Healthcare-associated infective endocarditis: source of infection and burden of previous healthcare exposure.

Objective: Prevention of healthcare-associated infective endocarditis (HAIE) is based on characterization of underlying factors. Our object was to describe the source of infection, microbiological etiology, and healthcare-related risk factors for HAIE. Design: Retrospective population-based study. Patients: Adult patients diagnosed with HAIE during 2013-2017 who resided in the study area in Southern Finland with adult population of 0.9 million. Results: Ninety-five HAIE episodes were included. Ten episodes were related to cardiac surgery. Of the remaining 85 episodes, 11 were classified as nosocomial (ie, acquired and diagnosed during ongoing hospitalization) and 74 as non-nosocomial HAIE. Staphylococcus aureus caused 45% of nosocomial episodes, but only 16% of non-nosocomial episodes (P = 0.039). Most common sources of infection in non-nosocomial HAIE were previous hospitalization (24%), dialysis (18%), and urologic procedures (15%). Enterococcus spp. caused 23% of non-nosocomial HAIE, and more than half of them were associated with urologic or gastrointestinal procedures. Two-thirds of the non-nosocomial HAIE patients had recent hospitalization or invasive procedure. We counted previous healthcare-related risk factors for IE and those who had two or more of them had higher in-hospital and one-year mortality. Conclusion: Our study indicates the importance of non-nosocomial acquisition of HAIE and S. aureus as the major pathogen in nosocomial episodes. Enterococcal infections dominate in non-nosocomial cases and further studies are needed to identify patients at risk for enterococcal IE after urological or gastrointestinal procedure.

Generalized infections of putative oral origin in Helsinki University Hospital in 2012 to 2017.

OBJECTIVE: Bacteria entering the bloodstream through oral mucosa cause bacteremia, which can lead to septic or distant infections. The underlying factors and need for dental treatment in patients referred for oral examination because of septic infection were investigated. It was expected that general diseases and poor socioeconomic status of patients would increase the risk of bacteremia. METHOD AND MATERIALS: This descriptive retrospective study included patients (N = 128) referred from medical clinics of the Helsinki University Hospital (HUH), during 2012 to 2017, to the Department of Oral and Maxillofacial Diseases due to bacteremia suspected to be of oral origin. Data were extracted from medical and dental records according to the World Health Organization International Classification of Diseases (ICD-10) for systemic or remote infections. Different groups were formed using modified Skapinakis classification for socioeconomic status (SES), from I (high) to V (low). Underlying medical conditions were retrieved according to McCabe classification: healthy, nonfatal, ultimately fatal, and rapidly fatal diseases. The data were analyzed using the statistical software package SPSS (IBM). RESULTS: Patients were referred most often from the Departments of Infectious Diseases and Internal Medicine. Because of infection, 12 patients needed aortic or mitral valve operations. Many of the patients were intravenous drug users. However, the majority of patients presented McCabe class I, indicating no systemic disease. The main SES was intermediate III. Tooth extraction was the principal mode of treatment. No demographic background variables were identified to explain increase of the risk for bacteremia except that most patients were men with untreated dental problems. CONCLUSIONS: Contrary to the authors' expectation, poor SES and underlying diseases did not seem to link to the outcome. However, untreated dental infections present an evident risk for life-threatening septic complications also in generally healthy individuals.

SARS-CoV-2 infections among healthcare workers at Helsinki University Hospital, Finland, spring 2020: Serosurvey, symptoms and risk factors.

BACKGROUND: Exposure, risks and immunity of healthcare workers (HCWs), a vital resource during the SARS-CoV-2 pandemic, warrant special attention. METHODS: HCWs at Helsinki University Hospital, Finland, filled in questionnaires and provided serum samples for SARS-CoV-2-specific antibody screening by Euroimmun IgG assay in March-April 2020. Positive/equivocal findings were confirmed by Abbott and microneutralization tests. Positivity by two of the three assays or RT-PCR indicated a Covid-19 case (CoV+). RESULTS: The rate of CoV(+) was 3.3% (36/1095) and seropositivity 3.0% (33/1095). CoV(+) was associated with contact with a known Covid-19 case, and working on a Covid-19-dedicated ward or one with cases among staff. The rate in the Covid-19-dedicated ICU was negligible. Smoking and age <55 years were associated with decreased risk. CoV(+) was strongly associated with ageusia, anosmia, myalgia, fatigue, fever, and chest pressure. Seropositivity was recorded for 89.3% of those with prior documented RT-PCR-positivity and 2.4% of those RT-PCR-negative. The rate of previously unidentified cases was 0.7% (8/1067) and asymptomatic ones 0% (0/36). CONCLUSION: Undiagnosed and asymptomatic cases among HCWs proved rare. An increased risk was associated with Covid-19-dedicated wards. Particularly high rates were seen for wards with liberal HCW-HCW contacts, highlighting the importance of social distancing also among HCWs.

The Characteristics of Postoperative Mediastinitis During the Changing Phases of Cardiac Surgery.

BACKGROUND: Mediastinitis is a serious complication of open heart surgery associated with high mortality, considerable health care costs, and prolonged hospital stay. We examined characteristics and incidence of mediastinitis during 29 years when indications and patient material have been in a process of change. METHODS: This was a retrospective population-based study comprising all mediastinitis patients more than 16 years of age after open heart surgery between 1990 and 2018 from a population of 1.7 million. Patient records of 50 mediastinitis patients from 2004 to 2014 were reviewed and compared with 120 patients from 1990 to 1999. RESULTS: Annual mediastinitis rate varied 0% to 1.5% with a decreasing trend-from a level exceeding 1.2% to approximately 0.3%-over the study period. In 2004 to 2014 patients with mediastinitis were older, more often smokers, and more often had diabetes mellitus and renal insufficiency than in 1990 to 1999. No difference in length of hospital treatment, antibiotic prophylaxis or treatment, intensive care unit treatment, or mortality was observed between 1990 to 1999 and 2004 to 2014. Coronary artery bypass graft surgery became less common and valve replacement and hybrid operations more common among operations leading to mediastinitis. Staphylococcus aureus increased (from 25% to 56%, p = .005) whereas coagulase-negative staphylococci (46% to 23%, P < .001) and gram-negative bacteria (18% to 12%, P = .033) decreased as causative agents. Surgery for mediastinitis remained similar except introduction of vacuum-assisted closure treatment. CONCLUSIONS: The rate of mediastinitis decreased during these 29 years. No difference in 30-day mortality in mediastinitis was seen: 0.9% in 1990 to 1999 and 2% in 2004 to 2014.

Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy.

BACKGROUND: CCAAT enhancer-binding protein epsilon (C/EBPε) is a transcription factor involved in late myeloid lineage differentiation and cellular function. The only previously known disorder linked to C/EBPε is autosomal recessive neutrophil-specific granule deficiency leading to severely impaired neutrophil function and early mortality. OBJECTIVE: The aim of this study was to molecularly characterize the effects of C/EBPε transcription factor Arg219His mutation identified in a Finnish family with previously genetically uncharacterized autoinflammatory and immunodeficiency syndrome. METHODS: Genetic analysis, proteomics, genome-wide transcriptional profiling by means of RNA-sequencing, chromatin immunoprecipitation (ChIP) sequencing, and assessment of the inflammasome function of primary macrophages were performed. RESULTS: Studies revealed a novel mechanism of genome-wide gain-of-function that dysregulated transcription of 464 genes. Mechanisms involved dysregulated noncanonical inflammasome activation caused by decreased association with transcriptional repressors, leading to increased chromatin occupancy and considerable changes in transcriptional activity, including increased expression of NLR family, pyrin domain-containing 3 protein (NLRP3) and constitutively expressed caspase-5 in macrophages. CONCLUSION: We describe a novel autoinflammatory disease with defective neutrophil function caused by a homozygous Arg219His mutation in the transcription factor C/EBPε. Mutated C/EBPε acts as a regulator of both the inflammasome and interferome, and the Arg219His mutation causes the first human monogenic neomorphic and noncanonical inflammasomopathy/immunodeficiency. The mechanism, including widely dysregulated transcription, is likely not unique for C/EBPε. Similar multiomics approaches should also be used in studying other transcription factor-associated diseases.

Factors associated with blood culture positivity in patients with complicated skin and skin structure infection-a population-based study.

Skin and skin structure infection (SSSI) is classified as complicated (cSSSI) if it involves deep subcutaneous tissue or requires surgery. Factors associated with blood culture sampling and bacteremia have not been established in patients with cSSSI. Moreover, the benefit of information acquired from positive blood culture is unknown. The aim of this study was to address these important issues. In this retrospective population-based study from two Nordic cities, a total of 460 patients with cSSSI were included. Blood cultures were drawn from 258 (56.1%) patients and they were positive in 61 (23.6%) of them. Factors found to be associated with more blood culture sampling in multivariate analysis were diabetes, duration of symptoms shorter than 2 days and higher C-reactive protein (CRP) level. Whereas factors associated with less frequent blood culture sampling were peripheral vascular disease and a surgical wound infection. In patients from whom blood cultures were taken, alcohol abuse was the only factor associated with culture positivity, as CRP level was not. Patients with a positive blood culture had antibiotic streamlining more often than non-bacteremic patients. A high rate of blood culture positivity in patients with cSSSI was observed. Factors related to more frequent blood culture sampling were different from those associated with a positive culture.

Impact of pre-operative antimicrobial treatment on microbiological findings from endocardial specimens in infective endocarditis.

Treatment of infective endocarditis (IE) should be initiated promptly. This might hamper the chances to identify the causative organism in blood cultures. Microbiological sampling of infected valve in patients undergoing surgery might identify the causative organism. The impact of pre-operative antimicrobial treatment on the yield of valve samples is not known. This study evaluated the impact of the duration of the pre-operative antibiotic treatment on valve culture and 16S rRNA PCR findings from resected endocardial samples. Patients meeting the modified Duke criteria of definite or possible IE and undergoing valve surgery due to IE during 2011-2016 were included from Southern Finland. Eighty-seven patients were included. In patients with shorter than 2 weeks of pre-operative antimicrobial treatment, PCR was positive in 91% (n = 42/46) and valve culture in 41% (n = 19/46) of cases. However, in patients who had 2 weeks or longer therapy before operation, PCR was positive in 53% (n = 18/34) and all valve cultures were negative. In 14% of patients, PCR had a diagnostic impact. In blood-culture negative cases (n = 13), PCR could detect the causative organism in ten patients (77%). These included five cases of Bartonella quintana, one Tropheryma whipplei, and one Coxiella burnetii. Long pre-operative antimicrobial treatment was shown to have a negative impact on microbiological tests done on resected endocardial material. After 2 weeks of therapy, all valve cultures were negative, but PCR was positive in half of the cases. PCR aided in diagnostic work-up, especially in blood culture negative cases.

Clinical features of patients with homozygous complement C4A or C4B deficiency.

INTRODUCTION: Homozygous deficiencies of complement C4A or C4B are detected in 1-10% of populations. In genome-wide association studies C4 deficiencies are missed because the genetic variation of C4 is complex. There are no studies where the clinical presentation of these patients is analyzed. This study was aimed to characterize the clinical features of patients with homozygous C4A or C4B deficiency. MATERIAL AND METHODS: Thirty-two patients with no functional C4A, 87 patients with no C4B and 120 with normal amount of C4 genes were included. C4A and C4B numbers were assessed with genomic quantitative real-time PCR. Medical history was studied retrospectively from patients' files. RESULTS: Novel associations between homozygous C4A deficiency and lymphoma, coeliac disease and sarcoidosis were detected. These conditions were present in 12.5%, (4/32 in patients vs. 0.8%, 1/120, in controls, OR = 17.00, 95%CI = 1.83-158.04, p = 0.007), 12.5% (4/32 in patients vs. 0%, 0/120 in controls, OR = 1.14, 95%CI = 1.00-1.30, p = 0.002) and 12.5%, respectively (4/32 in patients vs. 2.5%, 3/120 in controls, OR = 5.571, 95%CI = 1.79-2.32, p = 0.036). In addition, C4A and C4B deficiencies were both associated with adverse drug reactions leading to drug discontinuation (34.4%, 11/32 in C4A-deficient patients vs. 14.2%, 17/120 in controls, OR = 3.174, 95%CI = 1.30-7.74, p = 0.009 and 28.7%, 25/87 in C4B-deficient patients, OR = 2.44, 95%CI = 1.22-4.88, p = 0.010). CONCLUSION: This reported cohort of homozygous deficiencies of C4A or C4B suggests that C4 deficiencies may have various unrecorded disease associations. C4 gene should be considered as a candidate gene in studying these selected disease associations.

Unexpectedly High Prevalence of Common Variable Immunodeficiency in Finland.

BACKGROUND: Common variable immunodeficiency (CVID) is the most common primary immunodeficiency. Prevalence varies greatly between countries and studies. Most diagnostic criteria include hypogammaglobulinemia and impaired vaccine response. AIM: To evaluate the minimum prevalence as well as the clinical and immunological phenotypes of CVID in Southern Finland. METHODS: We performed a cross-sectional study to assess all adult CVID patients followed up in three hospital districts in Southern and South-Eastern Finland between April 2007 and August 2015. CVID diagnosis was based, with a minor modification, on the ESID/PAGID criteria for primary CVID. Antipolysaccharide responses to Pneumovax® were defined as impaired only if 50% or more of the serotypes did not reach a level of 0.35 µg/mL after vaccination. We further characterized the patients' B cell phenotypes and complications associated with CVID. RESULTS: In total, 9 patients were excluded due to potential secondary causes before diagnosis. ESID/PAGID criteria were met by 132 patients (males 52%), of whom, 106 had "probable" and 26 "possible CVID." Based on the population statistics in the three hospital districts, the minimum adult prevalence per 100,000 inhabitants in Finland for all CVID ("probable CVID," respectively) patients was 6.9 (5.5). In the highest prevalence district (Helsinki and Uusimaa), the prevalence was 7.7 (6.1). CVID patients suffer from frequent complications. Ten patients died during follow-up. Of probable CVID patients, 73% had more than one clinical phenotype. Intriguingly, gradual B cell loss from peripheral blood during follow-up was seen in as many as 16% of "probable CVID" patients. Patients with possible CVID displayed somewhat milder clinical and laboratory phenotypes than probable CVID patients. We also confirm that large granular lymphocyte lymphoproliferation is a CVID-associated complication. CONCLUSION: The prevalence of CVID in Finland appears the highest recorded, likely reflecting the genetic isolation and potential founder effects in the Finnish population. Studies to discover potential gene variants responsible for the high prevalence in Finland thus seem warranted. Increased awareness of CVID among physicians would likely lead to earlier diagnosis and improved quality of care.

[Fever and a mediastinal mass--infection or malignancy?]. / Mikrobilääkkeisiin reagoimaton kuume ja vahva syöpäepäily.

A seventyseven-year old woman had a history of osteomyelitis in the 1940s. Now, she was investigated for an antibiotic resistant fever. An unusual infection, an autoimmune disease or a malignancy was suspected. In the CT scan a mediastinal mass was detected and a mediastinoscopy was performed. Histology revealed a granulomatous infection but a tuberculous infection was ruled out. A favourable response to ordinary antibiotics was gained and the diagnosis of tularemia was confirmed by a serologic test.

Clinical symptoms and survival in non-smoking and smoking HIV-negative patients with non-tuberculous mycobacterial isolation.

BACKGROUND: Non-tuberculous mycobacteria (NTM) cause infections in patients with smoking-related chronic lung diseases and also in non-smoking healthy elderly women. We analyzed the clinical symptoms, underlying diseases and mortality in patients with NTM culture findings, with special emphasis on smoking status. METHODS: A total of 120 consecutive adult HIV-negative patients with NTM isolation were followed between 1990 and 1998 by retrieving data from their medical records for a period of at least 4 y, until 8 June 2006. Their clinical pictures and outcomes were analysed according to smoking status. RESULTS: In this study, 42% of the patients had never smoked. Females accounted for 72% of non-smokers, but only 30% of smokers (p < 0.001). Mycobacterium avium complex (MAC) accounted for 72% of all isolates in non-smokers and 41% in smokers (p = 0.001). Furthermore, 28% of non-smokers and 19% of smokers had no previous pulmonary diseases (p = 0.223). In nearly half of all patients (48%), symptoms of NTM infection started within a year prior to NTM isolation. Smokers had a higher risk of mortality compared to non-smokers (hazard ratio 1.64, p = 0.049), though this was not found after adjusting for underlying diseases. No fatal underlying diseases were found for 82% of non-smokers and 59% of smokers (p < 0.01). CONCLUSIONS: Non-smokers with NTM isolates had fewer previous lung diseases but had a higher incidence of MAC and bronchiectasis. Time from symptoms to NTM isolation was shorter than previously reported.

Pharmacokinetics of estradiol valerate and medroxyprogesterone acetate in different age groups of postmenopausal women.

OBJECTIVES: To study whether ageing affects the pharmacokinetics of estradiol valerate (E2V) or medroxyprogesterone acetate (MPA) in postmenopausal women. METHODS: Forty-six postmenopausal women from two essentially similar pharmacokinetic studies were divided into three age categories: under 60 years (n = 15), between 60 and 65 years (n = 18) and over 65 years (n = 13). They all were treated for 12 days or 14 days with four galenically identical tablets containing combinations of 1 mg or 2 mg E2V and 2.5 mg or 5 mg MPA. The studies followed an open, randomised cross-over design with no washout between the periods. Serum estradiol and MPA concentrations were measured at steady state on study day 12 or 14 of each period. RESULTS: No statistically significant differences were observed in the peak concentration (Cmax), time to peak (t(max)), AUC or elimination half-life for estradiol or MPA between the different age groups. In spite of the lack of statistical significance the AUC was on an average 1.6-fold and Cmax 1.40-fold higher in the oldest group of women than in the youngest group and age was found significant as a continuous variable for AUC and Cmax for MPA but not for estradiol. CONCLUSIONS: The results suggest that there would be no significant changes in the pharmacokinetics of estradiol between women under 60 and over 65 years of age. However, a significant trend towards higher MPA concentrations and bioavailability was observed with increasing age. The results suggest that from the pharmacokinetic point of view the relationship between estradiol and MPA dose to be used in elderly could be different from that in younger postmenopausal women, while no pharmacokinetic reasons to use lower estradiol doses in the elderly were observed.

High rate of monoclonal gammopathy among immunocompetent subjects with primary cytomegalovirus infection.

Serum samples from immunocompetent adults with primary cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection and from solid-organ or bone marrow transplant recipients with primary CMV infection were examined for paraproteins. Several immunocompetent patients with CMV infection but none with EBV infection presented with an M component, which implies that the M component connects CMV infection to a risk of B cell malignancy.