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      COVID-19 in patients with sickle cell disease – a case series from a UK tertiary hospital

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          Abstract

          At the time of this manuscript going to press, Europe remains the epicenter of the COVID-19 pandemic and new cases and deaths in the UK continue to demonstrate an exponential rise. 1 London has the highest number of reported UK cases. 2 Clinical reports indicate that older adults with comorbidities such as diabetes and hypertension are most at risk of severe COVID-19. 3,4 Overwhelming inflammation and cytokine associated lung injury are potential pathological features. Secondary hemophagocytic lymphohistiocytosis-like syndrome with raised pro-inflammatory cytokines has been associated with adverse outcomes. 5 King’s College Hospital is a teaching hospital in South London, caring for approximately 500 adults and 500 children with sickle cell disease (SCD). South London currently has some of the highest numbers of confirmed cases of COVID-19 in England 2 and a large local SCD cohort. It is thought that patients with SCD might demonstrate a more severe illness if infected with SARSCoV- 2 due to associated functional hyposplenia, high prevalence of concomitant chronic respiratory disease and increased levels of inflammation. 6 In this report we describe the clinical features of the first 10 confirmed cases of COVID-19 in patients with SCD in the King’s College Hospital. At the time of this report, there were 22,141 confirmed cases of COVID-19 in the UK, of which the majority of cases were from the boroughs of Lambeth and Southward in South London. 2 All patients underwent real-time quantitative PCR assay from RNA extracted from nasopharyngeal swabs using a locally validated procedure recommended by Public Health England. 7 All patients had homozygous SCD (HbSS) and presented with symptoms such as cough, fever, coryza and associated acute sickle vaso-occlusive pain. None had any recent travel history (Table 1). Apart from patient 9 who has severe pre-morbid disease with intensive care admission within the last 12 months due to SCD-related cerebrovascular disease, all patients had relatively mild clinical symptoms related to COVID-19 (Table 2). In this series, seven patients were female, and the median age was 37 years (range: 25-54 years). No children were seen with SCD and COVID-19. All but two patients were on some disease modification treatment, either hydroxycarbamide (2 of 10) or transfusions (6 of 10). Patients on top-up transfusions were on a 4-weekly program with a post-transfusion hemoglobin target of 120-130 g/L. One patient was on an angiotensin converting enzyme inhibitor (patient 6), and this was not discontinued during the period of illness. Two patients had a history of overt strokes and one patient had a history of recurrent transient ischemic attacks. All patients had ongoing comorbidities, ranging from end stage renal failure to hyperhemolysis. All admitted patients received standard thromboprophylaxis with low molecular weight heparin injection as per hospital venous thromboembolism prevention guidelines. The mean number of days from onset of symptoms to PCR testing was 2.5 days. Of the seven patients in this cohort needing hospital admission, the mean number of days from the onset of symptoms to hospital admission was two days. Nine of 10 patients made a full recovery. Two patients presenting with cough and hypoxia received early top up transfusions. See Figure 1 for the chest radiograph of patient 2 who was hypoxic on admission and received an additive transfusion. All in-patients received broad spectrum antibiotics to cover community acquired pneumonia. No COVID-19 specific treatment was given. The lymphocyte count fell significantly during infection compared to the baseline, from a median of 3.7 to 1.9 x109/L (P=0.037, Wilcoxon signed-rank test). One patient died of respiratory complications following COVID-19. She had multiple comorbidities, including a history of brittle asthma and hyperhemolysis with multiple red cell alloantibodies, making it difficult to transfuse her. Escalation to ventilation was deemed unsuitable due to existing comorbidities. Table 1. Characteristics of COVID-19 positive patients with sickle cell disease. Table 2. COVID-19 clinical features in SCD patients. Based on our small early cohort of 10 individuals with HbSS who have tested positive for COVID-19, patients seem to be experiencing a relatively mild course despite having significant associated comorbidities such as end stage renal failure, severe cerebral vasculopathy and recurrent painful episodes. Half were managed at home with regular telephone contact by the clinical team. Our first (and so far) only fatality was in an individual of >50 years with poor pre-infection performance status and severe pre-existing lung disease, who had had admissions to intensive therapy unit (ITU) within the last 12 months, as well as multiple red cell alloantibodies and a previous history of severe delayed hemolytic transfusion reactions, which precluded transfusion. This patient had lymphopenia, thrombocytopenia and a high C-reactive protein (CRP), which have been identified as poor prognostic markers in patients without SCD. Seven of 10 patients in this series were female, all patients were non-smokers and all but two were on a disease modifying treatments, such as regular a blood transfusion programme or hydroxycarbamide. These demographic features may have contributed to the mild clinical course in all but one patient. Figure 1. Chest radiograph of patient 2 who was hypoxic on admission and received an early additive transfusion. This showed bilateral congestive changes with no additional pulmonary parenchymal pathology and was obtained on day 2 of admission. SCD is mentioned in the Public Health England list of conditions which should prompt individuals to be shielded from infection, by rigorous self-isolation. Our series shows that patients with SCD can have a relatively mild course with COVID-19. It is difficult to speculate why this might be the case, and it may be postulated that most of our patients were already on some form of disease modification, which may have helped with the host response. It is unclear whether hyposplenism has played a role in the apparent lack of a hyperimmune syndrome and this is likely to be an area of research in the future. The one patient who died was in a poor prognostic group, based on risk factors identified in the general population. So far, we have seen no children with COVID-19 and SCD, suggesting that this may be a mild condition in children with SCD, as has been found in the general population. It is not entirely clear why more women are represented in this group. It is possible that with time, this ratio may become more skewed to the male sex. The relatively low case fatality is evidence that affected individuals should not be excluded from potentially lifesaving measures including respiratory support and artificial ventilation, particularly as our well-studied cohort have a median survival of 67 years. 8 Supplementary Material Disclosures and Contributions

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

            Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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              Host susceptibility to severe COVID-19 and establishment of a host risk score: findings of 487 cases outside Wuhan

              The recent outbreak of coronavirus disease 2019 (COVID-19), caused by a new zoonotic coronary virus, SARS-CoV-2 [1], is being a great threat to public health. Up to February 11, 2020, it is reported that over 70,000 persons have been infected with SARS-CoV-2 in China [2]. The COVID-19 caused by SARS-CoV-2 infection represents a spectrum of clinical severity [3–5]. Some patients are asymptomatic or have merely mild upper respiratory tract symptoms. However, SARS-CoV-2 causes pneumonia that can be severe and characterized by fever, cough, dyspnea, bilateral pulmonary infiltrates, and acute respiratory injury. It is estimated that approximately 20% of patients are developing severe respiratory illness, with the overall mortality around 2.3% [2]. Thereby, it is critical to identify individuals who confer intrinsic susceptibility to become severe or even critically ill upon infection, for the purposes of prevention and treatment, especially when there is no drug directly targeting at SARS-CoV-2 that has been proven to be clinically effective. In the study, we explored potential host risk factors associated with severe cases at admission in a retrospective cohort of 487 patients in Zhejiang Province of China and attempt to establish a score system to identify high-risk individuals. We reviewed medical records, laboratory findings, and pulmonary CT scan of each patient with COVID-19, provided by the local health authority and inputted into a pre-specified electronic data collection form. Clinical outcomes were followed up to February 17, 2020. The primary endpoint was occurrence of death and severe cases. A total of 487 COVID-19 patients were included for analysis, with 49 (10.1%) severe cases at admission. As shown in Table 1, severe cases are elderly (56 (17) vs. 45 (19), P < 0.001), with more male (73.5% vs. 50.9%, P = 0.003). They have a higher incidence of hypertension (53.1% vs. 16.7%, P < 0.001), diabetes (14.3% vs. 5.0%, P = 0.009), cardiovascular diseases (8.2% vs. 1.6%, P = 0.003), and malignancy (4.1% vs. 0.7%, P = 0.025), and less exposure to epidemic area (49.0% vs. 65.1%, P = 0.027), but more infected family members (P = 0.031). On multivariate analysis, elder age (OR 1.06 [95% CI 1.03–1.08], P < 0.001), male (OR 3.68 [95% CI 1.75–7.75], P = 0.001), and presence of hypertension (OR 2.71 [95% CI 1.32–5.59], P = 0.007) are independently associated with severe disease at admission, irrespective of adjustment of time to admission. Table 1 Demographic, epidermiological characteristics, and underlying comorbidities of patients with confirmed 2019-nCoV infection Variables Total (N = 487) Mild (N = 438) Severe (N = 49) P value Age (years) 46 (19) 45 (19) 56 (17) < 0.001 Sex  Male 259 (53.2%) 223 (50.9%) 36 (73.5%)  Female 228 (46.8%) 215 (49.1%) 13 (26.5%) 0.003 Occupation  Agricultural worker 140 (28.7%) 122 (27.9%) 18 (36.7%)  Self-employed 219 (45.0%) 203 (46.3%) 16 (32.7%)  Employee 82 (16.8%) 79 (18.0%) 3 (6.1%)  Retired 38 (7.8%) 26 (5.9%) 12 (24.5%)  Student 8 (1.6%) 8 (1.8%) 0 (0%) < 0.001 Smoking history  Yes 40 (8.2%) 34 (7.8%) 6 (12.2%)  No 434 (89.1%) 391 (89.3%) 43 (87.8%)  Unknown 13 (2.7%) 13 (2.7%) 0 (0%) 0.331 Comorbidities  Hypertension 99 (20.3%) 73 (16.7%) 26 (53.1%) < 0.001  Diabetes 29 (6.0%) 22 (5.0%) 7 (14.3%) 0.009  Cardiovascular disease 11 (2.3%) 7 (1.6%) 4 (8.2%) 0.003  Malignancy 5 (1%) 3 (0.7%) 2 (4.1%) 0.025  Chronic liver diseases 22 (4.5%) 20 (4.6%) 2 (4.1%) 0.877  Chronic renal diseases 7 (1.4%) 5 (1.1%) 2 (4.1%) 0.101  Others 32 (6.6%) 27 (6.1%) 5 (10.2%) 0.279 Exposure to confirmed cases 186 (38.2%) 173 (39.5%) 13 (26.5%) 0.077 Family cluster  0 392 (80.5%) 352 (80.4%) 40 (81.6%)  1 67 (13.8%) 63 (14.4%) 4 (8.2%)  2 12 (2.5%) 12 (2.7%) 0 (0%)  ≥ 3 16 (3.3%) 11 (2.5%) 5 (10.2%) 0.031 Recent travel or residence to/in epidemic area 309 (63.4%) 285 (65.1%) 24 (49.0%) 0.027 Time from onset of symptom to admission 2 (3) 2 (3) 3 (5) 0.10 Data are expressed as mean ± standard deviation (SD), median (interquartile range), or number (percent). Comparisons between mild and severe cases were performed by the Mann-Whitney U test or a chi-square test Then, we defined a host risk score on the basis of the three risk factors, to assess the intrinsic host susceptibility to develop severe cases of COVID-19 (Fig. 1a). As shown in Fig. 1b, a step-wise increase in the incidence of severe COVID-19 at admission was observed with the increment of the host risk score (P < 0.001). The performance of the score was also validated in 66 patients who presented mild at admission and were under follow-up during hospital stay. Fifteen patients progressed to severe COVID-19 within a median follow-up time of 15 days. No death was reported by the end of follow-up. A similar trend to the above was confirmed when analyzing the correlation between host risk score and occurrence of severe COVID-19 (P = 0.014) (see Fig. 1c). Fig. 1 Definition of host risk factor score and incidences of severe cases by host risk score. The host risk factor score was calculated by the sum of three variables (a). The incidences of severe cases at admission (b) or developing during hospitalization (c) were compared across the different score groups by a linear-by-linear association test In summary, by identifying host risk factors associated with severe COVID-19, this study shed light on the underlying mechanisms of disease progression. In particular, the major finding that hypertension is a host risk factor for severe COVID-19 may underscore the involvement of renin-angiotensin system (RAS) in the pathogenesis of this disease. Additionally, the host risk score provides a useful tool to identify high-risk individuals, which is helpful for designing specific strategies for prevention and treatment of this disease. But further studies, particularly those enrolling Wuhan patients, are needed to validate the findings.
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                Author and article information

                Journal
                Haematologica
                Haematologica
                HAEMA
                Haematologica
                Fondazione Ferrata Storti
                0390-6078
                1592-8721
                01 November 2020
                01 November 2020
                : 105
                : 11
                Affiliations
                King's College Hospital , London, UK
                Author notes
                Article
                10.3324/haematol.2020.254250
                7604654
                32527955
                Copyright© 2020 Ferrata Storti Foundation

                This article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

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