Sulfonamide allergy label and the risk of opportunistic infections in solid organ transplant recipients - A retrospective matched cohort study.

BACKGROUND: While a penicillin allergy label has been linked to various negative clinical outcomes, limited studies have specifically characterized the implication of sulfonamide allergy labels (SAL) on clinical outcomes. We examined the impact of SAL on clinical outcomes of solid organ transplant recipients. METHODS: In this retrospective matched cohort study, we utilized the TriNetX US collaborative Network, a multicenter de-identified US database, and identified solid organ transplant recipients with and without SAL. The 1-year probability of developing Pneumocystis jirovecii pneumonia (PJP), toxoplasmosis, and nocardiosis was estimated and contrasted between the two study groups. The hazard ratio (HR) and the 95% confidence interval (CI) quantified the strength and direction of the association between SAL and these outcomes. RESULTS: When comparing 1571 solid organ transplant recipients with SAL to an equal number of matched controls, patients with SAL had a higher probability of developing nocardiosis (HR 3.85; 95% CI, 1.44-10.30; p = .004; corrected p = .04), and toxoplasmosis (HR, 1.87; 95% CI, 1.10-3.17; p = .019; corrected p = .19), but no difference in the risk of developing PJP (HR, 1.64; 95% CI, 0.68-3.95; p = .27). There was no mortality difference (HR, 1.31; 95% CI, 0.99-1.75; p = .061; corrected p = .6). SAL influenced antibiotic prescription with overutilization of dapsone, atovaquone, and pentamidine and underutilization of trimethoprim and sulfamethoxazole. CONCLUSION: SAL is associated with an increased risk of opportunistic infections following solid organ transplantation. Measures to evaluate and de-label sulfonamide allergy prior to transplantation or desensitizing shortly after transplantation are advisable.

Impact of Sulfonamide Allergy Label on Clinical Outcomes in Patients with Pneumocystis jirovecii Pneumonia.

INTRODUCTION: The presence of antibiotic allergy labels can have harmful impacts on clinical outcomes, particularly among immunosuppressed patients, in whom there have been associations with increased complications, readmission rates, and mortality. We explore the effects of a sulfonamide allergy label (SAL) on clinical outcomes in adult patients with Pneumocystis jirovecii pneumonia (PJP). METHODS: In this retrospective matched cohort study, we utilized TriNetX, a multicenter national database, to match 535 adult patients with PJP and SAL to an equal number of controls. We identified cases indexed between 01/01/2010 and 01/01/2023 utilizing ICD-10 codes for PJP and allergy status to sulfonamides and through detection of P. jirovecii antigen with immunofluorescence or PCR. Propensity score matching was performed in a 1:1 fashion for demographics and comorbidities, and our analysis included clinical outcomes that occurred within 30 days after the occurrence of the index event. RESULTS: While hospitalization risk tended to be lower among patients with SAL as compared to controls (RR: 0.90; 95% CI 0.81-1.01), there were no major differences in the risk of respiratory failure (RR: 0.94; 95% CI 0.84-1.05), prednisone use (RR: 1; 95% CI 0.91-1.10), intensive level of care requirement (RR: 0.85; 95% CI 0.69-1.06), intubation (RR: 0.85; 95% CI 0.61-1.19), or mortality (RR: 0.98; 95% CI 0.68-1.42). The presence of SAL did however impact antibiotic prescription patterns, with an underutilization of trimethoprim (RR: 0.50; 95% CI 0.43-0.59) and sulfamethoxazole (RR, 0.47; 95% CI 0.40-0.56) and overuse of alternative agents by patients with SAL as compared to controls. Yet, there was no difference in the occurrence of adverse outcomes such as hepatotoxicity (RR: 1.09; 95% CI 0.49-2.45) or acute kidney injury (RR: 0.94; 95% CI 0.78-1.14) between patients with SAL and controls. CONCLUSIONS: The presence of SAL alters antibiotic prescription patterns among adults with Pneumocystis infection but has no clinically significant impact on outcomes.

Insulin secretion and sensitivity in healthy adults with low vitamin D are not affected by high-dose ergocalciferol administration: a randomized controlled trial.

BACKGROUND: Epidemiologic data suggest that low serum 25-hydroxyvitamin D [25(OH)D] increases insulin resistance and the risk of type 2 diabetes. Few interventional trials have assessed the effect of vitamin D on insulin metabolism, and published results are discordant. OBJECTIVE: The goal of this study was to perform a detailed assessment of the effect of ergocalciferol administration on glucose and insulin metabolism in healthy people with low total 25(OH)D(total). DESIGN: This was a 12-wk, double-blinded, randomized controlled trial. We enrolled 90 healthy volunteers aged 18-45 y with serum 25(OH)D ≤20 ng/mL (by immunoassay) and administered 50,000 IU ergocalciferol/wk or placebo for 12 wk. Primary endpoints were change in first-phase insulin response and insulin sensitivity as measured by intravenous glucose tolerance test. Secondary endpoints included change in homeostasis model assessment of insulin resistance; fasting glucose, insulin, and lipids; body mass index (BMI); and blood pressure. RESULTS: On-study 25(OH)D(total) was assessed by liquid chromatography-tandem mass spectrometry. In the treated group, 25(OH)D(total) rose from 18 ± 7 to 43 ± 12 ng/mL (P < 0.001) with no change in the placebo group. Despite this increase, at 12 wk, there were no between-group differences in either insulin response or insulin sensitivity; nor were there differences in any measured secondary endpoints. There was no evidence of effect modification by sex, race, glucose tolerance status, baseline 25(OH)D(total), or BMI. CONCLUSION: In healthy persons with low 25(OH)D(total), ergocalciferol administration for 12 wk normalizes 25(OH)D(total) but does not improve insulin secretion, insulin sensitivity, or other markers of metabolic health.

Prevalence and predictors of vitamin D deficiency in healthy adults.

OBJECTIVE: Vitamin D deficiency is highly prevalent in high-risk patient populations, but the prevalence among otherwise healthy adults is less well-defined. The goal of this study was to determine the prevalence and predictors of low 25-hydroxyvitamin D [25(OH)D] levels in healthy younger adults. METHODS: This was a cross-sectional study of 634 healthy volunteers aged 18-50 years performed between January, 2006 and May, 2008. We measured serum 25(OH)D and parathyroid hormone and recorded demographic variables including age, sex, race, and use of multivitamin supplements. RESULTS: Thirty-nine percent of subjects had 25(OH)D ≤ 20 ng/mL and 64% had 25(OH)D ≤ 30 ng/mL. Predictors of lower 25(OH)D levels included male sex, black or Asian race, and lack of multivitamin use (P<0.001 for each predictor). Seasonal variation in 25(OH)D levels was present in the overall cohort but was not observed in multivitamin users. Lower 25(OH)D levels were associated with increased risk of elevated parathyroid hormone. Regression models predicted 25(OH)D levels ≤ 20 or ≤ 30 ng/mL with areas under the receiver operating characteristic curves of 0.76 and 0.80, respectively. CONCLUSION: Low 25(OH)D levels are prevalent in healthy adults and may confer risk of skeletal disease. Black and Asian adults are at increased risk of deficiency and multivitamin use appears partially protective. Our models predicting low 25(OH)D levels may guide decision-making regarding whom to screen for vitamin D deficiency.

Randomized trial assessing the effects of ergocalciferol administration on circulating FGF23.

BACKGROUND AND OBJECTIVES: Fibroblast growth factor 23 is a phosphate- and vitamin D-regulating hormone. The objective of this study was to determine the effect of ergocalciferol administration on fibroblast growth factor 23 levels in healthy vitamin D-deficient subjects. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this 12-week trial conducted in a clinical research center, 18- to 45-year-old subjects (n=90) with 25-hydroxyvitamin D levels ≤20 ng/ml (by chemiluminescent immunoassay) were randomized to weekly ergocalciferol treatment of 50,000 international units or placebo, while consuming a self-selected diet. Changes in fibroblast growth factor 23, 25-hydroxyvitamin D (by liquid chromatography/tandem mass spectroscopy), 1,25-dihydroxyvitamin D, parathyroid hormone, and serum phosphate were measured. RESULTS: Mean 25-hydroxyvitamin D (P<0.0001), 1,25-dihydroxyvitamin D (P=0.01), and fibroblast growth factor 23 (P=0.003) increased in the treatment versus placebo group. In the treatment group, 25-hydroxyvitamin D increased from 18 ± 7 to 40 ± 12 ng/ml at week 4 (P<0.0001) and remained stable at 43 ± 12 ng/ml at week 12 (P<0.0001); 1,25-dihydroxyvitamin D increased from 42 ± 17 to 52 ± 18 pg/ml at week 4 (P<0.001) and then remained stable, and fibroblast growth factor 23 increased from 43 ± 17 to 60 ± 33 pg/ml at week 8 (P=0.001) and 74 ± 42 pg/ml at week 12 (P<0.0001). Urinary phosphate excretion increased within the treatment group, but parathyroid hormone and serum phosphate were unchanged. CONCLUSIONS: Ergocalciferol administration increases circulating fibroblast growth factor 23. When measuring fibroblast growth factor 23, concurrent 25-hydroxyvitamin D measurements should be obtained, because vitamin D deficiency may lower circulating fibroblast growth factor 23 levels.

Effects of hPTH(1-34) infusion on circulating serum phosphate, 1,25-dihydroxyvitamin D, and FGF23 levels in healthy men.

Fibroblast growth factor 23 (FGF23) promotes phosphaturia and suppresses 1,25-dihydroxyvitamin D [1,25(OH)(2)D] production. PTH also promotes phosphaturia, but, in contrast, stimulates 1,25(OH)(2)D production. The relationship between FGF23 and PTH is unclear, and the acute effect of pharmacologically dosed PTH on FGF23 secretion is unknown. Twenty healthy men were infused with human PTH(1-34) [hPTH(1-34)] at 44 ng/kg/h for 24 h. Compared with baseline, FGF23, 1,25(OH)(2)D, ionized calcium (iCa), and serum N-telopeptide (NTX) increased significantly over the 18-h hPTH(1-34) infusion (p < 0.0001), whereas serum phosphate (PO(4)) transiently increased and then returned to baseline. FGF23 increased from 35 +/- 10 pg/ml at baseline to 53 +/- 20 pg/ml at 18 h (p = 0.0002); 1,25(OH)(2)D increased from 36 +/- 16 pg/ml at baseline to 80 +/- 33 pg/ml at 18 h (p < 0.0001); iCa increased from 1.23 +/- 0.03 mM at baseline to 1.46 +/- 0.05 mM at hour 18 (p < 0.0001); and NTX increased from 17 +/- 4 nM BCE at baseline to 28 +/- 8 nM BCE at peak (p < 0.0001). PO(4) was 3.3 +/- 0.6 mg/dl at baseline, transiently rose to 3.7 +/- 0.4 mg/dl at hour 6 (p = 0.016), and then returned to 3.4 +/- 0.5 mg/dl at hour 12 (p = 0.651). hPTH(1-34) infusion increases endogenous 1,25(OH)(2)D and FGF23 within 18 h in healthy men. Whereas it is possible that the rise in PO(4) contributed to the observed increase in FGF23, the increase in 1,25(OH)(2)D was more substantial and longer sustained than the change in serum phosphate. Given prior data that suggest that neither PTH nor calcium stimulate FGF23 secretion, these data support the assertion that 1,25(OH)(2)D is a potent physiologic stimulator of FGF23 secretion.