Multi-year Population-Based Study of the Clinical and Epidemiological Risk Factors for Mortality in Nocardiosis: Survival Analysis from a Large Regional Canadian Healthcare Region

Multi-year Population-Based Study of the Clinical and Epidemiological Risk Factors for Mortality in Nocardiosis: Survival Analysis from a Large Regional Canadian Healthcare Region | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Multi-year Population-Based Study of the Clinical and Epidemiological Risk Factors for Mortality in Nocardiosis: Survival Analysis from a Large Regional Canadian Healthcare Region Deirdre Church, Alejandra Ugarte-Torres, Christopher Naugler This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6985944/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Feb, 2026 Read the published version in BMC Infectious Diseases → Version 1 posted 10 You are reading this latest preprint version Abstract BACKGROUND Nocardiae are ubiquitous environmental soil pathogens that primarily cause invasive infections by inhalation or direct skin inoculation in immunocompromised patients. This multi-year population-based study compared epidemiological and clinical features of all cases diagnosed in our region. METHODS Patients were enrolled in our large integrated healthcare region with culture-proven nocardiosis between 2010–2022. Clinical chart reviews were conducted to determine the clinical manifestations, risk factors, treatment and mortality including survival analysis. RESULTS Ninety-four adults had a mean age of 61 ± 17 yrs. More cases occurred in males (57%) than females (43%). Ninety-six percent of cases had underlying co-morbidities including diabetes, liver or renal failure, malignancy, transplant recipients, chronic lung disease, rheumatologic disease, or other inflammatory conditions. Pulmonary (53%) or skin and soft tissue infections (SSTIs) (30%) commonly occurred with infrequent diagnoses of central nervous system infection (CNS) (7%), bloodstream infection (BSI) (6%), and septic arthritis or intra-abdominal infection (IAI) (6%). Diverse Nocardia spp. were isolated, but 3 species complexes caused most cases [56/94 (60%)] including Nocardia farcinica (n = 21, 22.3%), Nocardia cyriacigeorgica (n = 16, 17%) and Nocardia nova (n = 19, 20.2%). Clinical presentation was not unique for individual Nocardia spp. infections. Overall mortality was 22.3% with a 1-year mortality of 12.2%. Delayed diagnosis (≥ 30 d) from symptom onset had higher mortality. Increased mortality occurred for N. nova > N. cyriacigeorgica > N. farcinica complex infections. CONCLUSIONS Prompt diagnosis of nocardiosis improves patient outcomes. Nocardia species-level identification predicts mortality for major species complexes causing nocardiosis in our region. Nocardia population-based epidemiology invasive infection pulmonary infection skin and soft tissue infection central nervous system infection bloodstream infection mortality survival Figures Figure 1 Figure 2 Figure 3 Figure 4 Importance The role of specific Nocardia species in human infections continues to expand as advanced methods enable better species complex and individual species identification. A multi-year population-based study (2010-2022) of nocardiosis amongst ninety-four adult patients with a mean age of 61 ± 17 yrs.; more cases occurred in males (57%). Most patients (96%) had one or more serious underlying co-morbidities. Cases mostly had pulmonary (53%) or skin and soft tissue infections (30%). Most cases [56/94 (60%)] were due to 3 species complexes Nocardia farcinica (n=21, 22.3%), Nocardia cyriacigeorgica (n=16, 17%) and Nocardia nova (n=19, 20.2%). Two-thirds of cases had appropriate initial therapy. Overall mortality was 22.3% with a 1-year mortality of 12.2% but delayed diagnosis (≥ 30 d) had a higher mortality. Survival analysis for infection showed mortality for N. nova < N. cyriacigeorgica < N. farcinica complex. Accurate identification of Nocardia spp. improves antibiotic management and may predict mortality. Background Nocardiae are part of the aerobic actinomycetes belonging to the class Actinobacteria in the order Corynbacteriales along with other clinically important genera including Corynebacterium and Mycobacterium ( 1 , 2 ). They are soil pathogens that are emerging as uncommon causes of invasive infections, primarily pulmonary, central nervous system (CNS), bloodstream (BSI) and skin and soft tissue infections (SSTIs) ( 1 – 3 ). The main routes of infection in humans are inhalation and direct inoculation of the skin ( 1 – 3 ). Although immunocompetent people may acquire nocardiosis, prior studies have documented that > 80% of patients are immunocompromised ( 4 – 14 ). The main underlying immunosuppressive conditions included solid organ or haematologic malignancy, solid organ, and hematopoietic stem cell transplantation, underlying inflammatory condition, and/or treatment with high dose corticosteroids or other T-cell immunosuppressing agents ( 5 , 8 , 9 , 12 , 14 – 16 )., Few population-based studies have yet been done ( 4 , 13 , 17 ), although prior studies were reported from a large referral healthcare system (i.e., Mayo Clinic) or tertiary hospitals. Our large regional centralized laboratory used advanced methods (i.e., fast partial sequencing of the 16S rRNA gene (V1 to V3 region) since 2009 and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) since 2018 for routine identification of Nocardia spp. ( 18 ). The regional microbiology database stored all laboratory confirmed nocardiosis cases with isolation of Nocardia spp. from at least one clinical specimen culture. Although rare, use of these advanced identification methods allowed diagnosis of increasing numbers of invasive infections in our region. Since few population-based studies have been done worldwide, so we performed a multiyear clinical and epidemiological analysis of the > 94 cases between 2010 and 2022. We sought to compare risk factors, clinical manifestations, treatment, and mortality in our multi-year retrospective population-based study. It was of interest to define the population-based prevalence of nocardiosis in our large integrated healthcare region and determine if there was any association between different Nocardia spp. and mortality. Materials and Methods Study Population : We conducted a retrospective population-based cohort study of all cases diagnosed with nocardiosis in the Alberta Health Services, Calgary Zone, from January 2010 through December 2022. The Calgary Zone provides medical and surgical care to the residents of Calgary and the surrounding area, covering a population of 1.6 million in Southern Alberta, Canada. Alberta Precision Laboratories (APL), Diagnostic & Scientific Centre (APL-DSC) (formerly Calgary Laboratory Services) is the central regional laboratory that serves the Calgary Zone. Clinical Data Collection : Nocardiosis was culture confirmed by growing Nocardia spp. from at least one clinical specimen submitted for analysis to the APL-DSC clinical microbiology laboratory. Basic demographic data such as patient age and sex, infectious diagnosis, underlying comorbidities and 1-year mortality were determined through a retrospective chart review of most patients’ electronic medical records by two of the investigators (AUT and DLC). All clinical diagnoses and the site(s) of nocardiosis infection were determined as clinician-defined from the problem list by a detailed clinical chart review. Community acquired (CA) had the first positive culture obtained < 72 hours after hospital admission or ≥ 72 hours after discharge. Hospital-acquired (HA) infections occurred when the first positive culture was ≥ 72 hours after hospital admission or < 72 hours after discharge. Disseminated nocardial infection was the presence of two different sites of concurrent infection or by the presence of BSI. Charlson comorbidity index (CCI) assessed illness severity ( 19 ). Nocardia spp. Bloodstream infection (BSI) occurred when one or more sets of blood culture bottles isolated Nocardia spp. Appropriate empiric antimicrobial therapy occurred when one or more antibiotics were prescribed that would be effective based on the Nocardia isolates reported antimicrobial susceptibility profile. Primary outcome was 1-year mortality according to the type of invasive Nocardia infection and specific Nocardia spp. for those that were most commonly isolates; secondary outcomes included survival according to the site/source of infection (i.e., pulmonary, or skin and soft tissue with and without dissemination), illness severity, and the choice of appropriate initial empiric antibiotic therapy. Microbiology Methods : We have previously reported the microbiological methods used for Nocardia spp. identification and strain characterization with a brief overview provided herein ( 20 ). Isolates grew aerobically on sheep blood agar (BA) and/or specialized growth media [(i.e., buffered charcoal yeast extract (BCYE)]. Gram stain demonstrated typical Gram-positive beaded branching bacilli that were catalase positive and modified acid fast positive but Ziehl-Neilsen stain negative. Isolate matrix-assisted laser desorption ionization – time of flight mass spectrometry (MALDI-TOF MS) (VITEK MS, bioMérieux, Laval, Que. Canada) analysis was done after isolate extraction ( 21 ) using the instrument’s most current database in accordance with the manufacturers’ instructions. Molecular identification occurred by fast PCR/fast cycle sequencing of the 16S rRNA gene (523 bp) with MicroSeq 500 kits and an ABI Prism 3500 XL sequencer (Applied Biosystems, Thermo Fisher Scientific, Foster City, CA USA) using standard methods previously described ( 18 ). Following bacterial sequence multi-alignment against a reference sequence, a BLAST search using the SmartGene Integrated Database Network System (IDNS) (Lausanne, Switzerland) bacterial database indicated the most closely related species complex or species ( http://www.Smartgene.com ) with an identify score of 99.9% (i.e., 0–2 base mismatches) according to interpretive criteria for targeted DMA sequencing analyses published by the Clinical and Laboratory Standards Institute (CLSI), Approved Guideline MM-18 ( 22 ). Statistical Analyses : Population based incidence rate calculations were based on Calgary region census data from 2010 and 2016. Categorical data was expressed as total numbers or percentages and compared using χ2 tests; continuous data were expressed as medians with interquartile ranges (IQRs) and compared using rank-sum test. A univariate analysis determined risk factors associated with 30-day mortality. A logistic regression model included all significant variables (P ≤ .05). Results were reported as odds ratios (ORs) with 95% confidence intervals. Statistical significance was a P-value ≤ .05 for all comparisons. One-year, all-cause mortality for the entire database of ninety-four cases as well as individually for the three most common species complexes ( N. cyriacigeorgica ; n = 16, N. farcinica ; n = 19, and N. nova ; n = 16) used Cox proportional hazards regression models including age, CCS ( 19 ), and sex. Statistical analysis used IBM SPSS Statistics version 29 software (IBM Corp. Released 2023. IBM SPSS Statistics for Windows, Version 29.0.2.0 Armonk, NY: IBM Corp). Results Population-based incidence: Figure 1 shows the nocardiosis cases diagnosed within each year. A total of 6 ± 0.5 cases per year occurred from 2010-2015 while 10 cases ± 0.5 cases were diagnosed in the later half of the study yielding yearly incidence rates of 0.0006% vs 0.0008%, respectively. There is an upwards trend in the regional incidence rate (IRR) from 0.6 per 100,000 populaces in 2010 to 0.8 per 100,000 populaces by 2016. Patient demographics and clinical characteristics: Ninety-four unique patients with nocardiosis were studied but electronic medical records were not available for three ambulatory patients. Ninety-one unique cases were analyzed. Most invasive nocardiosis (n=78/91, 86%) cases occurred in hospitalized patients. Table 1 outlines the demographics, underlying co-morbidities and overall mortality of the hospitalized nocardiosis cases. All patients were adults with a mean age of 61 ± 17 yrs. More patients were male (57%) than female (43%) but there was no age difference based on sex. Underlying co-morbidities were present in 96% of cases including diabetes, liver or renal failure, malignancy, transplant recipients, chronic lung disease, rheumatologic diseases, or other inflammatory conditions ( Table 1 ). Chronic lung diseases (n=19) included cystic fibrosis (n=8, 39%), bronchiectasis (n=18, 100%), pulmonary fibrosis (n=6, 33%), chronic obstructive pulmonary disease (n=7, 39%) and asthma (n=6, 33%). Active malignancies included acute myelogenous leukemia or chronic lymphocytic leukemia (n=2, 11%), various types of lymphoma (n=2, 11%) and solid organ tumours (n=13, 72%) [ (i.e., breast (n=5, 28%), lung (n=3, 17%), brain (n=2, 11%), gastrointestinal (N=2, 11%) and ureteral (n=1, 6%]). Transplanted organs most commonly were kidney (n=3, 37%), lung (n=2, 18%), pancreas (n=1, 1%), liver (n=1, 1%) and haematopoietic stem calls (HSCT) (n=3, 27%). Overall mortality was 23.7% with a 1-year mortality of 12.2% with those having disseminated disease, and those most likely to die had documented CNS disease. Pulmonary (53%) or SSTIs (30%) with less frequent diagnoses of central nervous system infections (7%), bloodstream infections (6%) and septic arthritis and intra-abdominal infections (6%). Three patients had both pulmonary and SSTI. All Nocardia BSIs originated from pulmonary infections except for one patient with prosthetic mitral valve endocarditis due to Nocardiopsis spp. Most patients presented with acute symptoms (30 days before presentation; almost half of all the patients (n=5, 38.4%) with 1-year mortality had a delayed presentation to care. Figure 2a outlines the main presenting symptoms of patient with pulmonary and/or skin infections due to Nocardia spp. The most frequent pulmonary symptoms were dyspnea (94%), exacerbation of cough (94%), and sputum production (83%). Hemoptysis (23%) and systemic symptoms including fever (36%) and chills (21%) were less common. Chest radiographs showed the presence of diffuse pulmonary nodules (45%) with infrequent cavitation (8%). Bilateral lung involvement (47%) with lung consolidation occurred in 40% of pulmonary nocardiosis cases. Multi-lobar and bilateral lung involvement were typical regardless of other radiographic findings. Pleural effusion (15%) and only interstitial syndrome (15%) presentations were less common. No unique pulmonary symptoms or radiographic features occurred for individual Nocardia spp. Skin lesions typically presented with abscesses, erythematous nodules, ulcerations, or erythematous indurated plaque (Data not shown). SSTI sites included a breast implant infection, scalp abscesses, mycetoma and disseminated skin lesions in three patients with underlying pulmonary infections. Figure 2b outlines the main presenting symptoms of patients with documented CNS disease (i.e., Nocardia spp. cultured from one or more cultures from cerebrospinal fluid or brain tissue specimens). N. farcinica complex caused most cases of CNS nocardiosis (n=4, 80%) with the remainder due to N. flavoresea , N. paucivorans and N. nova . All CNS nocardiosis cases had headache, confusion, and focal neurological signs. Decreased level of consciousness (40%) and acute seizures (40%) occurred less frequently. Magnetic resonance imaging (MRI) of the brain showed multiple brain lesions in all cases that were supratentorial in white matter locations in the cerebrum. Only 30% of cases also demonstrated infratentorial brain lesions. One-third of the cases had bi-hemispheric disease with acute cerebritis. Active signs of meningitis, ventriculitis and hydrocephalus occurred less frequently (17%). Microbiology of nocardiosis: Table 2 outlines the microbial etiology nocardiosis cases according to patient demographics and site(s) of infection. There was no difference in either gender or age distribution according to species-level identification of Nocardia spp. Although a wide variety of different Nocardia spp. were isolated, three species complexes caused most cases of nocardiosis [56/94 (60%)] including Nocardia farcinica (n=21, 22.3%), Nocardia cyriacigeorgica (n=16, 17%) and Nocardia nova (n=19, 20.2%). Figure 3 shows the types of Nocardia spp. infections for the major types of underlying co-morbidities and immunocompromise found. Diverse types of Nocardia spp. caused infection. No association occurred between the patient’s specific underlying conditions and infection with specific Nocardia spp., but immunosuppression was universal in those with disseminated disease. Clinical Management: Antimicrobial management data was available for 78 (86%) hospitalized cases. Seven patients with SSTIs with abscess formation had surgical incision and drainage and were prescribed antibiotics. No data was available for three ambulatory patients and three hospitalized patients (n=6, 6.6%) patients). According to site of infection, Nocardia spp. and their individual antibiograms, 54/78 (69.2%) of patients received appropriate antimicrobial therapy with one or more active agents. Trimethoprim-sulfamethoxazole (39, 72.2%) imipenem (10, 18.5%) or ceftriaxone (5, 9.3%) were initially started in most patients. Two-thirds of patients were initially prescribed a single active agent while the rest were started on two or three active agents, particularly those with invasive disease with CNS infection. Cases had a prolonged course of therapy with an average duration of 45 days ± 92.5 days (range = 5 to 510 days) (±2 SDs). All invasive pulmonary and disseminated nocardiosis cases received the longest antibiotic courses of 105 days ± 75 days (±2SD) (range = 14 to 510 days) Inappropriate antimicrobial agents that were used for initial empiric therapy in 24(31%) patients included cephalexin (n=6), piperacillin-tazobactam (n=4), amoxicillin-clavulanate (n=2), imipenem (n=2), ceftriaxone (n=2), ceftazidime + colistin (n=1), doxycycline (n=1), levofloxacin (n=1), cefazolin (n=2), and voriconazole (n=1) Mortality and Survival Analysis: A Cox proportional hazards regression model including age, Charleston comorbidity score (CCS), and gender was statistically significant overall, χ² (3) = 13.09, p = 0.004, indicating that the model significantly improved prediction of survival over a null model ( Figure 4a ). In the multivariable model, none of the individual predictors reached statistical significance (CCS: p = 0.084; age: p = 0.534; gender: p = 0.090). Separate univariate Cox regressions were done to explore individual effects. Both CCS ( p < 0.004) and age ( p = 0.031) were statistically significant predictors when entered alone, while gender remained non-significant ( p = 0.093). These findings suggest that age and CCS may share overlapping variance (multicollinearity) in predicting survival, which may have reduced the effect of each when included simultaneously. The overall regression model was marginally nonsignificant, χ² (3) = 9.639, p = 0.078 when analysis only the three largest species complexes ( N. cyriacigeorgica , N. farcinica , and N. nova ). There was, however, a trend towards improved survival in patients diagnosed with N. nova complex infections, compared with N. cyriacigeorgica and N. farcinica complex infections (Figure 4b). Discussion Nocardiosis is a rare opportunistic infection that affects immunocompromised patients. Ours is the first multi-year population-based study of this disease within a large integrated healthcare region. Although incidence and IRR for Nocardia spp. infection during the study was low, overall mortality (> 20%) was high in those with disseminated disease. The number of cases of nocardiosis is also increasing with a documented 25% increase in the incidence and IRR of cases in the later half of the study compared to the first. Ours is also the first study to document the importance of the type of Nocardia spp. causing infection and its’ association with mortality. Three main Nocardia spp. caused two-thirds of the infections in our region, and survival analysis showed an increased mortality N. nova < N. cyriacigeorgica < N. farcinica complex infections. As expected, individuals with higher comorbidities (as manifested by higher CCS), as well as older individuals had a higher risk of mortality. However, given the small number of events (n = 11), we did not have statistical power to assess these two predictors independently. Indeed, a strong positive correlation between CCS and age has previously been reported ( 23 , 24 ). The Cox regression model in our database comparing the three largest species complexes was only marginally nonsignificant, although there was a trend towards improved survival in patients with N. nova complex infections. This analysis was significantly underpowered with a total sample size of nine events and fifty-one total patients. Despite this, the trend towards improve survival in the subgroup of patients with N. nova complex infections may be due to earlier diagnosis of disseminated infection because it caused most BSIs and along with N. farcinica complex, caused most CNS infections as markers for disseminated disease. Future efforts to further elucidate differences in survivorship will require a larger sample size. Inappropriate initial antibiotic therapy did not contribute to mortality risk. Most patients with disseminated disease (~ 75%) were initiated on empiric antibiotic therapy with at least one agent and received a prolonged course of therapy. However, delayed diagnosis (≥ 30 d) from symptoms onset was associated with a high mortality. Our work confirms and expands the existing body of literature on manifestations and outcomes of nocardiosis. Longitudinal studies of nocardiosis in hospitalized patients have occurred in different healthcare jurisdictions including Taiwan, China, Australia, and Europe ( 8 , 9 , 14 , 15 ). Diverse Nocardia spp. cause pulmonary and SSTIs with dissemination to other body sites occurring in 5–16% of cases. All hospitalized patients had one or more underlying co-morbidities like the ones found in our study. Immunosuppression, therapy with high-dose steroids or post-hematopoietic stem cell transplantation (HSCT) is a major risk factor for nocardiosis and disseminated infection ( 8 , 9 , 14 , 15 ). All cause 1-year mortality for nocardiosis in these studies ranged from 14-36.8% of cases but was highest in those with immunosuppression and disseminated infections. The highest 1-year mortality (36.8%) occurred amongst 110 patients with disseminated nocardial infection and underlying immunocompromise due to autoimmune diseases who were receiving high-dose corticosteroid therapy ( 8 ). N. farcinica was the most common species complex recovered from clinical specimens and was also associated with a higher rate of dissemination (36.8%, p = 0002). Another longitudinal study at the Mayo Clinic compared 110 adults with culture-proven invasive nocardiosis who were transplant recipients versus nontransplant patients with chronic lung diseases, malignancy or rheumatologic conditions who received corticosteroids or other immunosuppressive drugs including chemotherapy ( 25 ). All cause 1-year mortality was 25% but there was no difference in mortality amongst the two patient groups. A high mortality rate was also reported for disseminated nocardiosis with CNS infection (22.8%) in a recent meta-analysis ( 12 ). Nocardia farcinica caused 39.6% of cases, followed by Nocardia nova (5.9%). Patients who underwent surgery had better survival than antimicrobial therapy alone. Delayed diagnosis has also been previously associated with a higher mortality rate. Liu and colleagues ( 14 ) studied 44 patients with nocardiosis receiving immunosuppressive therapy (n = 26, 59.1%) for various diseases, most commonly rheumatologic conditions. Delayed diagnosis (19.7 d) of nocardiosis was associated with poor prognosis in this cohort compared to those with resolved infection (7.3 d). Limitations should be considered for this retrospective regional multiyear study. Missed cases would occur if physicians did not submit appropriate clinical specimens for microbiological assessment. The trendline and increase in incidence and IRR for nocardiosis in our population is not due to improved laboratory detection and species-level identification of Nocardia isolates. A strength of this study is the consistent use of highly proficient molecular analysis on all recovered Nocardia spp. isolates during the entire study period, so it is less likely that cases not diagnosed or mis-identified due to the limitations of phenotypic and proteomics databases in providing an accurate species-level identification ( 26 ). Other large healthcare jurisdictions should conduct further studies to confirm our findings due to the rare population incidence and IRR for this important disease. Nocardiosis is a serious invasive infection with a high mortality in immunocompromised patients. Our work further enhances the emerging picture of unique clinical and epidemiological roles of Nocardia spp., which cause a widening spectrum of presentations. Prompt diagnosis is critical to improve patient outcomes. Nocardia species-level identification not only improves antibiotic management but is predictive of mortality for the major species causing nocardiosis in our region. Abbreviations APL Alberta precision laboratories APL-DSC Alberta precision laboratories-disgnositc and scientific centre BA Blood agar BCYE Buffered charcoal yeast extract agar BSI Bloodstream infeciton CA Community-acquired CCS Charlson comorbidity score CNS Central nervous system HA Hospital-acquired IAI Intra-abdominal infection IRR Incidence rate ratio SSTI Skin and soft tissue infection Declarations Ethics approval and consent to participate: The Conjoint Health Research Ethics Board (REB) reviewed and approved this study under certificate number REB22-1280. A waiver of consent requirement was obtained. Clinica trial number: Not applicable Consent for Publication: Not applicable Availability of data and materials: The data that support the findings of this study are available from Alberta Health Services (AHS), Alberta Precision Laboratories (APL) (formerly Calgary Laboratory Services) but restrictions apply to the availability to these data, which were analyzed under the ethics agreement for the current study and are not publicly available. Data are however available from the author upon reasonable request and with permission of AHS/APL. Competing Interests: None of the authors have a conflict of interest. Funding: This study was unsupported. CrediT authorship contribution statement DLC: Conceptualization, Data curation, Methodology, Project administration, Writing – original draft, Writing – review and editing. AUT: Data curation, Methodology, Writing – review and editing. CN: Data analysis, Methodology, Writing – review and editing. 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Supplementary Files Table1.PatientcharacteristicsJune162025V2FINAL.docx Table2DemographicsandSiteofInfectionNocardiosisSurvivalJune162025V2FINAL.docx Cite Share Download PDF Status: Published Journal Publication published 11 Feb, 2026 Read the published version in BMC Infectious Diseases → Version 1 posted Editorial decision: Revision requested 14 Oct, 2025 Reviews received at journal 03 Aug, 2025 Reviews received at journal 31 Jul, 2025 Reviewers agreed at journal 29 Jul, 2025 Reviewers agreed at journal 29 Jul, 2025 Reviewers invited by journal 29 Jul, 2025 Editor invited by journal 04 Jul, 2025 Editor assigned by journal 01 Jul, 2025 Submission checks completed at journal 01 Jul, 2025 First submitted to journal 26 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6985944","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":492651168,"identity":"a051e443-5650-408f-8989-c940ac400b31","order_by":0,"name":"Deirdre Church","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYDCCAzxgUg5IMB4gSYsxmCRJS2ID0Vr4jp89Jl1Rcyd9w/HDDw5+qbmX2MB++AFeLZJn8tIkzxx7lrvhTJrBYZljxYkNPGkGeLUY3OAxk2xsOJy74QaDwWEJtoTEBgkG4rSkG9xg/3BY4h9IC/sHorQkABkGBz+2gbTw4LdF8kyOsWXDscOGM8/kFBxm7EswbuPJKcCrhe/4GcObDTWH5fmOH9/48Me3BNl+9uMb8GpBAczAOHJsI149EDD+YGCwJ0nHKBgFo2AUjAgAAM9IUbbwi6zVAAAAAElFTkSuQmCC","orcid":"","institution":"University of Calgary","correspondingAuthor":true,"prefix":"","firstName":"Deirdre","middleName":"","lastName":"Church","suffix":""},{"id":492651170,"identity":"c60c8a3f-6209-4739-91d5-ca68a3495395","order_by":1,"name":"Alejandra Ugarte-Torres","email":"","orcid":"","institution":"University of Calgary","correspondingAuthor":false,"prefix":"","firstName":"Alejandra","middleName":"","lastName":"Ugarte-Torres","suffix":""},{"id":492651173,"identity":"e463e1c7-c4a7-4681-b138-4ee19db08279","order_by":2,"name":"Christopher Naugler","email":"","orcid":"","institution":"University of Calgary","correspondingAuthor":false,"prefix":"","firstName":"Christopher","middleName":"","lastName":"Naugler","suffix":""}],"badges":[],"createdAt":"2025-06-26 18:38:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6985944/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6985944/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12879-025-12456-3","type":"published","date":"2026-02-11T15:58:58+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":88095627,"identity":"87188f7a-11f4-4e01-b4e3-6423398b9257","added_by":"auto","created_at":"2025-08-01 10:54:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":29789,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6985944/v1/87ab818fba14cc6dd1896e82.png"},{"id":88098832,"identity":"f3b2340d-e265-4d1b-ae8e-050d556ff87c","added_by":"auto","created_at":"2025-08-01 11:10:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":65924,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6985944/v1/6f45650ed0d23f611dcf0eea.png"},{"id":88097050,"identity":"22414195-ea07-4ab1-95ac-beb73542405d","added_by":"auto","created_at":"2025-08-01 11:02:49","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":43739,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6985944/v1/b967d0b022b92871b428b0a2.png"},{"id":88095637,"identity":"adf33289-b256-441a-8861-128f6b0418a9","added_by":"auto","created_at":"2025-08-01 10:54:49","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":159208,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6985944/v1/0661f340705dd8960ae10835.png"},{"id":102786637,"identity":"1c181d83-8d02-44b1-a70a-e2f667a4986b","added_by":"auto","created_at":"2026-02-16 16:14:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":943981,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6985944/v1/e139e7f2-5642-45d4-8185-02be787271d6.pdf"},{"id":88095631,"identity":"11a27db1-c900-4782-970a-1a10d80103bd","added_by":"auto","created_at":"2025-08-01 10:54:48","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19234,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.PatientcharacteristicsJune162025V2FINAL.docx","url":"https://assets-eu.researchsquare.com/files/rs-6985944/v1/5f3198bd5c3eea9da2dd480c.docx"},{"id":88097048,"identity":"8a143de3-bb7a-4a7a-b81a-19f003d8f08b","added_by":"auto","created_at":"2025-08-01 11:02:49","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":23883,"visible":true,"origin":"","legend":"","description":"","filename":"Table2DemographicsandSiteofInfectionNocardiosisSurvivalJune162025V2FINAL.docx","url":"https://assets-eu.researchsquare.com/files/rs-6985944/v1/e5c5d36131eac38f0af8cb01.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Multi-year Population-Based Study of the Clinical and Epidemiological Risk Factors for Mortality in Nocardiosis: Survival Analysis from a Large Regional Canadian Healthcare Region","fulltext":[{"header":"Importance","content":"\u003cp\u003eThe role of specific \u003cem\u003eNocardia\u003c/em\u003e species in human infections continues to expand as advanced methods enable better species complex and individual species identification. A multi-year population-based study (2010-2022) of nocardiosis amongst ninety-four adult patients with a mean age of 61 \u0026plusmn; 17 yrs.; more cases occurred in males (57%). Most patients (96%) had one or more serious underlying co-morbidities. Cases mostly had pulmonary (53%) or skin and soft tissue infections (30%). Most cases [56/94 (60%)] were due to 3 species complexes \u003cem\u003eNocardia farcinica\u0026nbsp;\u003c/em\u003e(n=21, 22.3%), \u003cem\u003eNocardia cyriacigeorgica\u003c/em\u003e (n=16, 17%) and \u003cem\u003eNocardia nova\u0026nbsp;\u003c/em\u003e(n=19, 20.2%). Two-thirds of cases had appropriate initial therapy. Overall mortality was 22.3% with a 1-year mortality of 12.2% but delayed diagnosis (\u0026ge; 30 d) had a higher mortality. Survival analysis for infection showed mortality for \u003cem\u003eN. nova\u0026nbsp;\u003c/em\u003e\u0026lt; \u003cem\u003eN. cyriacigeorgica\u003c/em\u003e \u0026lt; \u003cem\u003eN. farcinica complex.\u003c/em\u003e Accurate identification of \u003cem\u003eNocardia\u003c/em\u003e spp. improves antibiotic management and may predict mortality.\u003c/p\u003e"},{"header":"Background","content":"\u003cp\u003eNocardiae are part of the aerobic actinomycetes belonging to the class Actinobacteria in the order Corynbacteriales along with other clinically important genera including \u003cem\u003eCorynebacterium\u003c/em\u003e and \u003cem\u003eMycobacterium\u003c/em\u003e (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). They are soil pathogens that are emerging as uncommon causes of invasive infections, primarily pulmonary, central nervous system (CNS), bloodstream (BSI) and skin and soft tissue infections (SSTIs) (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The main routes of infection in humans are inhalation and direct inoculation of the skin (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Although immunocompetent people may acquire nocardiosis, prior studies have documented that \u0026gt;\u0026thinsp;80% of patients are immunocompromised (\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The main underlying immunosuppressive conditions included solid organ or haematologic malignancy, solid organ, and hematopoietic stem cell transplantation, underlying inflammatory condition, and/or treatment with high dose corticosteroids or other T-cell immunosuppressing agents (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)., Few population-based studies have yet been done (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), although prior studies were reported from a large referral healthcare system (i.e., Mayo Clinic) or tertiary hospitals.\u003c/p\u003e\u003cp\u003eOur large regional centralized laboratory used advanced methods (i.e., fast partial sequencing of the 16S rRNA gene (V1 to V3 region) since 2009 and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) since 2018 for routine identification of \u003cem\u003eNocardia\u003c/em\u003e spp. (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). The regional microbiology database stored all laboratory confirmed nocardiosis cases with isolation of \u003cem\u003eNocardia\u003c/em\u003e spp. from at least one clinical specimen culture. Although rare, use of these advanced identification methods allowed diagnosis of increasing numbers of invasive infections in our region. Since few population-based studies have been done worldwide, so we performed a multiyear clinical and epidemiological analysis of the \u0026gt;\u0026thinsp;94 cases between 2010 and 2022. We sought to compare risk factors, clinical manifestations, treatment, and mortality in our multi-year retrospective population-based study. It was of interest to define the population-based prevalence of nocardiosis in our large integrated healthcare region and determine if there was any association between different \u003cem\u003eNocardia\u003c/em\u003e spp. and mortality.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cb\u003eStudy Population\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eWe conducted a retrospective population-based cohort study of all cases diagnosed with nocardiosis in the Alberta Health Services, Calgary Zone, from January 2010 through December 2022. The Calgary Zone provides medical and surgical care to the residents of Calgary and the surrounding area, covering a population of 1.6\u0026nbsp;million in Southern Alberta, Canada. Alberta Precision Laboratories (APL), Diagnostic \u0026amp; Scientific Centre (APL-DSC) (formerly Calgary Laboratory Services) is the central regional laboratory that serves the Calgary Zone.\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical Data Collection\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eNocardiosis was culture confirmed by growing \u003cem\u003eNocardia\u003c/em\u003e spp. from at least one clinical specimen submitted for analysis to the APL-DSC clinical microbiology laboratory. Basic demographic data such as patient age and sex, infectious diagnosis, underlying comorbidities and 1-year mortality were determined through a retrospective chart review of most patients\u0026rsquo; electronic medical records by two of the investigators (AUT and DLC). All clinical diagnoses and the site(s) of nocardiosis infection were determined as clinician-defined from the problem list by a detailed clinical chart review. Community acquired (CA) had the first positive culture obtained\u0026thinsp;\u0026lt;\u0026thinsp;72 hours after hospital admission or \u0026ge;\u0026thinsp;72 hours after discharge. Hospital-acquired (HA) infections occurred when the first positive culture was \u0026ge;\u0026thinsp;72 hours after hospital admission or \u0026lt;\u0026thinsp;72 hours after discharge. Disseminated nocardial infection was the presence of two different sites of concurrent infection or by the presence of BSI. Charlson comorbidity index (CCI) assessed illness severity (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). \u003cem\u003eNocardia\u003c/em\u003e spp. Bloodstream infection (BSI) occurred when one or more sets of blood culture bottles isolated \u003cem\u003eNocardia\u003c/em\u003e spp. Appropriate empiric antimicrobial therapy occurred when one or more antibiotics were prescribed that would be effective based on the \u003cem\u003eNocardia\u003c/em\u003e isolates reported antimicrobial susceptibility profile. Primary outcome was 1-year mortality according to the type of invasive \u003cem\u003eNocardia\u003c/em\u003e infection and specific \u003cem\u003eNocardia\u003c/em\u003e spp. for those that were most commonly isolates; secondary outcomes included survival according to the site/source of infection (i.e., pulmonary, or skin and soft tissue with and without dissemination), illness severity, and the choice of appropriate initial empiric antibiotic therapy.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMicrobiology Methods\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eWe have previously reported the microbiological methods used for \u003cem\u003eNocardia\u003c/em\u003e spp. identification and strain characterization with a brief overview provided herein (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Isolates grew aerobically on sheep blood agar (BA) and/or specialized growth media [(i.e., buffered charcoal yeast extract (BCYE)]. Gram stain demonstrated typical Gram-positive beaded branching bacilli that were catalase positive and modified acid fast positive but Ziehl-Neilsen stain negative. Isolate matrix-assisted laser desorption ionization \u0026ndash; time of flight mass spectrometry (MALDI-TOF MS) (VITEK MS, bioM\u0026eacute;rieux, Laval, Que. Canada) analysis was done after isolate extraction (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) using the instrument\u0026rsquo;s most current database in accordance with the manufacturers\u0026rsquo; instructions. Molecular identification occurred by fast PCR/fast cycle sequencing of the 16S rRNA gene (523 bp) with MicroSeq 500 kits and an ABI Prism 3500 XL sequencer (Applied Biosystems, Thermo Fisher Scientific, Foster City, CA USA) using standard methods previously described (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Following bacterial sequence multi-alignment against a reference sequence, a BLAST search using the SmartGene Integrated Database Network System (IDNS) (Lausanne, Switzerland) bacterial database indicated the most closely related species complex or species (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.Smartgene.com\u003c/span\u003e\u003cspan address=\"http://www.Smartgene.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) with an identify score of 99.9% (i.e., 0\u0026ndash;2 base mismatches) according to interpretive criteria for targeted DMA sequencing analyses published by the Clinical and Laboratory Standards Institute (CLSI), Approved Guideline MM-18 (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eStatistical Analyses\u003c/b\u003e:\u003c/p\u003e\u003cp\u003ePopulation based incidence rate calculations were based on Calgary region census data from 2010 and 2016. Categorical data was expressed as total numbers or percentages and compared using χ2 tests; continuous data were expressed as medians with interquartile ranges (IQRs) and compared using rank-sum test. A univariate analysis determined risk factors associated with 30-day mortality. A logistic regression model included all significant variables (P\u0026thinsp;\u0026le;\u0026thinsp;.05). Results were reported as odds ratios (ORs) with 95% confidence intervals. Statistical significance was a P-value\u0026thinsp;\u0026le;\u0026thinsp;.05 for all comparisons. One-year, all-cause mortality for the entire database of ninety-four cases as well as individually for the three most common species complexes (\u003cem\u003eN. cyriacigeorgica\u003c/em\u003e; n\u0026thinsp;=\u0026thinsp;16, \u003cem\u003eN. farcinica\u003c/em\u003e; n\u0026thinsp;=\u0026thinsp;19, and \u003cem\u003eN. nova\u003c/em\u003e; n\u0026thinsp;=\u0026thinsp;16) used Cox proportional hazards regression models including age, CCS (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), and sex. Statistical analysis used IBM SPSS Statistics version 29 software (IBM Corp. Released 2023. IBM SPSS Statistics for Windows, Version 29.0.2.0 Armonk, NY: IBM Corp).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePopulation-based incidence:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1\u0026nbsp;\u003c/strong\u003eshows the nocardiosis cases diagnosed within each year. A total of 6 \u0026plusmn; 0.5 cases per year occurred from 2010-2015 while 10 cases \u0026plusmn; 0.5 cases were diagnosed in the later half of the study yielding yearly incidence rates of 0.0006% vs 0.0008%, respectively. There is an upwards trend in the regional incidence rate (IRR) from 0.6 per 100,000 populaces in 2010 to 0.8 per 100,000 populaces by 2016.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient demographics and clinical characteristics:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNinety-four unique patients with nocardiosis were studied but electronic medical records were not available for three ambulatory patients. Ninety-one unique cases were analyzed. Most invasive nocardiosis (n=78/91, 86%) cases occurred in hospitalized patients. \u003cstrong\u003eTable 1\u003c/strong\u003e outlines the demographics, underlying co-morbidities and overall mortality of the hospitalized nocardiosis cases. All patients were adults with a mean age of 61 \u0026plusmn; 17 yrs. More patients were male (57%) than female (43%) but there was no age difference based on sex. Underlying co-morbidities were present in 96% of cases including diabetes, liver or renal failure, malignancy, transplant recipients, chronic lung disease, rheumatologic diseases, or other inflammatory conditions (\u003cstrong\u003eTable 1\u003c/strong\u003e). Chronic lung diseases (n=19) included cystic fibrosis (n=8, 39%), bronchiectasis (n=18, 100%), pulmonary fibrosis (n=6, 33%), chronic obstructive pulmonary disease (n=7, 39%) and asthma (n=6, 33%). Active malignancies included acute myelogenous leukemia or chronic lymphocytic leukemia (n=2, 11%), various types of lymphoma (n=2, 11%) and solid organ tumours (n=13, 72%) [ (i.e., breast (n=5, 28%), lung (n=3, 17%), brain (n=2, 11%), gastrointestinal (N=2, 11%) and ureteral (n=1, 6%]). \u0026nbsp;Transplanted organs most commonly were kidney (n=3, 37%), lung (n=2, 18%), pancreas (n=1, 1%), liver (n=1, 1%) and haematopoietic stem calls (HSCT) (n=3, 27%). Overall mortality was 23.7% with a 1-year mortality of 12.2% with those having disseminated disease, and those most likely to die had documented CNS disease.\u003c/p\u003e\n\u003cp\u003ePulmonary (53%) or SSTIs (30%) with less frequent diagnoses of central nervous system infections (7%), bloodstream infections (6%) and septic arthritis and intra-abdominal infections (6%). Three patients had both pulmonary and SSTI. All \u003cem\u003eNocardia\u003c/em\u003e BSIs originated from pulmonary infections except for one patient with prosthetic mitral valve endocarditis due to \u003cem\u003eNocardiopsis\u003c/em\u003e spp. Most patients presented with acute symptoms (\u0026lt;30 days duration), but twenty-nine patients (32%) reported chronic symptoms that had onset \u0026gt;30 days before presentation; almost half of all the patients (n=5, 38.4%) with 1-year mortality had a delayed presentation to care.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 2a\u003c/strong\u003e outlines the main presenting symptoms of patient with pulmonary and/or skin infections due to \u003cem\u003eNocardia\u0026nbsp;\u003c/em\u003espp. The most frequent pulmonary symptoms were dyspnea (94%), exacerbation of cough (94%), and sputum production (83%). Hemoptysis (23%) and systemic symptoms including fever (36%) and chills (21%) were less common. Chest radiographs showed the presence of diffuse pulmonary nodules (45%) with infrequent cavitation (8%). Bilateral lung involvement (47%) with lung consolidation occurred in 40% of pulmonary nocardiosis cases. Multi-lobar and bilateral lung involvement were typical regardless of other radiographic findings. Pleural effusion (15%) and only interstitial syndrome (15%) presentations were less common. No unique pulmonary symptoms or radiographic features occurred for individual \u003cem\u003eNocardia\u003c/em\u003e spp. Skin lesions typically presented with\u0026nbsp;abscesses, erythematous nodules, ulcerations, or erythematous indurated plaque (Data not shown). SSTI sites included a breast implant infection, scalp abscesses, mycetoma and disseminated skin lesions in three patients with underlying pulmonary infections.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 2b\u003c/strong\u003e outlines the main presenting symptoms of patients with documented CNS disease (i.e., \u003cem\u003eNocardia\u003c/em\u003e spp. cultured from one or more cultures from cerebrospinal fluid or brain tissue specimens). \u003cem\u003eN. farcinica\u003c/em\u003e complex caused most cases of CNS nocardiosis (n=4, 80%) with the remainder due to \u003cem\u003eN. flavoresea\u003c/em\u003e, \u003cem\u003eN. paucivorans\u003c/em\u003e and \u003cem\u003eN. nova\u003c/em\u003e. All CNS nocardiosis cases had headache, confusion, and focal neurological signs. Decreased level of consciousness (40%) and acute seizures (40%) occurred less frequently. Magnetic resonance imaging (MRI) of the brain showed multiple brain lesions in all cases that were supratentorial in white matter locations in the cerebrum. Only 30% of cases also demonstrated infratentorial brain lesions. One-third of the cases had bi-hemispheric disease with acute cerebritis. Active signs of meningitis, ventriculitis and hydrocephalus occurred less frequently (17%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMicrobiology of nocardiosis:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u0026nbsp;\u003c/strong\u003eoutlines the microbial etiology nocardiosis cases according to patient demographics and site(s) of infection. There was no difference in either gender or age distribution according to species-level identification of \u003cem\u003eNocardia\u003c/em\u003e spp. Although a wide variety of different \u003cem\u003eNocardia\u003c/em\u003e spp. were isolated, three species complexes caused most cases of nocardiosis [56/94 (60%)] including \u003cem\u003eNocardia farcinica\u003c/em\u003e (n=21, 22.3%), \u003cem\u003eNocardia cyriacigeorgica\u003c/em\u003e (n=16, 17%) and \u003cem\u003eNocardia nova\u003c/em\u003e (n=19, 20.2%). \u003cstrong\u003eFigure 3\u003c/strong\u003e shows the types of \u003cem\u003eNocardia\u003c/em\u003e spp. infections for the major types of underlying co-morbidities and immunocompromise found. Diverse types of Nocardia spp. caused infection. No association occurred between the patient\u0026rsquo;s specific underlying conditions and infection with specific \u003cem\u003eNocardia\u003c/em\u003e spp., but immunosuppression was universal in those with disseminated disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Management:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAntimicrobial management data was available for 78 (86%) hospitalized cases. Seven patients with SSTIs with abscess formation had surgical incision and drainage and were prescribed antibiotics. No data was available for three ambulatory patients and three hospitalized patients (n=6, 6.6%) patients). According to site of infection, \u003cem\u003eNocardia\u003c/em\u003e spp. and their individual antibiograms, 54/78 (69.2%) of patients received appropriate antimicrobial therapy with one or more active agents. Trimethoprim-sulfamethoxazole (39, 72.2%) imipenem (10, 18.5%) or ceftriaxone (5, 9.3%) were initially started in most patients. Two-thirds of patients were initially prescribed a single active agent while the rest were started on two or three active agents, particularly those with invasive disease with CNS infection. Cases had a prolonged course of therapy with an average duration of 45 days \u0026plusmn; 92.5 days (range = 5 to 510 days) (\u0026plusmn;2 SDs). All invasive pulmonary and disseminated nocardiosis cases received the longest antibiotic courses of 105 days \u0026plusmn; 75 days (\u0026plusmn;2SD) (range = 14 to 510 days)\u003c/p\u003e\n\u003cp\u003eInappropriate antimicrobial agents that were used for initial empiric therapy in 24(31%) patients included cephalexin (n=6), piperacillin-tazobactam (n=4), amoxicillin-clavulanate (n=2), imipenem (n=2), ceftriaxone (n=2), ceftazidime + colistin (n=1), doxycycline (n=1), levofloxacin (n=1), cefazolin (n=2), and voriconazole (n=1)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMortality and Survival Analysis:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA Cox proportional hazards regression model including age, Charleston comorbidity score (CCS), and gender was statistically significant overall, \u0026chi;\u0026sup2; (3) = 13.09, \u003cem\u003ep\u003c/em\u003e = 0.004, indicating that the model significantly improved prediction of survival over a null model (\u003cstrong\u003eFigure 4a\u003c/strong\u003e). In the multivariable model, none of the individual predictors reached statistical significance (CCS: \u003cem\u003ep\u003c/em\u003e = 0.084; age: \u003cem\u003ep\u003c/em\u003e = 0.534; gender: \u003cem\u003ep\u003c/em\u003e = 0.090). Separate univariate Cox regressions were done to explore individual effects. Both CCS (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.004) and age (\u003cem\u003ep\u003c/em\u003e = 0.031) were statistically significant predictors when entered alone, while gender remained non-significant (\u003cem\u003ep\u003c/em\u003e = 0.093). These findings suggest that age and CCS may share overlapping variance (multicollinearity) in predicting survival, which may have reduced the effect of each when included simultaneously.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe overall regression model was marginally nonsignificant, \u0026chi;\u0026sup2; (3) = 9.639, p = 0.078 when analysis only the three largest species complexes (\u003cem\u003eN. cyriacigeorgica\u003c/em\u003e, \u003cem\u003eN. farcinica\u003c/em\u003e, and \u003cem\u003eN. nova\u003c/em\u003e). There was, however, a trend towards improved survival in patients diagnosed with \u003cem\u003eN. nova\u003c/em\u003e complex infections, compared with \u003cem\u003eN. cyriacigeorgica\u003c/em\u003e and \u003cem\u003eN. farcinica\u003c/em\u003e complex infections\u003cstrong\u003e\u0026nbsp;(Figure 4b).\u003c/strong\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eNocardiosis is a rare opportunistic infection that affects immunocompromised patients. Ours is the first multi-year population-based study of this disease within a large integrated healthcare region. Although incidence and IRR for \u003cem\u003eNocardia\u003c/em\u003e spp. infection during the study was low, overall mortality (\u0026gt;\u0026thinsp;20%) was high in those with disseminated disease. The number of cases of nocardiosis is also increasing with a documented 25% increase in the incidence and IRR of cases in the later half of the study compared to the first.\u003c/p\u003e\u003cp\u003eOurs is also the first study to document the importance of the type of \u003cem\u003eNocardia\u003c/em\u003e spp. causing infection and its\u0026rsquo; association with mortality. Three main \u003cem\u003eNocardia\u003c/em\u003e spp. caused two-thirds of the infections in our region, and survival analysis showed an increased mortality \u003cem\u003eN. nova\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;\u003cem\u003eN. cyriacigeorgica\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;\u003cem\u003eN. farcinica\u003c/em\u003e complex infections. As expected, individuals with higher comorbidities (as manifested by higher CCS), as well as older individuals had a higher risk of mortality. However, given the small number of events (n\u0026thinsp;=\u0026thinsp;11), we did not have statistical power to assess these two predictors independently. Indeed, a strong positive correlation between CCS and age has previously been reported (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). The Cox regression model in our database comparing the three largest species complexes was only marginally nonsignificant, although there was a trend towards improved survival in patients with \u003cem\u003eN. nova\u003c/em\u003e complex infections. This analysis was significantly underpowered with a total sample size of nine events and fifty-one total patients. Despite this, the trend towards improve survival in the subgroup of patients with \u003cem\u003eN. nova\u003c/em\u003e complex infections may be due to earlier diagnosis of disseminated infection because it caused most BSIs and along with \u003cem\u003eN. farcinica\u003c/em\u003e complex, caused most CNS infections as markers for disseminated disease. Future efforts to further elucidate differences in survivorship will require a larger sample size. Inappropriate initial antibiotic therapy did not contribute to mortality risk. Most patients with disseminated disease (~\u0026thinsp;75%) were initiated on empiric antibiotic therapy with at least one agent and received a prolonged course of therapy. However, delayed diagnosis (\u0026ge;\u0026thinsp;30 d) from symptoms onset was associated with a high mortality.\u003c/p\u003e\u003cp\u003eOur work confirms and expands the existing body of literature on manifestations and outcomes of nocardiosis. Longitudinal studies of nocardiosis in hospitalized patients have occurred in different healthcare jurisdictions including Taiwan, China, Australia, and Europe (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Diverse \u003cem\u003eNocardia\u003c/em\u003e spp. cause pulmonary and SSTIs with dissemination to other body sites occurring in 5\u0026ndash;16% of cases. All hospitalized patients had one or more underlying co-morbidities like the ones found in our study. Immunosuppression, therapy with high-dose steroids or post-hematopoietic stem cell transplantation (HSCT) is a major risk factor for nocardiosis and disseminated infection (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). All cause 1-year mortality for nocardiosis in these studies ranged from 14-36.8% of cases but was highest in those with immunosuppression and disseminated infections. The highest 1-year mortality (36.8%) occurred amongst 110 patients with disseminated nocardial infection and underlying immunocompromise due to autoimmune diseases who were receiving high-dose corticosteroid therapy (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). \u003cem\u003eN. farcinica\u003c/em\u003e was the most common species complex recovered from clinical specimens and was also associated with a higher rate of dissemination (36.8%, p\u0026thinsp;=\u0026thinsp;0002). Another longitudinal study at the Mayo Clinic compared 110 adults with culture-proven invasive nocardiosis who were transplant recipients versus nontransplant patients with chronic lung diseases, malignancy or rheumatologic conditions who received corticosteroids or other immunosuppressive drugs including chemotherapy (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). All cause 1-year mortality was 25% but there was no difference in mortality amongst the two patient groups. A high mortality rate was also reported for disseminated nocardiosis with CNS infection (22.8%) in a recent meta-analysis (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). \u003cem\u003eNocardia farcinica\u003c/em\u003e caused 39.6% of cases, followed by \u003cem\u003eNocardia nova\u003c/em\u003e (5.9%). Patients who underwent surgery had better survival than antimicrobial therapy alone. Delayed diagnosis has also been previously associated with a higher mortality rate. Liu and colleagues (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) studied 44 patients with nocardiosis receiving immunosuppressive therapy (n\u0026thinsp;=\u0026thinsp;26, 59.1%) for various diseases, most commonly rheumatologic conditions. Delayed diagnosis (19.7 d) of nocardiosis was associated with poor prognosis in this cohort compared to those with resolved infection (7.3 d).\u003c/p\u003e\u003cp\u003eLimitations should be considered for this retrospective regional multiyear study. Missed cases would occur if physicians did not submit appropriate clinical specimens for microbiological assessment. The trendline and increase in incidence and IRR for nocardiosis in our population is not due to improved laboratory detection and species-level identification of \u003cem\u003eNocardia\u003c/em\u003e isolates. A strength of this study is the consistent use of highly proficient molecular analysis on all recovered \u003cem\u003eNocardia\u003c/em\u003e spp. isolates during the entire study period, so it is less likely that cases not diagnosed or mis-identified due to the limitations of phenotypic and proteomics databases in providing an accurate species-level identification (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Other large healthcare jurisdictions should conduct further studies to confirm our findings due to the rare population incidence and IRR for this important disease.\u003c/p\u003e\u003cp\u003eNocardiosis is a serious invasive infection with a high mortality in immunocompromised patients. Our work further enhances the emerging picture of unique clinical and epidemiological roles of \u003cem\u003eNocardia\u003c/em\u003e spp., which cause a widening spectrum of presentations. Prompt diagnosis is critical to improve patient outcomes. \u003cem\u003eNocardia\u003c/em\u003e species-level identification not only improves antibiotic management but is predictive of mortality for the major species causing nocardiosis in our region.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eAPL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eAlberta precision laboratories\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eAPL-DSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eAlberta precision laboratories-disgnositc and scientific centre\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eBA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eBlood agar\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eBCYE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eBuffered charcoal yeast extract agar\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eBSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eBloodstream infeciton\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eCommunity-acquired\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eCCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eCharlson comorbidity score\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eCNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eCentral nervous system\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eHA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eHospital-acquired\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eIAI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eIntra-abdominal infection\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eIRR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eIncidence rate ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eSSTI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eSkin and soft tissue infection\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e The Conjoint Health Research Ethics Board (REB) reviewed and approved this study under certificate number REB22-1280. A waiver of consent requirement was obtained.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinica trial number:\u003c/strong\u003e Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eThe data that support the findings of this study are available from Alberta Health Services (AHS), Alberta Precision Laboratories (APL) (formerly Calgary Laboratory Services) but restrictions apply to the availability to these data, which were analyzed under the ethics agreement for the current study and are not publicly available. Data are however available from the author upon reasonable request and with permission of AHS/APL.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u0026nbsp;\u003c/strong\u003eNone of the authors have a conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis study was unsupported.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCrediT authorship contribution statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDLC:\u0026nbsp;\u003c/strong\u003eConceptualization, Data curation, Methodology, Project administration, Writing \u0026ndash; original draft, Writing \u0026ndash; review and editing.\u003cstrong\u003e\u0026nbsp;AUT:\u0026nbsp;\u003c/strong\u003eData curation, Methodology, Writing \u0026ndash; review and editing.\u003cstrong\u003e\u0026nbsp;CN:\u0026nbsp;\u003c/strong\u003eData analysis, Methodology, Writing \u0026ndash; review and editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the Alberta Precision Laboratory \u0026ndash; Calgary Zone Microbiology staff for their help with sample processing and isolate analysis.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTraxler RM, Bell ME, Lasker B, Headd B, Shieh WJ, McQuiston JR. 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Development and evaluation of a novel fast broad-range 16S ribosomal DNA PCR and sequencing assay for diagnosis of bacterial infective endocarditis: multi-year experience in a large Canadian healthcare zone and a literature review. BMC Infect Dis. 2016;16:146.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCharlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChurch DL, Pierano G, Ugartes-Torres A, Guo M, Naugler C. Population-based microbiological characterization of \u003cem\u003eNocardia\u003c/em\u003e strains causing invasive infections during a multiyear period in a large Canadian health care region. Microbiol Spectr 2025 (In press).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcTaggart LR, Chen Y, Poopalarajah R, Kus JV. Incubation time and culture media impact success of identification of Nocardia spp. by MALDI-ToF mass spectrometry. Diagn Microbiol Infect Dis. 2018;92(4):270\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eClinical Laboratory Standards Institute (CLSI). Interpretive Criteria for Identification of Bacteria and Fungi byt Targeted DNA Sequencing. Wayne, PA USA: CLSI. 2018 July 16, 2018.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eQuan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol. 2011;173(6):676\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ede Groot V, Beckerman H, Lankhorst GJ, Bouter LM. How to measure comorbidity. a critical review of available methods. J Clin Epidemiol. 2003;56(3):221\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHarris DM, Dumitrascu AG, Chirila RM, Omer M, Stancampiano FF, Hata DJ, et al. Invasive Nocardiosis in Transplant and Nontransplant Patients: 20-Year Experience in a Tertiary Care Center. Mayo Clin Proc Innov Qual Outcomes. 2021;5(2):298\u0026ndash;307.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eClinical Laboratory Standards Institute (CLSI). Methods for the Identification of Cultured Microorganisms Using Matrix-Assisted Laser Desorption/Ionization Time-of-Fight Mass Spectrometry. Wayne, PA USA: CLSI. 2017 April, 26, 2017.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Nocardia, population-based epidemiology, invasive infection, pulmonary infection, skin and soft tissue infection, central nervous system infection, bloodstream infection, mortality, survival","lastPublishedDoi":"10.21203/rs.3.rs-6985944/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6985944/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBACKGROUND\u003c/h2\u003e\u003cp\u003eNocardiae are ubiquitous environmental soil pathogens that primarily cause invasive infections by inhalation or direct skin inoculation in immunocompromised patients. This multi-year population-based study compared epidemiological and clinical features of all cases diagnosed in our region.\u003c/p\u003e\u003ch2\u003eMETHODS\u003c/h2\u003e\u003cp\u003ePatients were enrolled in our large integrated healthcare region with culture-proven nocardiosis between 2010\u0026ndash;2022. Clinical chart reviews were conducted to determine the clinical manifestations, risk factors, treatment and mortality including survival analysis.\u003c/p\u003e\u003ch2\u003eRESULTS\u003c/h2\u003e\u003cp\u003eNinety-four adults had a mean age of 61\u0026thinsp;\u0026plusmn;\u0026thinsp;17 yrs. More cases occurred in males (57%) than females (43%). Ninety-six percent of cases had underlying co-morbidities including diabetes, liver or renal failure, malignancy, transplant recipients, chronic lung disease, rheumatologic disease, or other inflammatory conditions. Pulmonary (53%) or skin and soft tissue infections (SSTIs) (30%) commonly occurred with infrequent diagnoses of central nervous system infection (CNS) (7%), bloodstream infection (BSI) (6%), and septic arthritis or intra-abdominal infection (IAI) (6%). Diverse \u003cem\u003eNocardia\u003c/em\u003e spp. were isolated, but 3 species complexes caused most cases [56/94 (60%)] including \u003cem\u003eNocardia farcinica\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;21, 22.3%), \u003cem\u003eNocardia cyriacigeorgica\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;16, 17%) and \u003cem\u003eNocardia nova\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;19, 20.2%). Clinical presentation was not unique for individual \u003cem\u003eNocardia\u003c/em\u003e spp. infections. Overall mortality was 22.3% with a 1-year mortality of 12.2%. Delayed diagnosis (\u0026ge;\u0026thinsp;30 d) from symptom onset had higher mortality. Increased mortality occurred for \u003cem\u003eN. nova\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;\u003cem\u003eN. cyriacigeorgica\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;\u003cem\u003eN. farcinica\u003c/em\u003e complex infections.\u003c/p\u003e\u003ch2\u003eCONCLUSIONS\u003c/h2\u003e\u003cp\u003ePrompt diagnosis of nocardiosis improves patient outcomes. Nocardia species-level identification predicts mortality for major species complexes causing nocardiosis in our region.\u003c/p\u003e","manuscriptTitle":"Multi-year Population-Based Study of the Clinical and Epidemiological Risk Factors for Mortality in Nocardiosis: Survival Analysis from a Large Regional Canadian Healthcare Region","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-01 10:54:44","doi":"10.21203/rs.3.rs-6985944/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-14T19:13:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-03T21:12:09+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-31T06:30:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"20731078371906053079330526440169680371","date":"2025-07-29T12:02:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"8778051895581903173992250709333193591","date":"2025-07-29T09:20:48+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-29T08:48:46+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-07-04T16:58:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-01T23:20:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-01T23:19:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2025-06-26T18:31:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"61b91b27-eaf0-4bf2-b257-cc6342bb34cd","owner":[],"postedDate":"August 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-16T16:13:24+00:00","versionOfRecord":{"articleIdentity":"rs-6985944","link":"https://doi.org/10.1186/s12879-025-12456-3","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2026-02-11 15:58:58","publishedOnDateReadable":"February 11th, 2026"},"versionCreatedAt":"2025-08-01 10:54:44","video":"","vorDoi":"10.1186/s12879-025-12456-3","vorDoiUrl":"https://doi.org/10.1186/s12879-025-12456-3","workflowStages":[]},"version":"v1","identity":"rs-6985944","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6985944","identity":"rs-6985944","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}