Peer Reviewed Articles on Skin Assessments for Hospitalized Patients
Pathogens. 2021 Jun; 10(half dozen): 763.
Investigation of Long COVID Prevalence and Its Human relationship to Epstein-Barr Virus Reactivation
Jeffrey E. Gilt
oneWorld Organization, Watkinsville, GA 30677, USA
Ramazan A. Okyay
2Department of Public Health, Kahramanmaraş Sütçü İmam University, Kahramanmaraş 46040, Turkey; moc.liamg@10mizar
David J. Hurley
4College of Veterinarian Medicine, University of Georgia, Athens, GA 30602, Us; ude.agu@yelruhjd
Lisa Gralinski, Bookish Editor
Received 2021 May 26; Accustomed 2021 Jun 12.
Abstruse
Coronavirus illness 2019 (COVID-19) patients sometimes experience long-term symptoms following resolution of acute disease, including fatigue, brain fog, and rashes. Collectively these have become known as long COVID. Our aim was to first determine long COVID prevalence in 185 randomly surveyed COVID-xix patients and, subsequently, to determine if there was an association between occurrence of long COVID symptoms and reactivation of Epstein–Barr virus (EBV) in 68 COVID-19 patients recruited from those surveyed. We institute the prevalence of long COVID symptoms to be xxx.three% (56/185), which included 4 initially asymptomatic COVID-19 patients who later developed long COVID symptoms. Next, nosotros found that 66.7% (twenty/30) of long COVID subjects versus 10% (2/twenty) of command subjects in our primary study grouping were positive for EBV reactivation based on positive titers for EBV early antigen-diffuse (EA-D) IgG or EBV viral capsid antigen (VCA) IgM. The difference was significant (p < 0.001, Fisher'southward verbal test). A similar ratio was observed in a secondary grouping of 18 subjects 21–90 days afterwards testing positive for COVID-xix, indicating reactivation may occur soon after or meantime with COVID-nineteen infection. These findings suggest that many long COVID symptoms may not be a direct effect of the SARS-CoV-two virus merely may exist the result of COVID-xix inflammation-induced EBV reactivation.
Keywords: long COVID, mail-acute COVID-19 syndrome, PACS, chronic COVID syndrome, Epstein–Barr virus reactivation, Epstein–Barr virus, EBV, SARS-CoV-two, COVID-nineteen, coronavirus
i. Introduction
It has been reported that near xxx% of coronavirus disease 2019 (COVID-nineteen) patients experience long-term symptoms following resolution of astute disease [i]. These symptoms include fatigue, brain fog, slumber difficulties, arthralgia, pharyngitis, myalgia, headaches, fever, gastrointestinal upset, and skin rashes with a multifariousness of presentations [2,3,4,v]. Long-term symptoms associated with COVID-19 are collectively known every bit long COVID. Long COVID has besides been referred to as Post-Acute COVID-19 Syndrome (PACS) or chronic COVID syndrome (CCS) [half dozen]. Long COVID has been associated with patients who have had subacute, mild, or severe COVID-19 cases [two].
Epstein–Barr virus (EBV) is a human gamma herpesvirus. It is known to have infected and by and large become latent in more than than xc% of the global population [seven], including more than 95% of salubrious adults [viii]. It is establish at high rates in every region of the earth. This is due to both its lifelong persistence in the latent country and because of its intermittent recrudescence in many latently infected individuals [nine]. Primary EBV infection is often asymptomatic when contracted in childhood. When primary infection occurs in boyhood or adulthood, however, information technology commonly results in infectious mononucleosis, an acute condition inducing massive lymphocytosis. EBV sometimes causes chronic infections or serially reactivated infections, in which it can efficiently infect both epithelial cells and B cells. EBV can likewise switch between lytic and latent phases of its life cycles in many patients [10].
EBV reactivation is nigh commonly identified in clinical practice using serological testing for the presence of EBV early antigen-diffuse (EA-D) IgG or EBV viral capsid antigen (VCA) IgM [11,12,13]. EBV VCA IgM is usually simply detectable during the acute early stage of primary or reactivated EBV infection. In contrast, EBV EA-D is more than likely to exist detected only during the afterwards chronic stage of EBV infection [xiv]. Therefore, multiple testing methods are required to accurately detect EBV reactivation.
A diverseness of clinical manifestations have been associated with EBV reactivation. These include fatigue, psychoneurosis/brain fog, sleep disturbance, arthralgia, pharyngitis, myalgia, headaches, fever, gastrointestinal complaints, and various skin rashes [xi]. We observed that many symptoms attributed to long COVID are the same as, or very similar to, those that accept been associated with EBV reactivation.
Our aim in this retrospective study was to starting time determine long COVID prevalence among COVID-xix patients surveyed and, later on, to decide if there was prove of a relationship between occurrence of long COVID symptoms and EBV reactivation amid the subjects recruited from those surveyed.
2. Results
ii.1. Long COVID Prevalence
An analysis of the 185 subjects who practical to our study, all of whom provided evidence of confirmed COVID-19 infections, revealed that 30.three% (56/185) reported unabating long COVID symptoms at least 30 days after testing positive for COVID-19. This group included 13 subjects who had initially asymptomatic COVID-19 infections, among which xxx.8% (4/thirteen) went on to develop long COVID symptoms a few weeks after testing positive for COVID-nineteen. Applicants were non aware of our intent to study long COVID. This blinding of the report subjects limited cocky-pick bias in the reporting of long COVID symptoms. The prevalence charge per unit we observed was similar to the 30% prevalence charge per unit observed in a University of Washington survey of 177 COVID-19 subjects followed for several months afterward their initial COVID-19 diagnosis [1].
two.2. Analysis of Primary (Long-Term) Study Participants
We found that 66.seven% (twenty/30) of long-term long COVID subjects versus 10% (two/20) of long-term control subjects were positive for EBV reactivation based on positive titers for EBV EA-D IgG or EBV VCA IgM. The difference in the fraction showing reactivation between the groups was found to be meaning (p < 0.001, Fisher's exact examination). Eighteen of the long-term long COVID subjects were positive for EBV EA-D IgG, ane of which was also positive for EBV VCA IgM. Two additional long-term long COVID subjects were positive for EBV VCA IgM just non EBV EA-D IgG. Notably, two long-term long COVID subjects who were positive for EBV reactivation had asymptomatic COVID-nineteen, with long COVID symptoms developing a brusk time later. The two subjects in the long-term control group positive for EBV reactivation were positive for EBV EA-D IgG only. Complete EBV antibiotic titer assessments of long-term study subjects appear in Appendix A (Table A1 and Table A2).
two.three. Analysis of Secondary (Short-Term) Study Participants
As those subjects enrolled equally participants in the chief report were at least ninety days postal service-diagnosis of COVID-nineteen, we also examined a secondary population who were between 21 to 90 days (short-term) mail service-diagnosis of COVID-19. We observed a similar level of EBV reactivation amid these short-term subjects. We found that 66.7% (6/ix) of short-term long COVID subjects showed show of EBV reactivation based on positive titers for EBV EA-D IgG or EBV VCA IgM. Among the curt-term control subjects, 11.1% (one/9) tested positive for EBV reactivation based on positive titers for EBV EA-D IgG or EBV VCA IgM. The deviation in the fraction showing evidence of reactivation betwixt the short-term long COVID and control subjects was significant (p = 0.05, Fisher'southward verbal test). Six brusk-term long COVID subjects tested positive for EBV EA-D IgG, one of whom also tested positive for EBV VCA IgM. The unmarried subject in the short-term control group indicating EBV reactivation was positive only for EBV EA-D IgG. Complete EBV antibody titer assessments of brusque-term study subjects appear in Appendix A (Tabular array A3 and Table A4).
2.4. Assessment of EBV EA-D IgG, EBV VCA IgG, and EBNA-1 IgG Titers in All Subjects
Nosotros did three analyses comparing EBV EA-D IgG, EBV VCA IgG, and EBNA-one IgG antibody titer values against the number of long COVID symptoms reported by each of the 68 subjects making up our primary and secondary study groups to come across if any significant relationships were observed. Only EBV EA-D IgG (Figure 1) demonstrated a significant human relationship with the number of reported long COVID symptoms (r = 0.34, p < 0.001). Neither EBV VCA IgG (Effigy A1) nor EBNA-ane IgG (Figure A2), shown in Appendix A, showed a statistically pregnant relationship with the number of long COVID symptoms.
The human relationship between EBV early antigen-diffuse (EA-D) IgG antibody titers and reported long COVID symptoms in the 68 subjects making up the chief and secondary groups was pregnant (r = 0.34, p < 0.001).
ii.v. About Frequently Reported Symptoms
The most frequently reported symptoms among those who were positive for EBV reactivation from both our long-term and brusk-term long COVID groups were fatigue, insomnia, headaches, myalgia, and confusion (Figure 2). Seven subjects in the long-term long COVID grouping experienced tinnitus and/or some hearing loss. Seven subjects in the long-term long COVID group and 2 subjects in the short-term long COVID group with EBV reactivation experienced frequent skin rashes (Figure 3), including 2 with COVID toes (Effigy 4), a condition associated with some COVID-xix cases [15]. No formal statistical cess of the frequency of these long COVID manifestations was attempted; our findings were observational only.
The number of subjects reporting each of xiii clinical manifestations of long COVID, equally reported by the 29 subjects from both our long-term and brusque-term long COVID groups who tested positive for Epstein–Barr virus (EBV) reactivation. The pct of subjects with EBV reactivation reporting each symptom was: fatigue 58.half-dozen%, insomnia 48.3%, headaches 44.eight%, myalgia 44.8%, confusion/brain fog 41.4%, weakness 37.9%, rash 31.0%, pharyngitis 24.1%, abdominal pain 24.i%, tinnitus 24.1%, fever over 101° F 13.8%, neck lymphadenopathy 13.viii%, and balmy-to-moderate hearing loss 6.9%.
Peel manifestations of vi long COVID subjects positive for EBV reactivation (two photos of each subject).
Ane discipline experienced COVID toes at four months and another at nine months after testing positive for Coronavirus disease 2019 (COVID-19).
3. Discussion
EBV can be serially reactivated as the issue of a variety of stressor events [16]. Stress levels take been linked to the elapsing and intensity of reactivated EBV infections and variations of the steady-state expression of latent EBV [17,18].
Chen et al. (2021) of Remnin Hospital at Wuhan University in Wuhan, Hubei province, Mainland china were the first to certificate finding EBV reactivation in COVID-19 patients during the acute stage. They found that 55.2% of hospitalized COVID-19 patients between 9 January 2020 and 29 February 2020 with serological confirmation of by EBV infection likewise tested positive for EBV VCA IgM, indicating EBV reactivation within two weeks of testing positive for SARS-CoV-2 [19].
Paolucci et al. (2020) tested 104 COVID-19 patients, 42 in an intensive care unit of measurement (ICU) and 62 in a sub-intensive care unit (SICU) in Italia and observed EBV reactivation in 95.two% (40/42) of the ICU patients and in 83.6% (51/61) of the SICU patients. They farther determined that the median EBV DNA level in ICU patients was significantly higher than that of SICU patients [twenty]. A similar study in France found testify of EBV reactivation in 82% (28/34) of COVID-19 ICU patients. Further, they found EBV reactivation to be associated with longer median ICU stays (15 days versus 8 days, p < 0.05) [21].
Lehner et al. (2020) ran EBV and cytomegalovirus (CMV) Deoxyribonucleic acid tests on COVID-19 patients in the Medical ICU at the Medical University Innsbruck, Austria and institute that 78% of the COVID-19 patients they tested with respiratory failure requiring invasive ventilation had evidence of EBV viremia [22]. Notwithstanding, CMV viremia was not institute to be any more common in COVID-19 patients than in non-COVID-nineteen patients.
While a limitation of our study is that we were not able to pinpoint the exact timing of EBV reactivation in the subjects we studied, given that nosotros found similar reactivation frequencies in both long-term and short-term long COVID subjects, this indicates a likelihood that EBV reactivation occurs early on in SARS-CoV-2 infection. Early EBV reactivation has been previously documented in several studies of COVID-19 ICU patients [twenty,21,22,23].
More than 90% of adults carry antibodies indicating past EBV infection. These infections virtually often occur from childhood through the early twenties. When primary infection occurs in the teens or later, infectious mononucleosis tin can be the clinical result. In the Us, in that location is a recognized racial disparity in the typical age of primary EBV infection. Seroprevalence of prior EBV infection in those nether age xx is much college amid Hispanic Americans (85.4%, 95% CI 83.1–87.eight%) and Non-Hispanic Blacks (83.1%, 95% CI 81.1–85.1%) than in Non-Hispanic Whites (56.9%, 95% CI 54.1–59.8%). The greatest disparity is observed through age xiv [24].
Two tests used to detect prior EBV infection in clinical practice, EBV VCA IgG and EBV nuclear antigen 1 (EBNA-1) IgG, render a positive result soon afterwards primary EBV infection and typically remain positive for life. A positive upshot for both is typically indicative of past EBV infection. A positive event for EBV VCA IgG, but not for EBNA-1 IgG, may also betoken a past EBV infection in cases where patients were immunosuppressed or when individuals never produced EBNA-ane IgG at all [25].
EBV reactivation is typically identified by testing for the presence of EBV EA-D IgG or EBV VCA IgM [11,12,13]. EBV reactivation can also identified by testing for the presence of circulating EBV Deoxyribonucleic acid utilizing a serum EBV DNA quantitative real-time polymerase chain reaction (PCR) test. EBV EA-D IgG, EBV VCA IgM, and serum EBV Deoxyribonucleic acid are often detectable at separate times during the course of primary or reactivated EBV infection (Effigy 5), requiring the employ of multiple testing methods to accurately determine if an private is positive for EBV reactivation. While EBV DNA is nigh frequently detectable during the acute early on stage of master or reactivated EBV infection, EBV Dna can too be detected at other stages of EBV infection, depending on the sensitivity of the quantitative PCR tests used [26,27], besides as the frequency of testing.
The dynamics of EBV viral capsid antigen (VCA) IgM titers, EBV early on antigen-diffuse (EA-D) IgG titers, and serum EBV Deoxyribonucleic acid over fourth dimension after EBV infection or reactivation [xiv,26,27,28].
In club to investigate how serum EBV Deoxyribonucleic acid tests may help clinicians further identify patients with EBV reactivation, nosotros utilized a commercial EBV Dna quantitative real-fourth dimension PCR exam on all long-term and short-term long COVID subjects who tested negative for both EBV EA-D IgG and EBV VCA IgM. EBV Dna testing identified two additional subjects in the long-term long COVID group showing evidence of EBV reactivation based on the presence of circulating EBV DNA (465 copies/mL and 481 copies/mL) and i additional curt-term long COVID field of study positive for EBV reactivation based on the presence of circulating EBV DNA (578 copies/mL). The commercial assay source nosotros used indicated that a minimum of 200 copies/mL constituted a positive exam. Once those positive for EBV DNA were added to the dataset of subjects already found to be positive for EBV reactivation, we plant that 73.3% (22/30) of long-term long COVID subjects and 77.8% (seven/9) of short-term long COVID subjects showed show of EBV reactivation.
EBV reactivation is known to induce a diverse set of rashes and peel lesions that include urticaria [29], granuloma annulare [thirty], folliculitis [31], cryoglobulinemia [32,33], and Raynaud'due south phenomenon [34], which resembles COVID toes [35]. 1 of the earliest documented cases of COVID toes was described in Madrid, Spain by Nirenberg et al. in April 2020 in a 16-twelvemonth-erstwhile female who had a coinfection of EBV and COVID-19 [36]. A broad variety of skin manifestations were reported by ix subjects among our study groups who tested positive for EBV reactivation, including two who experienced COVID toes: i at iv months and the other at ix months mail service-diagnosis of COVID-nineteen.
EBV has been associated with tinnitus and hearing loss [37,38]. Tinnitus is a common long COVID symptom and was reported past seven subjects in our study groups who tested positive for EBV reactivation. Mild-to-moderate hearing loss was reported by two subjects in our study groups who tested positive for EBV reactivation. Unexplained hearing loss and tinnitus tied to SARS-CoV-ii have been documented in diverse instance reports and small studies [39,40,41].
In addition to the more common manifestations described earlier, EBV reactivation has also been associated with cardiovascular, hematological, and neurological complications [42]. EBV reactivation has been reported to play a role in the pathogenesis of myocarditis [43], inflammatory cardiomyopathy [44], and acute myocardial infarction [45]. EBV-associated multisystem failure has been documented to also upshot in astute liver injury, kidney injury, respiratory failure, and hemolytic anemia in immunocompetent patients [46]. EBV is likewise associated with a number of lymphoid and epithelial tumors [47]. While rare, given that EBV reactivation has been associated with many serious clinical manifestations, further report would exist prudent to determine if whatsoever of these get more frequent in COVID-19 patients.
Currently, there are no pharmaceuticals licensed to specifically treat EBV reactivation. Some anti-DNA viral agents have been used to attempt to reduce the viral load in reactivation of herpes viruses. Some level of efficacy in the direction of EBV illness has been demonstrated when using these drugs. Extended administration of valacyclovir is known to reduce the frequency of EBV-infected B cells and has been theorized as a treatment to eradicate EBV from the torso [48]. Spironolactone has been found in vitro to inhibit EBV VCA synthesis and capsid formation [49]. Spironolactone is also being studied as a potential therapeutic for SARS-CoV-2 infection itself [50,51]. Further show that EBV may be contributing to COVID-xix disease comes from a clinical report in Wuhan. This written report showed that treatment with ganciclovir, an anti-herpesvirus drug that blocks the replication of EBV, reduced the gamble of death in patients with severe affliction [52].
An awareness of the associations between SARS-CoV-2 and EBV reactivation creates new opportunities for long COVID diagnosis, management, and possible treatments. We believe that it would be prudent to determine if patients who have tested positive for COVID-19 take evidence of EBV reactivation, whether showing classical astute disease or non. If they exercise show signs of EBV reactivation, then it would be clinically appropriate to monitor for the evolution of known EBV illness manifestations, particularly those that are shared with the long COVID complex.
Our study opens up several new avenues for future enquiry. Long COVID patients' antibiotic responses to CMV could be studied alongside EBV to make up one's mind whether CMV may also be reactivated in some cases of long COVID. Given the numerous skin manifestations observed in long COVID cases, information technology would exist interesting to investigate if EBV viral loads tin exist observed in enriched T cells in such cases. Another area for study would exist to test peripheral blood mononuclear cells (PBMCs) of long COVID patients to decide if the cellular allowed compartment or serum factors facilitate EBV reactivation.
In conclusion, our results indicate that approximately 30% of COVID-nineteen patients report long COVID-like symptoms afterward acute disease. EBV reactivation may occur soon afterward or concomitantly with COVID-19 infection, including afterward initially asymptomatic infections. The SARS-CoV-2 virus may stimulate sequalae involving other infectious agents that contribute to many long COVID symptoms. Thus, information technology is worth considering that a portion of long COVID symptoms may exist the result of COVID-19 inflammation-induced EBV reactivation.
4. Materials and Methods
4.1. Written report Blueprint
We screened 357 applicants (Figure 6) using a Health Insurance Portability and Accountability Act (HIPAA)-compliant online form under which informed consent was obtained. Equally an assurance of confidentiality, simply 1 investigator performed recruitment, data collection, and validation. Patient data was kept in a secure database that was used simply in coded grade (to remove all patient identifiers) before the analysis of the data by the inquiry team. Thus, all patient records, examination data, and the identity of the subjects submitting photos of skin manifestations were kept by a single source.
Main inclusion: subjects were included only if they provided the requested background, including documentation of their COVID-19 diagnosis, nearly often in the class of SARS-CoV-2 polymerase chain reaction (PCR) results. Secondary inclusion: subjects were included only if between the ages of 21–74, with no exclusionary wellness weather condition.
four.ii. Patient Recruitment
Subjects were chosen from applicants who responded to online advertisements seeking recovered COVID-19 patients for this study. Potential subjects were only aware that we wished to collect data related to their experience with COVID-19 disease, thus limiting self-selection bias. Each applicant was required to upload documentation of their COVID-nineteen medical history. This included copies of COVID-19 exam results and hospitalization records, also equally completing an in-depth online survey in which they provided details related to their COVID-19 symptoms and outcomes on the HIPAA-compliant class. Follow-up was washed by ane investigator to verify that each subject met the written report criteria and to let subjects demonstrating pare manifestations to provide images of such for the record and to exist kept in blinded files for evaluation past the remaining researchers. Subjects in the report were selected randomly from all who practical and were a lucifer to the criteria for any of the study groups. Applicants were excluded if nether 21 years of age, over 74 years of historic period, if they were meaning, had been given a COVID-nineteen vaccine, or had symptoms similar to long COVID prior to testing positive for COVID-nineteen. The selection process continued until 68 qualified subjects were added to the report puddle. These subjects provided serological samples at a clinical laboratory to be tested for the relevant EBV parameters. The selection of applicants and serological testing was conducted from 11 December 2020 through eleven February 2021. A small stipend to help defray costs associated with providing records and blood samples was available to subjects.
4.3. Primary and Secondary Study Groups
We divided subjects into 4 groups: two primary (long-term) study groups and ii secondary (brusk-term) study groups. The "long-term long COVID grouping" consisted of 30 subjects; all had tested positive for COVID-19 at least 90 days prior to being enrolled, and all reported one or more of the long COVID symptoms utilized for this study. The "long-term command group" consisted of xx subjects; all had tested positive for COVID-19 at least 90 days prior to enrollment, and none reported whatsoever of the long COVID symptoms we were assessing. The "brusque-term long COVID group" consisted of 9 subjects; all had tested positive for COVID-nineteen 21–90 days prior to enrollment, and all reported one or more of the long COVID symptoms utilized for this study. The "short-term control group" consisted of 9 subjects; all had tested positive for COVID-19 21–90 days prior to enrollment, and none reported whatever of the long COVID symptoms we were assessing.
Long COVID subjects were those that reported one or more of the following unabating symptoms later recovering from initial SARS-CoV-2 infection: fatigue, indisposition, headaches, myalgia, defoliation/brain fog, weakness, rash, pharyngitis, abdominal pain, tinnitus, fever over 101° F, neck lymphadenopathy, or mild-to-moderate hearing loss.
The age and the sex activity of long-term long COVID subjects versus long-term control subjects (Tabular array 1) were commensurate with each other. Additionally, the geographic distribution of participants across United States census regions (Table 2) gave us no reason to conclude that the distribution was unequal. Therefore, nosotros believe there was footling chance significant bias was introduced by the option procedure for study applicants.
Table ane
Characteristics of participants in the principal (long-term) report groups (plus–minus values are ways ± SD).
| Characteristic | Long-Term Long COVID Grouping | Long-Term Control Group |
|---|---|---|
| Mean Historic period | 43.8 ± thirteen.iv | 43.9 ± 13.7 |
| ≤40 years—no. (%) | 14 (46.seven) | 9 (45.0) |
| >twoscore years—no. (%) | 16 (53.3) | 11 (55.0) |
| Female person—no. (%) | 23 (76.7) | fourteen (lxx.0) |
| Male—no. (%) | vii (23.3) | half dozen (30.0) |
Tabular array two
Geographic distribution of participants in the primary (long-term) study groups 1.
| U.s. Census Region | Long-Term Long COVID Group | Long-Term Control Group |
|---|---|---|
| Region i: Northeast—no. | x | 4 |
| Region 2: Midwest—no. | 5 | 3 |
| Region 3: Due south—no. | 5 | half-dozen |
| Region four: West—no. | 10 | 7 |
iv.4. Assessments
All study participants volunteered to provide claret samples through a clinical reference laboratory (Quest Diagnostics, Secaucus, NJ, Usa). The samples were tested for EBV VCA IgM, EBV VCA IgG, EBNA-i IgG, and EBV EA-D IgG, as shown in Appendix A (Tabular array A1, Table A2, Table A3 and Tabular array A4). Subjects with long COVID symptoms who did not test positive for EBV VCA IgM or EBV EA-D IgG were also tested for EBV DNA with a quantitative real-time PCR test with a linear range of 200–2,000,000 copies/mL.
EBV antibodies were measured using a LIAISON® Analyzer (DiaSorin, Centralino, Italy) to measure the chemiluminescence from a commercially bachelor immunoassay (CLIA) for the qualitative determination of IgG and IgM antibodies in human serum specimens. The method for qualitative determination of specific IgG and IgM antibodies to EBV was a competitive (indirect) CLIA. The principal components of the EBV VCA IgG and EBV VCA IgM tests were magnetic particles coated with VCA p18 constructed peptide, BSA, and a phosphate buffer containing < 0.i% sodium azide. The principal components of the EBNA-i IgG tests were magnetic particles coated with EBNA-1 synthetic peptide, BSA, and a phosphate buffer containing < 0.one% sodium azide. The principal components of the EBV EA-D IgG tests were magnetic particles coated with EA-D polypeptide (obtained in East. coli by recombinant DNA technology), BSA, and a phosphate buffer containing < 0.ane% sodium azide. The EBV DNA quantitative real-time PCR exam was developed in-business firm, and its analytical performance was validated by Quest Diagnostics.
When EBV VCA IgM tin can be detected but EBNA-1 IgG cannot, this generally indicates chief EBV infection or EBV reactivation. When EBV VCA IgM and EBNA-1 IgG are both detectable, this generally indicates EBV reactivation. EBV EA-D IgG is generally simply detected in patients with either primary infection or EBV reactivation. Thus, testing for the presence of EBV VCA IgM or EBV EA-D IgG has been commonly used to detect EBV reactivation [xi,12,13]. Some reactivation cases missed by titer tests can be detected through serum testing for the presence of EBV Deoxyribonucleic acid circulating following viral release during recrudescence. In our written report, a subject field was classified every bit having EBV reactivation if they exceeded any of these threshold values: EBV VCA IgM > 39.99 U/mL, EBV EA-D IgG > ix.99 U/mL, or EBV DNA quantitative, real-time PCR > 199 copies/mL.
4.5. Review of Photographs
Subjects with peel manifestations of long COVID provided photographs of their own skin problems. The investigators participating in this written report reviewed the blinded images of skin manifestations provided by the collecting investigator to determine if they were consistent with peel manifestations that were reported in other long COVID patients and people with recurring EBV reactivation. A consensus was found that the images presented here represented lesions described for both conditions. No formal statistical assessment of these manifestations was attempted, and the data was provided descriptively.
4.6. Statistical Analysis
We used Fisher's exact exam to compare reactivation rates in the long COVID groups versus the control groups. All calculations of statistical significance and power assay related to sample size were performed using R (The R Foundation for Statistical Computing, version 4.0.3, Vienna, Republic of austria). A value of p ≤ 0.05 was considered to indicate statistical significance. We planned for a sample size of 30 in the long-term long COVID group and a sample size of 20 in the long-term control group, yielding 99% power using an expected difference of 80% versus twenty%, respectively. (Assumptions: two-sided Z-test practical to the arcsine transformation of the proportions, alpha = 0.05.) All power analyses (for sample size) and calculations of statistical significance were completed independently by statisticians Nayak Polissar, PhD and Ljubomir Miljacic, PhD, MS (Seattle, WA, Usa).
Acknowledgments
We give thanks all study subjects and gratefully acknowledge the following contributors to this work, who did not receive any specific compensation for their contributions: Lawrence Due south. Young for helpful review of the manuscript, Matthew S. Carducci and Joy B. Chastain for their helpful discussions, and John M. Keating for the editing assistance.
Appendix A. Epstein–Barr Virus Antibiotic Panel Results
Table A1
Long-Term long COVID grouping Epstein–Barr virus antibody panel results (- = negative).
| ID | EBV EA-D IgG | EBV VCA IgM | EBV VCA IgG | EBNA-ane IgG |
|---|---|---|---|---|
| 06966 | - | 81.4 | >750 | >600 |
| 13444 | 148 | - | 143 | 460 |
| 13459 | - | - | 202 | 143 |
| 15170 | - | - | >750 | 532 |
| 15366 | 10.ii | - | 401 | 576 |
| 15994 | - | - | >750 | 548 |
| 16370 | 69.7 | - | >750 | - |
| 16381 | - | - | 153 | 74.4 |
| 16968 | 22.9 | - | >750 | >600 |
| 16979 | >150 | - | >750 | 273 |
| 17050 | - | - | >750 | 351 |
| 17113 | 77.viii | 69.1 | 106 | 490 |
| 17332 | 13.4 | - | 87.two | 97.8 |
| 17706 | - | - | 31.1 | 378 |
| 35143 | 18.ane | - | 81.9 | 582 |
| 35145 | >150 | - | 620 | 196 |
| 35188 | 26.7 | - | 602 | 446 |
| 35946 | 112 | - | >750 | 384 |
| 83584 | - | 67.1 | 364 | 588 |
| 83821 | >150 | - | 153 | 21 |
| 83860 | - | - | >750 | >600 |
| 83893 | 28 | - | 179 | 207 |
| 83925 | - | - | 95 | 506 |
| 83929 | 10.9 | - | 43.4 | 24.1 |
| 83938 | 31.3 | - | 639 | 126 |
| 87629 | - | - | >750 | 251 |
| 87634 | - | - | 74.iv | >600 |
| 87987 | 17.three | - | 289 | 175 |
| 87999 | 33 | - | >750 | 474 |
| 94332 | 22.9 | - | 29.1 | 287 |
Table A2
Long-term control group Epstein–Barr virus antibody panel results (- = negative).
| ID | EBV EA-D IgG | EBV VCA IgM | EBV VCA IgG | EBNA-ane IgG |
|---|---|---|---|---|
| 13481 | - | - | 198 | 372 |
| 16169 | - | - | 134 | 149 |
| 16199 | 16.8 | - | >750 | 502 |
| 16710 | - | - | 680 | >600 |
| 16715 | - | - | 573 | 187 |
| 16721 | - | - | 125 | >600 |
| 16755 | - | - | - | - |
| 16832 | - | - | 198 | 48.7 |
| 17783 | - | - | 91.9 | >600 |
| 17804 | - | - | 302 | >600 |
| 83740 | - | - | >750 | 460 |
| 83859 | - | - | 53 | 559 |
| 83911 | - | - | >750 | 400 |
| 83924 | - | - | 74.6 | 132 |
| 83966 | - | - | >750 | 589 |
| 84549 | - | - | 129 | 434 |
| 85068 | 9.51 | - | >750 | >600 |
| 87612 | - | - | >750 | 96.6 |
| 87994 | >150 | - | >750 | >600 |
| 93070 | - | - | >750 | 238 |
Table A3
Short-term long COVID group Epstein–Barr virus antibiotic console results (- = negative).
| ID | EBV EA-D IgG | EBV VCA IgM | EBV VCA IgG | EBNA-1 IgG |
|---|---|---|---|---|
| 13963 | - | - | >750 | 421 |
| 16378 | 43.6 | - | 92.iii | 536 |
| 16555 | - | - | 271 | 26.2 |
| 16717 | 38.ii | - | 392 | - |
| 16750 | 27.iii | - | 418 | - |
| 17106 | - | - | >750 | >600 |
| 17323 | >150 | - | 186 | 170 |
| 17387 | 12.5 | 47.five | >750 | 43.vii |
| 17390 | 11.8 | - | 140 | 395 |
Tabular array A4
Short-term control group Epstein–Barr virus antibody console results (- = negative).
| ID | EBV EA-D IgG | EBV VCA IgM | EBV VCA IgG | EBNA-one IgG |
|---|---|---|---|---|
| 07506 | - | - | 221 | 214 |
| 09092 | - | - | >750 | 549 |
| 15509 | xx.9 | - | 372 | >600 |
| 16406 | - | - | >750 | - |
| 16642 | - | - | 590 | 218 |
| 16770 | - | - | 256 | >600 |
| 92742 | - | - | >750 | - |
| 93074 | - | - | 527 | >600 |
| 94266 | - | - | >750 | - |
Figure A1
The relationship between EBV VCA IgG antibody titers and reported long COVID symptoms in the 68 subjects making upwardly the primary and secondary groups was not significant (r = −0.014, p = 0.75).
Figure A2
The relationship between EBV nuclear antigen 1 (EBNA-1) IgG antibiotic titers and reported long COVID symptoms in the 68 subjects making up the master and secondary groups was not significant (r = −0.23, p = 0.09).
Author Contributions
Conceptualization, J.East.G.; methodology, J.East.G. and D.J.H.; validation, J.East.Grand., R.A.O., West.East.Fifty. and D.J.H.; formal analysis, J.Due east.Yard. and D.J.H.; investigation, J.Due east.One thousand. and D.J.H.; resources, J.Due east.K.; data curation, J.East.G. and D.J.H.; writing—original draft training, J.E.Thou. and D.J.H.; writing—review and editing, J.E.G., R.A.O., W.E.L. and D.J.H.; visualization, J.Due east.K.; supervision, D.J.H.; and project administration, J.E.Thousand. All authors have read and agreed to the published version of the manuscript.
Funding
This inquiry received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Integrity IRB (Protocol number 40005; Date of approval: 9 December 2020).
Informed Consent Statement
Informed consent was obtained from all subjects in the written report.
Conflicts of Interest
The authors declare no disharmonize of interest.
Footnotes
Publisher's Annotation: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
1. Logue J.K., Franko N.M., McCulloch D.J., McDonald D., Magedson A., Wolf C.R., Chu H.Y. Sequelae in Adults at vi Months After COVID-nineteen Infection. JAMA Netw. Open. 2021;four:e210830. doi: 10.1001/jamanetworkopen.2021.0830. [PMC gratis article] [PubMed] [CrossRef] [Google Scholar]
2. Greenhalgh T., Knight M., A'Court C., Buxton M., Husain L. Management of post-acute covid-nineteen in main intendance. BMJ. 2020;370:m3026. doi: 10.1136/bmj.m3026. [PubMed] [CrossRef] [Google Scholar]
three. Al-Jahdhami I., Al-Naamani Chiliad., Al-Mawali A. The Postal service-acute COVID-nineteen Syndrome (Long COVID) Sultanate of oman Med. J. 2021;36:e220. doi: 10.5001/omj.2021.91. [PMC gratuitous article] [PubMed] [CrossRef] [Google Scholar]
4. Garrigues E., Janvier P., Kherabi Y., Le Bot A., Hamon A., Gouze H., Doucet L., Berkani S., Oliosi Due east., Mallart Eastward., et al. Post-discharge persistent symptoms and health-related quality of life afterward hospitalization for COVID-19. J. Infect. 2020;81:e4–e6. doi: x.1016/j.jinf.2020.08.029. [PMC free commodity] [PubMed] [CrossRef] [Google Scholar]
5. Huang C., Huang L., Wang Y., Li X., Ren L., Gu X., Kang 50., Guo Fifty., Liu M., Zhou 10., et al. half dozen-month consequences of COVID-19 in patients discharged from hospital: A cohort study. Lancet. 2021;397:220–232. doi: 10.1016/S0140-6736(20)32656-8. [PMC free commodity] [PubMed] [CrossRef] [Google Scholar]
6. Callard F., Perego Due east. How and why patients fabricated Long Covid. Soc. Sci. Med. 2021;268:113426. doi: ten.1016/j.socscimed.2020.113426. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
7. Neves Yard., Marinho-Dias J., Ribeiro J., Sousa H. Epstein-Barr virus strains and variations: Geographic or disease-specific variants? J. Med. Virol. 2017;89:373–387. doi: ten.1002/jmv.24633. [PubMed] [CrossRef] [Google Scholar]
8. Kanda T., Yajima M., Ikuta M. Epstein-Barr virus strain variation and cancer. Cancer Sci. 2019;110:1132–1139. doi: 10.1111/cas.13954. [PMC costless article] [PubMed] [CrossRef] [Google Scholar]
9. Misko I.Southward., Cross S.M., Khanna R., Elliott S.L., Schmidt C., Pye South.J., Silins South.50. Crossreactive recognition of viral, self, and bacterial peptide ligands by homo course I-restricted cytotoxic T lymphocyte clonotypes: Implications for molecular mimicry in autoimmune disease. Proc. Natl. Acad. Sci. The states. 1999;96:2279–2284. doi: 10.1073/pnas.96.5.2279. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
10. Houen Thou., Trier Due north.H. Epstein-Barr Virus and Systemic Autoimmune Diseases. Front. Immunol. 2020;eleven:587380. doi: 10.3389/fimmu.2020.587380. [PMC costless article] [PubMed] [CrossRef] [Google Scholar]
11. Straus S.E., Tosato G., Armstrong Thousand., Lawley T., Preble O.T., Henle Due west., Davey R., Pearson Chiliad., Epstein J., Brus I., et al. Persisting disease and fatigue in adults with show of Epstein-Barr virus infection. Ann. Intern. Med. 1985;102:seven–16. doi: 10.7326/0003-4819-102-1-7. [PubMed] [CrossRef] [Google Scholar]
12. Stowe R.P., Pierson D.50., Feeback D.L., Barrett A.D. Stress-induced reactivation of Epstein-Barr virus in astronauts. Neuroimmunomodulation. 2000;viii:51–58. doi: 10.1159/000026453. [PubMed] [CrossRef] [Google Scholar]
thirteen. Schaade L., Kleines M., Hausler M. Application of virus-specific immunoglobulin Chiliad (IgM), IgG, and IgA antibody detection with a polyantigenic enzyme-linked immunosorbent assay for diagnosis of Epstein-Barr virus infections in babyhood. J. Clin. Microbiol. 2001;39:3902–3905. doi: 10.1128/JCM.39.11.3902-3905.2001. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
xiv. Smatti K.G., Al-Sadeq D.West., Ali N.H., Pintus G., Abou-Saleh H., Nasrallah Yard.K. Epstein-Barr Virus Epidemiology, Serology, and Genetic Variability of LMP-1 Oncogene Among Salubrious Population: An Update. Front end. Oncol. 2018;viii:211. doi: 10.3389/fonc.2018.00211. [PMC complimentary article] [PubMed] [CrossRef] [Google Scholar]
fifteen. Baeck M., Herman A. COVID toes: Where practise nosotros stand with the current show? Int. J. Infect. Dis. 2021;102:53–55. doi: 10.1016/j.ijid.2020.10.021. [PMC gratis article] [PubMed] [CrossRef] [Google Scholar]
xvi. Kasl South.V., Evans A.S., Niederman J.C. Psychosocial risk factors in the developmental of infectious mononucleosis. Psychosom. Med. 1979;41:445–466. doi: x.1097/00006842-197910000-00002. [PubMed] [CrossRef] [Google Scholar]
17. Glaser R., Rice J., Sheridan J., Fertel R., Stout J., Speicher C., Pinsky D., Kotur M., Post A., Brook M., et al. Stress-related allowed suppression: Health implications. Encephalon Behav. Immun. 1987;i:7–20. doi: x.1016/0889-1591(87)90002-X. [PubMed] [CrossRef] [Google Scholar]
18. Glaser R., Kiecolt-Glaser J. Stress-associated allowed modulation and its implications for reactivation of latent herpesviruses. Hum. Herpesvirus Infect. 1994;13:245. [Google Scholar]
xix. Chen T., Song J., Liu H., Zheng H., Chen C. Positive Epstein-Barr virus detection in coronavirus disease 2019 (COVID-xix) patients. Sci. Rep. 2021;xi:10902. doi: 10.1038/s41598-021-90351-y. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
twenty. Paolucci S., Cassaniti I., Novazzi F., Fiorina L., Piralla A., Comolli G., Bruno R., Maserati R., Gulminetti R., Novati S., et al. EBV DNA increase in COVID-19 patients with impaired lymphocyte subpopulation count. Int. J. Infect. Dis. 2020;104:315–319. doi: 10.1016/j.ijid.2020.12.051. [PMC free commodity] [PubMed] [CrossRef] [Google Scholar]
21. Simonnet A., Engelmann I., Moreau A.S., Garcia B., Six S., Kalioubie A.Due east., Robriquet L., Hober D., Jourdain Thousand. High incidence of Epstein-Barr virus, cytomegalovirus, and human-canker virus-six reactivations in critically-ill patients with Covid-nineteen. Infect. Dis. Now. 2021;51:296–299. doi: 10.1016/j.idnow.2021.01.005. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
22. Lehner One thousand.F., Klein Southward.J., Zoller H., Peer A., Bellmann R., Joannidis M. Correlation of interleukin-6 with Epstein-Barr virus levels in COVID-19. Crit. Care. 2020;24:657. doi: 10.1186/s13054-020-03384-6. [PMC free commodity] [PubMed] [CrossRef] [Google Scholar]
23. Singh V., Upadhyay P., Reddy J., Granger J. SARS-CoV-2 Respiratory Co-Infections: Incidence of Viral and Bacterial Co-Pathogens. Int. J. Infect. Dis. 2021;105:617–620. doi: ten.1016/j.ijid.2021.02.087. [PMC gratis article] [PubMed] [CrossRef] [Google Scholar]
24. Dowd J.B., Palermo T., Brite J., McDade T.West., Aiello A. Seroprevalence of Epstein-Barr virus infection in U.S. children ages 6–19, 2003–2010. PLoS ONE. 2013;8:e64921. doi: 10.1371/journal.pone.0064921. [PMC gratuitous article] [PubMed] [CrossRef] [Google Scholar]
25. Bauer Thousand. Simplicity through complexity: Immunoblot with recombinant antigens equally the new gilt standard in Epstein-Barr virus serology. Clin. Lab. 2001;47:223–230. [PubMed] [Google Scholar]
26. Lam W.K.J., Jiang P., Chan Thousand.C.A., Cheng S.H., Zhang H., Peng W., Tse O.Y.O., Tong Y.K., Gai W., Zee B.C.Y., et al. Sequencing-based counting and size profiling of plasma Epstein-Barr virus DNA heighten population screening of nasopharyngeal carcinoma. Proc. Natl. Acad. Sci. USA. 2018;115:E5115–E5124. doi: 10.1073/pnas.1804184115. [PMC gratuitous commodity] [PubMed] [CrossRef] [Google Scholar]
27. Chan K.C.A., Woo J.M.S., King A., Zee B.C.Y., Lam W.G.J., Chan S.L., Chu S.W.I., Mak C., Tse I.O.L., Leung S.Y.M., et al. Assay of Plasma Epstein-Barr Virus DNA to Screen for Nasopharyngeal Cancer. North. Engl. J. Med. 2017;377:513–522. doi: ten.1056/NEJMoa1701717. [PubMed] [CrossRef] [Google Scholar]
28. Odumade O.A., Hogquist K.A., Balfour H.H., Jr. Progress and problems in understanding and managing main Epstein-Barr virus infections. Clin. Microbiol. Rev. 2011;24:193–209. doi: 10.1128/CMR.00044-10. [PMC gratuitous article] [PubMed] [CrossRef] [Google Scholar]
29. Drago F., Herzum A., Ciccarese G., Parodi A. May syphilis protect against human papillomavirus infection? An example of heterologous immunity. G. Ital. Dermatol. Venereol. 2019;154:719–721. doi: ten.23736/S0392-0488.18.05985-0. [PubMed] [CrossRef] [Google Scholar]
thirty. Spencer S.A., Fenske North.A., Espinoza C.G., Hamill J.R., Cohen L.E., Espinoza L.R. Granuloma annulare-like eruption due to chronic Epstein-Barr virus infection. Arch. Dermatol. 1988;124:250–255. doi: 10.1001/archderm.1988.01670020068020. [PubMed] [CrossRef] [Google Scholar]
31. Goodlad J. Epstein-Barr Virus Associated Lymphoproliferative Disorders in the Peel. [(accessed on xv June 2021)]; Available online: https://bit.ly/goodladj1.
32. Fiorini Thousand.F., Sinico R.A., Winearls C., Custode P., De Giuli-Morghen C., D'Amico G. Persistent Epstein-Barr virus infection in patients with blazon II essential mixed cryoglobulinemia. Clin. Immunol. Immunopathol. 1988;47:262–269. doi: ten.1016/S0090-1229(88)80004-7. [PubMed] [CrossRef] [Google Scholar]
33. Ichinose One thousand., Origuchi T., Tashiro Northward., Kawashiri South.Y., Iwamoto N., Fujikawa K., Aramaki T., Arima K., Tamai G., Yamasaki Due south., et al. An elderly patient with chronic agile Epstein-Barr virus infection with mixed cryoglobulinemia and review of the literature. Mod. Rheumatol. 2013;23:1022–1028. doi: x.3109/s10165-012-0731-9. [PubMed] [CrossRef] [Google Scholar]
34. Rabinowitz H.M. Infectious mononucleosis presenting as Raynaud's phenomenon. J. Fam. Pract. 1989;29:311–315. [PubMed] [Google Scholar]
36. Nirenberg Grand.S., Herrera M. Foot manifestations in a patient with COVID-19 and Epstein-Barr virus: A instance study. Foot. 2020;46:101707. doi: 10.1016/j.foot.2020.101707. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
37. Arslan F., Karagz Eastward., Bekz H.South., Ceylan B., Mert A. Epstein-Barr virus-associated haemophagocytic lymphohistiocytosis presenting with acute sensorineural hearing loss: A example study and review of the literature. Infez. Med. 2017;25:277–280. [PubMed] [Google Scholar]
38. Williams Fifty.Fifty., Lowery H.West., Glaser R. Sudden hearing loss following infectious mononucleosis: Possible consequence of altered immunoregulation. Pediatrics. 1985;75:1020–1027. [PubMed] [Google Scholar]
39. Dominicus R., Liu H., Wang X. Mediastinal Emphysema, Behemothic Bulla, and Pneumothorax Adult during the Course of COVID-nineteen Pneumonia. Korean J. Radiol. 2020;21:541–544. doi: 10.3348/kjr.2020.0180. [PMC gratuitous article] [PubMed] [CrossRef] [Google Scholar]
40. Fidan Five. New type of corona virus induced acute otitis media in adult. Am. J. Otolaryngol. 2020;41:102487. doi: x.1016/j.amjoto.2020.102487. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
41. Lechien J.R., Chiesa-Estomba C.M., Place S., Van Laethem Y., Cabaraux P., Mat Q., Huet Chiliad., Plzak J., Horoi Grand., Hans S., et al. Clinical and epidemiological characteristics of 1420 European patients with balmy-to-moderate coronavirus disease 2019. J. Intern. Med. 2020;288:335–344. doi: 10.1111/joim.13089. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
42. Yang Y., Gao F. Clinical characteristics of primary and reactivated Epstein-Barr virus infection in children. J. Med. Virol. 2020;92:3709–3716. doi: 10.1002/jmv.26202. [PubMed] [CrossRef] [Google Scholar]
43. Chimenti C., Verardo R., Grande C., Francone M., Frustaci A. Infarct-like myocarditis with coronary vasculitis and aneurysm formation caused by Epstein-Barr virus infection. ESC Heart Fail. 2020;vii:938–941. doi: x.1002/ehf2.12611. [PMC costless commodity] [PubMed] [CrossRef] [Google Scholar]
44. Chimenti C., Russo A., Pieroni Chiliad., Calabrese F., Verardo R., Thiene 1000., Russo M.A., Maseri A., Frustaci A. Intramyocyte detection of Epstein-Barr virus genome by laser capture microdissection in patients with inflammatory cardiomyopathy. Apportionment. 2004;110:3534–3539. doi: 10.1161/01.CIR.0000148823.08092.0E. [PubMed] [CrossRef] [Google Scholar]
45. Binkley P.F., Cooke G.E., Lesinski A., Taylor M., Chen M., Laskowski B., Waldman Due west.J., Ariza M.Due east., Williams M.V., Jr., Knight D.A., et al. Evidence for the office of Epstein Barr Virus infections in the pathogenesis of acute coronary events. PLoS I. 2013;8:e54008. doi: 10.1371/journal.pone.0054008. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
46. Jaumally B.A., Salem A., Robinett Grand. Epstein-Barr Virus-Related Multisystem Failure in an Immunocompetent Swain. Crit. Care Med. 2018;46:323. doi: 10.1097/01.ccm.0000528689.41046.a8. [CrossRef] [Google Scholar]
47. Immature 50.S., Yap 50.F., Murray P.G. Epstein-Barr virus: More than l years quondam and still providing surprises. Nat. Rev. Cancer. 2016;16:789–802. doi: x.1038/nrc.2016.92. [PubMed] [CrossRef] [Google Scholar]
48. Hoshino Y., Katano H., Zou P., Hohman P., Marques A., Tyring South.Yard., Follmann D., Cohen J.I. Long-term administration of valacyclovir reduces the number of Epstein-Barr virus (EBV)-infected B cells but not the number of EBV Deoxyribonucleic acid copies per B cell in salubrious volunteers. J. Virol. 2009;83:11857–11861. doi: 10.1128/JVI.01005-09. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
49. Verma D., Thompson J., Swaminathan S. Spironolactone blocks Epstein-Barr virus production by inhibiting EBV SM poly peptide function. Proc. Natl. Acad. Sci. U.s.a.. 2016;113:3609–3614. doi: ten.1073/pnas.1523686113. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
fifty. Kotfis M., Lechowicz K., Drozdzal S., Niedzwiedzka-Rystwej P., Wojdacz T.Thou., Grywalska East., Biernawska J., Wisniewska M., Parczewski Grand. COVID-19-The Potential Beneficial Therapeutic Effects of Spironolactone during SARS-CoV-two Infection. Pharmaceuticals. 2021;14:71. doi: x.3390/ph14010071. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
51. Mareev Five.Y., Orlova Y.A., Plisyk A.G., Pavlikova E.P., Matskeplishvili S.T., Akopyan Z.A., Seredenina E.M., Potapenko A.V., Agapov M.A., Asratyan D.A., et al. Results of Open-Label non-Randomized Comparative Clinical Trial: "BromhexIne and Spironolactone for Coronsmall a, CyrillicvirUs Infection requiring hospiTalization (BISCUIT) Kardiologiia. 2020;threescore:four–fifteen. doi: 10.18087/cardio.2020.11.n1440. [PubMed] [CrossRef] [Google Scholar]
52. Liu J., Zhang S., Wu Z., Shang Y., Dong X., Li G., Zhang L., Chen Y., Ye X., Du H., et al. Clinical outcomes of COVID-19 in Wuhan, China: A large cohort study. Ann. Intensive Intendance. 2020;ten:99. doi: 10.1186/s13613-020-00706-three. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
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