infections in renal transplant recipients Medicine (Baltimore) 1989;68(1):38–57 Table 1: general view of the 34 patients with nocardiosis from 2004 to 2014 year Age/ of diagno sis 2013 16/m 2013 9/f 2013 40/f 2013 main underlying condition sex immunosuppressi ve imagery Treatment Clinical form : Nocardia treatment Involved organs, bacteriemia strain / duration (weeks)/surgery outcomes cystic fibrosis bone marrow graft+bronchio litis obliterans SOT: lung (2011) no CNI, steroids/chemoth erapy CXR bronchial transvalensis CPF, colymicin (4) recurrence CXR bronchial nova ceftriaxone (2) cured CNI, AM, steroids T CT bronchial SFX-TMP, CBP, amoxicillin cured 24/m cystic fibrosis no No bronchial SFX-TMP (12) recurrence 2013 7/f cystic fibrosis no CXR bronchial cyriacigeorgic a cyriacigeorgic a cyriacigeorgic a 2010 74/m HBP, diabetes no CAP and cervical CT cutaneous tissue farcinica 2008 2010 94/f 83/m HBP Carcinoma of no no CAPh CT CXR cutaneous tissue cutaneous tissue brasiliensis brasiliensis SFX-TMP, colymicin (4) Ofloxacine, amoxicillineclavulanic acid (2)/surg doxycycline(12) SFX-TMP, Cured cured cured cured ampulloma of vater amoxicillin+ clavulanic acid/surg CNI, AM, Steroid CAPh CT D: lung, brain, bones cutaneous tissue, bacteriemia farcinica CBP, VC, AK(24) cured 88/m rectal cancer+ NHL chemotherapy abdomi nal US, h CT CXR D: bacteriemia farcinica SFXTMP,ceftriaxone, AK(28) cured 2008 57/m SOT: heart (2006) CNI, steroids CAPh CT D: brain, lung, arthritis abscessus 2013 76/m CLL chemotherapy CXR D: lung, bacteriemia nova 2004 63/m seborrheic pemphigus steroids CAPh CT D: lung, brain asiatica 2011 58/m IgG1 and IgG4 deficit no CAPh CT, b MRI D: lung, brain wallacei 2012 64/m AM, steroids CAPh CT D: lung, brain cyriacigeorgic a 2007 81/m steroids CAPh CT 2008 35/m 2007 57/m 2009 50/m 2013 69/f 73/m SOT: kidney (2004) 2007 2004 glomerulonep hritis ANCA Dysmyelopoeit ic syndrome SOT: kidney (2007) SOT: kidney (2007) SOT: kidney (2008) breast metastatic cancer CNI, AM, Steroids CNI/steroids CNI, AM, Steroids chemotherapy D: lung, brain, bacteriemia D: lung, kidney, pancreas, surrenal CAPh CT glands, bacteriemia D: lung, liver, CAPh CT kidney D: lung, cutaneous CAPh CT tissue, bacteriemia D: lung, CAP CT scutaneous tissue, bacteriemia CNI, AM, Steroids CAPh CT, hMRI, PET CT 2012 57/m SOT kidney (2012) 2010 46/f SOT: kidney (2008) CNI, AM, Steroids CAPh CT 2011 60/m SOT kidney (2011) CNI, AM, Steroids CAPh CT 2007 57/m Glioblastoma + lung cancer(2) steroids/chemoth erapy CAP CT 2004 54/m SOT: kidney (2002) CNI, AM, streroids 2005 70/f Waldenstrom disease steroid/chemothe rapy 2008 66/m NHL Steroids/chemoth erapy 2007 56/m 2009 51/m 2009 74/m 2010 2010 SOT: lung (2005) SOT: liver (2009) CAPh CT, hMRI CXR,h CT, hMRI CXR,h CT, hMRI unknown SFX-TMP, CBP( 56)/surg SFX-TMP, ticarcillin, pyostacin, cefotaxim(2) SFX-TMP, CBP, cefotaxim (32)/surg SFX-TMP, ceftriaxone, AK, izilox (52)/surg SFX-TMP, CBP/surg cefotaxim, CPF,MNZ (1) cured death-NR neurological sequellae neurological sequellae neurological sequellae death-R farcinica SFX-TMP, CBP, AK (56) hypoaccousi a abcessus SFX-TMP, CBP (36)/surg cured farcinica CPF, CBP (12) cured farcinica ceftriaxone, AK death-R farcinica SFX-TMP, CBP, CPF (28) cured abscessus SFX-TMP, CBP (24)/surg cured neocaledonie nsis SFX-TMP, CBP/surg recurrent laryngeal paralysis D:bacteriemia farcinica SFX-TMP, CBP (4)/surg death-NR D:lung and brain nova CBP, VC(8)/surg cured brain nova cefotaxim, CBP,VC, SFX-TMP, MNZ/surg cured brain abscessus SFX-TMP, CBP/surg death-NR D: lung, cutaneous tissue,bacteriemia D: lung, cutanous tissue D: lung, thyroid gland, arthritis, cutanous tissue CNI,AM, steroids CAP CT lung abscessus CNI, AM, steroids CAP CT lung cyriacigeorgic a SFX-TMP, CBP, gentamycin (2) SFXTMP, CBP, ofloxacin(3) Anal cancer no CAPh CT; PET CT lung abscessus SFX-TMP,CBP (24) cured 19/m cystic fibrosis no CAP CT lung farcinica CBP, mynocin, linezolid( 12) reccurence 76/f HBP no CAPh CT lung cyriacigeorgic a SFX-TMP (24) cured death-R death-R SFX-TMP, cured amoxicilline (24) CBP, amoxicilline SOT: lung 2013 25/f CNI, AM, Steroids lung wallacei and clavulanic Cured Th CT (2013) acid (16) Abbreviations:IS: immunosuppressive treatment , D: disseminated disease, SOT: solid organ transplant, NHL: non hodgkin’s lymphoma; surg: surgery; death-R: death-related to nocardiosis , NR death: non related death to nocardiosis , CNI:calcineurin inhibitor, AM :antimetabolite , AK : amikacine, TMP-SFZ: trimethoprim-sulfamethoxazole, VC vancomycine , CPF ciprofloxacine CBP: carbapenem; MNZ: metronidazole, CXR: chest X ray, CAP CT : chest, abdomen and pelvic computed tomography scan, h CT:head computed tomography scan , PET CT: positon emission tomography computed tomography scan, hRMI: head resonance magnetic imagery 2011 55/f SOT lung (2011) CNI, AM, steroids Th CT lung cyriacigeorgic a Table 2: microbiological characteristics population n=34 source of diagnosis Findings n (%) sputum (23.5) BAL blood culture (26.5) (26.5) abcess lymphatic nodd 14 (41.2) 1(20.5) Nocardia spp strains N.farcinica N.cyriacigeorgica N.abcessus N.nova N.wallacei N.brasiliensis N.asiatica N.neocaledoniensis N.transvalensis N takediensis N.carnea N.spp 9(26.5) (20.6) (17.6) (11.7) (5.9) (5.9) (2.9) (2.9) (2.9) 0 1(2.9) Antibiotic susceptibility (%) TMP-SFZ (n=26)* 61.2 carbapenem (n=23)** 95.6 *susceptibility calculated with over the 26 available antibiograms for TMP-SFZ ** susceptibility calculated with over the 23 available antibiograms for carbapenem BAL: bronchoalveolar lavage, TMP-SFZ: trimethoprim- sulfamethoxazole Table 3: characteristics of patients according to clinical form Parameters mean age (years) underlying condition SOT BMT malignancy :Solid cancer /haemopathy General n (%) 55.4 Disseminated form : 17 pts n (%) 61.5 (60-88) Visceral form : pts n (%) 52.5 (25-76) Cutaneous form : pts n (%) 84.2 (74-94) Bronchial form : pts n (%) 19.2 (7-40) 14 (41.2) (2.9) (26.5) 9(53) 5(29.4) 4(44,4) 3(33.3) 0 1(33.3) 1(20) 1(20) cystic fibrosis (11.7) 1(11.1) 3(60) immune disease (8.8) 3(17.6) 0 HBP 1(11.1) 1(33.3) HBP and diabete (2.9) 0 (33.3) immunosuppressive drugs Steroids 21 (61.8) 13 (76.5) 7(77.7) 1(20) CNI / antimetabolites 16 (47) 10(59) 4(44.4) 2(40) chemotherapy (20.6) 4(23.5) 2(22.2) 1(20) symptoms fever 21 (61.8) 15(88.2) (37.5) 2(66.6) (40) dyspnea (26.5) (35.3) (37.5) 0 cough 12 (35.3) 4(23.5) (37.5) (80) Neurological 11 (32.3) 8(47) (22.2) 0 deficit/confusion biology CRP (mg/L) 121 152 (53-323) 89 (3-200) 143 (63-223) 20 (8-32) leucocytes(G/L) 12.75 14.9 (2.75-24) 13.4 (7.4-30.8) 12.4 (7.9-19) 7.6 (6.4-9) main Nocardia spp strain N.farcinica N.farcinica N.abcessus N.brasiliensis N.cyriacigeorgica treatment hospitalization 30 (88.2) 17(100) 9(100) 2(66.6) 2(40) intensive care unit (26.5) 6(35) 3(33.3) 0 TMP-SFZ with other (23.5) 3(17.6) 2(22.2) 1(33.3) 2(40) antibiotics carbapenem with other (14.7) 3(17.6) 2(22.2) 0 antibiotics TMP-SFZ+carbapenem 15 (44) 9(53) 5(55.5) 1(20) mean duration of treatment 19 34 (8 -56)* 20 (12-24)* (2 -12) 7.6 (2-16) (weeks) surgery 13(38.2) 9(53) 2(22.2) 2(66.6) evolution death with nocardiosis (11.7) 2(11.7) 2(22.2) 0 cure without sequellae 27 (79.4) 10(58.8) 7(77.7) 3(100) 5(100) recurrence (8.8) (11.1) 2(40) sequellae (14.7) 5(29.4) 0 *Excluding patients who died the first month after diagnosis pts: patients, BMT: bone marrow transplantation, SOT: solid organ transplant, HBP: high blood pressure, CNI: calcineurin inhibitor, CRP: C reactive protein, TMP-SFZ: trimethoprim-sulfamethoxazole Table 4: review of largest series with more than 30 cases of nocardiosis from 1990 to 2014 refere nce count ry years No of patie nts underlying conditions Austra lia [5] (1995 2000) 35 Thaila nd [10] (1996 - 70 15 pulmonary diseases, neoplasia, SOT, AI diseases, healthy, 1HIV, 1tb 24 HIV, 12 AI diseases, neoplasia, Patie nts with steroi ds at diagn osis (%) 60 24.3 predomina nt Nocardia strain TMP-SFZ suscepti bility (%) dissemin ated nocardio sis (%) isolated lung nocardiosis (bronchial/pul monary disease) (%) isolate d brain nocardi osis (%) isolate d cutane ous nocardi osis (%) Relat ed deat h (%) N.asteroide s (60%) NR 10 NR NR NR 31 NR 42.1 11.4 44.3 22,8 20 2001) USA [22] 11 (1995 2005) 18 (1988 2006) 35 Spain [12] 12 (1995 2006) 37 Saudi Arabia [14] (1998 2006) 30 Spain [15] 12 (1997 2009) 30 Taiwa n [23] 12 (1998 2010) 100 israel [13] (1996 2011) 39 japon [18] 13(19 99- 59 Taiwa n [23] 81 DM, nephrotic syndroms, chronic renal failure, pulmonary diseases, mitral stenosis, Tb SOT 11 chronic lung diseases, DM, neoplasia, AI diseases, SOT, HIV 10 HIV, SOT, AI diseases, COPD, neoplasia 13 COPD, tb, bronchiectas ies, DM, SOT, chronic lung disease, neoplasia, 30 COPD with 12 HBP, dyslipidemia , neoplasia, chronic kidney failure, DM, chronic liver disease 19 neoplasia, 12 chronic kidney diseases, 10 DM, 11 chronic liver diseases, 10 chronic lung diseases, SOT, AI diseases, HIV neoplasia, connective tissue disease, chronic lung disease, BMT, HBP, DM, smoker, ischemic heart disease 13 COPD, 12 lung 100 N.nova 94.3 20 77,2 2.8 14 30 N.brasiliens is (57%) 94 16 29.6 54.3 14 62.2 N.cyriacige orgica (32 %) 89.2 16.2 70 2.7 5.4 22 6.6 NR NR 20 80 0 10 51.5 N.cyriacige orgica (56.7%) NR 3.3 96.6 0 33 17 N.brasiliens is (50%) NR 26 55 69.23 NR 75 36 NR 13 NR 32 1.2 N.asteroide s (68%) 73 1.2 98.8 0 NR 2012) neoplasia, chronic lung diseases, 20 histories of mycobacteri a pneumoniae , 11 pneumonoc oniosis, aspergillosis, CV disease, DM, AI diseases, chronic liver disease, kidney failure China 13 40 13 DM, AI 50 NR NR 30 60 10 [19] (2000 diseases, chronic lung 2013) diseases, SOT, chronic kidney diseases, histories of skin injury, HIV, none Franc 10 34 14 SOT, 61,7 N.farcinica 59 50 35.3 5.9 8,8 e (2004 neoplasia, (26.5%) (prese CF, AI nt 2014) diseases,2 study) HBP,1 BMT with chronic lung disease, DM Abbreviations: SOT: solid organ transplant, AI diseases: autoimmune diseases, HIV: human immunodeficiency virus, Tb: history of tuberculosis, DM: diabetes mellitus, HBP: high blood pressure, BMT: bone marrow transplantation, NR: non reported 15 12 ... during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain Nocardiosis in south of France during the last ten. .. providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during. .. reported in Spain (21.6%)12, in Thailand (20%)10, or in China in a cohort of pulmonary nocardiosis (18.7%)18 Underlying conditions determine bacteriological dissemination Steroid therapy is often