Management of Polypharmacy and Potential Drug-Drug Interactions in Patients with Pulmonary Aspergillosis: A 2-Year Study of a Multidisciplinary Outpatient Clinic.

Pulmonary aspergillosis mainly affects elderly patients, patients with pulmonary complications, patients with hematological malignancies, organ transplant recipients, or critically ill patients. Co-morbidities may result in a high rate of polypharmacy and a high risk of potential drug-drug interaction (pDDI)-related antifungal azoles, which are perpetrators of several pharmacokinetic- and pharmacodynamic-driven pDDIs. Here, we report the results of the first 2-year study of an outpatient clinic focusing on the management of therapies in patients with pulmonary aspergillosis. All patients who underwent an outpatient visit from May 2021 to May 2023 were included in this retrospective analysis. A total of 34 patients who were given an azole as an antifungal treatment (53% voriconazole, 41% isavuconazole, and 6% itraconazole) were included. Overall, 172 pDDIs were identified and classified as red- (8%), orange- (74%), or yellow-flag (18%) combinations. We suggested handling polypharmacy in those patients using specific diagnostic and pharmacologic interventions. As expected, red-flag pDDIs involved mainly voriconazole as a perpetrator (71%). However, nearly 30% of red-flag pDDIs were not related to antifungal therapy. These findings highlight the importance of conducting an overall assessment of the pharmacologic burden and the key role played by a multidisciplinary team for the optimization of therapies in patients with pulmonary aspergillosis.

Management of Polypharmacy and Potential Drug-Drug Interactions in Patients with Mycobacterial Infection: A 1-Year Experience of a Multidisciplinary Outpatient Clinic.

In 2022, we opened an outpatient clinic for the management of polypharmacy and potential drug-drug interactions (pDDIs) in patients with mycobacterial infection (called GAP-MyTB). All patients who underwent a GAP-MyTB visit from March 2022 to March 2023 were included in this retrospective analysis. Fifty-two patients were included in the GAP-MyTB database. They were given 10.4 ± 3.7 drugs (2.8 ± 1.0 and 7.8 ± 3.9 were, respectively, antimycobacterial agents and co-medications). Overall, 262 pDDIs were identified and classified as red-flag (2%), orange-flag (72%), or yellow-flag (26%) types. The most frequent actions suggested after the GAP-MyTB assessment were to perform ECG (52%), therapeutic drug monitoring (TDM, 40%), and electrolyte monitoring (33%) among the diagnostic interventions and to reduce/stop proton pump inhibitors (37%), reduce/change statins (14%), and reduce anticholinergic burden (8%) among the pharmacologic interventions. The TDM of rifampicin revealed suboptimal exposure in 39% of patients that resulted in a TDM-guided dose increment (from 645 ± 101 to 793 ± 189 mg/day, p < 0.001). The high prevalence of polypharmacy and risk of pDDIs in patients with mycobacterial infection highlights the need for ongoing education on prescribing principles and the optimal management of individual patients. A multidisciplinary approach involving physicians and clinical pharmacologists could help achieve this goal.

The performance of levothyroxine tablet is impaired by bariatric surgery.

OBJECTIVE: The aim was to evaluate if bariatric surgery can affect the LT4 performance. The endpoints were the following: 1) difference between LT4 daily dose before and 1 year after surgery, 2) difference between LT4 dose per weight before and 1 year after surgery, 3) difference among LT4 preparations. METHODS: The study period was between January 2018 and May 2022. Inclusion criteria were a) adults undergone bariatric surgery, b) with proven autoimmune hypothyroidism, c) on LT4 therapy before bariatric surgery, d) using any commercialized LT4 preparation. Excluded were patients a) proven to have or suspected for pre-surgical intestinal malabsorption, b) with other potential interfering factors on LT4 absorption; c) with heart, renal, and/or hepatic failure, d) with recent/current infection/inflammation, e) in pregnancy, f) with incomplete data about LT4 therapy. RESULTS: According to the selection criteria, 40 patients were included. Both TSH and LT4 daily doses were not significantly different with respect to baseline values. On the contrary, the LT4 dose per weight was significantly increased, especially in RYGB patients. An increased LT4 dose per weight was observed with the reduction of weight. CONCLUSION: One year after bariatric surgery 1) the daily dose of LT4 remains unchanged, and 2) despite the significant weight reduction, LT4 dose per weight increases. Most data are referred to LT4 tablet and the performance of LT4 caps should be further investigated.

Opioid-Free Anesthesia in Bariatric Surgery: a Propensity Score-Matched Analysis.

PURPOSE: Patients undergoing bariatric surgery are at particular high risk of postoperative nausea and vomiting (PONV). Few studies have shown the superiority of opioid-free anesthesia (OFA) over general anesthesia with opioids in bariatric surgery. The aim was to investigate the potential advantages of the OFA in bariatric surgery. MATERIALS AND METHODS: This is a retrospective study on a prospectively collected database that included bariatric patients over a 3-year period. All patients who underwent bariatric surgery at our institution were included and divided into opioid-free or standard anesthesia. The primary endpoint was the length of hospital stay. Data was collected and analyzed using a propensity score. RESULTS: We included 344 patients, of these 209 (60.8%) received opioid-free and 135 (39.2%) received a standard anesthesia. Mean age was 46.2 ± 11.2 years, 265 (77.0%) patients were female, and 238 (69.2%) had at least one associated medical problem. The two groups were similar in terms of age, gender, BMI, associated medical problems, and type of operations. Postoperatively, we observed no significant difference in opioid requirement, while significantly less doses of antiemetics were administered in the OFA group at postoperative day 1 (0.4 ± 0.7 vs. 0.7 ± 1.0 doses, p = 0.006) and 2 (0.1 ± 0.4 vs. 0.2 ± 0.6 doses, p = 0.022). Length of stay was significantly shorter in the OFA group (2.8 ± 0.9 vs. 3.5 ± 2.0 days, p < 0.001) both in the overall and in the propensity score-matched analyses. CONCLUSION: OFA is effective for patients undergoing bariatric surgery. Perioperative outcomes are similar, while OFA patients required less antiemetics and were discharged earlier from hospital.

Optical Coherence Tomography Angiography Findings of Iris Ischemia and Reperfusion in Cytomegalovirus Panuveitis.

PURPOSE: To report a case of iris ischemia in an eye affected by Cytomegalovirus (CMV)-related Chronic Retinal Necrosis (CRN) with partial reperfusion after antiviral therapy demonstrated by optical coherence tomography angiography (OCTA). METHODS: Retrospective case report. Multimodal imaging was performed at each follow-up visits. RESULTS: At baseline, the clinical findings and PCR on aqueous confirmed the diagnosis of CMV-induced CRN, while OCTA and Fluorescein Angiography showed multi-sectoral retinal and iris non-perfusion. After three weekly intravitreal injections of Foscarnet and retinal photocoagulation, the clinical and angiographic picture improved, with partial reperfusion of both retinal and iris vasculature. CONCLUSION: Retinal and iris non-perfusion in CRN can be partially reversible, if prompt treatment is administered. OCTA of the anterior segment allowed an accurate follow-up of the iris vasculature and its perfusion.

Photodynamic Therapy for the Treatment of Vascularized Intraretinal Tuberculoma.

PURPOSE: To report a case of intraretinal tubercular granuloma successfully treated with photodynamic therapy (PDT). METHODS: Retrospective case report. Multimodal imaging was performed at each follow-up visit. RESULTS: The tuberculoma did not regress and did not significantly reduce its exudation after anti-tubercular therapy (ATT), systemic steroid therapy and intravitreal anti-VEGF. Second line treatment with PDT was attempted. The lesion showed a regression with reduced sub-retinal fluid and intra-retinal exudates. A second PDT was performed for reactivation of the lesion 5 months after the first treatment. Further regression of the lesion was observed. CONCLUSION: PDT may be a valuable second-line therapeutic approach for vascularized intraretinal granulomas.

Retinal vessels modifications in acute and post-COVID-19.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2 primarily affecting the respiratory system which can damage vessels walls virtually in any body district. Changes affecting retinal vessels are a good marker for systemic vascular alterations. This study investigated retinal vessels during the acute phase of COVID-19 and after patients recovery. Fifty-nine eyes from 32 COVID-19 patients and 80 eyes from 53 unexposed subjects were included. Mean arteries diameter (MAD) and mean veins diameter (MVD) were assessed through semi-automatic analysis on fundus color photos at baseline and 6 months later in patients and subjects unexposed to the virus. At baseline MAD and MVD were significantly higher in COVID-19 patients compared to unexposed subjects (p < 0.0001). Both MAD and MVD significantly decreased in COVID-19 patients at follow-up (from 97.5 ± 10.9 to 92.2 ± 11.4 µm, p < 0.0001 and from 133.1 ± 19.3 to 124.6 ± 16.1 µm, p < 0.0001, respectively). Despite this reduction vessels diameter remained significantly higher in severe COVID-19 patients compared to unexposed subjects. Transient retinal vessels dilation could serve a biomarker for systemic inflammation while long-lasting alterations seen in severe COVID-19 likely reflect irreversible structural damage to the vessels walls and should be further investigated for their possible effects on tissues perfusion and function.

Histoplasmosis Diagnosed in Europe and Israel: A Case Report and Systematic Review of the Literature from 2005 to 2020.

Human histoplasmosis is a mycosis caused by two distinct varieties of a dimorphic fungus: Histoplasma capsulatum var. capsulatum and H. capsulatum var. duboisii. In Europe, it is usually imported by migrants and travellers, although there have been some autochthonous cases, especially in Italy; however, most European physicians are unfamiliar with its clinical and pathological picture, particularly among immunocompromised patients without HIV infection. This systematic review of all the cases of histoplasmosis reported in Europe and Israel between 2005 and 2020 identified 728 cases diagnosed in 17 European countries and Israel described in 133 articles. The vast majority were imported (mainly from Central and South America), but there were also seven autochthonous cases (six in Europe and one in Israel). The patients were prevalently males (60.4%), and their ages ranged from 2 to 86 years. The time between leaving an endemic region and the diagnosis of histoplasmosis varied from a few weeks to more than 40 years. Progressive disseminated histoplasmosis was the most frequent clinical picture among people living with HIV infection (89.5%) or a different immunocompromising condition (57.1%), but it was also recorded in 6.2% of immunocompetent patients. Twenty-eight cases were caused by Histoplasma duboisii. Immunocompromised patients without HIV infection had the worst outcomes, with a mortality rate of 32%.

Performance of the COVID19SEROSpeed IgM/IgG Rapid Test, an Immunochromatographic Assay for the Diagnosis of SARS-CoV-2 Infection: a Multicenter European Study.

This study assessed the diagnostic performance of the new COVID19SEROSpeed IgM/IgG rapid test (BioSpeedia, a spinoff of the Pasteur Institute of Paris) for the detection of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in comparison to other commercial antibody assays through a large cross-European investigation. The clinical specificity was assessed on 215 prepandemic sera (including some from patients with viral infections or autoimmune disorders). The clinical sensitivity was evaluated on 710 sera from 564 patients whose SARS-CoV-2 infection was confirmed by quantitative reverse transcription-PCR (qRT-PCR) and whose antibody response was compared to that measured by five other commercial tests. The kinetics of the antibody response were also analyzed in seven symptomatic patients. The specificity of the test (BioS) on prepandemic specimens was 98.1% (95% confidence interval [CI], 96.2% to 99.4%). When tested on the 710 pandemic specimens, BioS showed an overall clinical sensitivity of 86.0% (95% CI, 0.83 to 0.89), with good concordance with the Euroimmun assay (overall concordance of 0.91; Cohen's kappa coefficient of 0.62). Due in part to simultaneous detection of IgM and IgG for both S1 and N proteins, BioS exhibited the highest positive percent agreement at ≥11 days post-symptom onset (PSO). In conclusion, the BioS IgM/IgG rapid test was highly specific and demonstrated a higher positive percentage of agreement than all the enzyme-linked immunosorbent assay/chemiluminescence immunoassay (ELISA/CLIA) commercial tests considered in this study. Moreover, by detecting the presence of antibodies prior to 11 days PSO in 78.2% of the patients, the BioS test increased the efficiency of the diagnosis of SARS-CoV-2 infection in the early stages of the disease.

Preliminary observations on IGRA testing for TB infection in patients with severe COVID-19 eligible for immunosuppressive therapy.

COVID-19, the novel coronavirus pandemic, has already spread around the globe affecting more than 18 million people. As previously observed with other coronaviruses, SARS-CoV-2 deeply dysregulate the immune system eliciting respiratory failure and a state of systemic hyperinflammation in severely ill individuals. Immunotherapy is often used to downgrade the detrimental effects of the disease sustained by high-level of cytokines. Those treatments, however, are known to undermine patients' ability to contain tuberculosis (TB) infection. This study aims to describe interferon-γ release assay (IGRA) results in severe COVID-19 patients eligible for immunosuppressive treatment. Aggregate data were gathered from five hospitals in Milan, Italy, from March 1 to May 15, 2020 and retrospectively analyses. Results were summarized using absolute frequencies and percentages and compared using a two-sided Chi-squared test. Overall, 462 COVID-19 patients were eligible for immunosuppressive therapy, among which 335 were tested using IGRA testing. More than one-third of them (122/335; 36.4%) had an indeterminate IGRA result because of insufficient immune response to mitogen control, 19 (5.7%) tested positive and 194 (57.9) negative. The majority of patients with lymphocytopenia (i.e., total lymphocyte count [TLC] below 1000 cells/mm3) had indeterminate IGRAs (81/155; 52.3%). The proportion becomes even higher in patients with severe lymphocytopenia (i.e., TLC<500 cells/mm3) (36/57; 63%). Our results suggest a possible negative impact of COVID-19 related immune dysregulation on TB infection assessment and management. Close monitoring of individuals with or without retesting of individuals with indeterminate IGRAs and further basic science investigations should to be sought to better comprehend their implication on TB epidemiology.

Retinal findings in patients with COVID-19: Results from the SERPICO-19 study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has been associated to microvascular alterations. We screened the fundus of patients with COVID-19 to detect alterations of the retina and its vasculature and to assess possible correlations with clinical parameters. METHODS: Cross-sectional study. The presence of retinal alterations in patients with COVID-19 and subjects unexposed to the virus was assessed using fundus photographs and their prevalence was compared. Mean arteries diameter (MAD) and mean veins diameter (MVD) were compared between patients and unexposed subjects with multiple linear regression including age, sex, ethnicity, body mass index, smoking/alcohol consumption, hypertension, hyperlipidaemia, diabetes as covariates. The influence of clinical/lab parameters on retinal findings was tested in COVID-19 patients. FINDINGS: 54 patients and 133 unexposed subjects were enrolled. Retinal findings in COVID-19 included: haemorrhages (9·25%), cotton wools spots (7·4%), dilated veins (27·7%), tortuous vessels (12·9%). Both MAD and MVD were higher in COVID-19 patients compared to unexposed subjects (98·3 ± 15·3 µm vs 91·9 ± 11·7 µm, p = 0.006 and 138·5 ± 21·5 µm vs 123·2 ± 13·0 µm, p<0.0001, respectively). In multiple regression accounting for covariates MVD was positively associated with COVID-19 both in severe (coefficient 30·3, CI95% 18·1-42·4) and non-severe (coefficient 10·3, CI95% 1·6-19·0) cases compared to unexposed subjects. In COVID-19 patients MVD was negatively correlated with the time from symptoms onset (coefficient -1·0, CI 95% -1·89 to -0·20) and positively correlated with disease severity (coefficient 22·0, CI 95% 5·2-38·9). INTERPRETATION: COVID-19 can affect the retina. Retinal veins diameter seems directly correlated with the disease severity. Its assessment could have possible applications in the management of COVID-19. FUNDING: None.

30-day mortality in patients hospitalized with COVID-19 during the first wave of the Italian epidemic: A prospective cohort study.

Italy was the first European country hit by the COVID-19 pandemic and has the highest number of recorded COVID-19 deaths in Europe. This prospective cohort study of the correlates of the risk of death in COVID-19 patients was conducted at the Infectious Diseases and Intensive Care units of Luigi Sacco Hospital, Milan, Italy. The clinical characteristics of all the COVID-19 patients hospitalised in the early days of the epidemic (21 February -19 March 2020) were recorded upon admission, and the time-dependent probability of death was evaluated using the Kaplan-Meier method (censored as of 20 April 2020). Cox proportional hazard models were used to assess the factors independently associated with the risk of death. Forty-eight (20.6 %) of the 233 patients followed up for a median of 40 days (interquartile range 33-47) died during the follow-up. Most were males (69.1 %) and their median age was 61 years (IQR 50-72). The time-dependent probability of death was 19.7 % (95 % CI 14.6-24.9 %) 30 days after hospital admission. Age (adjusted hazard ratio [aHR] 2.08, 95 % CI 1.48-2.92 per ten years more) and obesity (aHR 3.04, 95 % CI 1.42-6.49) were independently associated with an increased risk of death, which was also associated with critical disease (aHR 8.26, 95 % CI 1.41-48.29), C-reactive protein levels (aHR 1.17, 95 % CI 1.02-1.35 per 50 mg/L more) and creatinine kinase levels above 185 U/L (aHR 2.58, 95 % CI 1.37-4.87) upon admission. Case-fatality rate of patients hospitalized with COVID-19 in the early days of the Italian epidemic was about 20 %. Our study adds evidence to the notion that older age, obesity and more advanced illness are factors associated to an increased risk of death among patients hospitalized with COVID-19.

Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in Milan, Italy.

BACKGROUND: Tocilizumab, a humanized monoclonal antibody, targets IL-6 receptors blocking downstream pro-inflammatory effects of IL-6. In preliminary reports it was suggested to be beneficial in patients with severe COVID-19. METHODS: In this open-label prospective study we describe clinical characteristics and outcome of 51 patients hospitalized with confirmed and severe COVID-19 pneumonia treated with tocilizumab intravenously. All patients had elevated IL-6 plasma level (>40 pg/mL) and oxygen saturation <93% in ambient air. Clinical outcomes, oxygen support, laboratory data and adverse events were collected over a follow-up of 30 days. RESULTS: Forty-five patients (88%) were on high-flow oxygen supplementation, six of whom with invasive ventilation. From baseline to day 7 after tocilizumab we observed a dramatic drop of body temperature and CRP value with a significant increase in lymphocyte count (p<0.001). Over a median follow-up time of 34 days from tocilizumab, 34 patients (67%) showed an improvement in their clinical severity class; 31 were discharged; 17 (33%) showed a worsening of their clinical status, of these 14 died (27%). The mortality rate was significantly associated with mechanical ventilation at baseline (83.3% vs 20% of patients on non-invasive oxygen support; p=0.0001). The most frequent side effects were an increase of hepatic enzymes (29%), thrombocytopenia (14%), and serious bacterial and fungal infections (27%). CONCLUSION: Tocilizumab exerts a rapidly beneficial effect on fever and inflammatory markers, although no significant impact on the clinical outcome can be inferred by our results. Critically ill patients seem to have a high risk of serious infections with this drug.