First imported case of Candida auris infection in Milan, Italy: genomic characterisation.

PURPOSE: Candida auris, an emerging multidrug-resistant yeast, has been reported worldwide. In Italy, the first case was reported in 2019. We describe the first case of C. auris, imported from Greece, in Milan, using whole genome sequencing to characterise mutations associated with antifungal resistance. CASE PRESENTATION: On October 2022 an 80-year-old Italian man was hospitalised in Greece. In the absence of clinical improvement, the patient was transferred to our hospital, in Italy, where blood culture resulted positive for C. auris. Despite therapy, the patient died of septic shock. In a phylogenetic analysis the genome was assigned to Clade I with strains from Kenya, United Arab Emirates and India. D1/D2 region resulted identical to a Greek strain, as for many other strains from different World regions, highlighting the diffusion of this strain. CONCLUSION: Importation of C. auris from abroad has been previously described. We report the first case of C. auris imported into Italy from Greece, according to phylogenetic analysis. This case reinforces the need for monitoring critically ill hospitalised patients also for fungi and addresses the need for the standardisation of susceptibility testing and strategies for diagnosis and therapy.

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.

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.

Challenges in Diagnosing COVID-19-Associated Pulmonary Aspergillosis in Critically Ill Patients: The Relationship between Case Definitions and Autoptic Data.

Critically ill COVID-19 patients can develop invasive pulmonary aspergillosis (CAPA). Considering the weaknesses of diagnostic tests/case definitions, as well as the results from autoptic studies, there is a debate on the real burden of aspergillosis in COVID-19 patients. We performed a retrospective observational study on mechanically ventilated critically ill COVID-19 patients in an intensive care unit (ICU). The primary objective was to determine the burden of CAPA by comparing clinical diagnosis (through case definitions/diagnostic algorithms) with autopsy results. Twenty patients out of 168 (11.9%) developed probable CAPA. Seven (35%) were females, and the median age was 66 [IQR 59-72] years. Thirteen CAPA patients (65%) died and, for six, an autopsy was performed providing a proven diagnosis in four cases. Histopathology findings suggest a focal pattern, rather than invasive and diffuse fungal disease, in the context of prominent viral pneumonia. In a cohort of mechanically ventilated patients with probable CAPA, by performing a high rate of complete autopsies, invasive aspergillosis was not always proven. It is still not clear whether aspergillosis is the major driver of mortality in patients with CAPA.

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.

The value of lamp to rule out imported malaria diagnosis: a retrospective observational study in Milan, Italy.

BACKGROUND: 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. METHODS: 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%. RESULTS: 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 by Plasmodium falciparum. Peripheral blood smear missed to identify three malaria cases, which tested positive with LAMP and PCR. One case of malaria caused by P. malariae in a naive tourist, one case by P. falciparum in a semi-immune pregnant women and one case by P. falciparum in a previously treated semi-immune patient. All the discordant cases were characterized by a very low parasitaemia. Microscopy when compared to LAMP showed a sensitivity of 93.9% (95% confidence interval (CI) 83.1-98.7%) and a specificity of 100% (95% CI 98.9-100%). CONCLUSIONS: In our non-endemic setting LAMP was able to identify malaria cases with low-level parasitaemia otherwise missed by blood microscopy.

Case Report: A Fatal Case of West Nile Virus Meningoencephalomyelitis in a Woman with Systemic Lupus Erythematosus Initially Misdiagnosed as SARS-CoV-2 Infection.

We present a fatal case of West Nile virus meningoencephalomyelitis initially misdiagnosed as COVID-19 in a 63-year-old Egyptian woman with a previous diagnosis of systemic lupus erythematosus. The patient's medical history and immunosuppressive therapy, as well as the COVID-19 pandemic, substantially broadened the differential diagnosis of her encephalitis.

Role of serum albumin and proteinuria in patients with SARS-CoV-2 pneumonia.

BACKGROUND: Hypoalbuminemia is frequently observed in patients with SARS-CoV-2 infection although its underlying mechanism and relationship with the clinical outcome still need to be clarified. METHODS: We retrospectively evaluated in patients with COVID-19 hospitalised at the Fatebenefratelli-Sacco Hospital in Milan, the prevalence of hypoalbuminemia, its association with the severity of COVID-19, with the levels of C-reactive protein, d-dimer and interleukin-6 and with clinical outcome over a follow-up period of 30 days. Urinalysis was evaluated in a subgroup of patients. RESULTS: Serum albumin levels <30 g/L were found in 105/207 (50.7%) patients at hospital admission. Overall, the median albumin value was 29.5 g/L (IQR 25-32.8). A negative association was found between albumin levels and severity of COVID-19 (P < .0001) and death (P = .003). An inverse correlation was observed between albumin and both C-reactive protein and D-dimer at hospital admission (r = -.487 and r = -.479, respectively; P < .0001). Finally, a positive correlation was found between albumin levels and eGFR (r = .137; P = .049). Proteinuria was observed in 75% of patients with available data and it did not differ between patients with hypoalbuminemia and those with albumin ≥30 g/L (81% and 67%, respectively; P = .09). CONCLUSION: In patients with COVID-19, hypoalbuminemia is common and observed in quite an early stage of pulmonary disease. It is strictly associated with inflammation markers and clinical outcome. The common finding of proteinuria, even in the absence of creatinine increase, indicates protein loss as a possible biomarker of local and systemic inflammation worthwhile to evaluate disease severity in COVID-19.

Trypanosoma cruzi infection in Latin American pregnant women living outside endemic countries and frequency of congenital transmission: a systematic review and meta-analysis.

BACKGROUND: Chagas 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. METHODS: The 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. RESULTS: The 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). CONCLUSIONS: Prevalence 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.

Loop-mediated isothermal amplification (LAMP) assay for the diagnosis of imported malaria: a narrative review.

Loop-mediated isothermal amplification (LAMP) is a molecular method to detect malaria recently introduced in the market. LAMP is simple to perform and does not require advanced equipment and training thus satisfying the qualification as a point-of-care diagnostic screening test. In this narrative review, we focus on the role of LAMP for malaria diagnosis in non-endemic settings. We searched PubMed, Embase, Scopus, and Google Scholar, using the following search terms: 'Malaria LAMP' in combination with 'imported malaria' or 'travellers' malaria' or 'non-endemic setting' or 'non-endemic region' or 'malaria screening' or 'malaria diagnosis'. References of each article were also reviewed for possible studies or reports not identified in our search. Overall, 18 studies encompassing 6289 tested samples with 1663 confirmed malaria diagnoses were retrieved. Most of these studies (13/18, 72.2%) were conducted in Europe, and almost half were retrospective. Fourteen studies (77.8%) employed real-time or nested-polymerase chain reaction as the reference method for confirming malaria diagnosis. Sensitivity of LAMP ranged from 93.9 to 100% and specificity from 93.8 to 100% with a negative predictive value of 99.6%-100%. The rate of reported invalid results requiring repeat of the test varied from 0.01% to 5.7%, but they were solved in the majority of cases with a secondary analysis. In non-endemic countries the adoption of LAMP malaria assay as the screening test for malaria diagnosis seems to perform better than conventional methods. However, blood microscopy remains essential to either identify Plasmodium species and quantify parasitaemia and adequately managing malaria cases.

Unexpectedly High Frequency of Enterococcal Bloodstream Infections in Coronavirus Disease 2019 Patients Admitted to an Italian ICU: An Observational Study.

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.

A case of crusted scabies with a delayed diagnosis and inadequate therapy.

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.

Bacterial and fungal infections among patients with SARS-CoV-2 pneumonia.

We reviewed studies reporting bacterial and fungal co-infections in patients with COVID-19. The majority were retrospective studies with poor quality data biased with short follow-up and selection of patients. Septic shock was reported in 4% to 33.1% of patients. Seventy-one to 100% of patients received antibacterial treatments. Invasive pulmonary aspergillosis seems to be an increasingly observed complication in critically ill patients with SARS-CoV-2 infection as previously reported in patients hospitalized in ICU with severe influenza. High quality prospective studies are urgently needed to verify the incidence of bacterial and fungal infections and their role on the outcome of COVID-19.

Imported dengue fever: a 16-years retrospective analysis in Milan (Italy) and a brief review of the European literature.

Dengue Fever (DF), transmitted by Aedes mosquitoes, is the most common arthropod-borne infection, it is almost ubiquitous in tropical and subtropical areas with an estimate of 360 million infections per year. A competent vector (A. albopictus) is present in most of Southern Europe and is endemic in Italy. We conducted a 16-year retrospective study of probable/confirmed dengue fever observed at the Department of Infectious Diseases of Luigi Sacco Hospital in Milan, Italy. Overall 122 patients were included in the study, 106 with probable and 16 with proven diagnosis of dengue fever. Most patients (91%) were Italian, with a median age of 35 years (IQR 29-46 years) and similar gender distribution, travelling for tourism (80%). Asia (mainly South East Asia and Indian Subcontinent) was the most frequent travel destination (55%), followed by Central America and the Caribbeans (22%). August-September was the peak season of presentation (42.6%). The majority of our diagnoses were based on serology alone. The most common signs and symptoms were fever (99,2%), maculopapular rash (50,8%), headache (50,8%), arthralgias (50,8%) and myalgias (46,7%). Leukopenia (77%), thrombocytopenia (81%) and altered LDH, AST and ALT (respectively 60,6%, 54,1% and 45,9%) were the most common laboratory test's abnormalities. No cases of severe DF were recorded. Our epidemiological and clinical findings are largely in accordance with most recent studies about imported DF in Europe. Although very similar in presentation to other arthropod-borne illnesses, some clinical features may help in differentiating DF from other causes of fever in the returning traveler.

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.

Chagas disease in Europe: A review for the internist in the globalized world.

Chagas disease (CD) or American trypanosomiasis identified in 1909 by Carlos Chagas, has become over the last 40years a global health concern due to the huge migration flows from Latin America to Europe, United States, Canada and Japan. In Europe, most migrants from CD-endemic areas are concentrated in Spain, Italy, France, United Kingdom and Switzerland. Pooled seroprevalence studies conducted in Europe show an overall 4.2% prevalence, with the highest infection rates observed among individuals from Bolivia (18.1%). However, in most European countries the disease is neglected with absence of screening programmes and low access to diagnosis and treatment. Physicians working in Europe should also be aware of the risk of autochthonous transmission of Trypanosoma cruzi to newborns by their infected mothers and to recipients of blood or transplanted organs from infected donors. Finally, physicians should be able to recognize and treat the most frequent and serious complications of chronic Chagas disease, namely cardiomyopathy, megacolon and megaesophagus. This review aims to highlights the problem of CD in Europe by reviewing papers published by European researchers on this argument, in order to raise the awareness of internists who are bound to increasingly encounter patients with the disease in their routine daily activities.

Severe Plasmodium falciparum malaria in the intensive care unit: A 6-year experience in Milano, Italy.

BACKGROUND: Severe imported Plasmodium falciparum malaria is a potentially life-threatening disease with a reported mortality rate of 5-10% when patients are admitted to the Intensive Care Unit. METHODS: To retrospectively review the clinical aspects, the value of severity predictive scores and the management of patients with severe P. falciparum malaria admitted to an ICU in Milano, Italy between January 2010 and December 2015. RESULTS: Twelve patients were included: seven were male and five female with a median age of 43 years. All were initially treated with intravenous quinine. Median parasitaemia upon admission was 14,5% (range 1-20%). At the time of ICU admission, 3 patients (25%) had 5 or more World Health Organization criteria for severe malaria while another 6 of them developed one or more of the latter during their stay in ICU. Five required mechanical ventilation because of respiratory failure due to ARDS. Four patients required renal replacement therapy. Three patients underwent blood exchange transfusion. All patients survived. CONCLUSIONS: Our retrospective evaluation of adults patients admitted to the ICU with severe imported P. falciparum malaria demonstrated a favourable outcome. Severity predictive scores currently in use probably overestimate the risk of malaria mortality in patients treated in health care systems of high income countries.