Sequelae of long COVID, known and unknown: A review of updated information.

Over three years have passed since the COVID-19 pandemic started. The dangerousness and impact of COVID-19 should definitely not be ignored or underestimated. Other than the symptoms of acute infection, the long-term symptoms associated with SARS-CoV-2 infection, which are referred to here as "sequelae of long COVID (LC)", are also a conspicuous global public health concern. Although such sequelae were well-documented, the understanding of and insights regarding LC-related sequelae remain inadequate due to the limitations of previous studies (the follow-up, methodological flaws, heterogeneity among studies, etc.). Notably, robust evidence regarding diagnosis and treatment of certain LC sequelae remain insufficient and has been a stumbling block to better management of these patients. This awkward situation motivated us to conduct this review. Here, we comprehensively reviewed the updated information, particularly focusing on clinical issues. We attempt to provide the latest information regarding LC-related sequelae by systematically reviewing the involvement of main organ systems. We also propose paths for future exploration based on available knowledge and the authors' clinical experience. We believe that these take-home messages will be helpful to gain insights into LC and ultimately benefit clinical practice in treating LC-related sequelae.

Dysregulated hematopoiesis in bone marrow marks severe COVID-19.

Severe coronavirus disease 2019 (COVID-19) is often indicated by lymphopenia and increased myelopoiesis; however, the underlying mechanism is still unclear, especially the alteration of hematopoiesis. It is important to explore to what extent and how hematopoietic stem cells contribute to the impairment of peripheral lymphoid and myeloid compartments in COVID-19 patients. In this study, we used single-cell RNA sequencing to assess bone marrow mononuclear cells from COVID-19 patients with peripheral blood mononuclear cells as control. The results showed that the hematopoietic stem cells in these patients were mainly in the G1 phase and prone to apoptosis, with immune activation and anti-viral responses. Importantly, a significant accumulation of immature myeloid progenitors and a dramatic reduction of lymphoid progenitors in severe cases were identified, along with the up-regulation of transcription factors (such as SPI1, LMO4, ETS2, FLI1, and GATA2) that are important for the hematopoietic stem cell or multipotent progenitor to differentiate into downstream progenitors. Our results indicate a dysregulated hematopoiesis in patients with severe COVID-19.

Three-Month Pulmonary Function and Radiological Outcomes in COVID-19 Survivors: A Longitudinal Patient Cohort Study.

BACKGROUND: This study aimed to investigate pulmonary function and radiological outcomes in a group of coronavirus disease 2019 (COVID-19) survivors. METHODS: One hundred seventy-two COVID-19 survivors in a follow-up clinic in a referral hospital underwent high-resolution computed tomography (CT) of the thorax and pulmonary function at 3 months after hospital discharge. RESULTS: The median duration from hospital discharge to radiological and pulmonary function test (interquartile range) was 90 (88-95) days. Abnormal pulmonary function was found in 11 (6.40%) patients, and abnormal small airway function (FEF25-75%) in 12 (6.98%). Six (3.49%) patients had obstructive ventilation impairment, and 6 (3.49%) had restrictive ventilatory impairment. No significant differences in lung function parameters were observed between the nonsevere and severe groups. Of 142 COVID-19 patients who underwent CT scan, 122 (85.91%) showed residual CT abnormalities and 52 (36.62%) showed chronic and fibrotic changes. The ground-glass opacities absorption in the lungs of severe cases was less satisfactory than that of nonsevere patients. The severe patients had higher CT scores than the nonsevere cases (2.00 vs 0.00; P < .001). CONCLUSIONS: Of the COVID-19 survivors in our study, 6.40% still presented pulmonary function abnormality 3 months after discharge, which did not vary by disease severity during hospitalization; 85.91% of patients had abnormalities on chest CT, with fibrous stripes and ground-glass opacities being the most common patterns.

Acute Kidney Injury and Early Predictive Factors in COVID-19 Patients.

Objectives: Our objective was to explore the incidence and early predictive factors of acute kidney injury in coronavirus disease 2019 (COVID-19) patients. Method: We established a retrospective cohort of 408 patients who were admitted to Shenzhen Third People's Hospital in Shenzhen, China, between January 1 and March 31, 2020. Clinical outcomes and renal function were monitored until April 12, 2020, with a median follow-up duration of 21 days [interquartile range (IQR) = 14-33]. Results: When first admitted to hospital (baseline), 19.36% (79/408) presented renal dysfunction [estimated glomerular filtration rate (eGFR) <90 ml/min/1.73 m2]. During follow-up, 3.9% (16/408) developed acute kidney injury (AKI). Age ≥60 years [hazard ratio (HR) = 4.78, 95% CI = 1.10-20.69], PaO2/FiO2 ratio <300 (HR = 3.48, 95% CI = 1.04-11.62), and higher creatinine (HR = 1.04, 95% CI = 1.01-1.07) at baseline independently predicted the risk of AKI. Respectively, 25.0% (102/408), 3.9% (16/408), 0.5% (2/408), 1.0% (4/408), and 0.2% (1/408) experienced G2, G3a, G3b, G4, and G5 as their most severe category during hospitalization, while 69.4% (283/408) had normal eGFRs throughout the follow-up period. When finally discharged from hospital, there were 12.5% (51/408) of patients with abnormal eGFRs. Conclusions: COVID-19 patients can be at risk of AKI and continuous eGFR decline during hospitalization, which can be early predicted by baseline factors. Some individuals still had renal dysfunction when finally discharged from hospital.

The time course of chest CT lung changes in COVID-19 patients from onset to discharge.

BACKGROUND & AIMS: Computed tomography (CT) is widely used to evaluate the severity of COVID-19 infection and track disease progression. We described the changes in chest CT to enable better understanding of the progression of COVID-19 during hospitalization. METHODS: Consecutively hospitalized COVID-19 patients admitted from January 11, 2020 to February 16, 2020 and followed until March 26, 2020 at the Third People's Hospital of Shenzhen, China were included. Semi- quantitative analysis was used to assess the shape, distribution, and range of lung lesions. For each image, the lungs were divided into six regions. The total CT score was the sum of individual region scores. RESULTS: 305 patients underwent a total of 1442 chest CT scans with a mean interval of 5 days (interquartile range (IQR) = 3-6 days). All patients were discharged after an average hospitalization of 25 days (IQR = 20-33 days). From the onset of initial symptoms, the total CT score peaked at an earlier date in the non-severe than the severe cases (13 days versus 15 days). Typical CT image of non-severe cases mainly presented as ground-glass opacities (GGO), whilst GGO mixed with consolidation was more seen in severe cases. In addition, severe versus non-severe cases had higher prevalence of fibrosis and air bronchogram in CT scans (P from <0.001 to 0.05, P = 0.001, respectively). The proportion of patients with fibrosis and air bronchogram appeared to decrease from the fourth (20 days from onset, IQR = 16-24) and the third pulmonary CT scan (15 days from onset, IQR = 12-19), respectively. CONCLUSION: COVID-19 pneumonia demonstrated progressions in early stage, with the greatest pulmonary damage on CT occurred at approximately 13 days after initial onset of symptoms. Worse bilateral pulmonary infiltrates were found in severe cases, indicating continuous health care for pulmonary rehabilitation and consecutive follow-up to monitor irreversible fibrosis and consolidation are necessary.

Clinical characteristics of recovered COVID-19 patients with re-detectable positive RNA test.

BACKGROUND: The characteristics, significance and potential cause of positive SARS-CoV-2 diagnoses in recovered coronavirus disease 2019 (COVID-19) patients post discharge (re-detectable positive, RP) remained elusive. METHODS: A total of 262 COVID-19 patients discharged from January 23 to February 25, 2020 were enrolled into this study. RP and non-RP (NRP) patients were grouped according to disease severity, and the characterization at re-admission was analyzed. SARS-CoV-2 RNA and plasma antibody levels were measured, and all patients were followed up for at least 14 days, with a cutoff date of March 10, 2020. RESULTS: A total of 14.5% of RP patients were detected. These patients were characterized as young and displayed mild and moderate conditions compared to NRP patients while no severe patients were RP. RP patients displayed fewer symptoms but similar plasma antibody levels during their hospitalization compared to NRP patients. Upon hospital readmission, these patients showed no obvious symptoms or disease progression. All 21 close contacts of RP patients were tested negative for viral RNA and showed no suspicious symptoms. Eighteen out of 24 of RNA-negative samples detected by the commercial kit were tested positive for viral RNA using a hyper-sensitive method, suggesting that these patients were potential carriers of the virus after recovery from COVID-19. CONCLUSIONS: Our results indicated that young patients, with a mild diagnosis of COVID-19 are more likely to display RP status after discharge. These patients show no obvious symptoms or disease progression upon re-admission. More sensitive RNA detection methods are required to monitor these patients. Our findings provide information and evidence for the management of convalescent COVID-19 patients.

Longitudinal changes of liver function and hepatitis B reactivation in COVID-19 patients with pre-existing chronic hepatitis B virus infection.

AIM: With the current coronavirus disease (COVID-19) pandemic and high endemic levels of chronic hepatitis B virus (HBV) infection worldwide, it is urgent to investigate liver function changes of COVID-19 patients with chronic HBV infection, and how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in turn affects the course of chronic HBV infection. METHOD: We undertook a retrospective study based on 347 COVID-19 patients (21 vs. 326 with vs. without chronic HBV infection). With the propensity score matching (PSM) method, we yielded 20 and 51 matched patients for the HBV group and the non-HBV group, respectively. RESULTS: At the end of follow-up, all of these 71 patients achieved SARS-CoV-2 clearance (P = 0.1). During the follow-up, 30% versus 31.4% in the HBV group versus non-HBV group progressed to severe COVID-19 (P = 0.97). After PSM, the longitudinal changes of median values for liver biochemistries were not significantly different between the two groups. In the HBV group versus non-HBV group, 35% (7/20) versus 37.25% (19/51) (P = 0.86) had abnormal alanine aminotransferase at least once during hospitalization, 30% (6/20) versus 31.37% (16/51) had abnormal aspartate aminotransferase (P = 0.91), 40% (8/20) versus 37.25% (19/51) had abnormal γ-glutamyltransferase (P = 0.83), and 45% (9/20) versus 39.22% (20/51) had abnormal total bilirubin levels (P = 0.91). Moreover, three patients in the HBV group had hepatitis B reactivation. CONCLUSIONS: Liver dysfunction presented in COVID-19 patients with/without chronic HBV. Moreover, those COVID-19 patients co-infected with chronic HBV could have a risk of hepatitis B reactivation. It is necessary to monitor liver function of COVID-19 patients, as well as HBV-DNA levels for those co-infected with HBV during the whole disease course.

COVID-19: Abnormal liver function tests.

BACKGROUND & AIMS: Recent data on the coronavirus disease 2019 (COVID-19) outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has begun to shine light on the impact of the disease on the liver. But no studies to date have systematically described liver test abnormalities in patients with COVID-19. We evaluated the clinical characteristics of COVID-19 in patients with abnormal liver test results. METHODS: Clinical records and laboratory results were obtained from 417 patients with laboratory-confirmed COVID-19 who were admitted to the only referral hospital in Shenzhen, China from January 11 to February 21, 2020 and followed up to March 7, 2020. Information on clinical features of patients with abnormal liver tests were collected for analysis. RESULTS: Of 417 patients with COVID-19, 318 (76.3%) had abnormal liver test results and 90 (21.5%) had liver injury during hospitalization. The presence of abnormal liver tests became more pronounced during hospitalization within 2 weeks, with 49 (23.4%), 31 (14.8%), 24 (11.5%) and 51 (24.4%) patients having alanine aminotransferase, aspartate aminotransferase, total bilirubin and gamma-glutamyl transferase levels elevated to more than 3× the upper limit of normal, respectively. Patients with abnormal liver tests of hepatocellular type or mixed type at admission had higher odds of progressing to severe disease (odds ratios [ORs] 2.73; 95% CI 1.19-6.3, and 4.44, 95% CI 1.93-10.23, respectively). The use of lopinavir/ritonavir was also found to lead to increased odds of liver injury (OR from 4.44 to 5.03, both p <0.01). CONCLUSION: Patients with abnormal liver tests were at higher risk of progressing to severe disease. The detrimental effects on liver injury mainly related to certain medications used during hospitalization, which should be monitored and evaluated frequently. LAY SUMMARY: Data on liver tests in patients with COVID-19 are scarce. We observed a high prevalence of liver test abnormalities and liver injury in 417 patients with COVID-19 admitted to our referral center, and the prevalence increased substantially during hospitalization. The presence of abnormal liver tests and liver injury were associated with the progression to severe pneumonia. The detrimental effects on liver injury were related to certain medications used during hospitalization, which warrants frequent monitoring and evaluation for these patients.

COVID-19 in a designated infectious diseases hospital outside Hubei Province, China.

BACKGROUND: The clinical characteristics of novel coronavirus disease (COVID-2019) patients outside the epicenter of Hubei Province are less understood. METHODS: We analyzed the epidemiological and clinical features of all COVID-2019 cases in the only referral hospital in Shenzhen City, China, from January 11, 2020, to February 6, 2020, and followed until March 6, 2020. RESULTS: Among the 298 confirmed cases, 233 (81.5%) had been to Hubei, while 42 (14%) did not have a clear travel history. Only 218 (73.15%) cases had a fever as the initial symptom. Compared with the nonsevere cases, severe cases were associated with older age, those with underlying diseases, and higher levels of C-reactive protein, interleukin-6, and erythrocyte sedimentation rate. Slower clearance of the virus was associated with a higher risk of progression to critical condition. As of March 6, 2020, 268 (89.9%) patients were discharged and the overall case fatality ratio was 1.0%. CONCLUSIONS: In a designated hospital outside Hubei Province, COVID-2019 patients could be effectively managed by properly using the existing hospital system. Mortality may be lowered when cases are relatively mild, and there are sufficient medical resources to care and treat the disease.

Obesity and COVID-19 Severity in a Designated Hospital in Shenzhen, China (preprint)

Background: Patients with obesity are at increased risk of exacerbations from viral respiratory infections. However, the association of obesity with severity of corona virus disease 2019 (COVID-19) is unclear. We hereby examined this association using data from the only referral hospital in Shenzhen, China.Methods: 383 COVID-19 patients admitted from 11 January to 16 February 2020 in the Third People’s Hospital of Shenzhen, China were included. Underweight was defined by body mass index (BMI) lower than 18·5 kg/m2, normal weight by 18·5-23·9 kg/m2 , overweight by 24·0- 27·9 kg/m2 and obesity as ≥28 kg/m2.Findings: Of them, 53·1% were normal weight, 4·2% were underweight, 32·0% were overweight, and 10·7% were obese. Patients with obesity, versus without, were tended to have cough (P=0·03) and fever (P=0·06). After adjusting for potential confounders, compared to normal weight, overweight showed 86% higher, and obesity group showed 2·42-fold higher odds of developing severe pneumonia. Despite a non-significant sex interaction was found (P=0·09), the association appeared to be more pronounced in men than in women. The odds ratios (95% confidence intervals) for severe pneumonia in overweight and obesity was 1·96 (0·78-4·98) and 5·70 (1·83-17·76) in men, and 1·51 (0·57-4·01) and 0·71 (0·07-7·3) in women, respectively.Interpretation: This is the first study showing that obesity, especially in men, significantly increases the risk of developing severe pneumonia in COVID-19 patients. As the 2019n-Cov may continue to spread worldwide, clinicians should maintain a high level of attention in obese patients. Obese patients should be carefully managed with prompt and aggressive treatment.Funding Statement: Sanming Project of Medicine in Shenzhen (SZSM201412003, SZSM201512005) and Bill & Melinda Gates Foundations, Shenzhen Science and Technology Research and Development Project (202002073000001).Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: This study was approved by the Ethics Committee of The Third People’s Hospital of Shenzhen (2020 108). All patients provided signed informed consent at admission.

Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study.

There is currently an outbreak of respiratory disease caused by a novel coronavirus. The virus has been named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease it causes has been named coronavirus disease 2019 (COVID-19). More than 16% of patients developed acute respiratory distress syndrome, and the fatality ratio was 1%-2%. No specific treatment has been reported. Herein, we examined the effects of favipiravir (FPV) versus lopinavir (LPV)/ritonavir (RTV) for the treatment of COVID-19. Patients with laboratory-confirmed COVID-19 who received oral FPV (Day 1: 1600 mg twice daily; Days 2-14: 600 mg twice daily) plus interferon (IFN)-α by aerosol inhalation (5 million international unit (IU) twice daily) were included in the FPV arm of this study, whereas patients who were treated with LPV/RTV (Days 1-14: 400 mg/100 mg twice daily) plus IFN-α by aerosol inhalation (5 million IU twice daily) were included in the control arm. Changes in chest computed tomography (CT), viral clearance, and drug safety were compared between the two groups. For the 35 patients enrolled in the FPV arm and the 45 patients in the control arm, all baseline characteristics were comparable between the two arms. A shorter viral clearance median time was found for the FPV arm versus the control arm (4 d (interquartile range (IQR): 2.5-9) versus 11 d (IQR: 8-13), P < 0.001). The FPV arm also showed significant improvement in chest CT compared with the control arm, with an improvement rate of 91.43% versus 62.22% (P = 0.004). After adjustment for potential confounders, the FPV arm also showed a significantly higher improvement rate in chest CT. Multivariable Cox regression showed that FPV was independently associated with faster viral clearance. In addition, fewer adverse events were found in the FPV arm than in the control arm. In this open-label before-after controlled study, FPV showed better therapeutic responses on COVID-19 in terms of disease progression and viral clearance. These preliminary clinical results provide useful information of treatments for SARS-CoV-2 infection.

Obesity and COVID-19 Severity in a Designated Hospital in Shenzhen, China

OBJECTIVE: Patients with obesity are at increased risk of exacerbations from viral respiratory infections. However, the association of obesity with the severity of coronavirus disease 2019 (COVID-19) is unclear. We examined this association using data from the only referral hospital in Shenzhen, China. RESEARCH DESIGN AND METHODS: A total of 383 consecutively hospitalized patients with COVID-19 admitted from 11 January 2020 to 16 February 2020 and followed until 26 March 2020 at the Third People's Hospital of Shenzhen were included. Underweight was defined as a BMI <18.5 kg/m(2), normal weight as 18.5-23.9 kg/m(2), overweight as 24.0-27.9 kg/m(2), and obesity as >/=28 kg/m(2). RESULTS: Of the 383 patients, 53.1% were normal weight, 4.2% were underweight, 32.0% were overweight, and 10.7% were obese at admission. Obese patients tended to have symptoms of cough (P = 0.03) and fever (P = 0.06) compared with patients who were not obese. Compared with normal weight patients, those who were overweight had 1.84-fold odds of developing severe COVID-19 (odds ratio [OR] 1.84, 95% CI 0.99-3.43, P = 0.05), while those who were obese were at 3.40-fold odds of developing severe disease (OR 3.40, 95% CI 1.40-2.86, P = 0.007), after adjusting for age, sex, epidemiological characteristics, days from disease onset to hospitalization, presence of hypertension, diabetes, cardiovascular disease, chronic obstructive pulmonary disease, liver disease and cancer, and drug used for treatment. Additionally, after similar adjustment, men who were obese versus those who were normal weight were at increased odds of developing severe COVID-19 (OR 5.66, 95% CI 1.80-17.75, P = 0.003). CONCLUSIONS: In this study, obese patients had increased odds of progressing to severe COVID-19. As the severe acute respiratory syndrome coronavirus 2 may continue to spread worldwide, clinicians should pay close attention to obese patients, who should be carefully managed with prompt and aggressive treatment.