Management of the Drug-Drug Interactions Between Valproic Acid and Dolutegravir-A Case Study.

OBJECTIVE: Preliminary evidence shows that concomitant administration of valproic acid can reduce the exposure to dolutegravir with limited clinical impacts. Here, we describe a male living with HIV who experienced a drastic reduction in dolutegravir trough concentrations a few weeks after starting valproic acid treatment as identified by therapeutic drug monitoring. Concomitantly, pharmacists recommended a supplementation of magnesium to improve insomnia. CASE REPORT: A 62-year-old man with HIV on antiretroviral therapy with dolutegravir and lamivudine recently added valproic acid to clonazepam and sertraline to treat severe sleep disturbances. An 84% reduction in dolutegravir trough concentrations was observed compared with the previous outpatient visit (418 versus 2714 ng/mL), with values close to the minimum effective drug concentration (300 ng/mL). Considering this, we strongly discourage the use of magnesium. CONCLUSIONS: We are confident that our findings can contribute to a better understanding of the clinical problems that infectious disease physicians encounter in their daily management of people with HIV and how therapeutic drug monitoring may add value in this context. This case also highlights the importance of multidisciplinary services for the optimal management of polypharmacy in people with HIV.

Prognostic Significance of NLR and PLR in COVID-19: A Multi-Cohort Validation Study.

INTRODUCTION: Recent studies have highlighted the prognostic value of easily accessible inflammatory markers, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) for predicting severe outcomes in patients affected by Coronavirus disease 2019 (COVID-19). Our study validates NLR and PLR cut-off values from a prior cohort at IRCCS Policlinico San Matteo (OSM) of Pavia, Italy, across two new cohorts from different hospitals. This aims to enhance the generalizability of these prognostic indicators. METHODS: In this retrospective cohort study, conducted at Milan's Ospedale Luigi Sacco (OLS) and IRCCS Ospedale Maggiore Policlinico (OMP) hospitals, we assess the predictive capacity of NLR and PLR for three main outcomes-non-invasive ventilation (NIV) or continuous positive airway pressure (CPAP) usage, invasive ventilation (IV), and death-in patients with COVID-19 at admission. For each outcome, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were computed separately for male and female cohorts. Distinct NLR and PLR cut-off values were used for men (7.00, 7.29, 7.00 for NLR; 239.22, 248.00, 250.39 for PLR) and women (6.36, 7.00, 6.28 for NLR; 233.00, 246.45, 241.54 for PLR), retrieved from the first cohort at OSM. RESULTS: A total of 3599 patients were included in our study, 1842 from OLS and 1757 from OMP. OLS and OMP sensitivity values for both NLR and PLR (NLR: 24-67%, PLR: 40-64%) were inferior to specificity values (NLR: 64-76%, PLR: 55-72%). Additionally, PPVs generally remained lower (< 63%), while NPVs consistently surpassed 68% for PLR and 72% for NLR. Finally, both PLR and NLR exhibited consistently higher NPVs for more severe outcomes (> 82%) compared to NPVs for CPAP/NIV. CONCLUSIONS: Consistent findings across diverse patient populations validate the reliability and applicability of NLR and PLR cut-off values. High NPVs emphasize their role in identifying individuals less likely to experience severe outcomes. These markers not only aid in risk stratification but also guide resource allocation in emergencies or limited-resource situations.

Bloodstream Infections in Intensive Care Unit during Four Consecutive SARS-CoV-2 Pandemic Waves.

Critically ill COVID-19 patients are at an increased risk of bloodstream infections (BSIs). We performed a retrospective observational single-center study on COVID-19 patients admitted to intensive care unit (ICU) to assess the incidence of BSIs in four consecutive periods: 21 February-31 July 2020 (W1), 1 August 2020-31 January 2021 (W2), 1 February-30 September 2021 (W3) and 1 October 2021 and 30 April 2022 (W4). BSIs that occurred 48 h after ICU admission were included. The crude incidence of BSIs was estimated by means of Poisson distribution normalized to 1000 patient-days. A total of 404 critically ill COVID-19 patients were admitted to ICU, of whom 284 (61%) developed at least one episode of BSI with an overall crude incidence of 87 events every 1000 patient-days (95% CI 77-98) without a significant difference in consecutive epidemic periods (p = 0.357). Gram-positive bacteria were the most frequent etiological agents of BSIs, contributing to 74.6% episodes. A progressive decrease in BSIs due to Enterococcus spp. was observed (W1 57.4%, W2 43.7%, W3 35.7% and W4 32.7%; p = 0.004). The incidence of BSIs remained stable during different epidemic periods. Enterococcus spp. prevalence was significantly reduced, although still accounted for one third of BSIs in more recent epidemic periods.

Delayed diagnosis among patients with visceral leishmaniasis.

We aimed to estimate the diagnostic latency of patients with visceral leishmaniasis (VL). A monocentric retrospective observational study was conducted including all confirmed cases of VL diagnosed from January 2005 to March 2022. Epidemiological and clinical characteristics of patients with VL were collected. The diagnostic latency was defined as the number of days between the first contact with a health-care provider for signs and/or symptoms referable to VL and the laboratory diagnosis of leishmaniasis. Twenty-four cases of VL were included in the study, mostly male (75%) and Italians (79.2%), with a median age of 40 years [Inter Quartile Range (IQR 30-48)]. Fourteen (58.3%) VL cases were people living with HIV (PLWH) and 4 (16.6%) subjects were on immunosuppressive therapy. For VL the median diagnostic latency was 54 days (IQR 28-162). The shorter diagnostic latency was observed in PLWH [31 days (IQR 20-47)] followed by immunocompetent patients [160 days (IQR 133-247)] and those on immunosuppressive therapy [329 days (IQR 200-678)]. Twelve patients (50%) reported at least one medical encounter before the diagnosis of VL and 6 patients received a wrong therapy. Diagnostic delay in VL was significant in patients under immune suppressive treatment.

Milan's forgotten epidemic of summer 1629, a few months before the last great plague: An investigation into the possible cause.

An epidemic not attributable to plague caused thousands of deaths in Milan in the summer of 1629, a time of war and famine that immediately preceded the even more fatal Great Plague of 1630 that killed an estimated ten of thousands of people. The 5,993 deaths of 1629 recorded in the Liber Mortuorum of Milan (a city with an estimated population of 130,000 inhabitants at the time) were 45.7% more than the average number recorded between 1601 and 1628. Registered deaths peaked in July, and 3,363 of the deaths (56,1%) were attributed to a febrile illness which, in most cases (2,964, 88%), was not associated with a rash or organ involvement. These deaths involved 1,627 males and 1,334 females and occurred at a median age of 40 years (range 0-95). In this paper, we discuss the possible cause of the epidemic, which may have been an outbreak of typhoid fever.

Chagas disease prevalence among migrants from El Salvador in Milan: a cross- sectional study of an often-overlooked population.

BACKGROUND: Chagas disease (CD) is considered to be highly endemic in El Salvador, where its prevalence is estimated to be 1.3-3.7%. Although more than 40,000 migrants from El Salvador are currently living in Europe (particularly in Spain and Italy), there are few data regarding the prevalence of CD in this population. The aim of this study was to evaluate the prevalence of CD among Salvadorans living in Italy. METHODS: A cross-sectional serological survey of CD among Salvadorans living in the metropolitan area of Milan was carried out between October 2017 and December 2019. The participants' blood samples were tested for Trypanosoma cruzi antibodies using two different serological assays. The collected demographic data included their biological sex, province of origin, the type of housing in their country of origin, and family history of CD. RESULTS: Of the 384 subjects who voluntarily participated in the study, five (1.3%, most coming from La Paz) were positive to both serological assays and therefore conclusively diagnosed as having CD. Five other subjects had discrepant serological results but were not positive to a third assay. Three of the five subjects with a diagnosis of CD completed medical staging, one of whom had chronic disease (digestive and cardiac involvement). CONCLUSIONS: The prevalence of CD among Salvadorans living in Milan is similar to that estimated by the WHO in 2010. Although they are often overlooked in CD surveys, Salvadoran migrants should be included in CD control programs in countries in which the disease is not endemic.

SARS-CoV-2 viremia and COVID-19 mortality: A prospective observational study.

BACKGROUND: SARS-CoV-2 viremia has been found to be a potential prognostic factor in patients hospitalized for COVID-19. OBJECTIVE: We aimed to assess the association between SARS-CoV-2 viremia and mortality in COVID-19 hospitalized patients during different epidemic periods. METHODS: A prospective COVID-19 registry was queried to extract all COVID-19 patients with an available SARS-CoV-2 viremia performed at hospital admission between March 2020 and January 2022. SARS-CoV-2 viremia was assessed by means of GeneFinderTM COVID-19 Plus RealAmp Kit assay and SARS-CoV-2 ELITe MGB® Kit using <45 cycle threshold to define positivity. Uni and multivariable logistic regression model were built to assess the association between SARS-CoV-2 positive viremia and death. RESULTS: Four hundred and forty-five out of 2,822 COVID-19 patients had an available SARS-CoV-2 viremia, prevalently males (64.9%) with a median age of 65 years (IQR 55-75). Patients with a positive SARS-CoV-2 viremia (86/445; 19.3%) more frequently presented with a severe or critical disease (67.4% vs 57.1%) when compared to those with a negative SARS-CoV-2 viremia. Deceased subjects (88/445; 19.8%) were older [75 (IQR 68-82) vs 63 (IQR 54-72)] and showed more frequently a detectable SARS-CoV-2 viremia at admission (60.2% vs 22.7%) when compared to survivors. In univariable analysis a positive SARS-CoV-2 viremia was associated with a higher odd of death [OR 5.16 (95% CI 3.15-8.45)] which was confirmed in the multivariable analysis adjusted for age, biological sex and, disease severity [AOR 6.48 (95% CI 4.05-10.45)]. The association between positive SARS-CoV-2 viremia and death was consistent in the period 1 February 2021-31 January 2022 [AOR 5.86 (95% CI 3.43-10.16)] and in subgroup analysis according to disease severity: mild/moderate [AOR 6.45 (95% CI 2.84-15.17)] and severe/critical COVID-19 patients [AOR 6.98 (95% CI 3.68-13.66)]. CONCLUSIONS: SARS-CoV-2 viremia resulted associated to COVID-19 mortality and should be considered in the initial assessment of COVID-19 hospitalized patients.

Evaluation of residual humoral immune response against SARS-CoV-2 by a surrogate virus neutralization test (sVNT) 9 months after BNT162b2 primary vaccination.

The humoral response to SARS-CoV-2 vaccination has shown to be temporary, although may be more prolonged in vaccinated individuals with a history of natural infection. We aimed to study the residual humoral response and the correlation between anti-Receptor Binding Domain (RBD) IgG levels and antibody neutralizing capacity in a population of health care workers (HCWs) after 9 months from COVID-19 vaccination. In this cross-sectional study, plasma samples were screened for anti-RBD IgG using a quantitative method. The neutralizing capacity for each sample was estimated by means of a surrogate virus neutralizing test (sVNT) and results expressed as the percentage of inhibition (%IH) of the interaction between RBD and the angiotensin-converting enzyme. Samples of 274 HCWs (227 SARS-CoV-2 naïve and 47 SARS-CoV-2 experienced) were tested. The median level of anti-RBD IgG was significantly higher in SARS-CoV-2 experienced than in naïve HCWs: 2673.2 AU/mL versus 610.9 AU/mL, respectively (p <0.001). Samples of SARS-CoV-2 experienced subjects also showed higher neutralizing capacity as compared to naïve subjects: median %IH = 81.20% versus 38.55%, respectively; p <0.001. A quantitative correlation between anti-RBD Ab and inhibition activity levels was observed (Spearman's rho = 0.89, p <0.001): the optimal cut-off correlating with high neutralization was estimated to be 1236.1 AU/mL (sensitivity 96.8%, specificity 91.9%; AUC 0.979). Anti-SARS-CoV-2 hybrid immunity elicited by a combination of vaccination and infection confers higher anti-RBD IgG levels and higher neutralizing capacity than vaccination alone, likely providing better protection against COVID-19.

Risk factors associated with bacteremia in COVID-19 patients admitted to intensive care unit: a retrospective multicenter cohort study.

PURPOSE: This multicenter observational study was done to evaluate risk factors related to the development of BSI in patients admitted to ICU for COVID-19. METHODS: All patients with COVID-19 admitted in two COVID-19 dedicated ICUs in two different hospital between 02-2020 and 02-2021 were recruited. RESULT: 537 patients were included of whom 265 (49.3%) experienced at least one BSI. Patients who developed bacteremia had a higher SOFA score [10 (8-12) vs 9 (7-10), p < 0.001], had been intubated more frequently [95.8% vs 75%, p < 0.001] and for a median longer time [16 days (9-25) vs 8 days (5-14), p < 0.001]. Patients with BSI had a median longer ICU stay [18 days (12-31.5) vs 9 days (5-15), p < 0.001] and higher mortality [54% vs 42.3%, p < 0.001] than those who did not develop it. Development of BSI resulted in a higher SOFA score [aHR 1.08 (95% CI 1.03-1.12)] and a higher Charlson score [csAHR 1.15 (95% CI 1.05-1.25)]. CONCLUSION: A high SOFA score and a high Charlson score resulted associated with BSI's development. Conversely, immunosuppressive therapy like steroids and tocilizumab, has no role in increasing the risk of bacteremia.

Family cluster of Chagas disease among Bolivian immigrants in Italy: High rate of maternal-fetal transmission.

BACKGROUND: Chagas disease (CD) or American trypanosomiasis is a neglected anthropozoonosis caused by Trypanosoma cruzi that affects 6-8 million people worldwide (mainly in Latin America), 30-40% of whom develop cardiac or digestive complications. Once confined to endemic areas of Latin America, CD has more recently become a global disease as a result of migration flows from endemic to non-endemic regions, particularly in northern America and Europe. Congenital transmission is a particular challenge as it may be sustained for multiple generations and perpetuate the infection even in non-endemic countries. METHODS: Subjects were identified during a cross-sectional survey of CD among Latin American people living in Milan, Italy. Serology was carried out using tests based on either a lysate and a recombinant antigen of Trypanosoma cruzi. They were also tested by a conventional Polymerase Chain Reaction (PCR) targeting the 330 bp variable region of the T. cruzi kinetoplast minicircle genome and a commercial real-time PCR. RESULTS: We here describe a Bolivian family cluster with seven affected people with at least two autochthonous congenital T. cruzi infection which was identified during the course of a CD screening programme. We also review the epidemiology, diagnosis and control of congenital CD, with particular emphasis on the challenges facing the control and management of such a complex and still largely hidden disease. CONCLUSIONS: Our experience confirms the need to screen for CD all family members once a case is diagnosed and shows the possible high rate of congenital CD also in non-endemic areas.

Mortality rates among COVID-19 patients hospitalised during the first three waves of the epidemic in Milan, Italy: A prospective observational study.

INTRODUCTION: This paper describes how mortality among hospitalised COVID-19 patients changed during the first three waves of the epidemic in Italy. METHODS: This prospective cohort study used the Kaplan-Meier method to analyse the time-dependent probability of death of all of the patients admitted to a COVID-19 referral centre in Milan, Italy, during the three consecutive periods of: 21 February-31 July 2020 (first wave, W1), 1 August 2020-31 January 2021 (second wave, W2), and 1 February-30 April 2021 (third wave, W3). Cox models were used to examine the association between death and the period of admission after adjusting for age, biological sex, the time from symptom onset to admission, disease severity upon admission, obesity, and the comorbidity burden. RESULTS: Of the 2,023 COVID-19 patients admitted to our hospital during the study period, 553 (27.3%) were admitted during W1, 838 (41.5%) during W2, and 632 (31.2%) during W3. The crude mortality rate during W1, W2 and W3 was respectively 21.3%, 23.7% and 15.8%. After adjusting for potential confounders, hospitalisation during W2 or W3 was independently associated with a significantly lower risk of death than hospitalisation during W1 (adjusted hazard ratios [AHRs]: 0.75, 95% confidence interval [CI] 0.59-0.95, and 0.58, 95% CI 0.44-0.77). Among the patients aged >75 years, there was no significant difference in the probability of death during the three waves (AHRs during W2 and W3 vs W1: 0.93, 95% CI 0.65-1.33, and 0.88, 95% CI 0.59-1.32), whereas those presenting with critical disease during W2 and W3 were at significantly lower risk of dying than those admitted during W1 (AHRs 0.61, 95% CI 0.43-0.88, and 0.44, 95% CI 0.28-0.70). CONCLUSIONS: Hospitalisation during W2 and W3 was associated with a reduced risk of COVID-19 death in comparison with W1, but there was no difference in survival probability in patients aged >75 years.

Mortality among Italians and immigrants with COVID-19 hospitalised in Milan, Italy: data from the Luigi Sacco Hospital registry.

BACKGROUND: To compare differences in the probability of COVID-19-related death between native Italians and immigrants hospitalised with COVID-19. METHODS: This retrospective study of prospectively collected data was conducted at the ASST Fatebenefratelli-Sacco Hospital in Milan, Italy, between 21 February and 31 November 2020. Uni- and multivariable Cox proportional hazard models were used to assess the impact of the patients' origin on the probability of COVID-19-related death. RESULTS: The study population consisted of 1,179 COVID-19 patients: 921 Italians (78.1%) and 258 immigrants (21.9%) who came from Latin America (99, 38%), Asia (72, 28%), Africa (50, 19%) and central/eastern Europe (37, 14%). The Italians were significantly older than the immigrants (median age 70 years, interquartile range (IQR) 58-79 vs 51 years, IQR 41-60; p < 0.001), and more frequently had one or more co-morbidities (79.1% vs 53.9%; p < 0.001). Mortality was significantly greater among the Italians than the immigrants as a whole (26.6% vs 12.8%; p < 0.001), and significantly greater among the immigrants from Latin America than among those from Asia, Africa or central/eastern Europe (21% vs 8%, 6% and 8%; p = 0.016). Univariable analysis showed that the risk of COVID-19-related death was lower among the immigrants (hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.30-0.63; p < 0.0001], but the risk of Latin American immigrants did not significantly differ from that of the Italians (HR 0.74, 95% CI 0.47-1.15; p = 0.183). However, after adjusting for potential confounders, multivariable analysis showed that there was no difference in the risk of death between the immigrants and the Italians (adjusted HR [aHR] 1.04, 95% CI 0.70-1.55; p = 0.831), but being of Latin American origin was independently associated with an increased risk of death (aHR 1.95, 95% CI 1.17-3.23; p = 0.010). CONCLUSIONS: Mortality was lower among the immigrants hospitalised with COVID-19 than among their Italian counterparts, but this difference disappeared after adjusting for confounders. However, the increased risk of death among immigrants of Latin American origin suggests that COVID-19 information and prevention initiatives need to be strengthened in this sub-population.