Interleukin-6 is upregulated and may be associated with myocardial injury in some patients who have recovered from COVID-19.

Coronavirus disease (COVID-19) causes myocardial injury by inducing a cytokine storm in severe cases. Studies have reported that myocardial injury persists for a prolonged period during COVID-19 recovery, and cardiac troponin is a useful indicator of myocardial injury. The interleukin-6 (IL-6) level is known to be associated with the morbidity and mortality of COVID-19, but this association has not been studied during recovery. The current study examined the association between IL-6 levels and myocardial damage during COVID-19 recovery. Four of 209 patients (1.9%) who recovered from COVID-19 had elevated IL-6 levels. All 4 patients tested positive for high-sensitivity troponin T, and 3 patients had subclinical left ventricular (LV) dysfunction according to echocardiography. Positivity for IL-6 during COVID-19 recovery suggests ongoing myocardial damage due to inflammation.

Potential usage of anterior nasal sampling in clinical practice with three rapid antigen tests for SARS-CoV-2

Introduction Anterior nasal sampling (AN) might be more convenient for patients than NP sampling to diagnose coronavirus disease. This study investigated the feasibility of rapid antigen tests for AN sampling, and the factors affecting the test accuracy. Methods This single-center prospective study evaluated one qualitative (ESP) and two quantitative (LUMI and LUMI-P) rapid antigen tests using AN and NP swabs. Symptomatic patients aged 20 years or older, who were considered eligible for reverse-transcription quantitative polymerase chain reaction using NP samples within 9 days of onset were recruited. Sensitivity, specificity, and positive and negative concordance rates between AN and NP samples were assessed for the rapid antigen tests. We investigated the characteristics that affected the concordance between AN and NP sampling results. Results A total of 128 cases were recruited, including 28 positive samples and 100 negative samples. The sensitivity and specificity of AN samples using ESP were 0.81 and 1.00, while those of NP samples were 0.94 and 1.00. The sensitivity of AN and NP samples was 0.91 and 0.97, respectively, and specificity was 1.00, for both LUMI and LUMI-P. The positive concordance rates of AN to NP sampling were 0.87, 0.94, and 0.85 for ESP, LUMI, and LUMI-P, respectively. No factor had a significant effect on the concordance between the sampling methods. Conclusions ESP, LUMI, and LUMI-P showed practical diagnostic accuracy for AN sampling compared to NP sampling. There was no significant factor affecting the concordance between AN and NP sampling for these rapid antigen tests.

Evaluation of the Detection of Pathogens in Hospitalized Patients with COVID-19 at a Tertiary Hospital in Japan.

The detection of other pathogens in patients with hospitalized coronavirus disease (COVID-19) are not frequent. Considering that data from Japan are limited, we conducted an observational study including patients with hospitalized COVID-19 at the National Center for Global Health and Medicine from January to September 2020. In total, 247 patients with COVID-19 were included in the study. Rapid diagnostic tests, such as immunochromatography, were performed in 31 patients (12.6%). The Film Array Respiratory Panel was performed in 18 (7.3%) patients, and none of the tests were positive for pathogens other than severe acute respiratory syndrome coronavirus 2. Respiratory bacterial culture was performed in 66 (26.7%) patients, with gram-positive bacteria, gram-negative bacteria and normal flora being detected in eight (12.1%), seven (10.6%), and 63 (95.5%) patients, respectively. Patients for whom cultures were performed were older, more severely ill, and more likely to have radiological evidence of pneumonia on admission. Culture was performed more frequently in the early than in the later period of the epidemic, without any differences being observed in bacterial detection rates. The proportion of viral and bacterial detection among hospitalized patients with COVID-19 in tertiary care hospitals in Japan was low. A larger cohort study is necessary to evaluate the effect of each pathogen on the clinical course of COVID-19.

Negative Results of Nucleic Acid Amplification Tests for SARS-CoV-2 in Clinical Practice May Vary among Six Molecular Assays in Patients with COVID-19.

Several commercial nucleic acid amplification tests (NAATs) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed. We used 6 kits available in Japan in 13 NAAT-positive specimens with crossing point values >36 and 7 NAAT-negative specimens from patients with coronavirus disease 2019 (COVID-19), and their results were compared. Specimens positive in ≥2 assays were considered true-positive and examined for concordance with the specimen results. The SARS-CoV-2 Detection Kit -Multi- (Toyobo M; Toyobo, Osaka, Japan) using extracted RNA had the highest concordance (κ = 1.00). This was followed by Cobas® SARS-CoV-2 (Roche, Basel, Switzerland) (κ = 0.79). There was a weak correlation between the number of negative results for each kit and the number of days between onset and testing (Spearman rank correlation: ρ = 0.44; P < 0.05). We believe that the variations in results among kits for specimens with low viral loads should not be problematic when these kits are used for screening infectious patients because these variations are more likely to be observed in specimens tested many days after onset (i.e., those that have lost their infectivity). However, it may be better to use a test for suspected late-stage COVID-19 with a low viral load, such as Toyobo M or Cobas.

Fatty liver on computed tomography scan on admission is a risk factor for severe coronavirus disease.

OBJECTIVES: To alleviate the overflow of coronavirus disease 2019 (COVID-19) patients in hospitals, less invasive and simple criteria are required to triage the patients. We evaluated the relationship between COVID-19 severity and fatty liver on plain computed tomography (CT) scan performed on admission. METHODS: In this retrospective cohort study, we considered all COVID-19 patients at a large tertiary care hospital between January 31 and August 31, 2020. COVID-19 severity was categorized into severe (moderate and severe) and non-severe (asymptomatic and mild) groups, based on the Japanese National COVID-19 guidelines. Fatty liver was detected on plain CT scan. Multivariate logistic regression analysis was performed to evaluate factors associated with severe COVID-19. RESULTS: Of 222 patients (median age: 52 years), 3.2%, 58.1%, 20.7%, and 18.0% presented with asymptomatic, mild, moderate, and severe COVID-19, respectively. Although 59.9% had no fatty liver on plain CT, mild, moderate, and severe fatty liver occurred in 13.1%, 18.9%, and 8.1%, respectively. Age and presence of fatty liver were significantly associated with severe COVID-19. CONCLUSION: Our study showed that fatty liver on plain CT scan on admission can become a risk factor for severe COVID-19. This finding may help clinicians to easily triage COVID-19 patients.

Extracorporeal membrane oxygenation may decrease the plasma concentration of remdesivir in a patient with severe coronavirus disease 2019.

Remdesivir is an antiviral drug that results in clinical improvement after five days of treatment and accelerates recovery by 31%. No studies have discussed the pharmacokinetic analysis of remdesivir in patients with severe COVID-19 requiring extracorporeal membrane oxygenation (ECMO). A 63-year-old American man who underwent mechanical ventilation and ECMO for severe COVID-19 was administered remdesivir for ten days. The loading dosage was 200 mg at 7 PM on day 12 and 100 mg daily at 0:00 PM from day 13-21, administered within 1 h. The pharmacokinetic analysis was performed. The serum creatinine concentration was within the normal range of 0.5-0.7 mg/dL during treatment. According to the pharmacokinetic analysis, the plasma concentrations of remdesivir and GS-441524 4 h after administration (C4) were 662 ng/mL and 58 ng/mL, respectively, and the concentrations 18 h after administration (C18) were 32 ng/mL and 44 ng/mL, respectively. Therefore, the half-life of remdesivir and GS-441524 was 3.2 and 35.1 h, respectively. Monitoring the plasma concentrations of remdesivir and GS-441524 in patients undergoing ECMO may be necessary.

Factors associated with high antibody titer following coronavirus disease among 581 convalescent plasma donors: A single-center cross-sectional study in Japan.

INTRODUCTION: The ability to predict which patients with a history of coronavirus disease (COVID-19) will exhibit a high antibody titer is necessary for more efficient screening of potential convalescent plasma donors. We aimed to identify factors associated with a high immunoglobulin G (IgG) titer in Japanese convalescent plasma donors after COVID-19. METHODS: This cross-sectional study included volunteers undergoing screening for convalescent plasma donation after COVID-19. Serum anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S-protein IgG antibodies were measured using a high-sensitivity chemiluminescence enzyme immunoassay. RESULTS: IgG antibodies were measured in 581 patients, 534 of whom had full information of selected independent variables. Multiple linear regression analysis revealed that increasing age (1.037 [1,025, 1.048]), days from symptom onset to sampling (0.997 [0.995, 0.998]), fever (1.664 [1.226, 2.259]), systemic corticosteroid use during SARS-CoV-2 infection (2.382 [1.576, 3.601]), and blood type AB (1.478 [1.032, 2.117]) predict antibody titer. CONCLUSION: Older participants, those who experienced fever during infection, those treated with systemic corticosteroids during infection, those from whom samples were obtained earlier after symptom onset, and those with blood type AB are the best candidates for convalescent plasma donation. Therefore, these factors should be incorporated into the screening criteria for convalescent plasma donation after SARS-CoV-2 infection.

Pulmonary histoplasmosis diagnosed in a Japanese woman after traveling to central and South America: A case report.

Histoplasmosis is a fungal infection caused by Histoplasma capsulatum, and Japan is considered a non-endemic area for histoplasmosis. Most patients diagnosed with histoplasmosis in the past usually have exposure to caves and bat guano with travel history to endemic areas. Therefore, travel history and risk activities should be comprehensively assessed when suspecting histoplasmosis because this important information may be overlooked. Although few, possibilities of indigenous cases have also been suggested. Moreover, it is assumed that the number of travelers and endemic mycoses has decreased with the recent coronavirus disease 2019 epidemic. However, clinicians should carefully consider the differential diagnosis of histoplasmosis for travelers traveling to endemic areas. In this case report, we describe an immunocompetent Japanese woman who developed histoplasmosis due to a history of travel to an endemic country. Our case report suggests that clinicians should not exclude histoplasmosis from the differential diagnosis even in the absence of risk features such as activities or immunodeficiencies during travel.

How we secured a COVID-19 convalescent plasma procurement scheme in Japan.

BACKGROUND: In order to tackle the COVID-19 pandemic, a COVID-19 convalescent plasma (CCP) procurement program was initiated in Japan in April 2020. The program was a collaboration between a government-managed national hospital, an infectious disease research institute, and a blood banking organization. Each party assumed different responsibilities: recruitment, SARS-CoV-2 antibody profiling, and plasmapheresis; conduction of screening tests; and SARS-CoV-2 blood testing, respectively. METHODS: We adopted a two-point screening approach before the collected CCP was labeled as a CCP product for investigational use, for which we mainly tested anti-SARS-CoV-2 antibody eligibility and blood product eligibility. Anti-SARS-CoV-2 spike protein titer was measured using enzyme-linked immunosorbent assay, and the IC50 value was denoted as the neutralizing activity. Blood donor eligibility was extended beyond the normal blood donation guidelines to include a broader range of participants. After both eligibility criteria were confirmed, participants were asked to revisit the hospital for blood donation, which is a unique aspect of the Japanese CCP program, as most donations are taking place in normal blood donation venues in other countries. Some donors were re-scheduled for repeat plasma donations. As public interest in anti-SARS-CoV-2 antibodies increased, test results were given to the participants. RESULTS: As of September 17, 2020, our collection of CCP products was sufficient to treat more than 100 patients. As a result, projects for administration and distribution are also being conducted. CONCLUSIONS: We successfully implemented a CCP procurement scheme with the goal to expand to other parts of the country to improve treatment options for COVID-19.

Evaluation of High-Sensitivity Cardiac Troponin T Levels in Japanese Patients Recently Recovered From Coronavirus Disease 2019.

BACKGROUND: Several studies have reported elevated troponin levels in coronavirus disease 2019 (COVID-19) patients, so we investigated myocardial damage by measuring high-sensitivity troponin T (hsTnT) levels and analyzed the relationship with comorbidities.Methods and Results:Of 209 patients who recently recovered from COVID-19, 65% had an elevated hsTnT level that was higher than levels in patients with acute phase infection despite most patients (79%) having a mild illness. The hsTnT levels correlated with disease severity, sex, comorbidities, and ACEi and ARB use. CONCLUSIONS: Myocardial damage occurs in the recovery phase of COVID-19, and its evaluation, regardless of patient age, should be considered.

Elevated high-sensitivity troponin is associated with subclinical cardiac dysfunction in patients recovered from coronavirus disease 2019.

The aim of this study is to investigate myocardial damage in recovering coronavirus disease 2019 (COVID-19) patients with high-sensitivity troponin levels (hsTnT) and echocardiography. In this single-center cohort study, 215 COVID-19 recovered patients were recruited from all over Japan between April and September 2020. Demographic characteristics, hsTnT levels, and echocardiography data were collected for 209 patients, after excluding those without serum samples or good-quality echocardiographic images. The mean (± standard deviation) age was 44 (± 12) years (range: 36-55 years), and 50.7% of the patients were males. The median time interval (interquartile range) from COVID-19 onset to post-recovery examination was 56 days (34-96 days). Seventy-four recovered patients (35.4%) had hsTnT less than detection sensitivity (< 3 pg/mL) and 135 recovered patients (64.6%) had hsTnT ≥ 3 pg/mL. Ejection fraction was more than 50% in all cases. Left ventricular global longitudinal strain (LVGLS) and right ventricular free-wall longitudinal strain (RVFWLS) were reduced in 62 (29.7%) and 8 patients (3.8%), respectively. They were significantly associated with elevated hsTnT levels. In cases with hsTnT above 5 pg/mL, the LVGLS was greatly reduced to 19.0 ± 2.2% (p < 0.001). Multivariate linear regression analysis showed that elevated hsTnT level was an independent predictor of reduced LVGLS (standardized ß = -0.34; p < 0.001). In recovered COVID-19 patients, even a slight increase in hsTnT above detection sensitivity was associated with decreased LVGLS. hsTnT and echocardiography may be useful tools to detect myocardial injury in recovered COVID-19 patients.

Direct hemoperfusion using a polymyxin B-immobilized polystyrene column for COVID-19.

OBJECTIVE: To evaluate the efficacy and safety of direct hemoperfusion using a polymyxin B-immobilized polystyrene column (PMX-DHP) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive pneumonia patients. METHODS: This study was a case series conducted at a designated infectious diseases hospital. Twelve SARS-CoV-2-positive patients with partial pressure of arterial oxygen/percentage of inspired oxygen (P/F) ratio < 300 were treated with PMX-DHP on two consecutive days each during hospitalization. We defined day 1 as the first day when PMX-DHP was performed. PMX-DHP efficacy was assessed on days 7 and 14 after the first treatment based on eight categories. Subsequently, improvement in P/F ratio and urinary biomarkers on days 4 and 8, malfunctions, and ventilator and extracorporeal membrane oxygenation avoidance rates were also evaluated. RESULTS: On day 14 after the first treatment, disease severity decreased in 58.3% of the patients. P/F ratio increased while urine ß2-microglobulin decreased on days 4 and 8. Cytokine measurement pre- and post-PMX-DHP revealed decreased levels of interleukin-6 and the factors involved in vascular endothelial injury, including vascular endothelial growth factor. Twenty-two PMX-DHPs were performed, of which seven and five PMX-DHPs led to increased inlet pressure and membrane coagulation, respectively. When the membranes coagulated, the circuitry needed to be reconfigured. Circuit problems were usually observed when D-dimer and fibrin degradation product levels were high before PMX-DHP. CONCLUSIONS: Future studies are expected to determine the therapeutic effect of PMX-DHP on COVID-19. Because of the relatively high risk of circuit coagulation, coagulation capacity should be assessed beforehand.

Non-COVID-19 Patients with Life-threatening Diseases Who Visited a Fever Clinic: A Single-center, Observational Study in Tokyo, Japan.

Objective In fever clinics screening coronavirus disease (COVID-19), there could be patients with life-threatening diseases that physicians should not overlook. We exploratorily investigated the final diagnosis among non-COVID-19 hospitalized patients who visited the fever clinic. Methods This was a retrospective, observational, and single-centered study conducted in the National Center for Global Health and Medicine (NCGM), Tokyo, Japan. We conducted a retrospective chart review of patients who visited the fever clinic in the NCGM from 11 March 2020 to 24 April 2020. Patients Patients who met the following clinical criteria visited the fever clinic in the NCGM: (1) body temperature >37.5°C, (2) any symptoms consistent with COVID-19 or (3) referral from local healthcare facilities. In the fever clinic, all patients who met the above criteria had severe acute respiratory syndrome coronavirus 2 polymerase chain reaction test with nasopharyngeal swab specimens. Patients with severe symptoms or an unstable condition were sent to an outpatient clinic for infectious diseases for further evaluation and treatment. Results Among 1,470 patients who visited the fever clinic, 84 patients were hospitalized, and 45 of them were diagnosed as having COVID-19. Among the remaining 39 non-COVID-19 patients, there were nine patients with life-threatening diseases. The life-threatening diseases included acute heart failure, septic shock, pneumocystis pneumonia, peritonsillar abscess, and necrotizing fasciitis. Conclusion Physicians should evaluate each patient carefully while considering other life-threatening conditions even in such a COVID-19 pandemic era.

Environmental surface and air contamination in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patient rooms by disease severity.

BACKGROUND: The coronavirus disease 2019 (COVID-19) continues to spread around the world. In addition to community-acquired infections, nosocomial infections are also a major social concern. The likelihood of environmental contamination and transmission of the virus based on disease severity is unknown. METHODS: We collected nasopharyngeal, environmental and air samples from patients with COVID-19 admitted to the National Centre for Global Health and Medicine between January 29th and February 29th, 2020. The patients were classified by severity of disease. The collected samples were tested using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) real-time reverse transcription polymerase chain reaction (real-time RT-PCR). RESULTS: SARS-CoV-2 was not detected in a subset of 11 air samples. Of the 141 environmental samples collected from three patient bays and two single rooms, four samples tested positive for SARS-CoV-2 by real-time RT-PCR. Detections were made on the surface of a stethoscope used in the care of a patient with severe disease, on the intubation tube of a patient classified as critical (and on ventilator management), and on the surface of a gown worn by the nurse providing care. CONCLUSIONS: Regardless of the patients' disease severity, SARS-CoV-2 was detected on very few environmental surfaces. However, detection of SARS-CoV-2 on stethoscopes used in the care of multiple patients and on the surface of gowns worn by clinical staff indicates that medical devices may be linked to the spread of infection.

Serum CCL17 level becomes a predictive marker to distinguish between mild/moderate and severe/critical disease in patients with COVID-19.

COVID-19, a novel coronavirus-related illness, has spread worldwide. Patients with apparently mild/moderate symptoms can suddenly develop severe pneumonia. Therefore, almost all COVID-19 patients require hospitalization, which can reduce limited medical resources in addition to overwhelming medical facilities. To identify predictive markers for the development of severe pneumonia, a comprehensive analysis of serum chemokines and cytokines was conducted using serial serum samples from COVID-19 patients. The expression profiles were analyzed along the time axis. Serum samples of common diseases were enrolled from a BioBank to confirm the usefulness of predictive markers. Five factors, IFN-λ3, IL-6, IP-10, CXCL9, and CCL17, were identified as predicting the onset of severe/critical symptoms. The factors were classified into two categories. Category A included IFN-λ3, IL-6, IP-10, and CXCL9, and their values surged and decreased rapidly before the onset of severe pneumonia. Category B included CCL17, which provided complete separation between the mild/moderate and the severe/critical groups at an early phase of SARS-CoV-2 infection. The five markers provided a high predictive value (area under the receiver operating characteristic curve (AUROC): 0.9-1.0, p < 0.001). Low expression of CCL17 was specifically observed in pre-severe COVID-19 patients compared with other common diseases, and the predictive ability of CCL17 was confirmed in validation samples of COVID-19. The factors identified could be promising prognostic markers to distinguish between mild/moderate and severe/critical patients, enabling triage at an early phase of infection, thus avoiding overwhelming medical facilities.

Effectiveness of personal protective equipment in preventing severe acute respiratory syndrome coronavirus 2 infection among healthcare workers.

INTRODUCTION: Information on the effectiveness of personal protective equipment (PPE) for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among healthcare workers (HCWs), especially among HCWs with frequent contact with patients with SARS-CoV-2, is limited. METHODS: We conducted a prospective cohort study on 49 HCWs who worked in close contact with patients with SARS-CoV-2 infection. HCWs had blood samples taken every 2 weeks to test for SARS-CoV-2 antibodies using two different types of assay. RESULTS: Forty-nine participants (31 nurses, 15 doctors, 3 other workers) were enrolled. In total, 112 blood samples are obtained from participants. The median work days in 2 weeks was 9 (interquartile range (IQR): 5-10) days. In a single work day, 30 of the 49 participants (61.5%) had contact with patients with suspected or conformed SARS-CoV-2 at least 8 times, and approximately 60% of participants had more than 10 min of contact with a single patient. The median self-reported compliance to PPE was 90% (IQR: 80-100%). Seven participants tested positive for SARS-CoV-2 antibody using enzyme-linked immunosorbent assay (ELISA); however, none were seropositive for SARS-CoV-2 neutralizing antibody, so the positive ELISA results were assumed to be false-positive. CONCLUSIONS: The study provides evidence that appropriate PPE is sufficient to prevent infection amongHCWs. It is necessary to establish a system that provides a stable supply of PPE for HCWs to perform their duties.

Evaluation of Coronavirus Disease 2019 Severity Using Urine Biomarkers.

SUBJECTS: Early detection of coronavirus disease 2019 in patients likely to develop severe manifestations enables appropriate interventions, including rapid ICU admission. This study was conducted to determine whether noninvasive urine biomarkers can predict the clinical severity of coronavirus disease 2019. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: This is single-center study, national center hospital designated for infectious disease. Fifty-eight patients who tested positive for severe acute respiratory syndrome coronavirus 2 in respiratory specimens through real-time reverse transcription-polymerase chain reaction were retrospectively studied. Urinary ß2-microglobulin, liver-type fatty acid-binding protein were serially measured. Serum interferon-γ and monocyte chemotactic protein-1 were also evaluated. The 58 patients were assigned into three groups. Patients requiring intensive care were assigned to the severe group (n = 12). Patients treated with oxygen were assigned to the moderate group (n = 13). Other patients were assigned to the mild group (n = 33). Urine tests revealed that low ß2-microglobulin and liver-type fatty acid-binding protein levels were associated with mild disease, whereas high levels were associated with severe disease. In severe cases, liver-type fatty acid-binding protein tended to be persistently high. The resulting cutoff values were ß2-microglobulin; severe versus moderate + mild: 2,457 µg/dL (specificity 76.9% and sensitivity 90.0%, area under the receiver operating characteristic curve 85.9%), liver-type fatty acid-binding protein; severe versus moderate + mild: 22.0 µg/gCre (specificity 84.6% and sensitivity 90%, area under the receiver operating characteristic curve 91.8%). Urinary ß2-microglobulin and serum interferon-γ/monocyte chemotactic protein-1 showed a similar trend. CONCLUSIONS: Evaluating urinary biomarkers such as ß2-microglobulin and liver-type fatty acid-binding protein may allow determination of coronavirus disease 2019 patients with active cytokines and recognition of patients likely to become critically ill and requiring careful observation and early intervention.