The Defenders of the Alveolus Succumb in COVID-19 Pneumonia to SARS-CoV-2 and Necroptosis, Pyroptosis, and PANoptosis.

Alveolar type II (ATII) pneumocytes as defenders of the alveolus are critical to repairing lung injury. We investigated the ATII reparative response in coronavirus disease 2019 (COVID-19) pneumonia, because the initial proliferation of ATII cells in this reparative process should provide large numbers of target cells to amplify severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus production and cytopathological effects to compromise lung repair. We show that both infected and uninfected ATII cells succumb to tumor necrosis factor-α (TNF)-induced necroptosis, Bruton tyrosine kinase (BTK)-induced pyroptosis, and a new PANoptotic hybrid form of inflammatory cell death mediated by a PANoptosomal latticework that generates distinctive COVID-19 pathologies in contiguous ATII cells. Identifying TNF and BTK as the initiators of programmed cell death and SARS-CoV-2 cytopathic effects provides a rationale for early antiviral treatment combined with inhibitors of TNF and BTK to preserve ATII cell populations, reduce programmed cell death and associated hyperinflammation, and restore functioning alveoli in COVID-19 pneumonia.

Limbic encephalitis in a COVID-19 patient?

We describe the case of a 79-year-old woman infected by SARS-CoV-2 and purely neurological confusional syndrome without clinically relevant respiratory disease and NMR alterations of the limbic system.

Bacteriophage therapy: an overview and the position of Italian Society of Infectious and Tropical Diseases.

In recent years, the increase of antibiotic resistance and the lack in the pipeline of novel antimicrobial molecules make bacterial infections difficult to treat. Among European countries, Italy is the one region with a higher number of deaths caused by antibiotic-resistant bacteria. Moreover, a major concern is represented by biofilm-related infections. The ability of bacteria to form biofilm in presence of implanted-medical devices represents a further challenge for the treatment of bacterial infections. Thus, the development of alternative strategies to fight multi-drug resistant bacteria embedded in biofilms is an urgent need. Nowadays, bacteriophage therapy represents one of the potential and promising treatment options to overcome antibiotic resistance phenomenon. Bacteriophages are viruses capable to infect and replicate within bacterial cell. They are widespread in soil and water and play a role in microbial physiology. Since their discovery at the beginning of the twentieth century bacteriophages were used with therapeutic purposes against bacterial infections. However, the advent of the antibiotic era spurred medical doctors to abandon phage therapy in return for the most promising antibiotic therapy. For historical reasons, only few countries in the world, including Georgia, Russia and Poland have carried on the use of phages for therapeutic purposes and have developed specialised research and treatment centres, where phage therapy is permitted and applied to cure infectious disease. Although the efficacy of bacteriophages for treatment of infections is widely documented, the introduction of phage therapy in common management of bacterial infections in European hospital is hindered by the lack of an appropriate legal and regulatory framework. Different strategies have been used to overcome this problem, like the "Magistral Phage" preparation in Belgium. Here, we provide a review of the fundamental concept on bacteriophage therapy and propose this treatment as a possible alternative choice when antibiotics and surgery are not enough to eradicate a bacterial infection. We believe that the introduction of phage therapy in Italy might improve the quality of life of patients suffering of chronic bacterial infections and fight antibiotic resistances problem. To reach this goal the support and the promotion of Italian government and the scientific authorities is essential. SIMIT, the Italian Society of Infectious and Tropical Diseases, proposes to support the creation of an Italian Task Force to improve knowledge on bacteriophage therapy, collect stronger evidence about their efficacy and develop appropriate protocols for phage administration.

Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.

BACKGROUND: COVID-19 is characterised by respiratory symptoms, which deteriorate into respiratory failure in a substantial proportion of cases, requiring intensive care in up to a third of patients admitted to hospital. Analysis of the pathological features in the lung tissues of patients who have died with COVID-19 could help us to understand the disease pathogenesis and clinical outcomes. METHODS: We systematically analysed lung tissue samples from 38 patients who died from COVID-19 in two hospitals in northern Italy between Feb 29 and March 24, 2020. The most representative areas identified at macroscopic examination were selected, and tissue blocks (median seven, range five to nine) were taken from each lung and fixed in 10% buffered formalin for at least 48 h. Tissues were assessed with use of haematoxylin and eosin staining, immunohistochemical staining for inflammatory infiltrate and cellular components (including staining with antibodies against CD68, CD3, CD45, CD61, TTF1, p40, and Ki-67), and electron microscopy to identify virion localisation. FINDINGS: All cases showed features of the exudative and proliferative phases of diffuse alveolar damage, which included capillary congestion (in all cases), necrosis of pneumocytes (in all cases), hyaline membranes (in 33 cases), interstitial and intra-alveolar oedema (in 37 cases), type 2 pneumocyte hyperplasia (in all cases), squamous metaplasia with atypia (in 21 cases), and platelet-fibrin thrombi (in 33 cases). The inflammatory infiltrate, observed in all cases, was largely composed of macrophages in the alveolar lumina (in 24 cases) and lymphocytes in the interstitium (in 31 cases). Electron microscopy revealed that viral particles were predominantly located in the pneumocytes. INTERPRETATION: The predominant pattern of lung lesions in patients with COVID-19 patients is diffuse alveolar damage, as described in patients infected with severe acute respiratory syndrome and Middle East respiratory syndrome coronaviruses. Hyaline membrane formation and pneumocyte atypical hyperplasia are frequent. Importantly, the presence of platelet-fibrin thrombi in small arterial vessels is consistent with coagulopathy, which appears to be common in patients with COVID-19 and should be one of the main targets of therapy. FUNDING: None.

Compassionate remdesivir treatment of severe Covid-19 pneumonia in intensive care unit (ICU) and Non-ICU patients: Clinical outcome and differences in post-treatment hospitalisation status.

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.

Is there a role for procalcitonin determination in avoiding unnecessary exposure to antibiotics in a non-intensive care setting?

The use of procalcitonin (PCT) as a tool to assist clinicians in using antibiotics in intensive care patients has been postulated. Here we evaluate the efficacy of procalcitonin determination in helping clinicians in the decision to start or discontinue an antibiotic treatment in patients admitted to infectious disease wards. A retrospective observational single centre study was conducted in two infectious disease wards. Descriptive and inferential statistical analysis was carried out and receiver operating characteristic curves and area under the curve (AUC) were used to assess the accuracy of PCT and C-reactive protein (CRP) in separating patients undergoing antibiotic treatment or otherwise. In all, 164 patients were analysed of whom 99 (60.4%) were not on antibiotic treatment at the time of PCT determination, whereas 65 (39.6%) took antibiotics. Regarding the accuracy of PCT and CRP in determining a subsequent antibiotic prescription in patients without an ongoing antibiotic treatment, no statistically significant difference between the two markers was detected [AUC, 0.75; confidence interval (CI) 95%: 0.66-0.84; vs 0.69; CI 95%: 0.59-0.79 for PCT and CRP, respectively; p=0.32]. Conversely, in patients with an ongoing antibiotic treatment a statistically significant difference between PCT and CRP AUC in their ability to determine an antibiotic interruption was observed [0.77 (CI 95%: 0.65-0.89) vs 0.59 (CI 95%: 0.45-0.73) (p=0.03)]. PCT determination appeared to be more helpful than CRP in determining discontinuation of an antibiotic treatment in non-intensive care patients. However, PCT should supplement and not supplant a careful clinical evaluation.

Gastrointestinal basidiobolomycosis: An emerging mycosis difficult to diagnose but curable. Case report and review of the literature.

BACKGROUND: Gastrointestinal basidiobolomycosis (GIB) is a rare mycosis affecting almost exclusively immunocompetent subjects. METHODS: We describe a case of GIB caused by Basidiobolus ranarum in a 25-year-old Italian immunocompetent man resident in Ireland who presented a 2-month history of epigastric pain. Suspecting colon cancer he underwent a right hemicolectomy subsequently leading to a diagnosis of GIB by means of molecular biology. After surgery a 9-month therapy with itraconazole was employed with a good outcome. A review of medical literature regarding GIB cases published in the period 1964-2017 is presented. RESULTS: One-hundred and two cases of GIB were included in this analysis. The disease was observed predominantly in male gender (74.5%) and children (41.2%). Abdominal pain was the single most common complaint (86.3%) followed by fever (40.2%) and evidence of an abdominal mass (30.4%). Peripheral blood eosinophilia was detected in 85.7% of cases. Most of the patients were diagnosed in Saudi Arabia (37.2%) followed by USA (21.6%) and Iran (20.6%). Surgery plus antifungal therapy was employed in the majority of patients (77.5%). An unfavourable outcome was documented globally in 18.6% of patients. CONCLUSIONS: GIB seems to be an emerging intestinal mycosis among immunocompetent patients living in the Middle East and Arizona.

Is imported onchocerciasis a truly rare entity? Case report and review of the literature.

BACKGROUND: Onchocerciasis is endemic in a number of tropical countries in Africa and South America, and it is occasionally diagnosed as an imported disease in non-endemic areas. METHODS: We describe the case of an African migrant with long-lasting pruritus and a cutaneous nodule who was diagnosed with onchocerciasis after nodulectomy, and review the medical literature regarding imported cases of onchocerciasis in the period 1994-2014. RESULTS: Twenty-nine cases of onchocerciasis diagnosed in migrants from endemic countries, and in expatriates and travellers from non-endemic areas were retrieved. They were predominantly males (73.3%), had a median age of 37 years (two were aged <15 years), and acquired the diseases in sub-Saharan Africa, most frequently in Cameroon (43.3%). Diagnosis of onchocercosis was proven in 73.3% of patients. The most frequent clinical manifestations in these and our own patient were pruritus (23/30, 76.7%), unilateral leg or forearm swelling (13/30, 43.3%) and rash (12/30, 40.0%), whereas only two (6.9%) complained of eye symptoms. Eosinophilia was observed in almost all of the patients (92.0%), with median counts of 2915/µL among migrants and 1960/µL among travellers/expatriates. Eighteen patients underwent a skin snip biopsy, which was positive in 10 cases (55.5%); in the other 13 patients the parasite was directly demonstrated by means of a skin or nodule biopsy (n = 5), nodulectomy (n = 5) or slit lamp examination (n = 3). Eighteen received ivermectin, alone, and seven ivermectin combined with diethylcarbamazine or doxycycline. Outcome details were available for only 14 patients, all of whom were asymptomatic after a median follow-up of 10 months (range 1-48). CONCLUSIONS: Onchocerciasis is a neglected tropical disease whose subtle and non-specific features may lead to under-diagnosis or underreporting in non-endemic areas. Physicians should consider this tropical disease when caring for migrants and travellers/expatriates with pruritus, skin lesions and eosinophilia.

Cytotoxic Epstein-Barr virus-positive large B cell lymphoma: a regulatory B cell-derived neoplasia?

AIMS: A new subtype of granzyme B (GrB)-producing regulatory B cells (Bregs ) has been described recently; these peculiar cytotoxic B cells are increased significantly in interleukin (IL)-21-rich settings, and in particular during HIV and Epstein-Barr virus (EBV) infection. Our aim is to report a unique case of an EBV-positive diffuse large B cell lymphoma (DLBCL) with cytotoxic features arisen in an HIV+ patient, and to understand if this lesion may represent a proliferation of neoplastic cytotoxic Bregs . METHODS AND RESULTS: We describe a 66-year-old male patient who presented with cervical lymph node enlargement and B symptoms; subsequently, HIV infection was diagnosed. Histopathological, immunohistochemical and molecular studies were performed, and revealed an EBV-positive DLBCL with cytotoxic features. Considering the immunological setting and unconventional phenotype observed, we tried to evaluate further the expression of GrB and IL-21 in another 150 aggressive B cell lymphomas (17 of 150 EBV+ , two of 150 EBV+ /HIV+ ). Minimal dot-like expression of GrB was found in seven lymphomas (in fewer than 1% of tumour cells), three of which were EBV-positive. CONCLUSIONS: Breg origin has never been reported in B cell lymphomas. We describe an exceptional case of EBV-positive DLBCL with aberrant expression of cytotoxic markers in a patient with a previously unknown HIV infection. We propose cytotoxic Bregs as a possible normal counterpart for this unusual tumour.

Fungal endocarditis observed over an 8-year period and a review of the literature.

BACKGROUND: Fungal endocarditis (FE) is a "modern" disease that is considered an emerging cause of infective endocarditis (IE). The most frequently identified fungal pathogens are Candida spp., which are responsible for up to two-thirds of all cases; the remaining cases are due to Aspergillus spp., Histoplasma capsulatum or, more rarely, other yeasts and moulds. OBJECTIVES: To describe the prevalence, clinical characteristics and outcome of FE diagnosed in a single tertiary centre and review the literature concerning FE. DESIGN AND SETTING: An 8-year retrospective review of the case records of patients attending a single Italian University Centre and diagnosed as having definite or probable IE as defined by the modified Duke criteria. RESULTS: Six patients were identified from 229 episodes of IE: five cases involved a prosthetic valve, and one a native valve of an intravenous drug user. Five cases were caused by Candida spp. (two by C. albicans, one each by C. lusitaniae, C. dubliniensis and C. glabrata) and one by Aspergillus flavus. Three patients were treated by means of surgery plus antifungal therapy; two received antifungal therapy alone. Three patients survived, but only the patient with Aspergillus endocarditis was followed up for a long time. CONCLUSIONS: FE is difficult to diagnose but generally associated with healthcare infections. The optimal treatment is poorly characterised, and international collaborative studies are urgently needed to evaluate newer antifungal agents.

Surgery and topic cidofovir for nasal squamous papillomatosis in HIV+ patient.

Intranasal schneiderian exophytic squamous papillomatosis is rare and often secondary to human papilloma virus infection. Treatment usually consists of repeated surgical or endoscopic excisions due to recurrences. The use of intravenous or intralesional or topically applied cidofovir, a cytidine nucleotide analogue suppressing viral replication, alone or as adjuvant therapy has been proposed and described in the literature for the treatment of other human papillomavirus (HPV)-related lesions. We firstly describe a successful combined approach of surgery and topical cidofovir for recurrent nasal HPV-related exophytic squamous papillomatosis in a HIV-infected patient. As no untoward effects were encountered this therapeutical option should be considered in the management of recurrent nasal papillomatosis in HIV-infected patients.