key: cord-0805632-zgix8quw authors: Benussi, A.; Pilotto, A.; Premi, E.; Libri, I.; Giunta, M.; Agosti, C.; Alberici, A.; Baldelli, E.; Benini, M.; Bonacina, S.; Brambilla, L.; Caratozzolo, S.; Cortinovis, M.; Costa, A.; Cotti Piccinelli, S.; Cottini, E.; Cristillo, V.; Delrio, I.; Filosto, M.; Gamba, M.; Gazzina, S.; Gilberti, N.; Gipponi, S.; Imarisio, A.; Invernizzi, P.; Leggio, U.; Leonardi, M.; Liberini, P.; Locatelli, M.; Masciocchi, S.; Poli, L.; Rao, R.; Risi, B.; Rozzini, L.; Scalvini, A.; Schiano di Cola, F.; Spezi, R.; Vergani, V.; Volonghi, I.; Zoppi, N.; Borroni, B.; Magoni, M.; Pezzini, A.; Padovani, A. title: Clinical features and outcomes of inpatients with neurological disease and COVID-19 date: 2020-05-02 journal: nan DOI: 10.1101/2020.04.28.20082735 sha: 027999497b4bb9837f53295f752def86671e002c doc_id: 805632 cord_uid: zgix8quw Objective: To report the clinical and laboratory characteristics, as well as treatment and clinical outcomes of patients admitted for neurological diseases with COVID-19 in a Neuro-COVID unit compared to patients without COVID-19. Methods: In this retrospective, single centre cohort study, we included all adult inpatients with confirmed COVID-19, who had been discharged or died by April 5, 2020. Demographic, clinical, treatment, and laboratory data were extracted from medical records. Results: 173 patients were included in this study, of whom 56 resulted positive for COVID-19 and 117 resulted negative for COVID-19. Patients with COVID-19 were older, had a different distribution regarding admission diagnoses, including cerebrovascular disorders, and had a higher quick Sequential Organ Failure Assessment (qSOFA) score on admission (all p<0.05). In-hospital mortality rates and incident delirium were significantly higher in the COVID-19 group (all p<0.05). COVID-19 and non-COVID patients with stroke had similar baseline characteristics but patients with COVID-19 had higher modified Rankin scale scores at discharge (p<0.0001), with a significantly lower number of patients with a good outcome (p<0.0001). Multivariable regressions showed increasing odds of in-hospital death associated with higher qSOFA scores (odds ratio 4.47, 95% CI 1.21-16.5; p=0.025), lower platelet count (0.98, 0.97-0.99; p=0.005) and higher lactate dehydrogenase (1.01, 1.00-1.03; p=0.009) on admission. Conclusions: COVID-19 patients admitted with neurological disease, including stroke, have a significantly higher in-hospital mortality, incident delirium and higher disability than patients without COVID-19. Since February 20, 2020, Lombardy, Italy, has experienced a major outbreak of coronavirus disease 2019 , caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with more than 50,000 cases and 9,000 deaths in the region as of April 5, 2020. 1 The clinical spectrum of SAR-CoV-2 appears to be wide, encompassing asymptomatic infections, mild upper respiratory tract illness and severe pneumonia with respiratory failure and death. 2 Several factors have been associated with increased mortality, as older age, high Sequential Organ Failure Assessment (SOFA) score, and increased d-dimer levels. 3 To date, only two retrospective case series from convenience samples from three hospitals in Wuhan, China, have been published 4 or posted on pre-print servers without peer review. 5 The most common neurological manifestations were dizziness (16.8%), headache (13.1%) and encephalopathy (2.8%). Stroke complicated COVID-19 infection in 5.9% of cases, with patients being older, with more cardiovascular comorbidities, and more severe pneumonia. 5, 6 It is yet unclear if patients with neurological disease and COVID-19 have a different neurological outcome compared to patients without COVID-19, and if this is achieved at the cost of days of hospitalization or increased mortality. Moreover, it is not known if stroke severity at admission and at discharge are similar in the two populations, and if acute phase treatments, as endovascular therapy and intravenous fibrinolysis have similar outcomes. We aim to describe the clinical and laboratory characteristics, as well as treatment and clinical outcomes of patients with neurological disease, with and without COVID-19. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04.28.20082735 doi: medRxiv preprint This retrospective cohort study included adult inpatients (≥18 years old) from the General Neurology Unit and Vascular Neurology Unit, Department of Neurological and Vision Sciences, ASST Spedali Civili Hospital, Brescia, Italy. This Hospital in the City of Brescia was designated as a "hub" for acute cerebrovascular diseases during the COVID-19 outbreak, in a metropolitan area of more than 1,200,000 people. 7 The original units were divided in two separate sections for patients affected (Neuro-COVID unit) and non-affected (non-COVID unit) by COVID-19, and staff neurologists were equally divided between the two units. 8 Our study enrolled all adult inpatients who were hospitalised for neurological diseases and had a definite outcome (discharge home or to a rehabilitation facility, or death). The criteria for discharge for patients with COVID-19 were absence of fever for at least 24 hours, a respiratory rate <22/min, and substantial improvement at chest x-ray or CT scan. The study was approved by the local ethics committee of the ASST Spedali Civili di Brescia Hospital and the requirement for informed consent was waived by the Ethics Commission (NP 4051, approved 06.04.2020). Epidemiological, demographical, clinical, laboratory, treatment, and outcome data were extracted from both printed and electronic medical records using standardised anonymised data collection forms. All data were imputed and checked by four physicians (AB, AP, MG and IL). The admission data of included patients ranged from February 21 to April 5, 2020. SARS-CoV-2 detection in respiratory specimens were performed by real-time RT PCR methods, as described elsewhere. 9 Both nasopharyngeal and oropharyngeal swabs were performed in all . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04.28.20082735 doi: medRxiv preprint patients. If two consecutive tests obtained at least 24 hours apart resulted negative, and there was high suspicion of COVID-19 (i.e. interstitial pneumonia at chest x-ray, low arterial partial pressure of oxygen), a bronchoalveolar lavage was performed. Routine blood examinations comprised complete blood count, erythrocyte sedimentation rate, serum biochemical tests including C-reactive protein, liver and renal function, lactate dehydrogenase, creatine kinase, high-sensitivity troponin I, serum ferritin and coagulation profile. High sensitivity troponin I, ferritin and d-dimer were performed only in a subset of patients (~20%). Fever was defined as axillary temperature of at least 37.5°C. The diagnosis of delirium was defined by the presence of features 1 and 2 and either 3 or 4 at the Confusion Assessment Method (CAM). 10 Antiviral treatment was defined as lopinavir/ritonavir 200/50 mg 2 cp BID, darunavir 800 mg 1 cp QD + ritonavir 100 mg 1 cp QD, or darunavir/cobicistat 800/150 mg 1 cp QD. In stroke patients, a good outcome was defined as a modified Rankin scale (mRS) score ≤ 2. Instrumental exams were defined as MRI (head), CT (head/thorax/abdomen), X-ray (thorax/abdomen), EEG, echography (heart/neck), and Holter monitor. Continuous and categorical variables are reported as median (interquartile range) and n (%) respectively. Differences between patients with and without COVID-19 were compared by Mann-Whitney U test, χ 2 test or Fisher's exact test where appropriate. To explore the risk factors associated with in-hospital death, univariable and multivariable logistic regression models were implemented. For multivariate analysis, to avoid overfitting in the model, variables were chosen based on previous findings and clinical constraints. 3 Previous studies have shown age, qSOFA scores and several laboratory findings to be associated with in-hospital . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04.28.20082735 doi: medRxiv preprint mortality. Therefore, we chose age, qSOFA scores, platelet count, C-reactive protein and lactate dehydrogenase for our multivariable logistic regression model. The analyses were not adjusted for multiple comparisons, and given the possibility of type I error, the results should be interpreted as exploratory and descriptive. A two-sided p<0.05 was considered statistically significant. Data analyses were carried out using SPSS software (version 21.0). All study data, including raw and analysed data, and materials will be available from the corresponding author, A.P., upon reasonable request. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04.28.20082735 doi: medRxiv preprint Two hundred fourteen adult patients were hospitalised in the Neurology and Vascular Neurology Unit of the ASST Spedali Civili di Brescia Hospital. After excluding 41 patients which were still hospitalised as of April 5, 2020, we included 173 inpatients in the final analysis. Of these, 56 (32.4%) resulted positive for COVID-19 and were admitted in the Neuro-COVID unit (see Fig. 1 ). Demographic, clinical and laboratory characteristics of included patients are reported in Table 1 . Laboratory analysis showed an increased neutrophil and platelet count, reduced lymphocyte count, increased C-reactive protein, erythrocyte sedimentation rate, high-sensitivity troponin I, lactate dehydrogenase, aspartate and alanine aminotransferase, prothrombin time and fibrinogen (all . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04.28.20082735 doi: medRxiv preprint p<0.05) in patients with COVID-19 compared to non-COVID-19 patients. No differences were observed for whole white blood cell count, haemoglobin, bilirubin, creatine kinase, creatinine, activated thromboplastin time, d-dimer or serum ferritin (all p>0.05) (see Table 1 ). We observed a significant increase in cerebrovascular disease rates in the COVID-19 group (n=43, 76.8% vs n=67, 57.3%, p=0.018), with a similar distribution between transient ischemic attack (n=5, 11.6% vs n=8, 11.9%), ischemic stroke (n=35, 81.4% vs n=50, 74.6%) and haemorrhagic stroke (n=3, 7.0% vs n=9, 13.4%) within groups, p=0.560 (see Table 2 ). Patients with ischemic stroke had similar baseline characteristics, including sex, comorbidities, premorbid mRS and National Institute of Health Stroke Scale (NIHSS) scores on admission. There were no differences in access to acute phase therapies as endovascular treatment (n=2, 5.0% vs n=8, 13 .8%, p=0.580), intravenous fibrinolysis (n=4, 10.0% vs n=2, 3.4%, p=0.192) or bridging therapy (n=3, 8.6% vs n=3, 6.0%, p=0.687). Patients with COVID-19 had higher mRS scores at discharge Moreover, patients with cerebrovascular disease and COVID-19 had an increased neutrophil and platelet count, reduced lymphocyte count, higher C-reactive protein, erythrocyte sedimentation rate, lactate dehydrogenase, aspartate and alanine aminotransferase, prothrombin time and fibrinogen levels compared to patients with cerebrovascular disease but without COVID-19 (see Table 2 ). In univariable analysis, age, higher qSOFA scores, thrombocytopenia, elevated C-reactive protein and lactate dehydrogenase were associated with in-hospital death in the COVID-19 group ( Table 3 ). In the multivariable logistic regression model, we found that higher qSOFA scores (odds ratio 4.47, 95% CI 1.21-16.50; p=0.025), lower platelets (0.98, 0.97-0.99; p=0.005) and higher lactate . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04.28.20082735 doi: medRxiv preprint dehydrogenase (1.01, 1.00-1.03; p=0.009) on admission were all associated with increased odds of death in COVID-19 patients ( Table 3) . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. This retrospective cohort study identified several differences between patients with and without COVID-19 who were hospitalised with a neurological disease. In particular, patients with COVID-19 were older, had higher qSOFA scores on admission, and had a higher rate of cerebrovascular disorders compared to patients without COVID-19. During hospitalization, COVID-19 patients had a higher incidence of delirium and fever, with prolonged hospital length of stay and increased inhospital mortality rates. Additionally, patients with COVID-19 had significant differences in laboratory values on admission, including blood count analysis, acute phase proteins and coagulation profiles. We identified potential risk factors for a poor prognosis at an early stage, as high qSOFA score, thrombocytopenia and increased lactate dehydrogenase levels. Previous reports have also found that SOFA and qSOFA scores were associated with in-hospital mortality, as well as d-dimer and older age, in adult inpatients with COVID-19. 3 The qSOFA is a bedside prompt scale that may identify patients with suspected infection who are at greater risk for a poor outcome outside the intensive care unit, and may be rapidly performed by the clinician without the need of laboratory analysis. 11 Interestingly, we observed a significant increase of stroke rates in patients with COVID-19, with worse outcomes compared to the non-COVID-19 group, including higher mRS scores at discharge and a significantly lower number of patients with a good outcome, at par with access to acute phase therapies. As recently suggested in a statement by the American Heart Association and by the American Stroke Association (AHA/ASA) Stroke Council Leadership, stroke mechanisms in COVID-19 could include different processes, including the release of pro-inflammatory cytokines with a direct effect on plaque rupture through local inflammation and activation of coagulation factors, or cardioembolism from virus-related cardiac injury. [12] [13] [14] [15] [16] Moreover, a direct effect of the virus on endothelial cells or on heart tissue could be hypothesized, considering that the receptor for SARS-CoV-2, the angiotensin converting enzyme 2, 17-19 is expressed on vascular endothelial cells and myocytes. [20] [21] [22] . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. We acknowledge that this study entails some limitations. First, due to the retrospective study design, not all laboratory tests were performed in all patients, including high sensitivity troponin I, ferritin and d-dimer, therefore their role could have not been thoroughly assessed in this study. Second, results on stroke do not take into account several factors due to the retrospective design, including stroke subtypes, infarct volume and recanalization rates. Third, interpretation of our findings could be limited by sample size and by the single-centre design. To the best of our knowledge, this is the largest retrospective cohort study among patients with neurological disorders and COVID-19, with a definite outcome. Patients with COVID-19 and . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04.28.20082735 doi: medRxiv preprint neurological disease have worse clinical and neurological outcomes, with higher in-hospital mortality rates compared to patients without COVID-19. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. . https://doi.org/10.1101/2020.04.28.20082735 doi: medRxiv preprint We would like to express our gratitude to the nurses, auxiliary staff, technicians and all the colleagues who collaborated for the management of patients during the COVID-19 outbreak. Moreover, we would like to thank Dr. Marco Trivelli, Dr. Camilo Rossi and Dr. Loretta Jacquot for their support in setting up a Neuro-COVID Unit. The authors declare no competing interests. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. White-cell count (mm 3 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 2, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 2, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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