Early Outpatient Treatment of COVID-19: A Retrospective Analysis of 392 Cases in Italy.

COVID-19 was declared a pandemic in March 2020. The knowledge of COVID-19 pathophysiology soon provided a strong rationale for the early use of both anti-inflammatory and antithrombotic drugs; however, its evidence was slowly and partially incorporated into institutional guidelines. The unmet needs of COVID-19 outpatients were taken care of by networks of physicians and researchers. We analyse the characteristics, management and outcomes in COVID-19 outpatients who were taken care of by physicians within the IppocrateOrg Association. In this observational retrospective study, volunteering doctors provided data on 392 COVID-19 patients. The mean age of patients was 48.5 years (range: 0.5-97), and patients were taken care of in COVID-19 stage 0 (15.6%), stage 1 (50.0%), stage 2a (28.8%) and stage 2b (5.6%). Many patients were overweight (26%) or obese (11.5%), with chronic comorbidities (34.9%), mainly cardiovascular (23%) and metabolic (13.3%). The most frequently prescribed drugs included: vitamins and supplements (98.7%), aspirin (66.1%), antibiotics (62%), glucocorticoids (41.8%), hydroxychloroquine (29.6%), enoxaparin (28.6%), colchicine (8.9%), oxygen therapy (6.9%), and ivermectin (2.8%). Hospitalization occurred in 5.8% of cases, mainly in stage 2b (27.3%). A total of 390 patients (99.6%) recovered; one patient was lost at follow up, and one patient died after hospitalization. This is the first real-world study describing the behaviours of physicians caring for COVID-19 outpatients, and the outcomes of COVID-19 early treatment. The lethality in this cohort was 0.2%, while overall, and over the same period, the COVID-19 lethality in Italy was over 3%. The drug use described in this study appears effective and safe. The present evidence should be carefully considered by physicians and political decision makers.

Evaluation of Midnight Salivary Cortisol as a Predictor Factor for Common Carotid Arteries Intima Media Thickness in Patients with Clinically Inapparent Adrenal Adenomas.

Purpose. The aim of the present study was to investigate the atherosclerotic vascular damage in a consecutive series of patients with AI and to correlate it with MSC. Methods. We studied 32 patients with AI matched with control subjects for age, sex, and cardiovascular risk factors. Either patients or control subjects underwent MSC measurement as outpatients and carotid arteries ultrasound (US) imaging studies. Results. The patients with AI had higher mean carotid artery IMT values and higher MSC levels than control subjects. In a multivariate analysis performed in AI age was the best predictor for IMT. We have stratified patients and control subjects by age (<60 yrs and ≥60 yrs). The patients showed significantly higher MSC levels than controls in both groups, whereas significantly higher IMT values were observed only in older subjects. Conclusions. Patients with AI have signs of accelerated atherosclerosis. Patients older than 60 years seem more susceptible to the possible detrimental effect of subclinical hypercortisolism on cardiovascular system. The MSC levels are not a strong predictor of the accelerated atherosclerosis, but they seem to indicate the subtle but not autonomous cortisol excess that may potentially raise the cardiovascular risk.

Practical treatment using mitotane for adrenocortical carcinoma.

PURPOSE OF REVIEW: Description of novel findings about the mechanism of action of mitotane and its activity as an adjunctive postoperative measure, or for treatment of advanced adrenocortical carcinoma. RECENT FINDINGS: Several in-vitro studies have shown that mitotane suppresses gene transcription of different enzymatic steps of the steroidogenetic pathway. Moreover, mitotane induces CYP3A4 expression, thus accelerating the metabolic clearance of a variety of drugs including steroids. Retrospective studies provided evidence that adjunctive mitotane can prolong recurrence-free survival of treated patients. The concept of a therapeutic window of mitotane plasma concentrations was confirmed also for adjunctive treatment, but the relationship between mitotane concentration and given dose is loose. Genetic variability of the P450-dependent enzymes metabolizing mitotane may explain individual differences. SUMMARY: Mitotane concentration of 14-20  mg/l should be reached and maintained during treatment also in an adjunctive setting. In advanced adrenocortical carcinoma, a high-dose starting regimen should be employed when mitotane is used as monotherapy. The combination of mitotane with other drugs should consider the possibility of pharmacologic interactions due to mitotane-induced activation of drug metabolism. This concept applies also to steroid replacement in mitotane-treated patients, who need higher doses to adjust for increased steroid metabolism.

Growth hormone values after an oral glucose load do not add clinically useful information in patients with acromegaly on long-term somatostatin receptor ligand treatment.

The optimal method of assessing GH status in acromegalic patients receiving medical therapy with somatostatin analogs (SSA) has been matter of debate. The aim of the study has been to investigate whether OGTT may add information in patients with discordant random GH (GHr) and IGF values. Moreover, we evaluated the association of GH nadir with the prevalence of co-morbidities observed in acromegalic patients on SSA therapy. We evaluated 130 patients with proven diagnosis of acromegaly on SSA. The patients were subdivided in three groups: patients with controlled disease (both safe random GH and normal IGF-I, group A, 20.0 %), patients with uncontrolled disease (both high random GH and IGF-I, group B, 34.6 %), and patients with discordant random GH and IGF-I values (group C, 35.4 %). A high concordance rate for GH nadir with random GH and IGF-I was observed in group B, while a significant reduced concordance rate has been observed in group A (100 % sensitivity, 64.5 % specificity). By contrast, in group C, we observed concordant results between GH nadir and IGF-I only in 14/59 patients. In group A, the prevalence of diabetes was lower than in group B or C. Safe random GH was the only single criteria associated with a lower prevalence of diabetes. Discrepant IGF-I and either GH nadir or random GH values are frequently observed in acromegalic patients treated with SSA. Concordant IGF-I and random GH may influence the prevalence of metabolic complications. GH nadir measurement may help to interpret discrepancies between random GH and IGF-I data only in few cases.

Screening of Cushing's syndrome in outpatients with type 2 diabetes: results of a prospective multicentric study in Italy.

CONTEXT: Cushing's syndrome may remain unrecognized among patients referred for metabolic syndrome; thus, a proactive screening has been suggested in certain patient populations with features of the disorder. However, conflicting data have been reported on the prevalence of Cushing's syndrome in patients with type 2 diabetes. OBJECTIVE: Our aim was to evaluate the prevalence of unsuspected Cushing's syndrome among outpatients with type 2 diabetes. DESIGN AND SETTING: This was a cross-sectional prospective study in 24 diabetes clinics across Italy. PATIENTS: Between June 2006 and April 2008, 813 patients with known type 2 diabetes without clinically overt hypercortisolism were evaluated. Follow-up of the study was closed in September 2010. Patients were not selected for characteristics conferring a higher pretest probability of hypercortisolism. Patients underwent a first screening step with the 1-mg overnight dexamethasone suppression test. RESULTS: Forty patients failed to suppress serum cortisol less than 5.0 µg/dl (138 nmol/liter) and underwent a standard 2-d, 2-mg dexamethasone suppression test, after which six patients (0.6% of the overall series) failed to suppress cortisol less than 1.8 µg/dl (50 nmol/liter), receiving a definitive diagnosis of Cushing's syndrome that was adrenal dependent in five patients. Four patients were cured, being able to discontinue, or reduce, the glucose-lowering agents. CONCLUSIONS: The present data do not support widespread screening of patients with type 2 diabetes for Cushing's syndrome; however, the disorder is less rare than previously thought when considering epidemiology of type 2 diabetes. Our results support a case-finding approach in patients with uncontrolled diabetes and hypertension despite appropriate treatment.

Cortisol secretion, bone health, and bone loss: a cross-sectional and prospective study in normal non-osteoporotic women in the early postmenopausal period.

OBJECTIVE: The aim of the study was to evaluate the relationship between cortisol secretion, bone health, and bone loss in a cohort of normal women in the early postmenopausal period. METHODS: We measured lumbar and hip bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) and heel ultrasound parameters in 82 healthy, nonosteoporotic (lumbar T-score ≥-2.0) women (median age 52.5 years, range 42-61). These women were examined in two sessions, 1 year apart, in the early postmenopausal period (onset of menopause between 6 and 60 months). Parameters of the hypothalamic-pituitary-adrenal (HPA) axis function were morning serum cortisol, morning and midnight salivary cortisol, 24-h urinary free cortisol (UFC), serum cortisol after 0.5 and 1 mg overnight dexamethasone, and DHEA-S. RESULTS: In multiple regression analyses, the following significant inverse correlations were found: i) lumbar BMD and either 24-h UFC (P<0.005) or morning serum cortisol (P<0.05), ii) total femur and femoral neck BMD with morning serum cortisol (P=0.05 and P<0.05), and iii) heel ultrasound stiffness index and midnight salivary cortisol (P<0.005). The annual rate of change in lumbar and femoral BMD did not correlate with any of the above-mentioned hormonal variables. No difference was found in the parameters of HPA axis function in slow (loss of BMD <1%) vs fast (loss of BMD ≥3%) bone losers. CONCLUSIONS: HPA axis may contribute to postmenopausal bone health, but differences in cortisol secretion do not influence the differential rate of bone loss between slow and fast bone losers in the early postmenopausal period, at least in healthy women.

The combined low-dose dexamethasone suppression corticotropin-releasing hormone test as a tool to rule out Cushing's syndrome.

OBJECTIVE: It remains to be evaluated whether the combined low-dose dexamethasone suppression corticotropin-releasing hormone test (LDDST-CRH test) may add to the diagnostic approach of patients suspected to have Cushing's syndrome (CS). The aim of the present study was to evaluate whether the LDDST-CRH test may have a place in the diagnostic strategy of CS. DESIGN: Prospective evaluation of a consecutive series of patients with suspected CS from 2004 to 2006. METHODS: All the subjects underwent the same screening protocol including 1 mg dexamethasone suppression test, 24-h urinary free cortisol (UFC), and midnight serum cortisol, followed by the LDDST-CRH test whose results were not used to establish a definitive diagnosis. Plasma dexamethasone concentration was measured 2 h after the last dose of dexamethasone. Patients qualified for CS when at least two screening tests were positive. RESULTS: Sixteen patients had CS while in the remaining 15 subjects CS was excluded. Even if not statistically significant, the sensitivity and the negative predictive value of the cortisol 15 min after CRH were better than the other tests; on the other hand, the test specificity was lower. All of the patients classified as indeterminate were correctly diagnosed by the LDDST-CRH test. Nevertheless, the repeated assessment of the screening tests and the active follow-up gave the same correct results. In all of the patients misclassified by the LDDST-CRH test, the plasma dexamethasone concentrations were in the normal range. CONCLUSIONS: Based on our findings, we suggest that the LDDST-CRH test may still find a place as a rule-out procedure in patients who present with indeterminate results after screening and may be unavailable to repeat testing during follow-up.

Secondary hypoadrenalism.

Secondary adrenal insufficiency (SAI) is a clinical disorder that results from hypothalamic or hypophyseal damage or from prolonged administration of supraphysiological doses of glucocorticoids. Since glucocorticoids are widely used for a variety of diseases, the prevalence of SAI is by far exceeding that of primary adrenal insufficiency. Although the presentation of adrenal insufficiency may be insidious and difficult to recognize, an appropriate adrenocortical hormone replacement could lead to a normal quality of life and longevity can be achieved. The spectrum of adrenal insufficiency ranges from overt adrenal crises to subtle dysfunctions in asymptomatic patients who may be at risk of developing acute adrenal insufficiency since their hypothalamic-pituitary-adrenal (HPA) axis cannot appropriately react to stress. Thus, identification of patients with subtle abnormalities of the HPA is mandatory for avoiding this life-threatening event in stressful conditions. The optimal tests and the optimal testing sequence for adrenal insufficiency are still matter of debate. Insulin tolerance test (ITT) could be the gold standard, as it tests the whole HPA axis, but there are some patients who pass the ITT failing the ACTH test. Various alternatives to the ITT, including the standard cosyntropin stimulation test (SST) and low-dose SST, have been proposed since the adrenal gland in SAI loses the capacity for a prompt response to ACTH stimulation. The standard ACTH dose, but not the 1 microg dose, increases adrenal blood flow and this may contribute to produce an early cortisol response of greater magnitude. Moreover, the loss of the early cortisol response to ACTH stimulation could be a specific property of adrenal insufficiency, thus being a sensitive and early marker of failing adrenal function. While the results of the SSTs are often positive in patients with long-standing and severe disease, in patients with mild or recent-onset SAI these tests, using either 250 microg or 1 microg ACTH, tend to give normal results; thus, a negative cosyntropin test result does not rule out the possibility of SAI. Further studies with a systematic comparison of the different tests in large series of patients submitted to a prolonged follow-up are needed to solve the controversy of the optimal diagnostic strategy of SAI.

Laboratory differentiation of Cushing's syndrome.

Cushing's syndrome (CS) is a complex of signs and symptoms due to chronic glucocorticoid excess from a variety of causes. Although CS is considered a rare disease, recent studies have suggested that it may be more frequent than previously expected in various clinical settings (i.e. subjects suffering from diabetes, osteoporosis or metabolic syndrome). If confirmed in large population-based studies, more widespread screening for CS may be warranted. Missed diagnosis of CS may have detrimental consequences because hypercortisolism, even if not clinically apparent, increases the probability of future cardiovascular events through induction/amplification of several risk factors (hypertension, central adiposity, thrombophilic state, etc.). Identifying CS has represented one of the most challenging problems for the clinical endocrinologist since no test is 100% sensitive and specific. This review article will be focus on diagnostic laboratory procedures that support a rationale approach in the screening evaluation and in the differential diagnosis of the endogenous CS. Notwithstanding the difficulties derived from laboratory reliability and the adoption of a hormonal cut-off close to the sensitivity of many commercially available assays, an increasing amount of data have provided novel information aimed to meet the demand of inexpensive, convenient and reliable laboratory procedures.

Screening of Cushing's syndrome in adult patients with newly diagnosed diabetes mellitus.

OBJECTIVE: Recent studies have shown that a relatively high number of diabetic patients may have unsuspected Cushing's syndrome (CS). The aim of the present study was to screen for CS in adult patients with newly diagnosed diabetes mellitus who were not selected for clinical characteristics, such as poor control and obesity, which may increase the pre-test probability of CS. DESIGN, PATIENTS AND MEASUREMENT: We prospectively evaluated 100 consecutive diabetic patients at diagnosis from 2003 to 2004. No patient had clear Cushingoid features. Screening was performed by using the overnight 1-mg dexamethasone suppression test (DST) after complete recovery from acute concomitant illnesses and attainment of satisfactory glycaemic control. The threshold of adequate suppression after DST was set at 110 nmol/l. RESULTS: Five patients failed to suppress cortisol after DST and underwent a repeated DST and a confirmatory standard 2-day, 2-mg DST after 3-6 months from the baseline evaluation. In one woman, a definitive diagnosis of CS was made by a surgically proven pituitary adenoma, and glycaemic control improved after cure of CS. CONCLUSIONS: The results of the present study support the view that unknown CS is not rare among patients with diabetes mellitus. This is the first demonstration that screening for CS may be feasible at the clinical onset of diabetes in an unselected cohort of patients. Therefore, early diagnosis and treatment of CS may provide the opportunity to improve the prognosis of diabetes.

Increased osteoprotegerin levels in Cushing's syndrome are associated with an adverse cardiovascular risk profile.

CONTEXT: Patients with Cushing's syndrome (CS) have a mortality rate four times higher than age- and sex-matched subjects, mainly due to cardiovascular events. Serum osteoprotegerin (OPG) levels are increased in patients with cardiovascular disease and/or excess bone resorption. OBJECTIVE: The aim of the study was to assess serum OPG and soluble receptor activator of nuclear factor-kappaB ligand (sRANKL) levels in CS and their possible relationship with coronary risk profile. DESIGN AND SETTING: We conducted a cross-sectional study at a tertiary referral center. PATIENTS: We studied 48 adult patients with CS and 48 age- and sex-matched controls. Twenty-six patients had pituitary-dependent CS; five patients had CS caused by ectopic ACTH secretion; and 17 patients had adrenal-dependent CS, accounted for by cortisol-secreting adenoma (n = 9), ACTH-independent macronodular bilateral adrenal hyperplasia (n = 4), or World Health Organization stage II cortisol-secreting carcinoma (n = 4). Patients underwent assessment of the absolute coronary risk and measurement of bone mineral density by dual-energy x-ray absorptiometry. Serum OPG and total sRANKL were measured by ELISA. RESULTS: Serum OPG (but not sRANKL) levels were significantly higher in CS patients than in controls (P < 0.01). In patients, serum OPG showed a positive correlation with age (r = 0.36; P = 0.01). OPG levels were higher in patients with the metabolic syndrome [median, 1262 (range, 199-2306) pg/ml vs. 867 (412-2479) pg/ml; P = 0.03], and showed a positive correlation with the absolute coronary risk (r = 0.36; P = 0.01). Serum OPG levels were higher in patients with pituitary-dependent CS in comparison with adrenal-dependent CS. CONCLUSIONS: In patients with CS, serum OPG levels are increased and appear to be associated with coronary risk.

[Subclinical Cushing's syndrome in adrenal incidentalomas]. / La sindrome di Cushing subclinica nei pazienti con incidentaloma surrenalico.

In the heyday of high-tech medicine, the incidental discovery of an adrenal mass is a frequent event owing to the routine use of sophisticated radiological techniques. The potential harm to health associated with incidentally discovered cortical adenoma, the most frequent tumor among adrenal incidentalomas, is unclear at present. Incidentally discovered adrenal adenoma may secrete cortisol autonomously, in a way that is no longer under close control by pituitary feedback, in 5 to 20% of cases. At present, data are insufficient to estimate the outcome of patients with subclinical Cushing's syndrome. However, evidence is gathering that subclinical Cushing's syndrome may contribute to develop the phenotype of insulin resistance thus portending to atherosclerosis and relevant cardiovascular complications. It is tempting to speculate that subclinical Cushing's syndrome represents a very mild variant of endogenous glucocorticoid excess syndrome. Even if progression to overt glucocorticoid excess is rare, subclinical Cushing's syndrome has the potential to carry an adverse prognosis. At present, data are insufficient to indicate the superiority of a surgical or nonsurgical approach to manage patients with subclinical hyperfunctioning adrenal cortical adenoma. It is of the utmost importance to establish collaborative prospective studies with clearly defined entry criteria and standardized evaluation protocols and treatment modalities to appraise the natural history and long-term morbidity of clinically inapparent adrenal adenoma and subclinical Cushing's syndrome.

Evaluation of the effectiveness of midnight serum cortisol in the diagnostic procedures for Cushing's syndrome.

OBJECTIVE: It is presently unclear whether the accuracy of midnight serum cortisol (F24) in the diagnosis of Cushing's syndrome (CS) may be replicated under usual conditions of clinical care. The aim of the present study was to assess retrospectively the effectiveness of F24 for confirming the diagnosis in a consecutive series of 106 patients, in 78 of whom a definitive diagnosis of CS was made. DESIGN AND METHODS: We have compared the results of F24, urinary free cortisol (UFC) and the overnight 1 mg dexamethasone suppression test (DST) with the definitive clinical diagnosis. Receiver operating characteristic (ROC) analysis has been performed to define the best cutoff values, the sensitivity (Se) and the specificity (Sp) of the tests. RESULTS: The best cutoff value for F24 was 8.3 microg/dl (Se 91.8%; Sp 96.4%). The best cutoff value for the DST was 4.0 microg/dl (Se 89.2%; Sp 90.9%). The best cutoff value for UFC was 238 microg/24 h (Se 73.2%; Sp 96.3%). The area under the curve of F24 was significantly greater than that of UFC, both in the overall series (P = 0.004) and in the subgroup of patients with mild CS (P = 0.02). The differences were analyzed by means of the two-tailed students's t-test. With the thresholds generated by the ROC analysis, UFC would have failed to achieve the correct diagnosis in a significantly higher percentage of cases than F24 (20.4% vs 7.9%; P = 0.01). The difference was analyzed by means of the chi-squared test with Yates correction. CONCLUSIONS: The present results show that F24 has excellent effectiveness in the diagnostic procedures for CS in stressed conditions (patients studied in a hospital ward in a nonsleeping state). The test appears to be accurate also for patients with mild hypercortisolism.

Hyperhomocysteinemia in patients with Cushing's syndrome.

We evaluated serum homocysteine concentrations and the C677T polymorphism of the gene encoding for methylene tetrahydrofolate reductase, a key enzyme for homocysteine metabolism, in 57 patients with Cushing's syndrome, 41 with active disease, and 16 in remission after successful surgery and 105 blood donors. The patients with active Cushing's syndrome had significantly higher serum homocysteine levels and lower folate concentrations than either the patients in remission or controls. The presence of a statistically significant difference in homocysteine concentrations among the three groups was confirmed after adjustment for confounding variables. In a multiple regression model, homocysteine levels were significantly associated with midnight serum cortisol levels (beta = 0.33, P = 0.01), which is the most sensitive marker of endogenous hypercortisolism, and serum folate levels (beta = -0.32, P = 0.02). The distribution of methylene tetrahydrofolate reductase genotypes was not different between patients and controls. In conclusion, active hypercortisolism is associated with hyperhomocysteinemia and reduced serum folate concentrations, whereas the patients in remission have homocysteine concentrations comparable with healthy subjects. Low serum folate concentrations do not fully account for the increase in homocysteine levels that are positively correlated with cortisol levels. Hyperhomocysteinemia may be key to the prothrombotic state and increased cardiovascular risk of Cushing's syndrome.