Antimicrobial Strategies for Cystic Fibrosis.

Lung infection is the leading cause of death in cystic fibrosis (CF), and antimicrobial therapies are the backbone of infection management. While many different strategies may be applied, rigorous microbiological surveillance, intensive eradication therapy, and long-term maintenance therapy based on inhaled antibiotics may be considered the main strategy for infection control in individuals with CF. While most of the existing evidence is based on infection with Pseudomonas aeruginosa, other important pathogens causing lung inflammation and deterioration exist and should be treated despite the evidence gap. In this chapter, we describe the approaches to the antimicrobial treatment of the most important pathogens in CF and the evidence behind.

Bacterial biofilms predominate in both acute and chronic human lung infections.

BACKGROUND: A basic paradigm of human infection is that acute bacterial disease is caused by fast growing planktonic bacteria while chronic infections are caused by slow-growing, aggregated bacteria, a phenomenon known as a biofilm. For lung infections, this paradigm has been thought to be supported by observations of how bacteria proliferate in well-established growth media in the laboratory-the gold standard of microbiology. OBJECTIVE: To investigate the bacterial architecture in sputum from patients with acute and chronic lung infections. METHODS: Advanced imaging technology was used for quantification and direct comparison of infection types on fresh sputum samples, thereby directly testing the acute versus chronic paradigm. RESULTS: In this study, we compared the bacterial lifestyle (planktonic or biofilm), growth rate and inflammatory response of bacteria in freshly collected sputum (n=43) from patient groups presenting with acute or chronic lung infections. We found that both acute and chronic lung infections are dominated by biofilms (aggregates of bacteria within an extracellular matrix), although planktonic cells were observed in both sample types. Bacteria grew faster in sputum from acute infections, but these fast-growing bacteria were enriched in biofilms similar to the architecture thought to be reserved for chronic infections. Cellular inflammation in the lungs was also similar across patient groups, but systemic inflammatory markers were only elevated in acute infections. CONCLUSIONS: Our findings indicate that the current paradigm of equating planktonic with acute and biofilm with chronic infection needs to be revisited as the difference lies primarily in metabolic rates, not bacterial architecture.

Biofilms of Mycobacterium abscessus Complex Can Be Sensitized to Antibiotics by Disaggregation and Oxygenation.

Pulmonary infection with the multidrug-resistant Mycobacterium abscessus complex (MABSC) is difficult to treat in individuals with cystic fibrosis (CF). MABSC grows as biofilm aggregates in CF patient lungs, which are known to have anaerobic niches. How aggregation and anoxic conditions affect antibiotic tolerance is not well understood. We sought to determine whether disaggregation and oxygen availability sensitize MABSC isolates to recommended antibiotics. We tested the susceptibilities of 33 isolates from 22 CF patients with MABSC infection and a reference strain to the following antibiotics: amikacin, azithromycin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, kanamycin, linezolid, moxifloxacin, rifampin, tigecycline, and sulfamethoxazole-trimethoprim. Isolates were grown in Mueller-Hinton broth with and without the disaggregating detergent Tween 80 (5%). Time-kill curves at days 1 and 3 were generated for oxic and anoxic amikacin treatment in 4-fold dilutions ranging from 2 to 512 mg liter-1 Scanning electron microscopy was used to visualize the aggregation patterns, while confocal laser scanning microscopy and microrespirometry were used to visualize biofilm growth patterns. Disruption of MABSC aggregates increased susceptibility to amikacin, tigecycline, kanamycin, azithromycin, imipenem, cefoxitin, and clarithromycin (P < 0.05, n = 29 to 31). Oxygenation enhanced the killing of disaggregated MABSC isolates by amikacin (P < 0.05) by 1 to 6 log units when 2 to 512 mg liter-1 of amikacin was used. This study explains why current drug susceptibility testing results correlate poorly with treatment outcomes. The conditions achieved by oxic culturing of planktonic isolates in vitro do not resemble the hypoxic conditions in CF patient lungs. Biofilm disruption and increased O2 availability during antibiotic therapy may be new therapeutic strategies for chronic MABSC infection.

Serodiagnosis of Mycobacterium abscessus complex infection in cystic fibrosis.

Early signs of pulmonary disease with Mycobacterium abscessus complex (MABSC) can be missed in patients with cystic fibrosis (CF). A serological method could help stratify patients according to risk. The objective of this study was to test the diagnostic accuracy of a novel method for investigating IgG activity against MABSC.A prospective study of all patients attending the Copenhagen CF Centre was conducted by culturing for MABSC during a 22-month period and then screening patients with an anti-MABSC IgG ELISA. Culture-positive patients had stored serum examined for antibody kinetics before and after culture conversion.307 patients had 3480 respiratory samples cultured and were then tested with the anti-MABSC IgG ELISA. Patients with MABSC pulmonary disease had median anti-MABSC IgG levels six-fold higher than patients with no history of infection (434 versus 64 ELISA units; p<0.001). The test sensitivity was 95% (95% CI 74-99%) and the specificity was 73% (95% CI 67-78%). A diagnostic algorithm was constructed to stratify patients according to risk.The test accurately identified patients with pulmonary disease caused by MABSC and was suited to be used as a complement to mycobacterial culture.

Shifting paradigms of nontuberculous mycobacteria in cystic fibrosis.

Important paradigms of pulmonary disease with nontuberculous mycobacteria (NTM) are currently shifting based on an increasing attention within the field of cystic fibrosis (CF). These shifts are likely to benefit the management of all patients with pulmonary NTM, regardless of underlying pathology. Currently several key areas are being revised: The first outbreak of human NTM transmission has been proven and new evidence of biofilm growth in vivo has been demonstrated. A better understanding of the clinical impact of NTM infection has led to increased diagnostic vigilance and new recommendations for lung transplantation are under way. While recent changes have reinvigorated the interest in NTM disease, the challenge remains, whether such advances can be successfully translated into improved management and care.

High linkage to care in a community-based rapid HIV testing and counseling project among men who have sex with men in Copenhagen.

INTRODUCTION: The aim of the study was to evaluate a community-based human immunodeficiency virus (HIV) testing program for its capacity to reach men who have sex with men (MSM) and successfully refer HIV-positive patients to treatment. METHODS: A walk-in clinic placed in the heart of the Copenhagen MSM community provided sexually transmitted infection counseling and rapid HIV testing. In addition, syphilis testing and hepatitis B vaccination were offered. The clinic was staffed with specially trained, predominantly non-health care personnel, and services were anonymous and free of charge. RESULTS: A total of 3012 HIV tests with concomitant counseling were performed between 2008 and 2012. The median age of users was 33 years (range, 16-73 years), 18% were non-Danish citizens, and 12% reported that this was their first HIV test. Thirty-eight individuals tested positive; however, 1 was found to be false positive by routine confirmatory testing. The remaining 37 users were true positive. All but 1 user was successfully linked to care at an infectious disease department and achieved full viral suppression after a median of 8 months (interquartile range, 5-19 months). The 37 positive patients accounted for 11% of all newly diagnosed HIV cases among MSM in Copenhagen in the period covered. Patients diagnosed in Checkpoint were younger than other newly diagnosed MSM, but had similar median CD4 counts at the time of diagnosis (420 [interquartile range, 260-590]). Seventy-six MSM (3%) were found syphilis positive in rapid testing and referred for confirmatory testing. Furthermore, 264 MSM completed a 3-shot hepatitis B vaccination program. CONCLUSIONS: Easily accessible, community walk-in clinics and targeted testing in high-risk settings are convenient for populations of MSM less likely to seek out the established health care system. Checkpoint diagnosed 37 new HIV cases, posed no barrier to successful linkage to care, was noninferior in quickly reducing community viral load, was cost-effective, reached younger MSM, and proved an ideal platform for trying out new interventions and test forms, which conventional health care providers have not yet embraced.

Urine lipoarabinomannan point-of-care testing in patients affected by pulmonary nontuberculous mycobacteria--experiences from the Danish Cystic Fibrosis cohort study.

BACKGROUND: The urine lipoarabinomannan (LAM) strip test has been suggested as a new point-of-care test for active tuberculosis (TB) among human immunodeficiency virus (HIV) infected individuals. It has been questioned if infections with nontuberculous mycobacteria (NTM) affect assay specificity. We set forth to investigate if the test detects LAM in urine from a Danish cystic fibrosis (CF) population characterized by a high NTM prevalence and negligible TB exposure. METHOD: Patients followed at the Copenhagen CF Center were comprehensively screened for pulmonary NTM infection between May 2012 and December 2013. Urine samples were tested for LAM using the 2013 Determine™ TB LAM Ag strip test. RESULTS: Three-hundred and six patients had a total of 3,322 respiratory samples cultured for NTM and 198 had urine collected (65%). A total of 23/198 (12%) had active pulmonary NTM infection. None had active TB. The TB-LAM test had an overall positive rate of 2.5% applying a grade 2 cut-point as positivity threshold, increasing to 10.6% (21/198) if a grade 1 cut-point was applied. Among patients with NTM infection 2/23 (8.7%) had a positive LAM test result at the grade 2 cut-point and 9/23 (39.1%) at the grade 1 cut -point. Test specificity for NTM diagnosis was 98.3% and 93.1 for grade 2 and 1 cut-point respectively. CONCLUSIONS: This is the first study to assess urine LAM detection in patients with confirmed NTM infection. The study demonstrated low cross-reactivity due to NTM infection when using the recommended grade 2 cut-point as positivity threshold. This is reassuring in regards to interpretation of the LAM test for TB diagnosis in a TB prevalent setting. The test was not found suitable for NTM detection among patients with CF.

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.

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.

Outcome of elexacaftor/tezacaftor/ivacaftor therapy in patients with cystic fibrosis and solid organ transplantation.

We report a case series of four patients with cystic fibrosis (CF) and previous solid organ transplantation (SOT) receiving elexacaftor/tezacaftor/ivacaftor therapy for 6 months or more. Data was collected retrospectively. The treatment was well tolerated and all patients reported subjective improvements.

Antimicrobial resistance of Pseudomonas aeruginosa in a cystic fibrosis population after introduction of a novel cephalosporin/ß-lactamase inhibitor combination.

Ceftolozane-tazobactam is a new ß-lactam/ß-lactamase inhibitor combination approved by the U.S. Food and Drug Administration in 2019 for the treatment of hospital-acquired and ventilator-associated pneumonia. The combination is a particularly potent inhibitor of penicillin-binding proteins with higher affinity than other ß-lactam agents. Persons with cystic fibrosis (pwCF) often harbour resistant Gram-negative bacteria in the airways and need antibiotics to prevent declining lung function. To test whether the introduction of ceftolozane-tazobactam in the period 2015-2020 led to a bacterial population level increase in cephalosporin resistance in a Danish CF population. In vitro, activity of ceftolozane-tazobactam was evaluated by susceptibility testing of clinical Pseudomonas aeruginosa isolated from pwCF from January 1, 2015, to June 1, 2020. Six thousand three hundred thirty two isolates collected from 210 adult pwCF were included. Thirty pwCF were treated with ceftolozane-tazobactam at least once. Ceftolozane-tazobactam exposure did not increase cephalosporin resistance on an individual or population level. However, resistance to ceftolozane-tazobactam was recorded despite no prior exposure in four pwCF. Compared to ceftazidime, ceftolozane-tazobactam had a better in vitro activity on P. aeruginosa. The percentage of non-mucoid P. aeruginosa isolates susceptible to ceftolozane-tazobactam were higher or equal to 5 other ß-lactams. Ceftolozane-tazobactam expands the armamentaria against P. aeruginosa with acceptable levels for a selection of drug resistance.

Implementation of a vaccination clinic for adult solid organ transplant candidates: A single-center experience.

Vaccination is an evidence-based strategy to prevent or reduce the severity of infectious diseases (ID). Here, we aimed to describe the experience of implementing a vaccination clinic specifically targeting liver, heart, lung, and combined dual organ transplantation at a single transplantation center in Denmark. In this cohort of 242 solid organ transplant (SOT) candidates, we investigated seroprotection and the proportion of recommended vaccinations documented before transplantation. Furthermore, we registered completed vaccinations after ID consultations. The median age in our cohort was 53 years (IQR, 42-60), 60% were males (n = 135), and liver transplants (n = 138; 57%) were the most frequently planned organ transplants. Before the consultation to the vaccination clinic, influenza and pneumococcal vaccines had the highest proportion of documented vaccination (58% and 37%, respectively). Serological protection was more frequently observed for measles, mumps, or rubella (MMR, approximately 90% for each), while only 30% (n = 72) of SOT candidates showed seroprotection against pneumococcal disease. All SOT candidates required at least one of the recommended vaccines, and over 90% required three or more. At least 10% of patients in our cohort needed a live attenuated vaccine for either MMR or yellow fever. The most frequently administered vaccine was the tetanus-diphtheria-acelullar pertussis (Tdap) booster (n = 217; 90%), influenza vaccination was either administered (n = 16; 7%) or recommended (n = 226; 93%), PCV13 was administered (n = 155; 64%) or recommended (n = 27; 11%), and PPSV23 was either administered (n = 18; 7.4%) or recommended (n = 140; 58%). All SOT candidates adhered completely to their vaccination schedules. Based on our findings, we recommend prioritizing vaccination before transplantation by providing ID consultations for SOT candidates.

Adaptive Immune Response to Mycobacterium abscessus Complex (MABSC) in Cystic Fibrosis and the Implications of Cross-Reactivity.

Background: We aimed to characterise the adaptive immune response to Mycobacterium abscessus complex (MABSC) and its cross-reactivity with Mycobacterium avium complex (MAC) and Mycobacterium bovis (Bacille Calmette-Guérin, BCG) in cystic fibrosis (CF) patients and non-CF controls in terms of lymphocyte proliferation and immunophenotyping, cytokine production and anti-MABSC IgG plasma levels. Methods: In this cross-sectional analysis, peripheral blood mononuclear cells (PBMC) from CF patients with MABSC (CF/MABSC, n=12), MAC infection history (CF/MAC, n=5), no NTM history (CF/NTM-, n=15), BCG-vaccinated (C/BCG+, n=9) and non-vaccinated controls (C/BCG-, n=8) were cultured for four days under stimulation with an in-house MABSC lysate and we used flow cytometry to assess lymphocyte proliferation (given by lymphoblast formation) and immunophenotypes. Cytokine production was assessed after overnight whole blood stimulation with the same lysate, and anti-MABSC IgG levels were measured in plasma from non-stimulated blood. Results: All CF/MABSC patients had increased CD3+ and CD19+ lymphoblast formation upon PBMC stimulation with MABSC lysate. There was a higher rate of CD3+ than CD19+ lymphoblasts, predominance of CD4+ over CD8+ lymphoblasts, IFN-γ, TNF-α and IL-2 production, low production of the Th17-associated IL-17, and discrete or no production of Th2/B cell-associated cytokines soluble CD40 ligand (CD40L), IL-4 and IL-5, indicating a Th1-dominated phenotype and infection restricted to the lungs. A similar pattern was seen in C/BCG+ controls, and CF/MAC patients, pointing to cross-reactivity. MABSC-IgG levels were higher in CF/MABSC patients than in both control groups, but not CF/NTM- patients, most of whom also had CD3+ and/or CD19+ lymphoblast formation upon PBMC stimulation, indicating previous exposure, subclinical or latent infection with MABSC or other NTM. Conclusion: The anti-MABSC immune response is Th1-skewed and underlines the cross-reactivity in the anti-mycobacterial immune response. The results, together with published clinical observations, indicate that BCG vaccination may cross-react against NTM in CF patients, and this should be investigated. Due to cross-reactivity, it would also be interesting to investigate whether a combination of MABSC-induced cytokine production by blood cells and anti-MABSC IgG measurement can be useful for identifying latent or subclinical infection both with MABSC and other NTM in CF patients.

Achromobacter spp. in a Cohort of Non-Selected Pre- and Post-Lung Transplant Recipients.

Achromobacter is an opportunistic pathogen that mainly causes chronic lung infections in cystic fibrosis (CF) patients and is associated with increased mortality. Little is known about Achromobacter spp. in the lung transplant recipient (LTXr) population. We aimed at describing rates of Achromobacter spp. infection in LTXr prior to, in relation to, and after transplantation, as well as all-cause mortality proportion in infected and uninfected LTXr. We included 288 adult LTXr who underwent lung transplantation (LTX) between 1 January 2010 and 31 December 2019 in Denmark. Bronchoalveolar lavage was performed at regular intervals starting two weeks after transplantation. Positive cultures of Achromobacter spp. were identified in nationwide microbiology registries, and infections were categorized as persistent or transient, according to the proportion of positive cultures. A total of 11 of the 288 LTXr had transient (n = 7) or persistent (n = 4) Achromobacter spp. infection after LTX; CF was the underlying disease in 9 out of 11 LTXr. Three out of the four patients, with persistent infection after LTX, also had persistent infection before LTX. The cumulative incidence of the first episode of infection one year after LTX was 3.8% (95% CI: 1.6-6.0). The incidence rates of transient and persistent infection in the first year after LTX were 27 (12-53) and 15 (5-37) per 1000 person-years of follow-up, respectively. The all-cause mortality proportion one year after LTX was 27% in the Achromobacter spp. infected patients and 12% in the uninfected patients (p = 0.114). Achromobacter spp. mainly affected LTXr with CF as the underlying disease and was rare in non-CF LTXr. Larger studies are needed to assess long-term outcomes of Achromobacter spp. in LTXr.

Use of inhaled antibiotics among Danish patients with cystic fibrosis.

BACKGROUND: Inhaled antibiotics are an important part of cystic fibrosis (CF) airway disease management and should be individualized to fit the microorganism and match patient needs. To investigate the implementation of personalized treatment, this study mapped the use of different types of inhaled antibiotics and adherence patterns. METHODS: We performed individual structured interviews in a cross-sectional study at the CF Centre in Copenhagen, Denmark. Patients with CF older than 15 years attending clinical consultations were included. Clinical data were obtained from centralized databases. RESULTS: Among 149 participants, 107 (72%) had indication for treatment with inhaled antibiotics. In this group, 97 (91%) reported the use of inhaled antibiotics within the last 12 months. Change from one inhaled antibiotic to another during that period was reported by 31 (29%), and 17 (25%) with Pseudomonas aeruginosa had used off-label antibiotics. Adherence to a minimum of one daily dose of antibiotic was reported by 78%, while adherence to all daily doses was 28 percentage points lower. Skipping inhalations was due to side effects and doubt about the effect in less than 5% of cases. CONCLUSION: Change of inhaled antibiotics and use of off-label antibiotics for inhalation were common and side effects were a rare cause of nonadherence. This suggests satisfactory implementation of the principle of tailored antibiotic inhalation prescription in the Copenhagen CF population. Adherence to at least one daily inhalation dose was markedly higher than adherence to multiple daily inhalations.

Predictors of unsafe sex among HIV patients in Denmark: a population-based cohort study.

UNLABELLED: Abstract Background: Sexual transmission continues to be the primary mode of human immunodeficiency virus (HIV) infection in Western Europe. We aimed to describe predictors of unsafe sex and reasons given for such behaviour. METHODS: We performed a survey examining sexual risk behaviours and reasons for unsafe sex in a nationwide cohort of adult Danish HIV-1-positive patients. Differences in characteristics between those who practiced safe and unsafe sex were estimated by binary logistic regression. The fraction with detectable viral load was determined in the 2 groups, and reasons for unsafe sex were evaluated. RESULTS: Of 812 eligible patients, a total of 275 (34%) had engaged in unsafe sex with an HIV-negative partner or a partner with unknown HIV status in the previous year. On multivariate analysis, men who have sex with men (MSM) was the only statistically significant risk factor associated with unsafe sex (odds ratio 3.24, 95% confidence interval 1.72-6.12). The main reason for practicing unsafe sex was that the partner did not wish to use a condom (53%). CONCLUSIONS: A high proportion of HIV-positive patients engage in unsafe sex, especially MSM. The reasons for unsafe sex are primarily linked to negotiation issues concerning condom use, including assumptions about the sexual partner's intent.

Cholinesterase modulations in patients with acute bacterial meningitis.

BACKGROUND: The circulating cholinesterases acetyl- and butyrylcholinesterase may be suppressed and subsequently released from the brain in acute bacterial meningitis. METHODS: We report serum activities of acetylcholinesterase and butyrylcholinesterase in paired arterial and jugular venous samples from seven patients with acute bacterial meningitis and eight healthy controls. Paraoxonase 1, which protects these enzymes from oxidative inactivation, was also measured. FINDINGS AND CONCLUSION: Acetyl- and butyrylcholinesterase activities were lower in patients, independently of changes in paraoxonase 1. Arterial and jugular venous enzyme activities were similar both in patients and controls, suggesting that no cerebral release was present.

At-Risk Groups of Men Who Have Sex With Men Can Be Reached Through Community-Based HIV Testing in Denmark.

This study evaluates whether the community-based HIV testing clinic Checkpoint could reach at-risk groups of men who have sex with men (MSM) and link patients to care. A prospective observational study of all Checkpoint visits during 2013-2016 and a retrospective registry study of all MSM diagnosed with HIV in Denmark during the same period were conducted. One percent of the 9,074 tests in Checkpoint were HIV-positive, accounting for 19% of all new HIV diagnoses among MSM in Denmark. Checkpoint testers reported frequent condomless anal sex. Two percent of migrant Checkpoint testers were HIV-positive compared to 1 % among Danish MSM. HIV-positive MSM identified through Checkpoint were significantly younger, more of them were migrant, and a smaller proportion were late testers compared to those testing through the conventional health care system. Checkpoint reaches at-risk populations of MSM and links patients successfully to care.

Associations Between Glucose Tolerance, Insulin Secretion, Muscle and Fat Mass in Cystic Fibrosis.

BACKGROUND: A frequent comorbidity in cystic fibrosis (CF) is CF related diabetes (CFRD) caused by a gradual decline in insulin secretion. The reduction in the anabolic hormone, insulin, might explain the weight loss that precedes onset of CFRD. We investigated the association between muscle and fat mass in relation to glucose tolerance and insulin function. METHODS: In a cross-sectional study with CF patients (⩾18 years), we conducted an oral glucose tolerance test and dual energy X-ray absorptiometry scan (DXA). Based on plasma glucose, glucose tolerance was defined as normal (NGT): 1-hour <11.1 mmol/L and 2-hour <7.8 mmol/L, impaired (IGT): 2-hour ⩾7.8 and <11.1 mmol/L or CFRD: 2-hour ⩾11.1 mmol/L. Insulin resistance (HOMA-IR) was derived from fasting levels of plasma glucose and plasma insulin, and fat-free and fat mass index (kg/m2) from DXA. Associations were evaluated using linear regression models adjusted for age, sex, and pancreas insufficiency. RESULTS: Among 79 CF patients with exocrine pancreas insufficiency, impairment of glucose tolerance corresponded to reduced insulin secretion. In the IGT group the fat-free mass index (FFMI) was 1.2 kg/m2 (95% CI: [-2.3, -0.03] kg/m2, P = .044) lower compared to the NGT group. FFMI increased insignificantly by 0.4 kg/m2 (95% CI: [-0.6, 1.5] kg/m2, P = .422) among the insulin-treated CFRD group compared to IGT. Fat mass index (FMI) was not different between groups but tended to decrease with glucose tolerance impairment. For each 100 pmol/L increase in fasting insulin FFMI increased by 1.77 kg/m2 (95% CI: [0.21, 3.33] kg/m2/pmol/L/100) and FMI increased by 6.15 kg/m2 (95% CI: [3.87, 8.44] kg/m2/pmol/L/100). In multivariate analyses, HOMA-IR was positively associated with FFMI (ß = 0.5 kg/m2/HOMA-IR, 95% CI: [0.08, 0.92] kg/m2/HOMA-IR, P = .021) and FMI (ß = 1.5 kg/m2/HOMA-IR, 95% CI: [0.87, 2.15] kg/m2/HOMA-IR, P < .001). CONCLUSIONS: Muscle mass was significantly lower among participants with impaired glucose tolerance (IGT), while muscle mass was normalized among those treated with insulin.