Challenged Urine Bicarbonate Excretion as a Measure of Cystic Fibrosis Transmembrane Conductance Regulator Function in Cystic Fibrosis.

BACKGROUND: In cystic fibrosis (CF), renal base excretion is impaired. Accordingly, challenged urine bicarbonate excretion may be an in vivo biomarker of cystic fibrosis transmembrane conductance regulator (CFTR) function. OBJECTIVE: To evaluate the association between challenged bicarbonate excretion and clinical characteristics at baseline, quantify the CFTR modulator drug elexacaftor/tezacaftor/ivacaftor-induced changes of challenged bicarbonate excretion after 6 months of treatment, and characterize the intraindividual variation in healthy adults. DESIGN: Prospective observational study. SETTING: Cystic fibrosis clinic, Aarhus University Hospital, Denmark. PATIENTS: Fifty adult patients with CF starting CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor between May 2020 and June 2021. MEASUREMENTS: Quantification of urine bicarbonate excretion after an acute oral sodium bicarbonate challenge before and 6 months after elexacaftor/tezacaftor/ivacaftor treatment. RESULTS: At baseline, challenged urine bicarbonate excretion was associated with several CF disease characteristics. Bicarbonate excretion was higher in patients with residual function mutations. A higher bicarbonate excretion was associated with better lung function, pancreatic sufficiency, and lower relative risk for chronic pseudomonas infections. Elexacaftor/tezacaftor/ivacaftor treatment increased bicarbonate excretion by 3.9 mmol/3 h (95% CI, 1.6 to 6.1 mmol/3 h), reaching about 70% of that seen in healthy control participants. In healthy control participants, individual bicarbonate excretion at each visit correlated with the individual mean bicarbonate excretion. The median coefficient of variation was 31%. LIMITATION: Single-center study without a placebo-controlled group. CONCLUSION: Although further studies are needed to address the performance and sensitivity of this approach, this early-stage evaluation shows that challenged urine bicarbonate excretion may offer a new, simple, and safe quantification of CFTR function and the extent of its pharmacologic improvement. Elexacaftor/tezacaftor/ivacaftor partially restores renal CFTR function in patients with CF, likely resulting in decreased risk for electrolyte disorders and metabolic alkalosis. PRIMARY FUNDING SOURCE: Innovation Fund Denmark.

SARS-CoV-2 infection among patients with haematological disorders: Severity and one-month outcome in 66 Danish patients in a nationwide cohort study.

OBJECTIVES: Patients with haematological disorders may be particularly vulnerable to respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, this is unknown. METHODS: We conducted a prospective, nationwide study including 66 patients in follow-up at Danish haematology departments with a malignant or non-malignant haematological disorder and with verified SARS-CoV-2 infection. Outcomes were intensive care unit (ICU) admission and one-month survival rate. RESULTS: Mean age was 66.7 years, 60.6% were males, 90.9% had comorbidity, and 13.6% had a BMI ≥ 30. The most frequent diagnoses were chronic lymphocytic leukaemia/lymphoma (47.0%), multiple myeloma (16.7%) and acute leukaemia/myelodysplastic syndrome (AL/MDS) (12.1%). Treatment for the haematological disease was ongoing in 59.1% of cases. Neutropenia was present in 6.5%, lymphopenia in 46.6% and hypogammaglobulinaemia in 26.3%. The SARS-CoV-2 infection was mild in 50.0%, severe in 36.4% and critical in 13.6%. After one month, 21.2% had been admitted to ICU, and 24.2% died. Mortality was highest in older patients, patients with severe/critical SARS-CoV-2 infection, high comorbidity score or high performance status score, purine analogue treatment and with AL/MDS. Although older patients and patients with comorbidities had the highest mortality rates, mortality was considerable among all haematological patients. CONCLUSION: Haematological patients with SARS-CoV-2 infection has a severe clinical course.

Impaired Renal HCO3- Excretion in Cystic Fibrosis.

BACKGROUND: Patients with cystic fibrosis (CF) do not respond with increased urinary HCO3- excretion after stimulation with secretin and often present with metabolic alkalosis. METHODS: By combining RT-PCR, immunohistochemistry, isolated tubule perfusion, in vitro cell studies, and in vivo studies in different mouse models, we elucidated the mechanism of secretin-induced urinary HCO3- excretion. For CF patients and CF mice, we developed a HCO3- drinking test to assess the role of the cystic fibrosis transmembrane conductance regulator (CFTR) in urinary HCO3-excretion and applied it in the patients before and after treatment with the novel CFTR modulator drug, lumacaftor-ivacaftor. RESULTS: ß-Intercalated cells express basolateral secretin receptors and apical CFTR and pendrin. In vivo application of secretin induced a marked urinary alkalization, an effect absent in mice lacking pendrin or CFTR. In perfused cortical collecting ducts, secretin stimulated pendrin-dependent Cl-/HCO3- exchange. In collecting ducts in CFTR knockout mice, baseline pendrin activity was significantly lower and not responsive to secretin. Notably, patients with CF (F508del/F508del) and CF mice showed a greatly attenuated or absent urinary HCO3--excreting ability. In patients, treatment with the CFTR modulator drug lumacaftor-ivacaftor increased the renal ability to excrete HCO3-. CONCLUSIONS: These results define the mechanism of secretin-induced urinary HCO3- excretion, explain metabolic alkalosis in patients with CF, and suggest feasibility of an in vivo human CF urine test to validate drug efficacy.

Review of cytomegalovirus coinfection in HIV-infected individuals in Africa.

BACKGROUND: Cytomegalovirus (CMV) infection among HIV-infected individuals may cause end-organ disease, which is an AIDS-defining condition. Evidence from high-income countries suggests that CMV may alter the outcome of HIV infection, other than causing end-organ diseases. We reviewed literature on HIV and CMV coinfection in Africa. METHODS: Systematic review of published studies on HIV and CMV coinfection in Africa using the PubMed database. RESULTS: High CMV seroprevalence was found throughout Africa, exceeding 90% in most populations. Retinitis, pneumonia, and colitis were the most commonly reported CMV manifestations in HIV-infected individuals. Among patients with pulmonary symptoms, the prevalence of CMV pneumonitis varied from 20% to over 60%, whereas CMV was found in 0% to 14% of patients with gastrointestinal manifestations. Cytomegalovirus retinitis was found in 0% to 2.6% of examined HIV-infected individuals. The diagnostics of CMV end-organ diseases were found complex and difficult to interpret in African settings. Cytomegalovirus viremia was correlated with significantly lower CD4 cell count and increase in activated and apoptosis vulnerable T-lymphocytes. Also, CMV coinfection was found to be associated with increased transmission and progression of HIV infection. Moreover, detectable CMV DNA was an independent predictor of HIV transmission and mortality among HIV-infected individuals. CONCLUSIONS: Cytomegalovirus is highly prevalent in Africa and a common cause of disease manifestations in HIV-infected individuals among all age groups. Cytomegalovirus coinfection in HIV-infected individuals in Africa is associated with increased transmission and mortality of HIV, but it is a neglected area of research.

Research Electronic Data Capture (REDCap®) used as an audit tool with a built-in database.

The aim of this study was to develop an audit tool with a built-in database using Research Electronic Data Capture (REDCap®) as part of an antimicrobial stewardship program at a regional hospital in the Central Denmark Region, and to analyse the need, if any, to involve more than one expert in the evaluation of cases of antimicrobial treatment, and the level of agreement among the experts. Patients treated with systemic antimicrobials in the period from 1 September 2015 to 31 August 2016 were included, in total 722 cases. Data were collected retrospectively and entered manually. The audit was based on seven flow charts regarding: (1) initiation of antimicrobial treatment (2) infection (3) prescription and administration of antimicrobials (4) discontinuation of antimicrobials (5) reassessment within 48 h after the first prescription of antimicrobials (6) microbiological sampling in the period between suspicion of infection and the first administration of antimicrobials (7) microbiological results. The audit was based on automatic calculations drawing on the entered data and on expert assessments. Initially, two experts completed the audit, and in the cases in which they disagreed, a third expert was consulted. In 31.9% of the cases, the two experts agreed on all elements of the audit. In 66.2%, the two experts reached agreement by discussing the cases. Finally, 1.9% of the cases were completed in cooperation with a third expert. The experts assessed 3406 flow charts of which they agreed on 75.8%. We succeeded in creating an audit tool with a built-in database that facilitates independent expert evaluation using REDCap. We found a large inter-observer difference that needs to be considered when constructing a project based on expert judgements. Our two experts agreed on most of the flow charts after discussion, whereas the third expert's intervention did not have any influence on the overall assessment.

Infective endocarditis in patients receiving chronic hemodialysis: A 21-year observational cohort study in Denmark.

BACKGROUND: Chronic hemodialysis is a risk factor for invasive bacterial infections. We conducted a nationwide study of risk and mortality of infective endocarditis (IE) among patients undergoing chronic hemodialysis. METHODS: In this observational cohort study, patients with end-stage renal disease who initiated hemodialysis in Denmark during 1990 to 2010 were matched on age, gender, and municipality with up to 19 population controls. We extracted information on first admissions with IE, comorbidity, and arteriovenous fistula surgery from medical administrative databases. Incidence rates (IRs) of IE were compared between patients undergoing hemodialysis and population controls using Poisson regression. Risk factors for IE were assessed by Cox regression. RESULTS: IE was diagnosed in 150 of 9392 patients undergoing hemodialysis (IR: 6.83 per 1000 person-years, 95% confidence interval [CI]; 5.82-8.01) and 250 of 176,369 population controls (IR: 0.18 per 1000 person-years, 95% CI; 0.16-0.20) yielding an incidence rate-ratio of 38.1 (95% CI; 31.2-46.7). Among patients undergoing hemodialysis, absence of arteriovenous fistula surgery was associated with increased risk of IE (hazard ratio [HR] = 1.57; 95% CI; 1.09-2.27) after adjusting for age, sex, valvular disease, diabetes and period of first hemodialysis. Age ≥70 years was associated with a lower risk of IE (HR = 0.59; 95% CI 0.37-0.93). The 90-day all-cause mortality following diagnose of IE was 27% (95% CI; 20-35) for patients undergoing hemodialysis and 23% (95% CI; 18-29) for controls. CONCLUSIONS: Patients undergoing hemodialysis have markedly elevated risk of IE compared to the general population. Future challenges will be to develop strategies to prevent IE, to reduce IE-related morbidity and mortality in this vulnerable population.

Risk and outcome of pyelonephritis among renal transplant recipients.

BACKGROUND: Urinary tract infection is the most common infectious disease requiring hospitalisation following renal transplantation. However, the risk and outcome of post-transplant pyelonephritis remains unclear. METHODS: This population-based cohort study was conducted from 1 January 1990 to 31 December 2009. Each member of a Danish population-based, nationwide cohort of first-time renal transplant recipients was matched by age and gender with up to 19 population controls. Information on hospital discharge diagnosis, emigration, and mortality was obtained from nationwide administrative databases. Individuals were observed from the date of first renal transplantation and until graft loss, emigration, or death. Risk factors were assessed by Poisson regression. RESULTS: The incidence rate (IR) of first-time hospitalisation for pyelonephritis was 18.5 (95 % confidence interval [CI]: 16.4-20.9) per 1,000 person-years of follow-up (PYFU) among renal transplant recipients (N = 2,656) and 0.26 (CI: 0.21-0.31) per 1,000 PYFU among population controls (N = 49,226) yielding an incidence rate-ratio (IRR) of 72.0 (95 % CI: 57.8-89.7). Among renal transplant recipients, the risk of pyelonephritis decreased during the entire study period and was lowest in 2005-09 (IRR = 0.46, CI: 0.31-0.68). The highest risk of pyelonephritis was observed within the first six months post-transplantation (IR = 69.9 per 1,000 PYFU; CI: 56.4-86.7). Other risk factors for post-transplant pyelonephritis included female gender, high Charlson comorbidity index score, HLA-DR mismatch, cause of renal failure, and calendar period. Interestingly, we found that the combined risk of graft loss and death was 45 %, (CI: 19-77 %) higher in renal transplant recipients following post-transplant pyelonephritis compared to those who had no admission due to pyelonephritis. CONCLUSIONS: The risk of first-time hospitalisation for pyelonephritis among renal transplant recipients is high. Further, post-transplant pyelonephritis was associated with excess risk of graft loss and death; this indicates that strategies aimed at reducing upper urinary tract infections are likely to enhance renal graft survival.

Moxifloxacin pharmacokinetic profile and efficacy evaluation in empiric treatment of community-acquired pneumonia.

When antimicrobials are used empirically, pathogen MICs equal to clinical breakpoints or epidemiological cutoff values must be considered. This is to ensure that the most resistant pathogen subpopulation is appropriately targeted to prevent emergence of resistance. Accordingly, we determined the pharmacokinetic (PK) profile of moxifloxacin at 400 mg/day in 18 patients treated empirically for community-acquired pneumonia. We developed a population pharmacokinetic model to assess the potential efficacy of moxifloxacin and to simulate the maximal MICs for which recommended pharmacokinetic-pharmacodynamic (PK-PD) estimates are obtained. Moxifloxacin plasma concentrations were determined the day after therapy initiation using ultra-high-performance liquid chromatography. Peak drug concentrations (Cmax) and area under the free drug concentration-time curve from 0 to 24 h (fAUC0-24) values predicted for each patient were evaluated against epidemiological cutoff MIC values for Streptococcus pneumoniae, Haemophilus influenzae, and Legionella pneumophila. PK-PD targets adopted were a Cmax/MIC of ≥12.2 for all pathogens, an fAUC0-24/MIC of >34 for S. pneumoniae, and an fAUC0-24/MIC of >75 for H. influenzae and L. pneumophila. Individual predicted estimates for Cmax/MIC and fAUC0-24/MIC as well as simulated maximal MICs resulting in target attainment for oral and intravenous administration of the drug were suitable for S. pneumoniae and H. influenzae but not for L. pneumophila. These results indicate that caution must be taken when moxifloxacin is used as monotherapy to treat community-acquired pneumonia caused by L. pneumophila. In conclusion, this report reveals key information relevant to the empirical treatment of community-acquired pneumonia while highlighting the robust and flexible nature of this population pharmacokinetic model to predict therapeutic success. (Clinical Trials Registration no. NCT01983839.).

Outpatient parenteral antimicrobial therapy (OPAT) in patients with cystic fibrosis.

BACKGROUND: To determine complications during outpatient parenteral antimicrobial therapy (OPAT) administrated through a peripheral venous line, PICC-line or PORT-A-CATH (PAC). METHODS: Catheter related complications in patients with cystic fibrosis during OPAT were identified through a retrospective review of patient files supplemented by an interview. RESULTS: In 64 treatment episodes with a peripheral venous line, 51 (79.7 %) used bolus injection and 13 (20.3 %) used infusion pump. 27 out of 51 (53.0 %) bolus injection episodes experienced complications, which required removal. None were observed for infusion pump treatments. The infectious complications requiring removal of peripheral venous line were 9 out of 23 (39.1 %) for the PICC line and 11 out of 26 (42.3 %) for the PAC. No anaphylaxis was observed during the OPAT treatments. CONCLUSIONS: Our data indicate that using an infusion pump to administer the antibiotic treatment minimized peripheral venous line complications. The frequency of complications leading to removal of the catheter is about the same for PICC-lines and PACs, but the average life-time of the latter is much longer. Allergic reactions are not a major problem.

Risk and prognosis of Staphylococcus aureus bacteremia among individuals with and without end-stage renal disease: a Danish, population-based cohort study.

BACKGROUND: Staphylococcus aureus is a leading cause of bloodstream infections among hemodialysis patients and of exit-site infections among peritoneal dialysis patients. However, the risk and prognosis of Staphylococcus aureus bacteremia among end-stage renal disease patients have not been delineated. METHODS: In this Danish nationwide, population-based cohort study patients with end-stage renal disease and matched population controls were observed from end-stage renal disease diagnosis/sampling until first episode of Staphylococcus aureus bacteremia, death, or end of study period. Staphylococcus aureus positive blood cultures, hospitalization, comorbidity, and case fatality were obtained from nationwide microbiological, clinical, and administrative databases. Incidence rates and risk factors were assessed by regression analysis. RESULTS: The incidence rate of Staphylococcus aureus bacteremia was very high for end-stage renal disease patients (35.7 per 1,000 person-years; 95% CI, 33.8-37.6) compared to population controls (0.5 per 1,000 person-years; 95% CI, 0.5-0.6), yielding a relative risk of 65.1 (95% CI, 59.6-71.2) which fell to 28.6 (95% CI, 23.3-35.3) after adjustment for sex, age, and comorbidity. After stratification for type of renal replacement therapy, we found the highest incidence rate of Staphylococcus aureus bacteremia among hemodialysis patients (46.3 per 1,000 person-years) compared to peritoneal dialysis patients (22.0 per 1,000 person-years) and renal transplant recipients (8.9 per 1,000 person-years). In persons with Staphylococcus aureus bacteremia, ninety-day case fatality was 18.2% (95% CI, 16.2%-20.3%) for end-stage renal disease patients and 33.7% (95% CI, 30.3-37.3) for population controls. CONCLUSIONS: Patients with end-stage renal disease, and hemodialysis patients in particular, have greatly increased risk of Staphylococcus aureus bacteremia compared to population controls. Future challenges will be to develop strategies to reduce Staphylococcus aureus bacteremia-related morbidity and death in this high-risk population.

Adherence to the cervical cancer screening program in women living with HIV in Denmark: comparison with the general population.

BACKGROUND: Women living with HIV (WLWH) are at increased risk of invasive cervical cancer (ICC). International HIV guidelines suggest cervical screening twice the first year after HIV diagnosis and thereafter annually. Adherence to the HIV cervical screening program in Denmark is unknown. METHODS: We studied women from a population-based, nationwide HIV cohort in Denmark and a cohort of age-matched females from the general population. Screening behaviour was assessed from 1999-2010. Adjusted odds ratios (OR's) for screening attendance in the two cohorts and potential predictors of attendance to guidelines were estimated. Pathology specimens were identified from The Danish Pathology Data Bank. RESULTS: We followed 1143 WLWH and 17,145 controls with no prior history of ICC for 9,509 and 157,362 person-years. The first year after HIV diagnosis 2.6% of WLWH obtained the recommended two cervical cytologies. During the different calendar intervals throughout the study period between 29-46% of WLWH followed the HIV cervical screening guidelines. Adjusted OR's of attendance to the general population screening program for WLWH aged 30, 40 and 50 years, compared to controls, were 0.69 (95% CI: 0.56-0.87), 0.67 (0.55-0.80) and 0.84 (0.61-1.15). Predictors of attendance to the HIV cervical screening program were a CD4 count > 350 cells/µL and HIV RNA < 500 copies/mL. Calendar period after 2002 and HIV RNA < 500 copies/mL predicted attendance to the general population cervical screening program. CONCLUSIONS: The majority of WLWH do not follow the HIV guidelines for cervical screening. We support the idea of cytology as part of an annual review and integration of HIV care and cervical screening in a single clinic setting.

Testing for hepatitis B virus and HIV in patients with chronic hepatitis C: screening performance and outcome.

BACKGROUND: Patients infected with hepatitis C virus (HCV) and co-infected with hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) are at increased risk for progression of liver disease. The aim of this study was to assess HBV and HIV screening performance and outcome in HCV patients followed at a Danish university hospital and affiliated regional outpatient clinics. METHODS: HBV and HIV serology data were extracted from a quality assurance database for the assessment of screening performance in patients diagnosed with chronic HCV infection during the period 1 January 1996 to 31 December 2011. Patients with incomplete and missing serology data had complementary serology tests performed to assess the prevalence of HBV and HIV co-infection and HBV immune status. RESULTS: Among 624 HCV patients, 10 (2%) were co-infected with chronic HBV and 32 (5%) with HIV. Approximately half of the cohort were non-immune to HBV or had an unknown HBV serology status. Serology results consistent with resolved infection and HBV vaccination were found in 209 (33%) and 65 (10%) patients, respectively. During the 16-y observation period, HBV and HIV screening coverage at HCV diagnosis increased from 23% to 92% and from 38% to 80%, respectively. CONCLUSION: Despite improvements throughout the study period, HBV and HIV serology screening remained incomplete. The majority of patients were either HBV non-immune or had an unknown HBV serology status. These findings thus call for a more proactive screening approach as well as an improved HBV vaccination strategy for patients with chronic HCV infection.

Pneumocystis jirovecii pneumonia in patients with end-stage renal disease: a comparison with the general population.

BACKGROUND: Data on occurrence and risk factors for pneumocystis pneumonia (PCP) in patients with end-stage renal disease (ESRD) are sparse. METHODS: This was a nationwide population-based study assessing occurrence and risk factors for PCP among patients with ESRD and population controls over a 21-year period (1/1 1990 to 31/12 2010). Using Danish registry data, first-time diagnoses of PCP were identified. RESULTS: We identified 13 296 adult patients with ESRD and 244 255 controls, yielding 63 560 and 2 223 660 person-years of follow-up (PYFU), respectively. Fifty-eight first-time diagnoses of PCP were recorded in the ESRD group. Forty-six episodes occurred among renal transplant recipients (RTx) and 12 among haemodialysis patients (HD), yielding incidence rates of 181 (136-242) and 43.1 (24.5-75.9) per 100 000 PYFU. Compared to population controls, we found incidence rate-ratios of 125.9 (78.4-204) among RTx and 29.9 (14.1-59.7) among HD patients. Risk factors for PCP in RTx were age 50-65 years, age > 65 years, diabetes, polycystic kidney disease and hypertensive kidney disease/nephrosclerosis with an IRR of 2.22 (1.14-4.31), 3.12 (1.35-7.21), 3.44 (1.16-10.2), 4.25 (1.55-11.7) and 3.87 (1.49-10.0), respectively, and more than 36 months of dialysis before transplantation with an IRR of 1.99 (1.03-3.84). Among RTx the risk of PCP was highest during the first 6 months post-transplantation and increased from the beginning (IR1990-94 = 111 (46.3-267) per 100 000 PYFU) towards the end of the study period (IR2005-10 = 299 (203-439)). CONCLUSION: The PCP risk is substantial in RTx within the first 6 months of transplantation, emphasizing the potential benefit of prophylactic treatment in the early post-transplant period. Importantly, we identified subgroups within the RTx group that require more attention.

Identifying people living with cystic fibrosis in the Danish National Patient Registry: A validation study.

BACKGROUND: The Danish National Patient Registry (DNPR) serves as a valuable resource for scientific research. However, to ensure accurate results in cystic fibrosis (CF) studies that rely on DNPR data, a robust case-identification algorithm is essential. This study aimed to develop and validate algorithms for the reliable identification of CF patients in the DNPR. METHODS: Using the Danish Cystic Fibrosis Registry (DCFR) as a reference, accuracy measures including sensitivity and positive predictive value (PPV) for case-finding algorithms deployed in the DNPR were calculated. Algorithms were based on minimum number of hospital contacts with CF as the main diagnosis and minimum number of days between first and last contact. RESULTS: An algorithm requiring a minimum of one hospital contact with CF as the main diagnosis yielded a sensitivity of 96.1 % (95 % CI: 94.2 %; 97.4 %) and a PPV of 84.9 % (82.0 %; 87.4 %). The highest-performing algorithm required minimum 2 hospital visits and a minimum of 182 days between the first and the last contact and yielded a sensitivity of 95.9 % (95 % CI: 94.1 %; 97.2 %), PPV of 91.0 % (95 % CI: 88.6 %; 93.0 %) and a cohort entry delay of 3.2 months at the 75th percentile (95th percentile: 38.7 months). CONCLUSIONS: The DNPR captures individuals with CF with high sensitivity and is a valuable resource for CF-research. PPV was improved at a minimal cost of sensitivity by increasing requirements of minimum number of hospital contacts and days between first and last contact. Cohort entry delay increased with number of required hospital contacts.

Decline in HbA1c during the first year of elexacaftor/tezacaftor/ivacaftor treatment in the Danish cystic fibrosis cohort: Short title: Decline in HbA1c after elexacaftor/tezacaftor/ivacaftor treatment.

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) has improved the clinical status of individuals with cystic fibrosis (CF), however, whether ETI impacts glucose tolerance remains unknown. We aimed to study the change in glycated hemoglobin (HbA1c) and CF related diabetes (CFRD) status after initiation of ETI. METHODS: We included individuals ≥12 years treated with ETI in Denmark in a longitudinal observational study. HbA1c was measured at baseline, 3, 6, 9 and 12 months after treatment initiation. Change in HbA1c was assessed in mixed models adjusted for age, sex, glucose tolerance and prior CFTR modulator treatment. In a sub-population with CFRD, we assessed the change in insulin usage, hypoglycemic events and the 30-day continuous glucose monitoring (CGM) parameters (i.e., average blood glucose, time below (≤3.9 mM) and above (>10.0 mM) normal range, and the variation in glucose) after 12 months of treatment. RESULTS: Among 321 individuals with CF, HbA1c declined by 2.1 mmol/mol [95 % confidence interval (CI): -2.6; -1.5 mmol/mol] after 3 months and by 2.3 mmol/mol [95 %CI: -2.8; -1.9 mmol/mol] after 12 months of ETI treatment. The decline was independent of glucose tolerance status at baseline. In 26 individuals with CFRD at baseline, the mean decline in HbA1c was 3.6 mmol/mol [95 %CI: -6.9; -0.4 mmol/mol] after 12 months, but we did not observe any change in insulin usage, weekly number of hypoglycemic events or CGM parameters. CONCLUSION: In the Danish CF cohort, HbA1c declined over 12 months of ETI treatment, however, among a subset with CFRD, we observed no change in insulin usage and CGM glucose levels.

Education, employment, and income among people living with cystic fibrosis across three decades - A matched cohort study using Danish health registries.

BACKGROUND: Past and ongoing advancements in cystic fibrosis (CF) care warrant long-term analysis of the societal impact of the condition. This study aims to evaluate changes in key socioeconomic factors across three decades among people living with CF (pwCF), compared with both the general population and an early-onset chronic disease population. METHODS: This nationwide, registry-based, matched cohort study included all pwCF ≥ 18 years in Denmark in the years 1990, 2000, 2010, and 2018. Each person living with CF was matched to five individuals in the general population and five individuals living with type 1 diabetes or juvenile arthritis based on age, sex, and municipality. RESULTS: The Danish adult CF population increased nearly fourfold from 88 in 1990 to 331 in 2018, and mean age increased by ten years. The educational level of pwCF was similar to the two comparator cohorts, while pwCF were less often in employment and more often permanently outside the labor force. Personal and household income levels of the CF cohort were higher than those of the comparator cohorts. CONCLUSIONS: The disadvantage in employment for pwCF remained, but, over time, the societal profiles of the one-year CF cohorts increasingly converged with those of the comparator cohorts, indicative of improved clinical management, extended life expectancy, and the supportive role of the Danish welfare system in reducing health inequalities. Further research should be done to evaluate the effects of the newly introduced modulator therapies on employment, considering the broader societal impact and impact on quality of life.

Close monitoring and early intervention: management principles for cystic fibrosis in Denmark.

Cystic fibrosis (CF) care in Denmark has been characterized by close monitoring and pre-emptive treatment of lung disease and other CF-related complications. Continuous evaluation through data collection and commitment to clinical research has incrementally improved outcomes. This approach has been in line with best practices set forth by European Standards of Care but has also gone beyond Society standards particularly pertaining to early treatment with high-dose combination antimicrobial therapy. Despite a high prevalence of severe CF variants, lung function has been among the best in Europe. In this review, the Danish approach to management of CF prior to the introduction of new CF modulator treatment is explained and benchmarked. Downsides to the Danish approach are discussed and include increased burden of treatment, risk of antimicrobial resistance, side-effects and costs.

Risk of human papillomavirus-related cancers among kidney transplant recipients and patients receiving chronic dialysis--an observational cohort study.

BACKGROUND: Individuals with end-stage renal disease (ESRD) have excess risk of various cancer types. However, the total burden of human papillomavirus-related cancers remains unknown. METHODS: We performed a nationwide observational cohort study during 1994-2010.For each person with ESRD, we sampled 19 population controls (without ESRD) matched on age, gender and municipality. Participants were followed until first diagnosis of human papillomavirus-related cancer, death, emigration, or 31 December 2010, whichever came first.Human papillomavirus-related cancers were extracted from Danish medical administrative databases. We considered cancers of the cervix, vulva, vagina, penis, anus, and subsets of head and neck cancers as human papillomavirus-related. We calculated incidence rates of human papillomavirus-related cancer and used Poisson regression to identify risk factors for human papillomavirus-related cancer. RESULTS: Among 12,293 persons with ESRD and 229,524 population controls we identified 62 and 798 human papillomavirus-related cancers, respectively. Incidence rates of human papillomavirus-related- cancer were 102 per 100,000 person-years (95% confidence interval [CI]; 79.5-131) among persons with ESRD and 40.8 per 100,000 person-years (95% CI; 38.1-43.7) among population controls. ESRD patients had 4.54 (95% CI, 2.48-8.31) fold increased risk of anal cancer and 5.81 fold (95% CI; 3.36-10.1) increased risk of vulvovaginal cancer. Adjusted for age, comorbidity, and sex, ESRD patients had 2.41 (95% CI; 1.83-3.16) fold increased risk of any human papillomavirus-related cancer compared with population controls. Compared with dialysis patients renal transplant recipients had an age-adjusted non-significant 1.53 (95% CI, 0.91-2.58) fold higher risk of human papillomavirus-related cancer. CONCLUSIONS: Persons with ESRD have excess risk of potentially vaccine-preventable human papillomavirus-related cancers.

Severe Ureaplasma urealyticum infection in a patient with ocrelizumab-induced hypogammaglobulinaemia.

Infections caused by Ureaplasma urealyticum in immune-competent people are typically simple and uncomplicated. However, in cases of immunosuppression, severe disseminated infections can occur.This case report describes the case of a severe, disseminated infection caused by U. urealyticum in a young female with unacknowledged humoral immunosuppression due to treatment with ocrelizumab for multiple sclerosis.The patient was admitted due to a recurrent episode of a tubo-ovarian abscess. Throughout the following 2 months of hospitalisation, treatment with several types of antibiotics and the placement of various drains led to no improvement. As extensive investigations indicated hypogammaglobulinaemia, U. urealyticum was suspected, and tests came back positive. Treatment with doxycycline and moxifloxacin led to a full recovery.This demonstrates how humoral immunosuppression is a risk factor for severe disseminated infections and how these may be avoided through monitoring of immunoglobulin levels in patients treated with ocrelizumab.