Availability of drugs and resistance testing for BPaLM regimen for rifampicin-resistant tuberculosis in Europe.

OBJECTIVES: Multidrug-resistant/Rifampicin-resistant tuberculosis (TB) is a major obstacle to successful TB control. The recommendation by the World Health Organization to use bedaquiline, pretomanid, linezolid and moxifloxacin (BPaL(M)) for 6 months, based on results of three trials with high efficacy and low toxicity, has revolutionized treatment options. METHODS: In this study, representatives of the Tuberculosis Network European Trialsgroup (TBnet) in 44/54 countries of the WHO Europe region document the availability of the medicines and drug susceptibility testing (DST) of the BPaL(M) regimen through a structured questionnaire between September to November 2023. RESULTS: 24/44 (54.5%), 42/44 (95.5%), 43/44 (97.7%), and 43/44 (97.7%) had access to pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, 23/44 (52.3%) had access to all the drugs composing the BPaL(M) regimen. 7/44 (15.9%), 28/44 (63.6%), 34/44 (77.3%) and 36/44 (81.8%) had access to DST for pretomanid, bedaquiline, linezolid and moxifloxacin, respectively. DST was available for all medicines composing the BPaL(M) regimen in 6/44 (13.6%) countries. CONCLUSION: Only in about half of the countries participating in the survey clinicians have access to all the BPaL(M) regimen drugs. In less than a fifth of countries, a complete DST is possible. Rapid scale up of DST capacity to prevent unnoticed spread of drug resistance and equal access to new regimens are urgently needed in Europe.

Liver injury in patients with COVID-19 in comparison to patients with the pandemic influenza A (H1N1) 2009: a population-based study.

BACKGROUND: Elevated liver tests in patients with COVID-19 are widely reported. Population-based studies utilizing a validated analysis of drug-induced liver injury (DILI), with a control group of other viral illnesses and follow-up are largely lacking. MATERIALS AND METHODS: All hospitalized patients in Iceland with SARS-CoV-2 in 2020 and pandemic influenza A (H1N1) in 2009 were included in this retrospective, population-based study. Liver tests were compared between the two groups and the correlation to inflammatory markers and persistence of alanine aminotransferase (ALT) elevations were assessed. Potential DILI cases were reviewed using the Roussel Uclaf Causality Assessment Method (RUCAM). RESULTS: 225 SARS-CoV-2-positive and 73 influenza A (H1N1)-positive patients were included. Liver test values were similar between the groups, except for aspartate aminotransferase (AST) which was significantly lower in COVID-19, with a mean difference of 26 U/L (95%CI 4.2-47). Ferritin elevation was positively correlated with ALT, AST and alkaline phosphatase. No patient had persistently elevated ALT in COVID-19 and none had a probable DILI. Only 3 patients had a possible DILI according to the RUCAM. CONCLUSIONS: Elevated liver enzymes are not specific for COVID-19. Hyperferritinemia was associated with elevated liver tests. DILI was very rare in COVID-19 and an unlikely cause of elevated liver enzymes in COVID-19. Abnormal liver tests are nonpersistent and generally not clinically important in these patients.

Adults with symptoms of pneumonia: a prospective comparison of patients with and without infiltrates on chest radiography.

OBJECTIVE: Most studies on patients hospitalized with community-acquired pneumonia (CAP) require confirmation of an infiltrate by chest radiography, but in practice admissions are common among patients with symptoms of pneumonia without an infiltrate (SPWI). The aim of this research was to compare clinical characteristics, microbial etiology, and outcomes among patients with CAP and SPWI. METHODS: Adults suspected of CAP were prospectively recruited at Landspitali University Hospital over a 1-year period, 2018 to 2019. The study was population based. Those admitted with two or more of the following symptoms were invited to participate: temperature ≥38°C or ≤36°C, sweating, shaking/chills, chest pain, a new cough, or new onset of dyspnea. Primary outcome was mortality at 30 days and one year. RESULTS: Six hundred twenty-five cases were included, 409 with CAP and 216 with SPWI; median age was 75 (interquartile range [IQR] 64-84) and 315 (50.4%) were females. Patients with CAP were more likely to have fever (≥38.0°C) (66.9% [273/408]) vs. 49.3% (106/215), p < 0.001), a higher CRP (median 103 [IQR 34-205] vs. 55 (IQR 17-103), p < 0.001), identification of Streptococcus pneumoniae (18.0% [64/355]) vs. 6.3% (10/159) of tested, p = 0.002) and to receive antibacterial treatment (99.5% [407/409]) vs. 87.5% (189/216), p < 0.001) but less likely to have a respiratory virus detected (25.4% [33/130]) vs. 51.2% (43/84) of tested, p < 0.001). The adjusted odds ratios for 30-day and 1 year mortality of SPWI compared to CAP were 0.86 (95% CI 0.40-1.86) and 1.46 (95% CI 0.92-2.32), respectively. DISCUSSION: SPWI is a common cause of hospitalization and despite having fever less frequently, lower inflammatory markers, and lower detection rate of pneumococci than patients with CAP, mortality is not significantly different.

Development of a prognostic model of COVID-19 severity: a population-based cohort study in Iceland.

BACKGROUND: The severity of SARS-CoV-2 infection varies from asymptomatic state to severe respiratory failure and the clinical course is difficult to predict. The aim of the study was to develop a prognostic model to predict the severity of COVID-19 in unvaccinated adults at the time of diagnosis. METHODS: All SARS-CoV-2-positive adults in Iceland were prospectively enrolled into a telehealth service at diagnosis. A multivariable proportional-odds logistic regression model was derived from information obtained during the enrollment interview of those diagnosed between February 27 and December 31, 2020 who met the inclusion criteria. Outcomes were defined on an ordinal scale: (1) no need for escalation of care during follow-up; (2) need for urgent care visit; (3) hospitalization; and (4) admission to intensive care unit (ICU) or death. Missing data were multiply imputed using chained equations and the model was internally validated using bootstrapping techniques. Decision curve analysis was performed. RESULTS: The prognostic model was derived from 4756 SARS-CoV-2-positive persons. In total, 375 (7.9%) only required urgent care visits, 188 (4.0%) were hospitalized and 50 (1.1%) were either admitted to ICU or died due to complications of COVID-19. The model included age, sex, body mass index (BMI), current smoking, underlying conditions, and symptoms and clinical severity score at enrollment. On internal validation, the optimism-corrected Nagelkerke's R2 was 23.4% (95%CI, 22.7-24.2), the C-statistic was 0.793 (95%CI, 0.789-0.797) and the calibration slope was 0.97 (95%CI, 0.96-0.98). Outcome-specific indices were for urgent care visit or worse (calibration intercept -0.04 [95%CI, -0.06 to -0.02], Emax 0.014 [95%CI, 0.008-0.020]), hospitalization or worse (calibration intercept -0.06 [95%CI, -0.12 to -0.03], Emax 0.018 [95%CI, 0.010-0.027]), and ICU admission or death (calibration intercept -0.10 [95%CI, -0.15 to -0.04] and Emax 0.027 [95%CI, 0.013-0.041]). CONCLUSION: Our prognostic model can accurately predict the later need for urgent outpatient evaluation, hospitalization, and ICU admission and death among unvaccinated SARS-CoV-2-positive adults in the general population at the time of diagnosis, using information obtained by telephone interview.

[Effects of the COVID-19 pandemic and associated non-pharmaceutical interventions on diagnosis of myocardial infarction and selected infections in Iceland 2020].

INTRODUCTON: Nonpharmaceutical interventions to contain the spread of COVID-19 infections in Iceland in 2020 were successful, but the effects of these measures on incidence and diagnosis of other diseases is unknown. The aim of this study was to evaluate the impact of the COVID-19 pandemic on the diagnosis of myocardial infarction (MI) and selected infections with different transmission routes. MATERIALS AND METHODS: Health records of individuals 18 years or older who were admitted to Landspitali University Hospital (LUH) in 2016-2020 with pneumonia or MI were extracted from the hospital registry. We acquired data from the clinical laboratories regarding diagnostic testing for Chlamydia trachomatis, influenza, HIV and blood cultures positive for Enterobacterales species. Standardized incidence ratio (SIR) for 2020 was calculated with 95% confidence intervals (95%CI) and compared to 2016-2019. RESULTS: Discharge diagnoses due to pneumonia decreased by 31% in 2020, excluding COVID-19 pneumonia (SIR 0.69 (95%CI 0.64-0.75)). Discharge diagnoses of MI decreased by 18% (SIR 0.82 (95%CI 0.75-0.90)), and emergency cardiac catheterizations due to acute coronary syndrome by 23% (SIR 0.77 (95%CI 0.71-0.83)), while there was a 15% increase in blood stream infections for Enterobacterales species (SIR 1.15 (95%CI 1.04-1.28)). Testing for Chlamydia trachomatis decreased by 14.8% and positive tests decreased by 16.3%. Tests for HIV were reduced by 10.9%, while samples positive for influenza decreased by 23.6% despite doubling of tests being performed. CONCLUSION: The number of pneumonia cases of other causes than COVID-19 requiring admission dropped by a quarter in 2020. MI, chlamydia and influensa diagnoses decreased notably. These results likely reflect a true decrease, probably due to altered behaviour during the pandemic.

Acetylsalicylic acid use is associated with improved survival in bacteremic pneumococcal pneumonia: A long-term nationwide study.

BACKGROUND: Pneumonia is commonly caused by Streptococcus pneumoniae (pneumococcus) and associated with subsequent cardiovascular complications and increased mortality. Potential short-term survival benefits conferred by acetylsalicylic acid (ASA) use in pneumonia remain controversial, and long-term outcomes have not been studied. OBJECTIVES: To evaluate the association between ASA use and survival for up to 1 year following bacteremic pneumococcal pneumonia. METHODS: All bacteremic pneumococcal episodes in Iceland from 1975 to 2019 were reviewed. The study cohort consisted of individuals at least 18 years of age with symptoms and imaging results consistent with pneumonia. Differences in survival were assessed at 30 days, 90 days and 1 year using propensity score weighting (inverse probability weighting). Splitting and stratifying on survival at 7 days was done for the 30-day survival, because of nonproportionality. RESULTS: In total, 815 bacteremic pneumococcal pneumonia episodes (median age 67 years, females 48%) were identified. Cox regression using propensity score weighting on the association of ASA with survival at 30 days showed an average hazard ratio (HR) of 0.60 (95% confidence interval [CI] 0.34-1.05). A significantly improved survival was observed within 7 days (HR = 0.42, 95% CI 0.19-0.92) but not during days 7-30 (HR = 1.08, 95% CI 0.46-2.55). ASA was associated with survival at 90 days (HR = 0.53, 95% CI 0.32-0.87) and 1 year (HR = 0.48, 95% CI 0.31-0.75). CONCLUSION: Use of ASA upon admission for bacteremic pneumococcal pneumonia is associated with significantly reduced mortality for up to 1 year after diagnosis. ASA therapy in patients with pneumonia and other infectious syndromes warrants further study.

Detailed Multiplex Analysis of SARS-CoV-2 Specific Antibodies in COVID-19 Disease.

A detailed understanding of the antibody response against SARS-CoV-2 is of high importance, especially with the emergence of novel vaccines. A multiplex-based assay, analyzing IgG, IgM, and IgA antibodies against the receptor binding domain (RBD), spike 1 (S1), and nucleocapsid proteins of the SARS-CoV-2 virus was set up. The multiplex-based analysis was calibrated against the Elecsys® Anti-SARS-CoV-2 assay on a Roche Cobas® instrument, using positive and negative samples. The calibration of the multiplex based assay yielded a sensitivity of 100% and a specificity of 97.7%. SARS-CoV-2 specific antibody levels were analyzed by multiplex in 251 samples from 221 patients. A significant increase in all antibody types (IgM, IgG, and IgA) against RBD was observed between the first and the third weeks of disease. Additionally, the S1 IgG antibody response increased significantly between weeks 1, 2, and 3 of disease. Class switching appeared to occur earlier for IgA than for IgG. Patients requiring hospital admission and intensive care had higher levels of SARS-CoV-2 specific IgA levels than outpatients. These findings describe the initial antibody response during the first weeks of disease and demonstrate the importance of analyzing different antibody isotypes against multiple antigens and include IgA when examining the immunological response to COVID-19.

Clinical spectrum of coronavirus disease 2019 in Iceland: population based cohort study.

OBJECTIVE: To characterise the symptoms of coronavirus disease 2019 (covid-19). DESIGN: Population based cohort study. SETTING: Iceland. PARTICIPANTS: All individuals who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse transcription polymerase chain reaction (RT-PCR) between 17 March and 30 April 2020. Cases were identified by three testing strategies: targeted testing guided by clinical suspicion, open invitation population screening based on self referral, and random population screening. All identified cases were enrolled in a telehealth monitoring service, and symptoms were systematically monitored from diagnosis to recovery. MAIN OUTCOME MEASURES: Occurrence of one or more of 19 predefined symptoms during follow-up. RESULTS: Among 1564 people positive for SARS-CoV-2, the most common presenting symptoms were myalgia (55%), headache (51%), and non-productive cough (49%). At the time of diagnosis, 83 (5.3%) individuals reported no symptoms, of whom 49 (59%) remained asymptomatic during follow-up. At diagnosis, 216 (14%) and 349 (22%) people did not meet the case definition of the Centers for Disease Control and Prevention and the World Health Organization, respectively. Most (67%) of the SARS-CoV-2-positive patients had mild symptoms throughout the course of their disease. CONCLUSION: In the setting of broad access to RT-PCR testing, most SARS-CoV-2-positive people were found to have mild symptoms. Fever and dyspnoea were less common than previously reported. A substantial proportion of SARS-CoV-2-positive people did not meet recommended case definitions at the time of diagnosis.

Incidence, Etiology, and Outcomes of Community-Acquired Pneumonia: A Population-Based Study.

BACKGROUND: The microbial etiology of community-acquired pneumonia (CAP) is often unclear in clinical practice, and previous studies have produced variable results. Population-based studies examining etiology and incidence are lacking. This study examined the incidence and etiology of CAP requiring hospitalization in a population-based cohort as well as risk factors and outcomes for specific etiologies. METHODS: Consecutive admissions due to CAP in Reykjavik, Iceland were studied. Etiologic testing was performed with cultures, urine-antigen detection, and polymerase chain reaction analysis of airway samples. Outcomes were length of stay, intensive care unit admission, assisted ventilation, and mortality. RESULTS: The inclusion rate was 95%. The incidence of CAP requiring hospitalization was 20.6 cases per 10000 adults/year. A potential pathogen was detected in 52% (164 of 310) of admissions and in 74% (43 of 58) with complete sample sets. Streptococcuspneumoniae was the most common pathogen (61 of 310, 20%; incidence: 4.1/10000). Viruses were identified in 15% (47 of 310; incidence: 3.1/10000), Mycoplasmapneumoniae were identified in 12% (36 of 310; incidence: 2.4/10000), and multiple pathogens were identified in 10% (30 of 310; incidence: 2.0/10000). Recent antimicrobial therapy was associated with increased detection of M pneumoniae (P < .001), whereas a lack of recent antimicrobial therapy was associated with increased detection of S pneumoniae (P = .02). Symptoms and outcomes were similar irrespective of microbial etiology. CONCLUSIONS: Pneumococci, M pneumoniae, and viruses are the most common pathogens associated with CAP requiring hospital admission, and they all have a similar incidence that increases with age. Symptoms do not correlate with specific agents, and outcomes are similar irrespective of pathogens identified.

Mortality in healthcare-associated pneumonia in a low resistance setting: a prospective observational study.

BACKGROUND: The classification of pneumonia as community-acquired pneumonia (CAP) or healthcare-associated pneumonia (HCAP) has implications for selection of initial antimicrobial therapy. HCAP has been associated with an increased prevalence of multidrug-resistant (MDR) pathogens and with high mortality leading to recommendations for broad empiric therapy. METHODS: We performed a prospective, population-based study on consecutive adults (≥ 18 years) admitted for pneumonia over 1 calendar year. Patients were classified by pneumonia type and severity. Microbial etiologic testing was performed on all patients. Treatment, length of stay, and mortality rates were compared. RESULTS: A total of 373 admissions were included, 94% of all eligible patients. They were classified as CAP (n = 236, 63%) or HCAP (n = 137, 37%). Chronic underlying disease was more commonly found among patients with HCAP compared with CAP (74% vs 51%, p < 0.001). Mycoplasma pneumoniae was more common among CAP patients (p < 0.01), while gram-negative bacteria were more often found among HCAP patients (p = 0.02). No MDR pathogens were detected, and rates of Staphylococcus aureus were similar in the two groups. HCAP patients were not more likely to receive ineffective initial antimicrobial therapy. HCAP patients had worse prognostic scores on admission and higher in-house mortality than CAP patients (10% vs 1%, respectively, p < 0.01). CONCLUSIONS: Even in a low resistance setting, patients with HCAP have increased mortality compared with patients with CAP. This is most likely explained by a higher prevalence of co-morbidities. Our data do not support broad-spectrum empiric antibiotic therapy for HCAP.

Severity of influenza A 2009 (H1N1) pneumonia is underestimated by routine prediction rules. Results from a prospective, population-based study.

BACKGROUND: Characteristics of patients with community-acquired pneumonia (CAP) due to pandemic influenza A 2009 (H1N1) have been inadequately compared to CAP caused by other respiratory pathogens. The performance of prediction rules for CAP during an epidemic with a new infectious agent are unknown. METHODS: Prospective, population-based study from November 2008-November 2009, in centers representing 70% of hospital beds in Iceland. Patients admitted with CAP underwent evaluation and etiologic testing, including polymerase chain reaction (PCR) for influenza. Data on influenza-like illness in the community and overall hospital admissions were collected. Clinical and laboratory data, including pneumonia severity index (PSI) and CURB-65 of patients with CAP due to H1N1 were compared to those caused by other agents. RESULTS: Of 338 consecutive and eligible patients 313 (93%) were enrolled. During the pandemic peak, influenza A 2009 (H1N1) patients constituted 38% of admissions due to CAP. These patients were younger, more dyspnoeic and more frequently reported hemoptysis. They had significantly lower severity scores than other patients with CAP (1.23 vs. 1.61, P= .02 for CURB-65, 2.05 vs. 2.87 for PSI, P<.001) and were more likely to require intensive care admission (41% vs. 5%, P<.001) and receive mechanical ventilation (14% vs. 2%, P= .01). Bacterial co-infection was detected in 23% of influenza A 2009 (H1N1) patients with CAP. CONCLUSIONS: Clinical characteristics of CAP caused by influenza A 2009 (H1N1) differ markedly from CAP caused by other etiologic agents. Commonly used CAP prediction rules often failed to predict admissions to intensive care or need for assisted ventilation in CAP caused by the influenza A 2009 (H1N1) virus, underscoring the importance of clinical acumen under these circumstances.

[Evaluation of thromboprophylactic therapy at Landspítali - The National University Hospital of Iceland; a cross-sectional study on acute wards]. / Frammistada Landspitala i forvornum gegn blaaedasegasjukdomum; thversnidsrannsokn a bradadeildum.

OBJECTIVE: Venous thromboembolic disease is a serious and often fatal complication following hospital admission. Studies show that thromboprophylactic therapy for this condition is often underutilized. The aim of this study was to evaluate the performance of thromboprophylactic therapy at Landspítali - The University Hospital of Iceland in adult patients admitted to acute wards. METHODS AND MATERIALS: On 2 December 2009 hospital charts of admitted patients on acute wards were reviewed and assessed for appropriate thromboprophylactic treatment according to the 2008 guidelines from The American College of Chest Physicians. The results were compared to those of other countries from the multinational Endorse study from 2008. RESULTS: 251 patient were included of whom 47% were considered at risk for venous thromboembolic disease. Of those 57% received appropriate thromboprophylactic treatment or 78% of surgical and 26% of medical patients. CONCLUSIONS: Adherence to clinical guidelines for thromboprophylactic treatment at surgical wards of Landspítali - The National University Hospital of Iceland was good and well above the average compared to the results of the Endorse study. Performance on the medical wards was on the other hand below average. Our results show that application of thromoboprophylactic treatment at Landspítali could be improved and thereby enhance patient safety.