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Background: A significant increased risk of complications and mortality in immunocompromised patients affected by COVID-19 has been described. However, the impact of COVID-19 in solid organ transplant (SOT) recipients is an issue still on debate, due to conflicting evidence emerged from different observational studies. Objective: We performed a systematic review with meta-analysis to assess the clinical outcome in SOT recipients with COVID-19 compared to general population. Data source: PubMed-MEDLINE and Scopus were independently searched until 13 October 2021. Study eligibility criteria: Prospective or retrospective observational studies comparing clinical outcome in SOT recipients versus general populations affected by COVID-19. Primary endpoint was 30-day mortality. Participants: Patients with confirmed COVID-19. Intervention: Solid organ transplant recipients. Assessment of risk of bias: Quality of included studies was independently assessed according to ROBINS-I tool for observational studies. Methods of data synthesis: Meta-analysis was performed by pooling odds ratio (OR) retrieved from studies providing adjustment for confounders using a random-effect model with inverse variance method. Multiple subgroup and sensitivity analyses were conducted to investigate source of heterogeneity. Results: 3,501 articles were screened, and thirty-one observational studies (N=590,375; 5,759 SOT recipients vs. 584,616 general population) were included in the meta-analyses. No difference in 30-day mortality rate was found in primary analysis including studies providing adjustment for confounders (N=17; 3,752 SOT recipients vs. 159,745 general population; OR 1.13, 95%CI 0.94-1.35; I2=33.9%). No evidence of publication bias was reported. Higher risk of ICU admission (OR 1.56, 95%CI 1.03-2.63) and occurrence of acute kidney injury (OR 2.50 95%CI 1.81-3.45) was found in SOT recipients. Conclusions: No increased risk in mortality was found in SOT recipients affected by COVID-19 compared to general population when adjusted for demographic and clinical features and COVID-19 severity.

Background. Intra-abdominal candidiasis (IAC) is burdened by high mortality rates. However, the correct management of a critically ill patient with suspected IAC is an issue still on debate. The aim of our study was to evaluate the safety of pulse high-dose of liposomal amphotericin B (L-AmB) in patients with suspected IAC managed with a Beta-D-Glucan (BDG)-guided strategy. Methods. Phase 2 prospective study enrolling adult patients with intra-abdominal sepsis following surgery. Patients received a single dose of L-AmB 5mg/kg on day 1. At day 3, L-AmB was discontinued in case of negativity of basal serum (1, 3)-Beta-D-Glucan (BDG) and was continued (3 mg/kg/daily) in case of positive basal BDG, or microbiologically confirmed IAC. The main endpoint was occurrence of adverse events according with common toxic criteria definition. Results. Overall, 40 patients were enrolled from January 2019 until August 2022. Of them 15 (37.5%) were male, median age was 65 (49–76) years. Urgent surgery accounted for 31 (77.5%) cases, principal indication was secondary/tertiary peritonitis (22, 55%), half of patients had a previous surgical operation within 30 days. Five (12.5%) patients had criteria for septic shock at enrolment. The median APACHE II score at ICU admission was 12 (10–15). In 33 (85%) cases IAC was excluded, whereas 5 (12.5%) and 2 (5%) patients had a probable and proven IAC, respectively. The single dose of L-AmB 5 mg/Kg was well tolerated in all patients, no early and late severe adverse events related to the drug were reported. L-AmB was discontinued in 65% of patients following a negative basal BDG result. All-cause 30-day mortality rate was 15%, in none case death was related to L-AmB administration or uncontrolled IAC. More specifically, mortality rates between patients with and without proven IAC was 0% vs. 15.8%, p = 0.99. Conclusions. The rate of proven IAC among critically ill high-risk patients was low, attesting at 5%. A single dose of L-AmB 5 mg/Kg following prompt withdrawal in case of basal negative BDG result seems to be a safe and effective approach in such population.

The diagnosis of malaria in returning travellers could be a challenge in non-endemic settings. We aimed to assess the performance of LAMP in comparison with standard conventional diagnostic methods using real-time-polymerase chain reaction (PCR) in case of discordant results.All travellers returning from malaria-endemic areas who presented to our Emergency Department (ED) from January 2017 to December 2020 with signs and symptoms suggestive for malaria were included. Blood microscopy was the reference diagnostic method applied at our laboratory with LAMP implemented as an additional method to aid in malaria diagnosis. PCR was employed only in case of between test's discordant results. Sensitivity and specificity of microscopy compared to LAMP were calculated with the confidence interval of 95%.Four-hundred and eight patients (55.6% male, median age 42 years) were screened for malaria. The diagnosis was confirmed in 49 cases (12%): 44 cases (90%) caused byIn our non-endemic setting LAMP was able to identify malaria cases with low-level parasitaemia otherwise missed by blood microscopy.

Background The role of culturing the graft preservation fluid (PF) is controversial and its impact on graft arteritis development remains unclear. Methods Systematic literature search retrieving all-languages observational studies comparing SOT recipients with culture positive PF versus culture negative PF. Graft site arteritis within 180 days from transplant was selected as primary outcome. Data were independently extracted using a pre-specified form, and quality of included studies was independently assessed according to ROBINS-I tool for observational studies. Meta-analysis was performed using Mantel-Haenszel random-effect models. Results 2,492 articles were screened, and twenty-one observational studies (N=2,208 positive PF vs. 4,458 negative) were included in the meta-analyses. Among positive PF, 857 (38.8%) were classified as high-risk group pathogens (fungi, Gram negative, Enterococcus spp., beta-hemolytic streptococci and Staphylococcus aureus) and 1,351 (61.2%) as low-risk (mostly coagulase negative Staphylococci) pathogens. A significant higher risk of graft arteritis was found in SOT recipients with a PF yielding a high-risk pathogen (odds ratio [OR] 18.43, 95%CI 7.83-43.40), with low heterogeneity (I²=2.24%). Similar results were found considering separately high-risk bacteria (OR 12.02, 95%CI 4.88-29.60) and fungi (OR 71.00, 95%CI 28.07–179.56), with no heterogeneity (I²=0%), and in the subgroup analyses of liver (OR 16.78, 95%CI 2.95–95.47) and kidney (OR 19.90, 95%CI 4.78–82.79) recipients. However, data about diagnostic features of graft arteritis were very limited, indeed for only 11 of the 93 events histological or microbiological results were reported. Conclusion Our results may support the performance of PF culturing and a preemptive diagnostic or therapeutic management upon isolation of high-risk pathogen. Further studies based on reliable diagnosis of graft arteritis are needed to confirm our findings. Disclosures All Authors: No reported disclosures.

Background Solid organ transplant (SOT) recipients are at higher risk than general population for complicated COVID-19 course. Moreover COVID-19 vaccination in this setting is associated with a suboptimal immune response. However, the impact of this finding on the risk of breakthrough infection (BI) in SOT recipients has to be yet determined. Methods Single-center prospective longitudinal cohort of adult SOT recipients who received three doses of mRNA COVID-19 vaccine between February and December 2021 and were followed up to March 30 2022. Patients were tested for antibody response at several timepoints (1 st dose, 2 nd dose, 3±1 month after 1 st dose, and 1 month after 3 rd dose). Main endpoints were: i) BI defined as laboratory confirmed SARS-CoV2 infection diagnosed ≥14 day after 2 nd dose; ii) positive antibody response (AbR) defined as anti-rapid binding domain titer ≥5 U/ml determined by Elecsys Anti-SARS-CoV-2 ECLIA assay (Roche Diagnostics, CH), the last available determination before BI was considered. Results Study cohort consists of 642 SOT (277 kidney, 191 liver, 144 heart, 37 lung) recipients: 63.9% males, median age 54 ± 14.5 years. Of them, 111 (17.8%) developed BI, BI rates were 19.9%, 18.1%, 15.2% and 10.8% among liver, heart, kidney and lung transplant recipients, respectively. Positive-AbR was observed in 60% of all patients, but rates varied from 8.7% to 91.3% among patients with BI and without BI, respectively. Predictors of BI infection at multivariable analysis were liver (vs. other grafts) transplant (OR 2.98, 95%CI 1.47-6.03), mycophenolate (1.63, 0.92-2.88) and steroids (1.8, 1.05- 3.33), while positive-AbR (0.61, 0.35-1.04) and age (0.97, 0.95-0.99) were protective. On the other hand, liver transplant (1.94, 1.02-3.69), time from transplant (1.09, 1.05-1.21), and Moderna vaccine (2.32, 1.46-3.70) were associated with positive-AbR, while age (0.97, 0.95-0.98), heart transplant (0.56, 0.33-0.96), mycophenolate (0.65, 0.39-1.06) and steroids (0.39, 0.23-0.65) with lower probability of positive-AbR. Conclusion Although associated with positive-AbR, liver transplant and younger age were also BI predictors, suggesting the importance of social factors and the controversial role of immune monitoring. Disclosures All Authors: No reported disclosures.

The role of culturing the graft preservation fluid (PF) is controversial and its impact on graft arteritis development remains unclear.Systematic literature search retrieving observational studies comparing solid organ transplant (SOT) recipients with culture-positive PF versus culture-negative PF. The quality of included studies was independently assessed according to the ROBINS-I tool for observational studies. Meta-analysis was performed using Mantel-Haenszel random-effect models. Graft site arteritis within 180 days from transplant was selected as the primary outcome.Twenty-one observational studies (N = 2208 positive PF vs. 4458 negative) were included. Among positive PF, 857 (38.8%) were classified as high-risk group pathogens and 1351 (61.2%) as low-risk pathogens. Low-risk and negative PF showed similar odds ratios. A significant higher risk of graft arteritis was found in SOT recipients with a PF yielding a high-risk pathogen (odds ratio [OR] 18.43, 95% confidence interval [CI] 7.83-43.40) compared to low-risk and negative PF, with low heterogeneity (IOur results may support the performance of PF culturing and a preemptive diagnostic or therapeutic management upon isolation of high-risk pathogens. Further studies based on a reliable diagnosis of graft arteritis are needed.

Background: We assessed the impact of the coronavirus disease 2019 (COVID-19) pandemic on HIV suppression rates in people living with HIV (PLWH) attending a large Italian HIV clinic. Setting: The HIV outpatient clinic of the Infectious Diseases Department of Luigi Sacco Hospital, Milan, Italy, which serves more than 5000 PLWH per year. Methods: A before and after quasi-experimental study design was used to make a retrospective assessment of the monthly trend of HIV-RNA determinations of ≥50 among the PLWH attending our clinic, with “before” being the period from January 1, 2016 to February 20, 2020, and “after” being the period from February 21, 2020 to December 31, 2020 (the COVID-19 period). Interrupted time series analysis was used to evaluate any changes in the trend. Results: During the study period, 70,349 HIV-RNA viral load determinations were made, and the percentage of HIV-RNA viral load determinations of

Biological sex could affect the natural history of severe acute respiratory syndrome coronavirus 2 infection. We enrolled all COVID‐19 patients admitted to two COVID‐19 hospitals in Milan in a prospective observational study. The primary outcome was death during the study period and the secondary outcome was critical disease at hospital admission. The association(s) between clinically relevant, noncollinear variables, and the primary outcome was assessed with uni‐ and multivariable Logistic regression models. A total of 520 patients were hospitalized of whom 349 (67%) were males with a median age 61 (interquartile range: 50–72). A higher proportion of males presented critically ill when compared to females (30.1% vs. 18.7%, p

Background Patients with coronavirus disease 2019 (COVID-19) are often elderly, with comorbidities, and receiving polypharmacy, all of which are known factors for potentially severe drug–drug interactions (DDIs) and the prescription of potentially inappropriate medications (PIMs). Objective The aim of this study was to assess the risk of DDIs and PIMs in COVID-19 patients at hospital discharge. Method Patients with a proven diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who were hospitalized between 21 February and 30 April 2020, treated with at least two drugs, and with available information regarding pharmacological treatments upon admission and at discharge were considered. The appropriateness of drug prescriptions was assessed using INTERcheck®. Results A significant increase in the prescription of proton pump inhibitors and heparins was found when comparing admission with hospital discharge (from 24 to 33% [p 65 years had at least one PIM upon admission, with an insignificant increment at discharge (58%). Conclusion An increased number of prescribed drugs was observed in COVID-19 patients discharged from our hospital. The addition of heparins is appropriate according to the current literature, while the use of proton pump inhibitors is more controversial. Particular attention should be paid to the risk of bleeding complications linked to heparin-based DDIs.

Supplemental Digital Content is available in the text., OBJECTIVES: We aimed to assess the frequency of ICU-acquired bloodstream infections in coronavirus disease 2019 patients. DESIGN: Retrospective observational study. SETTING: The emergency expansion of an ICU from eight general beds to 30 coronavirus disease 2019 beds. PARTICIPANTS: Patients with coronavirus disease 2019 admitted to the ICU of Luigi Sacco Hospital (Milan, Italy) for greater than or equal to 48 hours between February 21, 2020, and April 30, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The frequency of bloodstream infections per 1,000 days of ICU stay was calculated in 89 coronavirus disease 2019 patients, and the cumulative probability of bloodstream infection was estimated using death and ICU discharge as competing events. Sixty patients (67.4%) experienced at least one of the 93 recorded episodes of bloodstream infection, a frequency of 87 per 1,000 days of ICU stay (95% CI, 67–112).The patients who experienced a bloodstream infection had a higher Sequential Organ Failure Assessment score upon ICU admission (9.5; interquartile range, 8–12 vs 8, interquartile range, 5–10; p = 0.042), a longer median ICU stay (15 d; interquartile range, 11–23 vs 8, interquartile range, 5–12; p < 0.001), and more frequently required invasive mechanical ventilation (98.3% vs 82.8%; p = 0.013) than those who did not. The median time from ICU admission to the first bloodstream infection episode was 10 days. Gram-positive bacteria accounted for 74 episodes (79.6%), with Enterococcus species being the most prevalent (53 episodes, 55.8%). Thirty-two isolates (27.3%) showed multidrug resistance. CONCLUSIONS: Coronavirus disease 2019 seemed to increase the frequency of bloodstream infections (particularly Enterococcus-related bloodstream infection) after ICU admission. This may have been due to enteric involvement in patients with severe coronavirus disease 2019 and/or limitations in controlling the patient-to-patient transmission of infectious agents in extremely challenging circumstances.

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 p p p p 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.

Background To assess differences in the probability of COVID-19-related death between native Italians and immigrants hospitalised with COVID-19. Methods This was a retrospective study of prospectively collected data 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%) from Latin America (99, 38.4%), Asia (72, 27.9%), Africa (50, 19.4%) and central/eastern Europe (37, 14.3%). The Italians were older (p vs 12.8%; p vs 8.3%, 6% and 8.1%, respectively; p = 0.016). Multivariate analyses showed that a Latin American origin was independently associated with an increased risk of death (adjusted hazard ratio 1.95, 95% confidence interval 1.17–3.23). Conclusions Our findings support the need to strengthen COVID-19 information and prevention initiatives in the Latin American community living in Milan.

Background Studies of the malaria parasites infecting various non-human primates (NHPs) have increased our understanding of the origin, biology and pathogenesis of human Plasmodium parasites. This review considers the major discoveries concerning NHP malaria parasites, highlights their relationships with human malaria and considers the impact that this may have on attempts to eradicate the disease. Results The first description of NHP malaria parasites dates back to the early 20th century. Subsequently, experimental and fortuitous findings indicating that some NHP malaria parasites can be transmitted to humans have raised concerns about the possible impact of a zoonotic malaria reservoir on efforts to control human malaria. Advances in molecular techniques over the last 15 years have contributed greatly to our knowledge of the existence and geographical distribution of numerous Plasmodium species infecting NHPs, and extended our understanding of their close phylogenetic relationships with human malaria parasites. The clinical application of such techniques has also made it possible to document ongoing spillovers of NHP malaria parasites (Plasmodium knowlesi, P. cynomolgi, P. simium, P. brasilianum) in humans living in or near the forests of Asia and South America, thus confirming that zoonotic malaria can undermine efforts to eradicate human malaria. Conclusions Increasing molecular research supports the prophetic intuition of the pioneers of modern malariology who saw zoonotic malaria as a potential obstacle to the full success of malaria eradication programmes. It is, therefore, important to continue surveillance and research based on one-health approaches in order to improve our understanding of the complex interactions between NHPs, mosquito vectors and humans during a period of ongoing changes in the climate and the use of land, monitor the evolution of zoonotic malaria, identify the populations most at risk and implement appropriate preventive strategies.

BackgroundChagas disease, as a consequence of globalization and immigration, is no more restricted to Central and Latin America. Therefore, congenital transmission represents a growing public health concern in non-endemic countries.MethodsThe aim of this study was to assess the prevalence of Trypanosoma cruzi infection in pregnant Latin American (LA) women living outside endemic countries and the rate of congenital transmission. Data were extracted from studies indexed in PubMed, Scopus, Embase, Lilacs and SciELO databases without language restriction. Two investigators independently collected data on study characteristics, diagnosis, prevalence of infection in pregnant women and congenital infection rate. The data were pooled using a random effects model.ResultsThe search identified 1078 articles of which 29 were eligible regarding prevalence of T. cruzi infection among pregnant women and 1795 articles of which 32 were eligible regarding the congenital transmission rate. The estimated pooled prevalence of T. cruzi infection in LA pregnant women was 4.2% [95% confidence interval (CI): 3.0–5.5]. The prevalence of T. cruzi infection in pregnant women from Bolivia was 15.5% (95% CI: 11.7–19.7) and 0.5% (95% CI: 0.2–0.89) for those coming from all other LA countries. The estimated global rate of congenital transmission was 3.5% (95% CI: 2.5–4.5); excluding poor-quality studies, the rate of congenital transmission was 3.8% (95% CI: 2.4–5.1).ConclusionsPrevalence of Chagas disease among LA pregnant women living outside endemic countries is high, particularly in Bolivian women. The rate of vertical transmission of T. cruzi infection is similar to the rate reported in South and Central American countries.

Crusted scabies is an infrequent disease caused by Sarcoptes scabiei that usually affects patients with underlying medical conditions leading to immunosuppression. Here, we present the case of an 81 years old man, diagnosed with crusted scabies who came to our attention after multiple misdiagnosis and incorrect and potentially detrimental treatment with steroids. He was admitted to our inpatients ward and treated with oral ivermectin plus local permethrin. The hospitalization was complicated by a secondary bacterial skin infection caused by methicillin-sensitive Staphylococcus aureus. Crusted scabies is commonly misdiagnosed in elderly and immunosuppressed people due to its unusual occurrence and atypical clinical presentation. It should be considered in the differential diagnosis of skin lesions associated with pruritus in patients with underling medical conditions leading to immunosuppression. A prompt diagnosis and treatment are warranted due to the potential secondary infections and subsequent related morbidity and mortality.

BackgroundItaly was the first European country hit by the COVID-19 pandemic and has the highest number of recorded COVID-19 deaths in Europe.MethodsThis 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.ResultsForty-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.ConclusionsCase-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.

Graphical abstract, SARS-CoV-2 is causing an increasing number of deaths worldwide because no effective treatment is currently available. Remdesivir has shown in vitro activity against coronaviruses and is a possible antiviral treatment for SARS-CoV-2 infection. This prospective (compassionate), open-label study of remdesivir, which was conducted at Luigi Sacco Hospital, Milan, Italy, between February 23 and March 20, 2020, involved patients with SARS-CoV-2 pneumonia aged ≥18 years undergoing mechanical ventilation or with an oxygen saturation level of ≤94% in air or a National Early Warning Score 2 of ≥4. The primary outcome was the change in clinical status based on a 7-category ordinal scale (1 = not hospitalised, resuming normal daily activities; 7 = deceased). The 35 patients enrolled from February 23 to March 20, 2020, included 18 in intensive care unit (ICU), and 17 in our infectious diseases ward (IDW). The 10-day course of remdesivir was completed by 22 patients (63%) and discontinued by 13, of whom eight (22.8%) discontinued because of adverse events. The median follow-up was 39 days (IQR 25-44). At day 28, 14 (82.3%) patients from IDW were discharged, two were still hospitalized and one died (5.9%), whereas in ICU 6 (33.3%) were discharged, 8 (44.4%) patients died, three (16.7%) were still mechanically ventilated and one (5.6%) was improved but still hospitalized. Hypertransaminasemia and acute kidney injury were the most frequent severe adverse events observed (42.8% and 22.8% of the cases, respectively). Our data suggest that remdesivir can benefit patients with SARS-CoV-2 pneumonia hospitalised outside ICU where clinical outcome was better and adverse events are less frequently observed. Ongoing randomised controlled trials will clarify its real efficacy and safety, who to treat, and when.

Background chronic viral infections by both HCV and HIV may lead to polyclonal activation of B cells resulting in hypergammaglobulinemia. This study retrospectively analyzed the effect of HCV eradication with interferon-free direct-acting antiviral agents (DAAs) on the gamma globulin levels in HCV-infected patients with or without HIV coinfection to identify factors potentially associated with gamma globulins decrease. Methods The charts of patients treated with DAAs for HCV chronic infection between January 2015-June 2019 were retrospectively reviewed. Gamma globulin levels before treatment and 12 weeks after the end of anti-HCV therapy were evaluated along with liver tests, liver fibrosis stage by elastography, SVR achievement, HIV-coinfection. Multivariate analyses were carried out to assess the factors and the potential confounders related to the changes in gamma globulin levels. Results A significant decrease of gamma globulin concentration was found in both cirrhotic and non-cirrhotic HCV-infected patients after treatment (from mean ± SD of 1.5 ± 0.44 g/dL to 1.31 ± 0.37 g/dL; p = 0.0001). Adjusted linear regression analyses of serum gamma globulin changes from baseline to SVR12 showed a positive significant association with pre-treatment gamma-globulin levels (β-coefficient −0.23; p = 0.0001), Metavir fibrosis score (β-coefficient -0.74; p = 0.008), ALT values and baseline HCV-RNA levels > 800,000. No difference was found between HIV-infected and HIV-uninfected patients. Conclusions Our study confirms previous preliminary observation of the decrease of serum gamma globulins after HCV eradication either achieved with interferon-based therapy or with DAAs, suggesting a leading role of the virus on the activation of B cell compartment and gamma globulins production.

Chagas disease (CD) is an emerging infection in Italy as the consequence of the huge immigration from Latin American countries observed during the last ten-fifteen years. However, the interest of Italian researchers on CD dates back to the '80-90s of the last century with studies conducted in collaboration with Brazilian and Argentinian colleagues by Italian cardiologists and pathologists. Moreover, the first demonstration of the existence in the pre-Columbian America of Chagas disease in a Peruvian mummy was made by a group of Italian paleopathologists. Seroprevalence studies performed between 2010-2014 in Negrar (Verona), Bergamo, Milan, Florence and Rome shows Trypanosoma cruzi infection ranging from 3.9% to 17.1% with people coming from Bolivia as the most affected. As observed in Latin America about 30% of screened subjects in Italy are affected by cardiac or digestive forms of CD. More than 20% of subjects treated with benznidazole discontinued it permanently due to adverse events.

Graphical abstract, 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.

Severe COVID-19 associated pneumonia patients may exhibit features of systemic hyper-inflammation designated under the umbrella term of macrophage activation syndrome (MAS) or cytokine storm, also known as secondary haemophagocytic lymphohistocytosis (sHLH). This is distinct from HLH associated with immunodeficiency states termed primary HLH -with radically different therapy strategies in both situations. COVID-19 infection with MAS typically occurs in subjects with adult respiratory distress syndrome (ARDS) and historically, non-survival in ARDS was linked to sustained IL-6 and IL-1 elevation. We provide a model for the classification of MAS to stratify the MAS-like presentation in COVID-19 pneumonia and explore the complexities of discerning ARDS from MAS. We discuss the potential impact of timing of anti-cytokine therapy on viral clearance and the impact of such therapy on intra-pulmonary macrophage activation and emergent pulmonary vascular disease.