Lung function trajectories in mild COVID-19 with two-year follow-up.

OBJECTIVE: To characterize lung function dynamics in individuals with mild COVID-19 from pre-infection to two years post-infection. METHODS: We re-invited participants two years after infection from our matched cohort study of the Copenhagen General Population who had initially been examined 5.4 months after infection. We repeated lung tests and questionnaires. Linear mixed models were used to estimate lung volume changes in individuals with COVID-19 patients versus uninfected controls over two intervals: from pre-infection to six months post-infection and six months post-infection to two years post-infection. RESULTS: 52 individuals (48.6%) attended the two-year examination at median 1.9 years (IQR 1.8; 2.4) after COVID-19, all with mild infection. Individuals with COVID-19 had an adjusted excess decline in FEV1 of 13.0 mL per year (CI 23.5; 2.5), p=0.02 from prior infection to 6 months after infection compared to uninfected controls. From 6 to 24 months after infection, they had an excess decline of 7.5 mL per year (CI 25.6; 9.6), p=0.40. A similar pattern was observed for FVC. Participants had a mean increase in DLco of 3.33 (SD 7.97) between the 6- and 24-month examination. CONCLUSION: Our results indicate that mild COVID-19 infection affects lung function at time of infection with limited recovery two years after infection.

A Dedicated Mycosis Flask Increases the Likelihood of Identifying Candidemia Sepsis.

INTRODUCTION: Candidemia is a severe condition associated with high mortality, and fungi are often not covered by empiric antimicrobial regimes for sepsis. Therefore, the shortest possible time to detection of yeast in the blood is of the essence. MATERIALS AND METHODS: We performed a cohort study of blood culture flasks drawn from patients aged 18 or older in the capital region of Denmark. In 2018 a blood cultures set consisted of two aerobic and two anaerobic flasks. This was changed in 2020 to two aerobic, one anaerobic, and one mycosis flask. We used time-to-event statistics to model time to positivity and compared 2018 with 2020; further, we stratified analyses on the blood culture system used (BacTAlert™ vs. BACTEC™) and high-risk vs. low-risk departments. RESULTS: We included 175,416 blood culture sets and 107,077 unique patients. We found an absolute difference in the likelihood of identifying fungi in a blood culture set of 1.2 (95% CI: 0.72; 1.6) pr. 1.000 blood culture sets corresponding to the number needed to treat 853 (617; 1382). In high-risk departments, the absolute difference was profound, whereas it was negligible and statistically non-significant in low-risk departments 5.2 (95% CI: 3.4; 7.1) vs. 0.16 (-0.17; 0.48) pr. 1.000 blood culture sets. CONCLUSIONS: We found that including a mycosis flask in a blood culture set increases the likelihood of identifying candidemia. The effect was mainly seen in high-risk departments.

Lung Abnormalities in Severe Acute Respiratory Syndrome Coronavirus 2 Infection: An Analysis of Paired Computed Tomography Scans Before and After Infection.

Background: Studies on the pulmonary consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are impeded by limited access to pre-SARS-CoV-2 examinations. Methods: We invited Copenhagen General Population Study participants with a confirmed SARS-CoV-2 polymerase chain reaction (PCR) test during the first and second coronavirus disease 2019 waves in Denmark for a repeat chest computed tomography (CT) scan. Paired CT scans were independently assessed for interstitial and noninterstitial abnormalities by 2 trained radiologists. A semiquantitative CT score (ranging from 0 to 20) was used to quantify the extent of interstitial abnormalities. Results: Of 111 SARS-CoV-2-infected individuals, 102 (91.2%) experienced symptoms and 12 (11.2%) were hospitalized. Follow-up examination was performed at median of 5.4 (interquartile range, 4.1-7.8) months after a positive SARS-CoV-2 PCR test. Of 67 individuals with paired CT scans, ground glass opacities and reticulation were present in 31 (46.3%) individuals post-SARS-CoV-2 compared to 23 (34.1%) pre-SARS-CoV-2 (mean CT score, 3.0 vs 1.3; P = .011). Results were similar for nonhospitalized individuals. We did not detect development of bronchiectasis, emphysema, or nodules. Conclusions: SARS-CoV-2 infection in predominantly nonhospitalized individuals with mild disease was associated with a small increase in only interstitial lung abnormalities.

Early Biomarker-Guided Prediction of Bloodstream Infection in Critically Ill Patients: C-Reactive Protein, Procalcitonin, and Leukocytes.

Background: Bloodstream infections (BSIs) often lead to critical illness and death. The primary aim of this study was to determine the diagnostic accuracy of the biomarkers C-reactive protein (CRP), procalcitonin (PCT), and leukocyte count for the diagnosis of BSI in critically ill patients. Methods: This was a nested case-control study based on the Procalcitonin And Survival Study (PASS) trial (n = 1200). Patients who were admitted to the intensive care unit (ICU) <24 hours, and not expected to die within <24 hours, were recruited. For the current study, we included patients with a BSI within ±3 days of ICU admission and matched controls without a BSI in a 1:2 ratio. Diagnostic accuracy for BSI for the biomarkers on days 1, 2, and 3 of ICU admission was assessed. Sensitivity, specificity, and negative and positive predictive values were calculated for prespecified thresholds and for a data-driven cutoff. Results: In total, there were 525 patients (n = 175 cases, 350 controls). The fixed low threshold for all 3 biomarkers (CRP = 20 mg/L; leucocytes = 10 × 109/L; PCT = 0.4 ng/mL) resulted in negative predictive values on day 1: CRP = 0.91; 95% CI, 0.75-1.00; leukocyte = 0.75; 95% CI, 0.68-0.81; PCT = 0.91; 95% CI, 0.84-0.96). Combining the 3 biomarkers yielded similar results as PCT alone (P = .5). Conclusions: CRP and PCT could in most cases rule out BSI in critically ill patients. As almost no patients had low CRP and ∼20% had low PCT, a low PCT could be used, along with other information, to guide clinical decisions.

Lung Function Decline in Relation to COVID-19 in the General Population: A Matched Cohort Study With Prepandemic Assessment of Lung Function.

BACKGROUND: To quantify the potential decline in dynamic lung volumes following coronavirus disease 2019 (COVID-19) in the general population. METHODS: A prospective matched cohort study of adult Copenhagen General Population Study (CGPS) participants with a prepandemic spirometry available. CGPS individuals with positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) test performed repeat spirometry, a questionnaire regarding respiratory symptoms, and diffusing capacity test for carbon monoxide. A matched uninfected CGPS control sample was used, and simple regression and linear mixed effect models were computed to study lung function decline. RESULTS: A total of 606 individuals were included; 92/107 (85.9%) with positive SARS-CoV-2 PCR test experienced coronavirus disease 2019 (COVID-19) symptoms and 12 (11.2%) were hospitalized. Spirometry was performed at median 5.6 months (interquartile range, 3.9-12.8) after positive SARS-CoV-2 PCR test. COVID-19 was associated with adjusted 7.3 mL (95% confidence interval [CI], .3-14.3) and 22.6 mL (95% CI, 13.1-32.0) steeper decline in annual forced expiratory volume in first second (FEV1) and FVC or total 113.8 and 301.3 mL lower FEV1 and FVC from baseline to follow-up. Results were robust in analyses restricted to individuals not requiring hospitalization. CONCLUSIONS: COVID-19-related declines of dynamic lung volume in the general population not requiring hospitalization were small but measurable.

Stenotrophomonas maltophilia bacteraemia: 61 cases in a tertiary hospital in Denmark.

BACKGROUND: Stenotrophomonas maltophilia is an opportunistic pathogen and a dreaded cause of bacteraemia with 30-day mortality rates ranging from 14 to 69%. The purpose of this cohort study was to evaluate outcomes of S. maltophilia bacteraemia, at Rigshospitalet, a tertiary hospital in Copenhagen, Denmark. METHODS: We included all patients with a blood culture positive for S. maltophilia, from January 1, 2015 to April 1, 2020. We extracted data on antimicrobial susceptibility, treatment, central venous catheter intervention and severe haematological disease. RESULTS: Sixty-one cases of S. maltophilia bacteraemia were identified. The overall 90-day mortality was 18%. Sixty percent of patients had a central venous catheter intervention performed. Seventy-nine percent of patients were treated with trimethoprim/sulfamethoxazole (TMP/SMX). Patients with central venous catheter intervention had significantly better survival than those without (HR: 0.16 [95% CI: 0.03-0.73]). Severe haematological disease and patients, who received intensive care unit (ICU) care, were at higher risk of death than other patients (HR: 5.93 [95% CI: 1.18 - 29.94] and HR: 8.37 [95% CI: 1.79 - 39.20], respectively). We found no evidence that any antibiotic regime was superior with regard to 90-day mortality. CONCLUSIONS: We did not find evidence to support a change in the current standard-of-care regimen of TMP/SMX and CVC removal. Larger clinical trials are needed to guide such recommendations.

Incidence of Chronic Obstructive Pulmonary Disease in People With Human Immunodeficiency Virus and Their Parents and Siblings in Denmark.

BACKGROUND: People with human immunodeficiency virus (PWH) may be at increased risk of several respiratory syndromes including chronic obstructive pulmonary disease (COPD). In matched cohort studies, we examined risk factors for COPD in PWH and their parents and siblings compared with population controls. METHODS: Using data from national registries, competing risk regression models were constructed and used to calculate adjusted hazard ratios (aHRs) for COPD. We evaluated the effect of human immunodeficiency virus characteristics, smoking, and educational attainment on COPD incidence in PWH. RESULTS: A total of 226 PWH and 1029 population controls were diagnosed with COPD during 63 661 and 562 171 person-years of follow-up. PWH had increased risk of being diagnosed with COPD compared to controls (aHR, 2.02 [95% confidence interval, 1.75-2.33]). Parents and siblings of PWH were also more likely to be diagnosed with COPD compared to controls. CD4+ T-cell counts were not associated with COPD, but unsuppressed viral replication, smoking status, and educational attainment were associated with COPD in PWH. No COPD diagnoses were registered in PWH with high educational attainment and absence of smoking. CONCLUSIONS: PWH have an increased risk of being diagnosed with COPD, as have their parents and siblings. This seems to be driven primarily by smoking and low socioeconomic status.

Decrease of contact allergy to hydroxyisohexyl 3-cyclohexene carboxaldehyde in Europe prior to its ban and diagnostic value.

BACKGROUND: Hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) has been the most reported fragrance chemical for two decades and will be prohibited in cosmetic products from August 2021. OBJECTIVES: To describe the time trend of HICC contact allergy in European patients with dermatitis in 2009 to 2019, and the added value of testing HICC separately in the baseline series. METHODS: Data were reviewed for 124 472 patients with dermatitis who were patch tested with HICC 5% pet. in the baseline series in the European Surveillance System on Contact Allergy (ESSCA) network (2009 to 2018) and at the Herlev-Gentofte Hospital Department of Dermatology and Allergy (2009 to 2019). RESULTS: Contact allergy to HICC was found in 1.98% of 9865 patients in Gentofte and 1.62% of 114 607 patients in the ESSCA network. Overall, the prevalence decreased annually, with 0.156 percentage points (P = .001) in Gentofte and 0.051 percentage points (P = .0002) in ESSCA. The frequency of missed contact allergy to HICC when testing only with fragrance mix II (FMII) was 0.17% (17/9865) and 0.35% (405/114607) of the whole test population in the Gentofte and ESSCA populations, respectively. CONCLUSIONS: This is the first study to demonstrate a significant decline in HICC allergy in European patients with dermatitis, most likely attributed to the upcoming European ban.

Compartmental immunophenotyping in COVID-19 ARDS: A case series.

BACKGROUND: Severe immunopathology may drive the deleterious manifestations that are observed in the advanced stages of coronavirus disease 2019 (COVID-19) but are poorly understood. OBJECTIVE: Our aim was to phenotype leukocyte subpopulations and the cytokine milieu in the lungs and blood of critically ill patients with COVID-19 acute respiratory distress syndrome (ARDS). METHODS: We consecutively included patients less than 72 hours after intubation following informed consent from their next of kin. Bronchoalveolar lavage fluid was evaluated by microscopy; bronchoalveolar lavage fluid and blood were assessed by 10-color flow cytometry and a multiplex cytokine panel. RESULTS: Four mechanically ventilated patients (aged 40-75 years) with moderate-to-severe COVID-19 ARDS were included. Immature neutrophils dominated in both blood and lungs, whereas CD4 and CD8 T-cell lymphopenia was observed in the 2 compartments. However, regulatory T cells and TH17 cells were found in higher fractions in the lung. Lung CD4 and CD8 T cells and macrophages expressed an even higher upregulation of activation markers than in blood. A wide range of cytokines were expressed at high levels both in the blood and in the lungs, most notably, IL-1RA, IL-6, IL-8, IP-10, and monocyte chemoattactant protein-1, consistent with hyperinflammation. CONCLUSION: COVID-19 ARDS exhibits a distinct immunologic profile in the lungs, with a depleted and exhausted CD4 and CD8 T-cell population that resides within a heavily hyperinflammatory milieu.

Algorithmic prediction of HIV status using nation-wide electronic registry data.

BACKGROUND: Late HIV diagnosis is detrimental both to the individual and to society. Strategies to improve early diagnosis of HIV must be a key health care priority. We examined whether nation-wide electronic registry data could be used to predict HIV status using machine learning algorithms. METHODS: We extracted individual level data from Danish registries and used algorithms to predict HIV status. We used various algorithms to train prediction models and validated these models. We calibrated the models to mimic different clinical scenarios and created confusion matrices based on the calibrated models. FINDINGS: A total 4,384,178 individuals, including 4,350 with incident HIV, were included in the analyses. The full model that included all variables that included demographic variables and information on past medical history had the highest area under the receiver operating characteristics curves of 88·4% (95%CI: 87·5% - 89·4%) in the validation dataset. Performance measures did not differ substantially with regards to which machine learning algorithm was used. When we calibrated the models to a specificity of 99·9% (pre-exposure prophylaxis (PrEP) scenario), we found a positive predictive value (PPV) of 8·3% in the full model. When we calibrated the models to a sensitivity of 90% (screening scenario), 384 individuals would have to be tested to find one undiagnosed person with HIV. INTERPRETATION: Machine learning algorithms can learn from electronic registry data and help to predict HIV status with a fairly high level of accuracy. Integration of prediction models into clinical software systems may complement existing strategies such as indicator condition-guided HIV testing and prove useful for identifying individuals suitable for PrEP. FUNDING: The study was supported by funds from the Preben and Anne Simonsens Foundation, the Novo Nordisk Foundation, Rigshospitalet, Copenhagen University, the Danish AIDS Foundation, the Augustinus Foundation and the Danish Health Foundation.

Risk of Diabetes Mellitus among Patients Diagnosed with Giant Cell Arteritis or Granulomatosis with Polyangiitis: Comparison with the General Population.

OBJECTIVE: Patients with organ- or life-threatening vasculitis receive high cumulative glucocorticoid (GC) doses during their disease course. GC have diabetogenic effects, but the risk of diabetes mellitus (DM) related to vasculitis therapy is not well characterized. We assessed the DM risk among patients diagnosed with giant cell arteritis (GCA) or granulomatosis with polyangiitis (GPA), i.e., patients with relatively common forms of systemic vasculitis. METHODS: We used Danish healthcare registries to identify 1682 patients diagnosed with GCA and 342 patients diagnosed with GPA from 1997 to 2015 and to obtain information regarding medication exposures. Each patient with vasculitis was matched with 9 population controls. Date of new-onset DM was defined as date of first claimed prescription for an antidiabetic drug. We used Cox regression analyses to calculate incidence rate ratios (IRR) for DM as a measure of the DM risk among patients relative to population controls. Logistic regression was used to study the association between prednisolone/prednisone (PRED) dose and DM. RESULTS: Median duration of followup was 6.5 years [interquartile range (IQR) 2.6-10.4] in the GCA cohort and 5.8 years (IQR 1.7-10.6) in the GPA cohort. During the first year after diagnosis of vasculitis, the IRR for DM was 7.0 (95% CI 5.2-9.3) among patients with GCA and 10.4 (95% CI 4.4-24) among patients with GPA. IRR for DM were not significantly increased in either cohort during later followup periods. Within the first year, treatment with high cumulative prednisolone/PRED doses was associated with new-onset DM among the patients with vasculitis. CONCLUSION: Patients diagnosed with GCA or GPA have a markedly increased risk of new-onset DM during early treatment phases.

Impact of pre-existing co-morbidities on mortality in granulomatosis with polyangiitis: a cohort study.

OBJECTIVE: To assess the impact of pre-existing co-morbidities on mortality among patients affected by granulomatosis with polyangiitis (GPA). METHODS: By means of the Danish National Hospital Register, we identified a cohort of patients hospitalized for GPA during 1994-2010 (n = 308). The burden of pre-existing co-morbidities among the patients was quantified according to the Charlson Comorbidity Index (CCI). Each patient was matched with five age- and gender-matched population controls with no pre-existing co-morbidities captured by the CCI (CCI score = 0). The study subjects were followed throughout 2010. Cox regression analyses were used to calculate mortality rate ratios (MRRs). RESULTS: The median duration of follow-up in the GPA cohort was 5.8 years (interquartile range 2.3-10.0). Compared with their matched population controls, the MRR for patients presenting with a CCI score of 0 (n = 246) was 3.9 (95% CI 2.0, 7.5) during years 0-2 and 1.4 (95% CI 0.9, 2.0) from the second year of follow-up onwards. The corresponding MRRs were 13.3 (95% CI 5.8, 31) and 1.9 (95% CI 1.1, 3.6) for patients with a CCI score ⩾1 (n = 62). In a direct comparison, GPA patients with a CCI score ⩾1 were found to have significantly higher mortality than GPA patients with a CCI score of 0 during years 0-2 [adjusted MRR 3.4 (95% CI 1.6, 7.0)] but not after >2 years of follow-up [adjusted MRR 1.3 (95% CI 0.7, 2.6)]. CONCLUSION: During early follow-up periods, the mortality among GPA patients with pre-existing co-morbidities is markedly higher than that among GPA patients with no pre-existing illnesses. Our analyses identify an increased CCI score for pre-existing co-morbidities as an important risk factor for a fatal outcome in GPA.

Long-Term Mortality in HIV-Infected Individuals 50 Years or Older: A Nationwide, Population-Based Cohort Study.

BACKGROUND: Although the prevalence of HIV-infection among individuals ≥ 50 years of age has increased, the impact of HIV-infection on risk of death in this population remains to be established. Our aim was to estimate long-term mortality among HIV-infected individuals who were 50 years or older, when compared with an individually-matched cohort from the background population. METHODS: Population-based cohort-study including HIV-infected individuals ≥ 50 years, who were alive 1 year after HIV-diagnosis (n = 2440) and a comparison cohort individually-matched by age and gender extracted from the background population (n = 14,588). Cumulative survival was evaluated using Kaplan-Meier method and Mortality Rate Ratios (MRRs) were estimated using Cox Regression Models. Study period 1996-2014. RESULTS: Estimated median survival time from age 50 years for HIV-infected individuals increased from 11.8 years (95% CI: 10.2 to 14.5) during 1996-1999 to 22.8 years (20.0-24.2) in 2006-2014. MRR decreased with increasing age from 3.8 (3.1-4.7) for 50-55 years to 1.6 (1.0-2.6) for 75-80 years. In a cohort of well-treated HIV-infected individuals ≥ 50 years without AIDS-defining events or comorbidity at study inclusion (n = 517). MRR was 1.7 (1.2-2.3) compared with population controls without comorbidity. CONCLUSION: Among HIV-infected individuals estimated median survival time from age 50 years has increased by more than 10 years from 1996-1999 to 2006-2014, but is still substantially lower than in the background population. Even among well-treated HIV-infected individuals ≥ 50 years without comorbidity or AIDS-defining events the estimated median survival time remains lower than in the general population.