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1. Extensive activation, tissue trafficking, turnover and functional impairment of NK cells in COVID-19 patients at disease onset associates with subsequent disease severity

Author

Bozzano, F., Dentone, C., Perrone, C., Di Biagio, A., Fenoglio, D., Parodi, A., Mikulska, M., Bruzzone, B., Giacobbe, D. R., Vena, A., Taramasso, L., Nicolini, L., Patroniti, N., Pelosi, P., Gratarola, A., de Palma, R., Filaci, G., Bassetti, M., de Maria, A., Alessandrini, A., Camera, M., Delfino, E., Dodi, F., Ferrazin, A., Mazzarello, G., Toscanini, F., Balletto, E., Portunato, F., Schenone, E., Rosseti, N., Baldi, F., Berruti, M., Briano, F., Dettori, S., Labate, L., Magnasco, L., Mirabella, M., Pincino, R., Russo, C., Sarteschi, G., Sepulcri, C., Tutino, S., Pontremoli, R., Beccati, V., Casciaro, S., Casu, M., Gavaudan, F., Ghinatti, M., Gualco, E., Leoncini, G., Pitto, P., Salam, K., Bixio, M., Amelia, A., Balestra, A., Ballarino, P., Bardi, N., Boccafogli, R., Caserza, F., Calzolari, E., Castelli, M., Cenni, E., Cortese, P., Cuttone, G., Feltrin, S., Giovinazzo, S., Giuntini, P., Natale, L., Orsi, D., Pastorino, M., Perazzo, T., Pescetelli, F., Schenone, F., Serra, M. G., Sottano, M., Brunetti, I., Robba, C., Ball, L., Loconte, M., Battaglini, D., de Rito, M. R., Cerana, M., Fasce, R., Insorsi, A., Molin, A., Tallone, R., Amelotti, M., Majabo, M. J., Merlini, M., Perazzo, F., Ahamd, N., Barbera, P., Bovio, M., Cam-Podonico, P., Collida, A., Cutuli, O., Lomeo, A., Fezza, F., Genti-Lucci, N., Hussein, N., Malvezzi, E., Massobrio, L., Motta, G., Pastorino, L., Pollicardo, N., Sartini, S., Virga, P. V. V., Porto, I., Bezante, G. P., Bona, R. D., Malfa, G. L., Valbusa, A., V. G., Ad, Barisione, E., Bellotti, M., Teresita, A., Blanco, A., Grosso, M., Piroddi, M. G., Moscatelli, P., Caiti, M., Magnani, O., Sukkar, S., Cogorno, L., Gradaschi, R., Guiddo, E., Martino, E., Pisciotta, L., Cavagliere, B., Cristina, R., Francesca, F., Garibotto, G., Esposito, P., Passalacqua, G., Bagnasco, D., Braido, F., Riccio, A., Tagliabue, E., Gustavino, C., Ferraiolo, A., Giuffrida, S., Rosso, N., Morando, A., Papalia, R., Passerini, D., Tiberio, G., Orengo, G., Battaglini, A., Ruffoni, S., and Caglieris, S.

Subjects
RNA viruses, Male, Viral Diseases, Coronaviruses, medicine.medical_treatment, Cytotoxicity, Cell, NK cells, Aged, Aged, 80 and over, COVID-19, Cohort Studies, Female, Flow Cytometry, Humans, Interferon-gamma, Italy, Killer Cells, Natural, Lymphocyte Activation, Middle Aged, Severity of Illness Index, Toxicology, 0302 clinical medicine, Medical Conditions, Spectrum Analysis Techniques, Cellular types, 80 and over, Killer Cells, Lymphocytes, Biology (General), Receptor, Immune Response, Pathology and laboratory medicine, 0303 health sciences, medicine.diagnostic_test, Immune cells, hemic and immune systems, Medical microbiology, Cytokine, medicine.anatomical_structure, Infectious Diseases, Spectrophotometry, Viruses, Natural, White blood cells, Cytophotometry, medicine.symptom, SARS CoV 2, Pathogens, Research Article, Cell biology, Blood cells, SARS coronavirus, Precursor Cells, QH301-705.5, Immunology, Inflammation, chemical and pharmacologic phenomena, Biology, Research and Analysis Methods, Microbiology, Flow cytometry, 03 medical and health sciences, Immune system, Signs and Symptoms, Virology, Genetics, medicine, Molecular Biology, 030304 developmental biology, Medicine and health sciences, Biology and life sciences, Organisms, Viral pathogens, Covid 19, RC581-607, NKG2D, Microbial pathogens, Perforin, Animal cells, biology.protein, Parasitology, Clinical Medicine, Immunologic diseases. Allergy, 030215 immunology
Abstract

The SARS-CoV-2 infection causes severe respiratory involvement (COVID-19) in 5–20% of patients through initial immune derangement, followed by intense cytokine production and vascular leakage. Evidence of immune involvement point to the participation of T, B, and NK cells in the lack of control of virus replication leading to COVID-19. NK cells contribute to early phases of virus control and to the regulation of adaptive responses. The precise mechanism of NK cell dysregulation is poorly understood, with little information on tissue margination or turnover. We investigated these aspects by multiparameter flow cytometry in a cohort of 28 patients hospitalized with early COVID-19. Relevant decreases in CD56brightCD16+/- NK subsets were detected, with a shift of circulating NK cells toward more mature CD56dimCD16+KIR+NKG2A+ and “memory” KIR+CD57+CD85j+ cells with increased inhibitory NKG2A and KIR molecules. Impaired cytotoxicity and IFN-γ production were associated with conserved expression of natural cytotoxicity receptors and perforin. Moreover, intense NK cell activation with increased HLA-DR and CD69 expression was associated with the circulation of CD69+CD103+ CXCR6+ tissue-resident NK cells and of CD34+DNAM-1brightCXCR4+ inflammatory precursors to mature functional NK cells. Severe disease trajectories were directly associated with the proportion of CD34+DNAM-1brightCXCR4+ precursors and inversely associated with the proportion of NKG2D+ and of CD103+ NK cells. Intense NK cell activation and trafficking to and from tissues occurs early in COVID-19, and is associated with subsequent disease progression, providing an insight into the mechanism of clinical deterioration. Strategies to positively manipulate tissue-resident NK cell responses may provide advantages to future therapeutic and vaccine approaches., Author summary This is a detailed study of activating and inhibitory receptors in NK cells of COVID-19 patients when first admitted to the hospital for respiratory insufficiency. NK cells are known to be the first line of defense against invading viruses, and regulate downstream B and T cell responses, including antibody production. We observed intense NK cell activation with decreased functional activity, as well as intense circulation of putative tissue resident CD69+CD103+CXCR6+ NK cells, with a related surge in inflammatory CD34+ precursors from the bone marrow. The findings suggest that there is unprecedented trafficking of NK cells from peripheral tissues, their increased death with recruitment of emergency precursors from the bone marrow, and a relationship with the subsequent course of the disease of the patients. This in turn suggests possible areas of treatment and prevention.

Published
2021

2. The role of the intensive care unit in real-time surveillance of emerging pandemics: the Italian GiViTI experience

Author

Bertolini, G, Nattino, G, Langer, M, Tavola, M, Crespi, D, Mondini, M, Rossi, C, Previtali, C, Marshall, J, Poole, D, Abascià, A, Acquarolo, A, Adorni, A, Agnelli, V, Agostini, F, Alampi, D, Alberti, A, Alborghetti, A, Alleva, S, Ambrosoni, S, Antonini, B, Arditi, E, Avalli, L, Babini, M, Bagalini, G, Balata, A, Balicco, B, Barbagallo, M, Bartoli, T, Bassi, G, Becarelli, S, Beck, E, Bellin, M, Bellonzi, A, Bellorini, M, Benanti, C, Bensi, M, Bernasconi, Mo, Berruto, F, Bertolini, R, Besozzi, A, Biamino, C, Bianchi, T, Bianchin, A, Boccalatte, D, Bocchi, A, Bonaccorso, G, Bonazzi, M, Balsamo, C, Bonicalzi, V, Boniotti, C, Bonizzoli, M, Bottazzi, A, Breschi, C, Brizio, E, Brunetti, B, Brunori, E, Bubbico, G, Buscaglia, G, Calicchio, G, Calligaro, P, Calva, S, Candido, M, Capitanio, G, Caroleo, S, Casagli, S, Casalini, P, Castiglione, G, Cerana, M, Chiani, C, Chierego, G, Ciani, A, Ciceri, R, Cigada, Mg, Cima, M, Cingolani, E, Cinque, E, Coletta, Rp, Colombo, L, Colombo, R, Converso, M, Corrado, A, Cortis, G, Costagli, V, Crema, L, Crestan, E, Da, D, Cero, Pd, Ferro, Md, De Blasi RA, De Blasio, E, De Cristofaro MG, De Luca, A, Di Pasquale, D, Doroni, L, Fabi, Mc, Facondini, F, Fagoni, Nazzareno, Falzetti, G, Faraldi, L, Fiore, G, Fiume, C, Galeotti, E, Galleschi, N, Gallo, M, Gamberini, E, Garelli, A, Giacomello, S, Gianni, M, Giudici, R, Giuntini, R, Gnesin, P, Gorietti, A, Grassitelli, S, Greco, M, Irpino, A, Guadagna, A, Guadagnucci, A, Guagliardi, C, Laici, C, Lain, G, Lanza, G, Lefons, U, Leggieri, C, Lembo, R, Librenti, M, Liverani, C, Longobardo, A, Madeira, Sm, Madonna, R, Magatti, Mf, Mamprin, F, Mannolini, G, Marafon, S, Marchesi, G, Marifoglou, D, Martinelli, P, Martinelli, S, Escobar, Rm, Mastroianni, A, Mastropierro, R, Mediani, Ts, Messina, M, Milan, B, Molesi, A, Alberto, Cm, Mongelli, P, Morigi, A, Mosti, G, Muttini, S, Nardini, M, Nascimben, E, Natalini, G, Negri, G, Negro, G, Neri, M, Netto, R, Nonini, S, Odetto, L, Olivieri, C, Candida, Mo, Osti, D, Palmer, M, Parnigotto, A, Parrini, V, Pasculli, M, Pasetti, G, Passafiume, M, Pastorini, S, Patrignani, L, Pedeferri, M, Pegoraro, M, Pelati, E, Pelosi, G, Pera, L, Perino, P, Pero, A, Perzolla, D, Peta, M, Pinna, C, Pizzali, M, Postiglione, M, Potalivo, A, Raffaeli, M, Randellini, R, Rech, A, Renda, B, Ricciardi, G, Rizzi, S, Romagnoli, S, Rossi, G, Rossi, M, Rutta, C, Sagliaschi, U, Salcuni, R, Salvi, G, Scalera, M, Scarrone, S, Schiavuzzi, M, Aurelio, Ps, Selvaggi, P, Sicignano, A, Sorbara, C, Spagarino, E, Sparicio, D, Spinazzola, Ar, Sucre, Mj, Terzitta, M, Tetamo, R, Tibaldi, G, Todesco, L, Tomaselli, P, Torta, M, Turriziani, I, Ughi, L, Vaccari, C, Vaj, M, Vanzino, R, Vardanega, A, Vecchiarelli, P, Vedovati, S, Zanni, V, Zappa, S, Zardin, M, Zaro, G, Zuccaro, F, Barattini, M, Chieregato, A, Fumagalli, R, Livigni, S, Mengoli, F, Nardi, G, Palma, D, Portolani, L, Radrizzani, D, Terzitta, M., Bertolini, G, Nattino, G, Langer, M, Tavola, M, Crespi, D, Mondini, M, Rossi, C, Previtali, C, Marshall, J, Poole, D, Abascia, A, Acquarolo, A, Adorni, A, Agnelli, V, Agostini, F, Alampi, D, Alberti, A, Alborghetti, A, Alleva, S, Ambrosoni, S, Antonini, B, Arditi, E, Avalli, L, Babini, M, Bagalini, G, Balata, A, Balicco, B, Barbagallo, M, Bartoli, T, Bassi, G, Becarelli, S, Beck, E, Bellin, M, Bellonzi, A, Bellorini, M, Benanti, C, Bensi, M, Bernasconi, M, Berruto, F, Besozzi, A, Biamino, C, Bianchi, T, Bianchin, A, Boccalatte, D, Bocchi, A, Bonaccorso, G, Bonazzi, M, Balsamo, C, Bonicalzi, V, Boniotti, C, Bonizzoli, M, Bottazzi, A, Breschi, C, Brizio, E, Brunetti, B, Brunori, E, Bubbico, G, Buscaglia, G, Calicchio, G, Calligaro, P, Calva, S, Candido, M, Capitanio, G, Caroleo, S, Casagli, S, Casalini, P, Castiglione, G, Cerana, M, Chiani, C, Chierego, G, Ciani, A, Ciceri, R, Cigada, M, Cima, M, Cingolani, E, Cinque, E, Coletta, R, Colombo, L, Colombo, R, Converso, M, Corrado, A, Cortis, G, Costagli, V, Crema, L, Crestan, E, Da, D, Cero, P, Ferro, M, De Blasi, R, De Blasio, E, De Cristofaro, M, De Luca, A, Di Pasquale, D, Doroni, L, Fabi, M, Facondini, F, Fagoni, N, Falzetti, G, Faraldi, L, Fiore, G, Fiume, C, Galeotti, E, Galleschi, N, Gallo, M, Gamberini, E, Garelli, A, Giacomello, S, Gianni, M, Giudici, R, Giuntini, R, Gnesin, P, Gorietti, A, Grassitelli, S, Greco, M, Irpino, A, Guadagna, A, Guadagnucci, A, Guagliardi, C, Laici, C, Lain, G, Lanza, G, Lefons, U, Leggieri, C, Lembo, R, Librenti, M, Liverani, C, Longobardo, A, Madeira, S, Madonna, R, Magatti, M, Mamprin, F, Mannolini, G, Marafon, S, Marchesi, G, Marifoglou, D, Martinelli, P, Martinelli, S, Escobar, R, Mastroianni, A, Mastropierro, R, Mediani, T, Messina, M, Milan, B, Molesi, A, Alberto, C, Mongelli, P, Morigi, A, Mosti, G, Muttini, S, Nardini, M, Nascimben, E, Natalini, G, Negri, G, Negro, G, Neri, M, Netto, R, Nonini, S, Odetto, L, Olivieri, C, Candida, M, Osti, D, Palmer, M, Parnigotto, A, Parrini, V, Pasculli, M, Pasetti, G, Passafiume, M, Pastorini, S, Patrignani, L, Pedeferri, M, Pegoraro, M, Pelati, E, Pelosi, G, Pera, L, Perino, P, Pero, A, Perzolla, D, Peta, M, Pinna, C, Pizzali, M, Postiglione, M, Potalivo, A, Raffaeli, M, Randellini, R, Rech, A, Renda, B, Ricciardi, G, Rizzi, S, Romagnoli, S, Rossi, G, Rossi, M, Rutta, C, Sagliaschi, U, Salcuni, R, Salvi, G, Scalera, M, Scarrone, S, Schiavuzzi, M, Aurelio, P, Selvaggi, P, Sicignano, A, Sorbara, C, Spagarino, E, Sparicio, D, Spinazzola, A, Sucre, M, Terzitta, M, Tetamo, R, Tibaldi, G, Todesco, L, Tomaselli, P, Torta, M, Turriziani, I, Ughi, L, Vaccari, C, Vaj, M, Vanzino, R, Vardanega, A, Vecchiarelli, P, Vedovati, S, Zanni, V, Zappa, S, Zardin, M, Zaro, G, Zuccaro, F, Barattini, M, Chieregato, A, Fumagalli, R, Livigni, S, Mengoli, F, Nardi, G, Palma, D, Portolani, L, and Radrizzani, D

Subjects
medicine.medical_specialty, Epidemiology, surveillance system, law.invention, 03 medical and health sciences, Influenza A Virus, H1N1 Subtype, 0302 clinical medicine, Public health surveillance, law, Infectious disease epidemiology, influenza, pandemic, Humans, Influenza, Human, Intensive Care Units, Italy, Public Health Surveillance, Pandemics, Pandemic, medicine, human, 030212 general & internal medicine, medicine (all), Intensive care medicine, business.industry, Public health, Outbreak, 030208 emergency & critical care medicine, Monitoring system, medicine.disease, Intensive care unit, infectious disease epidemiology, humans, influenza a virus, h1n1 subtype, intensive care units, italy, public health surveillance, pandemics, infectious diseases, epidemiology, Infectious Diseases, Human mortality from H5N1, Medical emergency, business
Abstract

SUMMARYThe prompt availability of reliable epidemiological information on emerging pandemics is crucial for public health policy-makers. Early in 2013, a possible new H1N1 epidemic notified by an intensive care unit (ICU) to GiViTI, the Italian ICU network, prompted the re-activation of the real-time monitoring system developed during the 2009–2010 pandemic. Based on data from 216 ICUs, we were able to detect and monitor an outbreak of severe H1N1 infection, and to compare the situation with previous years. The timely and correct assessment of the severity of an epidemic can be obtained by investigating ICU admissions, especially when historical comparisons can be made.

Published
2015
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3. The prognostic importance of chronic end-stage diseases in geriatric patients admitted to 163 Italian ICUs

Author

Poole, D., Finazzi, S., Nattino, G., Radrizzani, D., Gristina, G., Malacarne, P., Livigni, S., Bertolini, G., Sorgato, C., Mannoni, R., Agnelli, V., Chiani, C., Lanza, G., Venturini, E., Gianni, M., Olivieri, M. C., Guerriero, B., Della Mora, E., Palmer, M., Blasetti, A., Coletta, R., Covani Frigieri, F., Guarducci, M. D., Caracciolo, A., Lain, G., Bernard, M., DE Blasio, E., Zanni, V., Marchesi, G., Madeira, S. M., Spagarino, E., Potalivo, A., Mengoli, F., Parrini, V., Sagliaschi, U., Prandini, A., Rosano, A., Natalini, G., Piccioni, G., Schiavuzzi, M., Bronzini, N., Piva, S., Besozzi, A., Napoleone, A., Patrignani, L., Pisu, M., Mancosu, S., Chiarello, M., Pastorini, S., Bassi, G., Negro, G., Orsini, I., Marifoglou, D., Pota, V., Pegoraro, M., Sucre, M. J., DI Masi, P., Castiglione, G., Morello, G., Garofalo, G., Caroleo, S., Visconti, M. G., Gamberini, E., Mastroianni, A., Liccardi, M. M., Anelati, D., Martinelli, S., Bonato, A., Adorni, A., Colombo, D., Dal Cero, P., Crema, L., Petrucci, N., Beck, E., Alleva, S., Giuntini, R., DA Re, D., Casalini, P., Fabi, M. C., Galeotti, E., Bagalini, G., Bellonzi, A., Zoppellari, R., Lamborghini, S., Pera, L., Doni, L., Bonizzoli, M., Librenti, M., Barattini, M., Mangani, V., Terzitta, M., Guagliardi, C., Bruzzone, C., Arditi, E., Cerana, M., Tavola, M., Falini, S., Vespignani, M. G., Salvi, G., Ramello, P. L., Molesi, A., Ceradelli, M., Buonanno, R., Righini, E., DI Cocco, A., DI Martino, R., Cinque, E., Bonfiglio, M., Ciceri, R., Colombo, L., Nardini, M., Rossi, G., Boccalatte-Rosa, D. L., Babini, M., Zompanti, V., Negri, G., Antonini, B., Baratta, A., Zuccaro, F., Rossi, M., Pedeferri, M., Bellin, M., Sicignano, A., Pezzi, A., Leggieri, C., Fontana, G., Faraldi, L., Cigada, M. G., Magenta, P., Colombo, R., Colombo, S., Gonzi, S., Pizzali, M., Girardis, M., Piccinini, P., Bignone, P., Padovan, L., Bianchin, A., Caria, F. C., Randellini, R., Roticiani, V., Grassi, M., Belluomo Anello, C., Decristofaro, M., Postiglione, M., Giacomello, S., Olivieri, C., Vaccari, C., Dal Ferro, M., Messina, M., Belgiorno, N., Odetto, L., Pasetti, G. S., Balicco, B., Pizzaballa, M. L., Muraro, L., Pignataro, A., Guadagna, A., Fabbri, P. G., Tetamo, R., Bottazzi, A., Mediani, T. S., Gorietti, A., Breschi, C., Ciani, A., Segalini, P., Codeluppi, V., Berruto, F., Pastorelli, M., Comite, C., Pelati, E., Bertolini, R., Lefons, U., DI Pasquale, D. A., Mannolini, G., Vlassich, F., Becarelli, S., Garelli, A., Salsi, P., Rossi, S., Facondini, F., Alampi, D., Cingolani, E., Molino, F. M., Nardi, G., Casula, M., DE Blasi, R. A., Vulcano, G. A., Azzolini, M., Bernasconi, M. O., Bellato, V., Calicchio, G., Righetti, F., Turati, M., Dei Poli, M., Zaro, G., Brizio, E., Coaloa, M., Falzetti, G., Mamprin, F., Liverani, C. M., Clementi, S., Bonucci, P., Varesio, V., Pannacci, R., Fiore, G., Gallo, M., Torta, M., Selvaggi, P., Bert, P. P., Segala, V., Pettazzi, G., Bensi, M., Bocchi, A., Cima, M., Morbelli, M., Peta, M., DI Stella, R., Maggiolo, C., Lembo, R., Pero, A., Marafon, S., Carnevale, L., Vanzino, R., Vecchiarelli, P., and Marino, G.

Subjects
Male, medicine.medical_specialty, Cirrhosis, Disease, Severity of Illness Index, law.invention, 03 medical and health sciences, 0302 clinical medicine, Patient Admission, Postoperative Complications, law, Internal medicine, 80 and over, aged, critical care, prognosis, Medicine, Dementia, Humans, Hospital Mortality, Elective surgery, Aged, Retrospective Studies, Aged, 80 and over, business.industry, Critical care, Prognosis, Female, Intensive Care Units, Italy, Chronic Disease, 030208 emergency & critical care medicine, Odds ratio, medicine.disease, Comorbidity, Intensive care unit, Anesthesiology and Pain Medicine, 030228 respiratory system, Cohort, business
Abstract

BACKGROUND The number of elderly patients undergoing major surgical interventions and then needing admission to intensive care unit (ICU) grows steadily. We investigated this issue in a cohort of 232,278 patients admitted in five years (2011-2015) to 163 Italian general ICUs. METHODS Surgical patients older than 75 registered in the GiViTI MargheritaPROSAFE project were analyzed. The impact on hospital mortality of important chronic conditions (severe COPD, NYHA class IV, dementia, end-stage renal disease, cirrhosis with portal hypertension) was investigated with two prognostic models developed yearly on patients staying in the ICU less or more than 24 hours. RESULTS 44,551 elderly patients (19.2%) underwent emergency (47.3%) or elective surgery (52.7%). At least one severe comorbidity was present in 14.6% of them, yielding a higher hospital mortality (32.4%, vs. 21.1% without severe comorbidity). In the models for patients staying in the ICU 24 hours or more, cirrhosis, NYHA class IV, and severe COPD were constant independent predictors of death (adjusted odds ratios [ORs] range 1.67-1.97, 1.54-1.91, and 1.34-1.50, respectively), while dementia was statistically significant in four out of five models (adjusted ORs 1.23-1.28). End-stage renal disease, instead, never resulted to be an independent prognostic factor. For patients staying in the ICU less than 24 hours, chronic comorbidities were only occasionally independent predictors of death. CONCLUSIONS Our study confirms that elderly surgical patients represent a relevant part of all ICUs admissions. About one of seven bear at least one severe chronic comorbidity, that, excluding end-stage renal disease, are all strong independent predictors of hospital death.

Published
2017

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