Background: Inflammation in the initial COVID-19 episode may be associated with post-recovery mortality. The goal of this study was to determine the relationship between systemic inflammation in COVID-19 hospitalized adults and mortality after recovery from COVID-19.
Methods: An analysis of electronic health records (EHR) for patients from 1 January, 2020 through 31 December, 2021 was performed for a cohort of COVID-19 positive hospitalized adult patients. 1,207 patients were followed for 12 months post COVID-19 episode at one health system. 12-month risk of mortality associated with inflammation, C-reactive protein (CRP), was assessed in Cox regressions adjusted for age, sex, race and comorbidities. Analyses evaluated whether steroids prescribed upon discharge were associated with later mortality.
Results: Elevated CRP was associated other indicators of severity of the COVID-19 hospitalization including, supplemental oxygen and intravenous dexamethasone. Elevated CRP was associated with an increased mortality risk after recovery from COVID-19. This effect was present for both unadjusted (HR = 1.60; 95% CI 1.18, 2.17) and adjusted analyses (HR = 1.61; 95% CI 1.19, 2.20) when CRP was split into high and low groups at the median. Oral steroid prescriptions at discharge were found to be associated with a lower risk of death post-discharge (adjusted HR = 0.49; 95% CI 0.33, 0.74).
Discussion: Hyperinflammation present with severe COVID-19 is associated with an increased mortality risk after hospital discharge. Although suggestive, treatment with anti-inflammatory medications like steroids upon hospital discharge is associated with a decreased post-acute COVID-19 mortality risk.
The impact of coronavirus disease 2019 (COVID-19) has been immense. In terms of directly measured outcomes, as of February, 2022, worldwide more than 5.9 million people have died from directly linked COVID-19 episodes. More than 950,000 direct deaths from COVID-19 have been documented in the United States (1). Some evidence has suggested that some patients with COVID-19 may be at risk for developing health problems after the patient has recovered from the initial episode (2–4). Common sequelae that have been noted are fatigue, shortness-of-breath, and brain fog. Perhaps more concerningly, in addition to these symptoms, several studies have shown that following recovery from the initial COVID-19 episode, some patients are at risk for severe morbidity and mortality (5–8). Patients who have recovered from COVID-19 are at increased risk for hospitalization and death within 6–12 months after the initial episode. This morbidity and mortality is typically not listed or considered as a COVID-19 linked hospitalization or death in the medical records and thus are underreported as a post-acute COVID-19 sequelae.
The reason for this phenomenon of severe outcomes as post-acute sequelae of COVID-19 is not well understood. Early in COVID-19 episode, the disease is primarily driven by the replication of SARS-CoV-2. COVID-19 also exhibits a dysregulated immune/inflammatory response to SARS-CoV-2 that leads to tissue damage. The downstream impact of the initial COVID-19 episode is consistently higher in people with more severe acute infection (5, 6, 9). Cytokine storm, hyperinflammation, and multi-organ failure have also been indicated in patients with a severe COVID-19 episode (10). Cerebrospinal fluid samples indicate neuroinflammation during acute COVID-19 episodes (11). Moreover, even 40–60 days post-acute COVID-19 infection there is evidence of a significant remaining inflammatory response in patients (12). Thus, it could be hypothesized that the hyperinflammation that some COVID-19 patients have during the initial COVID-19 episode creates a systemic damage to multiple organ systems (13, 14). Consequently, that hyperinflammation and the corresponding systemic damage to multiple organ systems may lead to severe post-acute COVID-19 sequelae.
Following from this hyperinflammation, the use of steroids as anti-inflammatory treatments among patients with high inflammation during the initial COVID-19 episode may do more than just help in the initial episode but may act as a buffer to the downstream morbidity and mortality from the initial COVID-19 episode (14, 15).
The purpose of this study was to examine the relationship between substantial systemic inflammation, as measured by C-reactive protein (CRP), with post-acute COVID-19 sequelae among patients hospitalized with COVID-19. This 12-month mortality risk was examined in a longitudinal cohort of patients who tested positive for COVID-19 as determined by Polymerase Chain Reaction (PCR) testing within a large healthcare system.
The data for this project comes from a de-identified research databank containing electronic health records (EHR) of patients tested for or diagnosed with COVID-19 in any setting in the University of Florida (UF) Health system. Usage of the databank for research is not considered human subjects research, and IRB review was not required to conduct this study.
Definition of Cohort
The cohort for this study consisted of all adult patients aged 18 and older who were tested for COVID-19 between January 01, 2020 and December 31, 2021 within the UF Health system, in any encounter type (ambulatory, Emergency Department, inpatient, etc.). Although a patient in the cohort could have had a positive test administered in any of these settings, a patient was only included into the cohort if that patient experienced a hospitalization for COVID-19. Since this study included data from the early stages of the pandemic before consistent coding standards for documenting COVID-19 in the EHR had been established, a patient was considered to have been hospitalized for COVID-19 if they experienced any hospitalization within 30 days of a positive test for COVID-19. The databank contained EHR data for all patients in the cohort current through December 31, 2021. COVID-19 diagnosis was validated by PCR. Baseline dates for COVID-19 positive patients were established at the date of their earliest recorded PCR-confirmed positive COVID-19 test. Each patient was only included once in the analysis. For patients with multiple COVID-19 tests, if at least one test gave a positive result, the patient was classified as COVID-19 positive, and the date of their earliest positive COVID-19 test result was used as their baseline date. Patients who did not have a positive COVID-19 test were not included in the analysis. Patients were tested in the context of seeking care for COVID-19; the tests were not part of general screening and surveillance.
Only patients with at least 365 days of follow-up time after their baseline date were retained in the cohort. Patients with more than 365 days of follow-up were censored at 365 days. The cohort was also left censored at the 30-day mark post-hospital discharge to ensure that health care utilization was post-acute and not part of the initial COVID-19 episode of care (e.g., not a readmission).
C-reactive protein (CRP) was used as the measure of inflammation in this study. The UF Health laboratory measured CRP in serum using latex immunoturbidimetry assay. CRP measures were sourced from patient EHR data. The cohort was restricted to only include patients with at least one CRP measurement within their initial COVID-19 episode of care (between the date of their initial positive COVID-19 test and the left-hand censoring date). For patients with multiple measurements of CRP, the maximum value available was used.
Intravenous dexamethasone during their initial COVID-19 hospitalization was assessed. Prescriptions for oral steroids (tablets of dexamethasone) that were prescribed either at or post-hospital discharge for their initial COVID-19 episode of care were included into the analysis. Prescriptions were identified using RxNorm codes available in each patient’s EHR.
Severity of Initial COVID-19 Hospitalization
We also measured the severity of the initial episode of COVID-19 hospitalization. This severity should track with the level of inflammation in the initial COVID-19 episode. We used the National Institutes of Health’s “Therapeutic Management of Hospitalized Adults With COVID-19” disease severity levels and definitions (16). The recommendations are based on four ascending levels: hospitalized but does not require supplemental oxygen, hospitalized and requires supplemental oxygen, hospitalized and requires supplemental oxygen through a high-flow device or noninvasive ventilation, hospitalized and requires mechanical ventilation or extracorporeal membrane oxygenation. For this study, because of the general conceptual model of severity moving from no supplemental oxygen to supplemental oxygen to mechanical ventilation, we collapsed the two supplemental non-mechanical ventilation oxygen into one intermediate category of severity.
The primary outcome investigated in this study was the 365-day all-cause mortality. Mortality data was sourced both from EHR data and the Social Security Death Index (SSDI), allowing for the assessment of deaths which occurred outside of UF’s healthcare system. When conflicting dates of death were observed between the EHR and SSDI, the date recorded in the patient’s medical record was used. Patients who died within their 365-day follow-up window were censored at the date of their recorded death. The cause of death was not available in the EHR based database and was not routinely and reliably reported in either the SSDI or EHR. We were unable to estimate the cause of death.
Comorbidities and demographic variables which could potentially confound the association between inflammation represented by CRP and mortality post-acute COVID-19 were collected at baseline for each member of the cohort. Demographic variables included patient age, race, ethnicity, and sex. The Charlson Comorbidity Index was also calculated, accounting for the conditions present for each patient at their baseline. The Charlson Comorbidity Index was designed to be used to predict 1-year mortality and is a widely used measure to account for comorbidities (17).
CRP was evaluated using descriptive statistics. We performed a median split of the CRP levels and defined elevated inflammation as a CRP level at or above the median and levels below the median as low inflammation. Additionally, as a way to examine greater separation between high and low inflammation, we segmented CRP levels into tertiles and categorized elevated inflammation as the top tertile and compared it to the first tertile by chi-square tests.
CRP level was also cross classified by severity of COVID-19 hospitalization and associations between the two variables were assessed using one-way ANOVA tests.
Kaplan-Meier curves comparing the survival probabilities of the high and low inflammation groups were created and compared using a log-rank test. Hazard ratios for the risk of death for post-acute COVID-19 complications by COVID-19 status were determined using Cox proportional hazard models. We obtained hazard ratios for mortality based on tertile and median splits of CRP. These analyses were then modified to control for age, sex, race, ethnicity, and the Charlson Comorbidity Index.
Additional analyses stratified by use of steroids were performed to compare the strength of the association between inflammation and death. The proportional hazards assumption was confirmed by inspection of the Schoenfeld residual plots for each variable included in the models and testing of the time-dependent beta coefficients. Analyses were conducted using the survival package in R v4.0.5.
A total of 1,207 patients were included in the final cohort (Table 1). The characteristics of the patients are featured in Table 1. The mean CRP rises with the severity of illness in these COVID-19 inpatients. The mean CRP in the lowest severity (no supplemental oxygen) is 59.4 mg/L (SD = 61.8 mg/L), while the mean CRP in the intermediate severity group (supplemental oxygen) is 126.9 mg/L (SD = 98.6 mg/L), and the mean CRP in the highest severity group (ventilator or ECMO) is 201.2 mg/L (SD = 117.0 mg/L) (p < 0.001). Similarly, since dexamethasone is only recommended for the most severe patients with COVID-19, patients with dexamethasone had higher CRP (158.8 mg/L; SD = 114.9 mg/L) than those not on Dexamethasone (102.8 mg/L; SD = 90/8 mg/L) (p < 0.001).TABLE 1
Table 1. Characteristics of the patients in the cohort.
Figure 1 presents the Kaplan-Meier curves comparing the risk of mortality by inflammation over time. A log-rank test indicated there was a statistically significant difference in survival probabilities between the two groups (p = 0.002).FIGURE 1
Figure 1. All-cause mortality Kaplan-Meier curve comparing individuals with median or greater vs. below median C-reactive protein levels. Log rank test = p.002.
Table 2 shows the relationship between levels of inflammation and mortality post-recovery from COVID-19. In both unadjusted and adjusted analyses, elevated inflammation has a significantly increased risk compared to those with low inflammation in the initial COVID-19 episode. This finding of higher inflammation during the initial COVID-19 hospitalization and increased mortality risk after recovery was similar when CRP was split at the median and when the third tertile of CRP was compared to the first tertile of CRP. The proportional hazards assumption was met when the Schoenfeld plots.TABLE 2
Table 2. All-cause mortality hazard ratios by inflammation and steroid use.
We examined the hypothesized relationship that potentially decreasing inflammation in COVID-19 patients with an initial severe episode may have beneficial downstream effects on post-acute COVID-19 sequelae. Oral steroid prescriptions at discharge among these hospitalized COVID-19 patients were found to be associated with a lower risk of death post-discharge (Table 2).
The results of this study reaffirm the importance of post-acute COVID-19 sequelae. This study is the first to show the impact of inflammation in the initial COVID-19 hospitalization episode on downstream mortality after the patient has recovered. This expands our understanding of post-acute COVID-19 sequelae by providing a better concept of why certain patients have post-acute COVID-19 mortality risk.
Previous studies have shown that patients who are hospitalized with COVID-19 have an increased risk of mortality 12 months after recovery (5). Those findings suggest that prevention of COVID-19 hospitalizations is of paramount importance. However, some patients will be hospitalized. The finding that elevated inflammation during the initial hospitalization episode is associated with mortality risk after recovery suggests that it may be worthwhile treating the viral episode but also consider treating the hyperinflammation. The NIH recommendations for care of COVID-19 hospitalized patients recommend steroids only for patients who need supplemental oxygen (16). The finding that the use of steroids prescribed upon discharge from the hospital and the corresponding reduced risk of mortality indicate that treating inflammation after the acute COVID-19 episode may act as a buffer to the downstream mortality risk from the initial COVID-19 episode (14, 15). Perhaps this requires a reconceptualization of COVID-19 as both an acute disease and potentially a chronic disease because of the lingering risks. Future research is needed to see if ongoing treatment for inflammation in a clinical trial has positive benefits.
There are several strengths and limitations to this study. The strengths of this study include the PCR validated COVID-19 tests at baseline for the cohort. Further, the linked electronic health record allows us to look not only at health care utilization like hospitalizations and both inpatient and outpatient medication but also laboratory tests like CRP levels. The cohort also allows us to have a substantial follow-up time.
In terms of limitations, the first that needs to be considered is that the analysis was based on hospitalized patients seen in one health system with a regional catchment area. Although more than 1200 hospitalized patients with PCR validated COVID-19 diagnoses were included in the analysis, and the cohort was followed for 12 months, the primary independent variable was systemic inflammation which should not be substantially affected by region of the country. Second, the data are observational. Thus, the analyses related to steroids and downstream mortality require a clinical trial to confirm these suggestive findings. Third, we did not have death certificates available to us to compute cause of death. The Social Security Death Index in partnership with the EHR allows us to be confident that the patient died and so we have a strong measure of all-cause mortality but we were unable to determine specific causes of death within this database. Fourth, although there are a variety of other markers of inflammation (e.g., D dimer, IL 6), CRP is one of the most robust measures of systemic inflammation. Moreover, it is much more widely used and was the most prevalent marker among the patients in the study.
In conclusion, hyperinflammation present with severe COVID-19 is associated with an increased mortality risk after hospital discharge. Although suggestive, treatment with anti-inflammatory medications like steroids upon hospital discharge is associated with a decreased post-acute COVID-19 mortality risk. This suggests that treating inflammation may also benefit other post-acute sequelae like long COVID. A reconceptualization of COVID-19 as both an acute and chronic condition may be useful.
1. COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU). Available online at: https://coronavirus.jhu.edu/map.html (accessed February 28, 2022).
2. Bell ML, Catalfamo CJ, Farland LV, Ernst KC, Jacobs ET, Klimentidis YC, et al. Post-acute sequelae of COVID-19 in a non-hospitalized cohort: results from the Arizona CoVHORT. PLoS ONE. (2021) 16:e0254347. doi: 10.1371/journal.pone.0254347
3. Garrigues E, Janvier P, Kherabi Y, Le Bot A, Hamon A, Gouze H, et al. Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19. J Infect. (2020) 81:e4–6. doi: 10.1016/j.jinf.2020.08.029
4. Alkodaymi MS, Omrani OA, Fawzy NA, Shaar BA, Almamlouk R, Riaz M, et al. Prevalence of post-acute COVID-19 syndrome symptoms at different follow-up periods: a systematic review and meta-analysis. Clin Microbiol Infect. (2022). doi: 10.1016/j.cmi.2022.01.014. [Epub ahead of print].
7. Bhaskaran K, Rentsch CT, Hickman G, Hulme WJ, Schultze A, Curtis HJ, et al. Overall and cause-specific hospitalisation and death after COVID-19 hospitalisation in England: a cohort study using linked primary care, secondary care, and death registration data in the OpenSAFELY platform. PLoS Med. (2022) 19:e1003871. doi: 10.1371/journal.pmed.1003871
12. Doykov I, Hällqvist J, Gilmour KC, Grandjean L, Mills K, Heywood WE. ‘The long tail of Covid-19’ – The detection of a prolonged inflammatory response after a SARS-CoV-2 infection in asymptomatic and mildly affected patients. F1000Res. (2020) 9:1349. doi: 10.12688/f1000research.27287.1
15. Keller MJ, Kitsis EA, Arora S, Chen JT, Agarwal S, Ross MJ, et al. Effect of systemic glucocorticoids on mortality or mechanical ventilation in patients with COVID-19. J Hosp Med. (2020) 15:489–93. doi: 10.12788/jhm.3497
Long COVID continues to be a lingering problem for more and more coronavirus patients in the months following their infection. Now, a new study contends that the life-threatening inflammation many patients experience — causing long-term damage to their health — is turning COVID-19 into a chronic condition.
“When someone has a cold or even pneumonia, we usually think of the illness being over once the patient recovers. This is different from a chronic disease, like congestive heart failure or diabetes, which continue to affect patients after an acute episode. We may similarly need to start thinking of COVID-19 as having ongoing effects in many parts of the body after patients have recovered from the initial episode,” says first author Professor Arch G. Mainous III, vice chair for research in the Department of Community Health and Family Medicine at the University of Florida Gainesville, in a media release.
“Once we recognize the importance of ‘long COVID’ after seeming ‘recovery’, we need to focus on treatments to prevent later problems, such as strokes, brain dysfunction, and especially premature death.”
COVID inflammation increases risk of death one year later
The study finds COVID patients experiencing severe inflammation while in the hospital saw their risk of death skyrocket by 61 percent over the next year post-recovery.
Inflammation raising the risk of death after an illness is a seemingly confusing concept. Typically, inflammation is a natural part of the body’s immune response and healing process. However, some illnesses including COVID-19 cause this infection-fighting response to overshoot. Previous studies call this the “cytokine storm,” an event where the immune system starts attacking healthy tissue.
“COVID-19 is known to create inflammation, particularly during the first, acute episode. Our study is the first to examine the relationship between inflammation during hospitalization for COVID-19 and mortality after the patient has ‘recovered’,” Prof. Mainous says.
“Here we show that the stronger the inflammation during the initial hospitalization, the greater the probability that the patient will die within 12 months after seemingly ‘recovering’ from COVID-19.”
There is a way to stop harmful inflammation
The study examined the health records of 1,207 adults hospitalized for COVID-19 in the University of Florida health system between 2020 and 2021. Researchers followed them for at least one year after discharge — keeping track of their C-reactive protein (CRP) levels. This protein is secreted by the liver and is a common measure of systemic inflammation.
Results show patients with a more severe case of the virus and those needing oxygen or ventilation had higher CRP levels during their hospitalization. The patients with the highest CRP concentrations had a 61-percent increased risk of death over the next year after their release from the hospital.
However, the team did find that prescribing anti-inflammatory steroids after hospitalization lowered the risk of death by 51 percent. Study authors say their findings show that the current recommendations for care after a coronavirus infection need to change. Researchers recommend more widespread use of orally taken steroids following a severe case of COVID.
mRNA COVID-19 vaccines have emerged as a new form of vaccination that has proven to be highly safe and effective against COVID-19 vaccination. Rare adverse events including myocarditis have been reported in the literature.
Data were gathered from the electronic medical record of four patients personally treated by the authors.
Four patients, ages 20 to 30, presented with myocarditis characterized by chest pain, elevations in troponin-I and C-reactive protein, and negative viral serologies two to four days following mRNA vaccine administration. One had a cardiac MRI showing delayed gadolinium enhancement in a subpericardial pattern. All experienced symptom resolution by the following day, and the two who have returned for follow-up had normal troponin-I and CRP values.
Along with previously reported instances, these cases raise suspicion for a possible link between mRNA vaccines and myocarditis.
In 2020 SARS-CoV-2 spread across the globe, inducing hypoxic respiratory failure, acute respiratory distress syndrome, hypercoagulability, and severe systemic inflammation. Cardiovascular manifestations of COVID-19, the disease caused by SARS-CoV-2, include myocardial infarction, transient systolic and diastolic dysfunction, and myocarditis. Both preexisting cardiovascular disease and COVID-induced myocarditis are associated with higher mortality.
Myopericarditis refers to simultaneous myocarditis and pericarditis, inflammatory conditions of the myocardium and pericardium, respectively. Characteristic symptoms and objective findings raise suspicion for myocarditis. Symptoms include chest pain, dyspnea on exertion, palpitations, and unexplained cardiogenic shock. Objective findings include arrhythmias, conduction delays, troponin-I elevations, and functional or structural abnormalities on cardiac imaging. Often cardiac magnetic resonance imaging (CMR) demonstrates characteristic late gadolinium enhancement, supporting this diagnosis. However, definitive diagnosis requires endomyocardial biopsy, the sensitivity of which is low due to the focal and transient nature of infiltrates. Pericarditis is diagnosed by the presence of two or more of the following: pleuritic chest pain, pericardial friction rub, new pericardial effusion, and ECG changes including down-sloping PR depression and diffuse ST elevations.
In early 2020, researchers developed vaccines against SARS-CoV-2 utilizing a novel vaccination strategy of inoculating liposome-encapsulated recombinant mRNA encoding the SARS-CoV-2 spike protein. Phase 3 multicenter randomized controlled trials showed 94–95% efficacy in prevention of severe COVID-19 , . In the Moderna trial, 1.5% of vaccine recipients and 1.3% of placebo recipients reported grade 3 adverse reactions, side effects altering daily activity. Similar numbers were reported in the Pfizer trial, with 1.2% of vaccine recipients and 0.7% of placebo recipients reporting severe adverse events. In both trials the most common systemic reactions were fatigue, headache, muscle pain, and chills. These effects occurred most frequently after the second dose and in participants in the youngest age group. They resolved on average 2–3 days post-vaccine. Neither study reported major cardiovascular adverse events, including myocarditis , . Due to the efficacy and safety demonstrated in these clinical trials, the Food and Drug Administration granted emergency use authorization to both mRNA vaccines in December 2020.
2. Case 1
A 23-year-old woman presented with chest pain 5 days after receiving her second dose of the Moderna vaccine. She had an ECG (Fig. 1) with down-sloping PR depressions and diffuse ST elevations, as well as a troponin of 14,045 pg/mL and an elevated CRP (Table 1). Her troponin peaked the following day. Coxsackie, HCV, CMV, and EBV serologies were all negative. Transthoracic echocardiography (TTE) demonstrated a left ventricular ejection fraction (LVEF) of 55 to 60%, with basal inferior and basal inferolateral hypokinesis. CMR (Fig. 2, Fig. 3, Fig. 4) revealed late gadolinium enhancement involving the basal inferior, basal to mid inferolateral, mid anterolateral, apical lateral, apical septal, and apical inferior wall segments in a subepicardial distribution pattern, consistent with myocarditis. Her symptoms resolved quickly, and her CRP declined to 11 mg/L by the third day of her hospitalization. She was discharged on hospital day 3. She presented to clinic for follow-up two weeks after discharge, where her CRP had declined to 0.8 mg/L and she had no residual symptoms.
Table 1. Summary of clinical findings. All patients presented 2 to 5 days following their 2nd vaccine dose with troponin and CRP elevation, and the viral serologies that were tested were negative. ECG and TTE abnormalities may be compared as well.
Down-sloping PR depressions, diffuse ST elevations
LVEF 55–60%, basal inferior and basal inferolateral hypokinesis
Down-sloping PR depressions, diffuse ST elevations
LVEF 45%, apical septal hypokinesis
Down-sloping PR depressions, diffuse ST elevations
LVEF 55%, no regional wall motion abnormalities
T-wave inversions in lateral leads
LVEF 65–70%, no regional wall motion abnormalities
CRP: C-reactive protein.
TTE: transthoracic echocardiogram.
LVEF: left ventricular ejection fraction.a
Coxsackie virus, EBV, CMV.
3. Case 2
A 20-year-old man presented with a 2-day history of progressive chest pain, 2 days after receiving his second dose of the Moderna vaccine. His symptoms started with a viral prodrome approximately ten days prior to the onset of his chest pain. His ECG had down-sloping PR depressions and diffuse ST elevations; his troponin-I was 22,638 and CRP was markedly elevated (Table 1). Troponin-I peaked the following day. Viral serologies for HIV, hepatitis B and C viruses, coxsackie virus type b, and EBV were all undetectable. TTE revealed a LVEF of 45% with moderate hypokinesis of the apex and apical septum. Outpatient CMR remains pending. His chest pain resolved the following day. He was discharged on hospital day 3. He presented to clinic eleven days after discharge, where he his troponin had normalized to 0.03 ng/dL, and his CRP to 2.5 mg/L.
4. Case 3
A 29-year-old man presented with chest pain 4 days after receiving his second dose of the Moderna vaccine. His ECG had diffuse ST elevations with no PR depressions; initial troponin-I was 3785 pg/mL and CRP was notably elevated (Table 1). Troponin-I peaked the next day. TTE revealed and EF of 55% with no regional wall motion abnormalities. He did not undergo CMR or viral serology testing. An autoimmune workup showed an anti-nuclear antibody titer of 1:80 in a speckled pattern and negative double stranded DNA, rheumatoid factor, ribonucleic protein IgG, scleroderma-70, anti–Sjögren’s-syndrome-related antigen A, and anti-Smith autoantibodies were negative. His chest pain resolved on the first day of his hospitalization, and he was discharged the following day.
5. Case 4
A 30-year-old man presented on with chest pain 4 days after receiving his second dose of the Pfizer vaccine. ECG was notable only for T-wave inversions in the lateral leads that resolved on follow-up ECG. Troponin-I was 2447 pg/mL and CRP was notably elevated (Table 1). Troponin-I peaked the next day. EBV, CMV, and coxsackie serologies were all negative. CMR was not performed. TTE was unremarkable with normal LVEF and no regional wall motion abnormalities. His symptoms resolved on first day of hospitalization, and he was discharged on hospital day 3.
This is among the first series to report multiple cases of myocarditis in adults following vaccination against SARS-CoV-2. All four patients were young, between 20 and 30. All presented with chest pain two to five days after their second vaccine dose. All had significantly elevated troponin-I levels. Though one had a viral prodrome, all had negative serologies. None reported prior COVID-19 infection. None had stigmata of autoimmune disease, and the one who underwent a rheumatologic workup while hospitalized had unremarkable autoimmune serologies. Reassuringly, the two patients who have returned for follow up in the weeks following discharge had normalized CRP values and denied symptom recurrence.
Myocarditis is most often caused by direct viral injury or by autoimmune mechanisms but has been sporadically linked to vaccination. Over 50 cases had been reported to the Department of Defense Smallpox Vaccination Program . Myopericarditis has also been reported soon after vaccines against anthrax, haemophilus influenzae type b, hepatitis B virus, inactivated influenza, and live attenuated zoster vaccines .
Neither clinical trial reported adverse cardiac events including myocarditis , . As vaccination rates increase among younger patients, however, several cases of post-vaccine myocarditis are being reported in adolescents and young adults , , . In addition to these anecdotes, a multinational cohort study analyzed electronic health record databases and found the incidence of myocarditis and pericarditis among vaccine recipients aged 18 to 35 to be approximately 0.016% for women and 0.037% for men . The CDC has since warned clinicians to be wary of post-vaccine myocarditis in teens and young adults . It remains unclear why younger patients are more prone to develop this adverse effect. A possible explanation could be related to the stronger immune response in younger patients, which can also explain the higher prevalence of side effects to the vaccines in this patient population .
While certainly a pattern worth exploring, this case series has numerous limitations, including a small sample size, variation in workup and treatment strategies, and retrospective analysis insufficient to establish causality. Nevertheless, the odds of incidental seronegative viral myocarditis occurring in four patients presenting to a single medical center within days of vaccine administration would be long. The authors would encourage further investigation and reporting of potential cases of post-vaccine myocarditis. The authors seek not to frustrate vaccination efforts, but rather to prepare patients and providers for a rare but potential adverse effect. Furthermore, the authors hope the dramatic improvement in all four patients will reassure those who do suffer from myocarditis following vaccination.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
The authors would like to recognize Drs. R David Anderson, MD and Joshua Latner, MD who diagnosed and treated the first case.
X. Li, A. Ostropolets, R. Makadia, et al.Characterizing the incidence of adverse events of special interest for COVID-19 vaccines across eight countries: a multinational network cohort studymedRxiv (2021), 10.1101/2021.03.25.21254315[E-pub ahead of print] View PDFGoogle Scholar[
9]National Center for Immunization and Respiratory DiseasesClinical Considerations: Myocarditis and Pericarditis After Receipt of mRNA COVID-19 Vaccines Among Adolescents and Young Adults. Centers for Disease Control and Prevention(2021)28 MayGoogle Scholar[
10]J. Li, A. Hui, X. Zhang, et al.Safety and immunogenicity of the SARS-CoV-2 BNT162b1 mRNA vaccine in younger and older Chinese adults: a randomized, placebo-controlled, double-blind phase 1 studyNat. Med. (2021), 10.1038/s41591-021-01330-9Apr 22 [E-pub ahead of print]
In a retrospective study of 39 COVID-19 patients and 32 control participants in China, we collected clinical data and examined the expression of endothelial cell adhesion molecules by enzyme-linked immunosorbent assays. Serum levels of fractalkine, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and vascular adhesion protein-1 (VAP-1) were elevated in patients with mild disease, dramatically elevated in severe cases, and decreased in the convalescence phase. We conclude the increased expression of endothelial cell adhesion molecules is related to COVID-19 disease severity and may contribute to coagulation dysfunction.Keywords: COVID-19, fractalkine, endothelial cell adhesion molecules, D-dimer, coagulopathy
In December 2019, a severe public health event, manifested mainly with fever and respiratory tract symptoms, broke out in Wuhan, China, and quickly spread throughout the country and the world , which was named coronavirus disease 2019 (COVID-19) by the World Health Organization. As of 1 May 2020, more than 3 million cases have been confirmed, while more than 200 000 patients have died, and the number is continuing to increase.
COVID-19 causes a systemic inflammatory response, involving dysregulation and misexpression of many inflammatory cytokines . The recruitment and activation of inflammatory cells depend on the expression of many classes of inflammatory mediators, such as cytokines (interleukin [IL]-1, IL-6, and IL-18), chemokines (fractalkine [FKN]), and adhesion molecules (intercellular adhesion molecule 1 [ICAM-1)] and vascular cell adhesion molecule-1 [VCAM-1]) . Pathological evidence of venous thromboembolism, direct viral infection of the endothelial cells, and diffuse endothelial inflammations have been reported in recent studies [2, 3]. Therefore, it is of significance to investigate the expression of endothelial cell adhesion molecules in COVID-19.
Here, we collected clinical data and blood samples from confirmed COVID-19 patients in the Fourth People’s Hospital of Yiyang in Hunan, China, and performed enzyme-linked immunosorbent assays (ELISAs) to study the expression of inflammatory mediators and endothelial cell adhesion molecules in COVID-19 patients.Go to:
A retrospective study was conducted. From 1 February to 10 March 2020, 39 COVID-19 patients were recruited at the Infectious Disease Ward in the Fourth People’s Hospital of Yiyang, Hunan, China, and 32 uninfected participants were recruited from the physical examination center of Hunan Provincial People’s Hospital. All patients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and were hospitalized. Nine patients were diagnosed with severe pneumonia, while 30 had mild disease. Mild pneumonia was defined as positivity in quantitative reverse transcription polymerase chain reaction (qRT-PCR) tests, with typical chest tomography imaging features of viral pneumonia , while severe pneumonia was defined as mild pneumonia plus 1 of the following criteria: (1) respiratory distress with a respiratory rate ≥ 30 times per minute;
(2) oxygen saturation ≤ 93% at rest; (3) oxygenation index ≤ 300 mmHg (1 mmHg = 0.133 kPa); (4) respiratory failure requiring ventilation; (5) refractory shock; and
(6) admission to the intensive care unit for other organ failure. All patients were given interferon-α2b (5 million units twice daily, atomization inhalation) and lopinavir plus ritonavir (500 mg twice daily, orally) as antiviral therapy. All patients with severe disease received preventive anticoagulant treatment with low-molecular-weight heparin (LMWH) 5000 IU/day by subcutaneous injection for 7 days. No patients died during the observation period.
The criteria for discharge were: (1) absence of fever for at least 3 days; (2) significant improvement in both lungs on chest computed tomography (CT); (3) clinical remission of respiratory symptoms; and (4) repeated negativity in RT-PCR tests of throat swab samples at least 24 hours apart.
Clinical data were measured at enrolment. The study was approved by the Medical Ethics Review Board of Hunan Provincial People’s Hospital (No. 2020-10). All study participants provided written informed consent.
Blood samples were collected at admission from each patient in a fasting state and repeated during the convalescence period for severe cases. Serum lipids, glucose, C-reaction protein (CRP), and D-dimer were determined by conventional laboratory methods. Blood samples of control subjects were also collected and tested. The obtained blood samples were placed in tubes containing EDTA and immediately centrifuged at 1500g and stored at −80°C.
Enzyme-Linked Immunosorbent Assay
Quantitative determination of IL-18, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), FKN, VCAM-1, ICAM-1, and vascular adhesion protein-1 (VAP-1) was performed using commercially available ELISA kits (BOSTER).
Categorical variables were reported as number and percentages, and significance was detected by χ2 or Fisher exact test. The continuous variables were compared using independent group t tests and described using mean and standard deviation if normally distributed, or compared using the Mann-Whitney U test and Kruskal-Wallis H test and described using median and interquartile range (IQR) value if not. Paired comparisons of the severe group were analyzed with the Nemenyi test. Statistical analysis was performed by SPSS version 19.0. Two-sided P values < .05 were considered statistically significant.
Patient and Public Involvement
In this retrospective study, no patients were directly involved in the study design, question proposal, or the outcome measurements. No patients were asked for input concerning interpretation or recording of the results.
Demographic information is shown in Table 1. Briefly, 20 patients were male, 19 patients were female, 16 controls were male, and 16 were female, and the median ages in the control, mild, and severe groups were 52, 49, and 54 years, respectively. Nine patients had severe disease, while 30 cases had mild disease. No significant differences were found between patients with mild disease and control participants in age, smoking, cardiovascular disease (CVD), autoimmune disease, low-density lipoprotein cholesterol (LDL-C), triglycerides, total cholesterol (CHO), glucose, and D-dimer. Significant differences in D-dimer were observed between the severe disease and control participants (median, 4.49 vs 0.34, respectively; P < .05), while no significant differences in age, smoking, CVD, autoimmune disease, and the levels of triglycerides, LDL-C, CHO, and glucose were observed. Significant differences in age (median, 54 vs 49; P < .05), triglycerides (median, 0.93 vs 1.29; P < .05), D-dimer (median, 4.49 vs 0.35; P < .05), and length of stay (mean, 16.6 vs 10.6; P < .05) were observed between patients with severe and mild disease, respectively, while no significant differences in smoking, CVD, autoimmune disease, and the levels of LDL-C, CHO, and glucose were observed.
Characteristics of Study Participants
Sex, male/female, n/n
Age, y, median (25, 75 percentile)a
50 (42, 57)
52 (44, 60)
49 (25, 55)
54 (47, 75)*
Current smoker, n (%)
Cardiovascular disease, n (%)
Autoimmune disease, n (%)
LDL-C, mmol/L, median (25, 75 percentile)a
1.81 (1.53, 2.17)
1.81 (1.45, 2.03)
1.81 (1.52, 2.34)
2.11 (1.58, 2.41)
Triglycerides, mmol/L, median (25, 75 percentile)a
Expression of Inflammatory Mediators and Endothelial Cell Adhesion Molecules in COVID-19 Patients and Uninfected Participants
The serum levels of the following were higher in patients with mild disease than in control participants: FKN (median, 880.1 vs 684.6 pg/mL; P < .01); VCAM-1 (median, 3742.3 vs 891.4 pg/mL; P < .01); ICAM-1 (median, 2866.1 vs 1287.4 pg/mL; P < .01); VAP-1 (median, 16.81 vs 16.68 pg/mL; P = .41) (Figure 1A–D); CRP (median, 10.75 vs 1.59 mg/L; P < .01); IL-18 (median, 415.4 vs 276.5 pg/mL; P = .09); TNF-α (median, 257.1 vs 242.9 pg/mL; P < .01); and IFN-γ (median, 46.00 vs 42.51 pg/mL; P = .50) (Supplementary Figure 1A–D). Of these, CRP, TNF-α, FKN, VCAM-1, and ICAM-1 were significantly elevated.
Expression of endothelial cell adhesion molecules in COVID-19 patients and uninfected participants, the horizontal lines represent median with interquartile range: (A) fractalkine; (B) vascular cell adhesion molecule-1 (VCAM-1); (C) intercellular adhesion molecule 1 (ICAM-1); and (D) vascular adhesion protein-1 (VAP-1). * P < .05; ** P < .01.
The serum levels of the following were significantly higher in patients with severe disease than in control participants: FKN (median, 1457.5 vs 684.6 pg/mL; P < .01); VCAM-1 (median, 4991.3 vs 891.4 pg/mL; P < .01); ICAM-1 (median, 4498.2 vs 1287.4 pg/mL; P < .01); VAP-1 (median, 28.80 vs 16.68 pg/mL; P < .01) (Figure 1A–D); CRP (median, 43.64 vs 1.59 mg/L; P < .01); IL-18 (median, 670.7 vs 276.5 pg/mL; P < .01); TNF-α (median, 274.2 vs 242.9 pg/mL; P < .01); and IFN-γ (median, 76.50 vs 42.51 pg/mL; P < .01) (Supplementary Figure 1A–D).
The serum levels of the following were significantly higher in patients with severe disease than in patients with mild disease: FKN (median, 1457.5 vs 880.1 pg/mL; P < .01); VCAM-1 (median, 4991.3 vs 3742.3 pg/mL; P < .05); ICAM-1 (median, 4498.2 vs 2866.1 pg/mL; P < .05); VAP-1 (median, 28.80 vs 16.81 pg/mL; P < .01) (Figure 1A–D); CRP (median, 43.64 vs 10.75 mg/L; P < .01); IL-18 (median, 670.7 vs 415.4 pg/mL; P < .01); TNF-α (median, 274.2 vs 257.1 pg/mL; P < .05); and IFN-γ (median, 76.50 vs 46.00 pg/mL; P < .01) (Supplementary Figure 1A–D).
For severe cases, the serum levels of the following were lower in the convalescence phase than during the acute phase: FKN (median, 1028.2 vs 1457.5 pg/mL; P < .05); VCAM-1 (median, 3420.9 vs 4991.3 pg/mL; P < .01); ICAM-1 (median, 3046.9 vs 4498.2 pg/mL; P < .01); VAP-1 (median, 23.90 vs 28.80 pg/mL; P = .17) (Figure 1A–D); CRP (median, 10.20 vs 43.64 mg/L; P < .01); IL-18 (median, 514.6 vs 670.7 pg/mL; P < .01); TNF-α (median, 265.1 vs 274.2 pg/mL; P < .01); IFN-γ (median, 66.30 vs 76.50 pg/mL; P = .05) (Supplementary Figure 1A–D); and D-dimer (median, 0.45 vs 4.49; P < .01) (Supplementary Figure 2). Of these, IL-18, TNF-α, FKN, VCAM-1, ICAM-1, and D-dimer were significantly lower.Go to:
Three novel findings were identified in our study. First, the endothelial cell adhesion markers FKN, VCAM-1, and ICAM-1 were elevated in COVID-19 patients. Second, the severity of COVID-19 was associated with the serum levels of CRP, IL-18, TNF-α, IFN-γ, FKN, VCAM-1, ICAM-1, and VAP-1. Third, recovery from severe COVID-19 was associated with reductions in serum CRP, IL-18, TNF-α, FKN, VCAM-1, ICAM-1, and D-dimer levels.
Endothelial activation is related to severe COVID-19, and antiphospholipid antibodies, von Willebrand factor, and factor VIII may play a role in coagulopathy . Endothelial cells express angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 , and the interaction of SARS-CoV-2 and ACE2 possibly mediates endothelial activation. Endothelial cells are an essential component of the coagulation system and their integrity and functionality are critical to maintaining hemostasis, whereas endothelial cell activation or injury may result in platelet activation, thrombosis, and inflammation . Dysfunctional endothelial cells activated by proinflammatory cytokines may contribute to the pathogenesis of thrombosis by altering the expression of pro- and antithrombotic factors [8, 9].
In this cohort of COVID-19 patients, although apparent thrombosis formation was excluded by Doppler ultrasound in deep veins in the lower extremities and repeated chest CT scans, we found an interesting phenomenon in patients with severe disease, that is serum D-dimer levels were elevated during the acute phase and decreased significantly during the convalescence phase. As an indirect marker of coagulation activation, elevated D-dimer has been reported in several studies and confirmed to correlate with an increased likelihood of death in COVID-19 patients . We consider that the relationship between prethrombosis levels of D-dimer and thrombotic disease is likely partly attributable to subclinical clot formation.
Severe COVID-19 is commonly complicated by coagulopathy, while disseminated intravascular coagulation may contribute to most deaths . Anticoagulant treatment may decrease mortality due to coagulopathy . In patients with severe disease, serum FKN, ICAM-1, VCAM-1, and D-dimer levels declined significantly after antiviral and anticoagulant treatment. In addition to stimulating the immune system to suppress viral replication and clear pathogens, interferon-α also inhibits the inflammatory immune response that leads to histological damage . Hence, we speculate that the dynamic changes in these molecules resulted from the alleviation of endothelial cell injuries, the anti-inflammatory effect of medications, or recovery from COVID-19.
Limitations should be noted when interpreting the results of this study. First, the number of patients with severe disease was low, which may lead to statistical deviation. Second, due to tissue sample inaccessibility, the expression of endothelial activation molecules was not measured in tissues. Third, because we did not measure the direct biomarkers in the coagulation system, the specific disturbed pathways and mechanisms are still unknown. Fourth, due to the anti-inflammatory effect of interferon-α, the relationship between the anticoagulant effect of LMWH and the decreased expression of endothelial cell adhesion molecules in COVID-19 is still uncertain, and requires further study.
In conclusion, based on the results of this study, increased expression of endothelial cell adhesion molecules is related to COVID-19 and disease severity, and may contribute to coagulation dysfunction.
Supplementary materials are available at The Journal of Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Acknowledgments. We sincerely thank clinicians at the Forth People’s Hospital of Yiyang, Hunan, China.
Financial support. This work was supported by the Key Research and Development Program of Hunan Province (grant number 2020SK3011).
Potential conflicts of interest. All authors: No reported conflicts of interests. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.Go to:
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Coronavirus disease-19 (COVID-19) is an ongoing global pandemic caused by the “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2), which was isolated for the first time in Wuhan (China) in December 2019. Common symptoms include fever, cough, fatigue, dyspnea and hypogeusia/hyposmia. Among extrapulmonary signs associated with COVID-19, dermatological manifestations have been increasingly reported in the last few months.
The polymorphic nature of COVID-19-associated cutaneous manifestations led our group to propose a classification, which distinguishes the following six main clinical patterns: (i) urticarial rash, (ii) confluent erythematous/maculopapular/morbilliform rash, (iii) papulovesicular exanthem, (iv) chilblain-like acral pattern, (v) livedo reticularis/racemosa-like pattern, (vi) purpuric “vasculitic” pattern. This review summarizes the current knowledge on COVID-19-associated cutaneous manifestations, focusing on clinical features and therapeutic management of each category and attempting to give an overview of the hypothesized pathophysiological mechanisms of these conditions.Keywords: COVID-19, Cutaneous manifestations, SARS-CoV-2Go to:
In December 2019, a novel zoonotic RNA virus named “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2) was isolated in patients with pneumonia in Wuhan, China. Since then, the disease caused by this virus, called “coronavirus disease-19” (COVID-19), has spread throughout the world at a staggering speed becoming a pandemic emergency . Although COVID-19 is best known for causing fever and respiratory symptoms, it has been reported to be associated also with different extrapulmonary manifestations, including dermatological signs . Whilst the COVID-19-associated cutaneous manifestations have been increasingly reported, their exact incidence has yet to be estimated, their pathophysiological mechanisms are largely unknown, and the role, direct or indirect, of SARS-CoV-2 in their pathogenesis is still debated. Furthermore, evidence is accumulating that skin manifestations associated with COVID-19 are extremely polymorphic . In this regard, our group proposed the following six main clinical patterns of COVID-19-associated cutaneous manifestations in a recently published review article: (i) urticarial rash, (ii) confluent erythematous/maculopapular/morbilliform rash, (iii) papulovesicular exanthem, (iv) chilblain-like acral pattern, (v) livedo reticularis/racemosa-like pattern, (vi) purpuric “vasculitic” pattern (shown in Fig. Fig.1)1) . Other authors have attempted to bring clarity in this field, suggesting possible classifications of COVID-19-associated cutaneous manifestations [4, 5, 6]. Finally, distinguishing nosological entities “truly” associated with COVID-19 from cutaneous drug reactions or exanthems due to viruses other than SARS-CoV-2 remains a frequent open problem.
Clinical features of COVID-19-associated cutaneous manifestations.
Herein, we have striven to provide a comprehensive overview of the cutaneous manifestations associated with COVID-19 subdivided according to the classification by Marzano et al. , focusing on clinical features, histopathological features, hypothesized pathophysiological mechanisms and therapeutic management.Go to:
Clinical Features and Association with COVID-19 Severity
It is well known that urticaria and angioedema can be triggered by viral and bacterial agents, such as cytomegalovirus, herpesvirus, and Epstein-Barr virus and mycoplasma. However, establishing a cause-effect relationship may be difficult in single cases [7, 8]. Urticarial eruptions associated with COVID-19 have been first reported by Recalcati  in his cohort of hospitalized patients, accounting for 16.7% of total skin manifestations. Urticaria-like eruptions have been subsequently described in other cohort studies. Galván Casas et al.  stated that urticarial rash occurred in 19% of their cohort, tended to appear simultaneously with systemic symptoms, lasted approximately 1 week and was associated with medium-high severity of COVID-19. Moreover, itch was almost always present . Freeman et al.  found a similar prevalence of urticaria (16%) in their series of 716 cases, in which urticarial lesions predominantly involved the trunk and limbs, relatively sparing the acral sites. As shown in Table Table1,1, urticaria-like signs accounted for 11.9% of cutaneous manifestations seen in an Italian multicentric cohort study on 159 patients [unpubl. data]. Urticarial lesions associated with fever were reported to be early or even prodromal signs of COVID-19, in the absence of respiratory symptoms, in 3 patients [11, 12, 13]. Therefore, the authors of the reports suggested that isolation is needed for patients developing such skin symptoms if COVID-19 infection is suspected in order to prevent possible SARS-CoV-2 transmission [11, 12, 13]. COVID-19-related urticaria occurred also in a familial cluster, involving 2 patients belonging to a Mexican family of 5 people, all infected by SARS-CoV-2 and suffering also from anosmia, ageusia, chills and dizziness . Angioedema may accompany COVID-19-related urticaria, as evidenced by the case published in June 2020 of an elderly man presenting with urticaria, angioedema, general malaise, fatigue, fever and pharyngodynia . Urticarial vasculitis has also been described in association with COVID-19 in 2 patients .
Prevalence of different clinical patterns in the main studies on COVID-19-associated cutaneous manifestations
First author (total size of study population)
Number of patients with urticarial rash (%)
Number of patients with confluent erythematous/maculopapular/morbilliform rash (%)
Number of patients with papulo-vesicular exanthem (%)
Number of patients with chilblain-like acral pattern (%)
Number of patients with livedo reticularis/racemosa-like pattern (%)
Number of patients with purpuric “vasculitic” pattern (%)
Histopathological studies of urticarial rashes are scant. In a 60-year-old woman with persistent urticarial eruption and interstitial pneumonia who was not under any medication, Rodriguez-Jiménez et al.  found on histopathology slight vacuolar interface dermatitis with occasional necrotic keratinocytes curiously compatible with an erythema multiforme-like pattern. Amatore et al.  documented also the presence of lichenoid and vacuolar interface dermatitis, associated with mild spongiosis, dyskeratotic basal keratinocytes and superficial perivascular lymphocytic infiltrate, in a biopsy of urticarial eruption associated with COVID-19 (Fig. (Fig.22).
Histopathological features of the main cutaneous patterns associated with COVID-19. a Urticarial rash. b Confluent erythematous maculopapular/morbilliform rash. c Chilblain-like acral lesions. d Purpuric “vasculitic” pattern.
Shanshal  suggested low-dose systemic corticosteroids as a therapeutic option for COVID-19-associated urticarial rash. Indeed, the author hypothesized that low-dose systemic corticosteroids, combined with nonsedating antihistamines, can help in managing the hyperactivity of the immune system in COVID-19, not only to control urticaria, but also to improve possibly the survival rate in COVID-19.Go to:
Clinical Features and Association with COVID-19 Severity
Maculopapular eruptions accounted for 47% of all cutaneous manifestations in the cohort of Galván Casas et al. , for 44% of the skin manifestations included in the study by Freeman et al. , who further subdivided this group of cutaneous lesions into macular erythema (13%), morbilliform exanthems (22%) and papulosquamous lesions (9%), and for 30.2% of the cutaneous manifestations included in the unpublished Italian multicentric study shown in Table Table1.1. The prevalence of erythematous rash was higher in other studies, like that published by De Giorgi et al.  in May 2020, in which erythematous rashes accounted for 70% of total skin manifestations. In the series by Freeman et al. , macular erythema, morbilliform exanthems and papulosquamous lesions were predominantly localized on the trunk and limbs, being associated with pruritus in most cases. In the same series, these lesions occurred more frequently after COVID-19 systemic symptoms’ onset . The clinical picture of the eruptions belonging to this group may range from erythematous confluent rashes to maculopapular eruptions and morbilliform exanthems. Erythematous lesions may show a purpuric evolution  or coexist from the beginning with purpuric lesions . Erythematous papules may also be arranged in a morbilliform pattern . In a subanalysis of the COVID-Piel Study  on maculopapular eruptions including also purpuric, erythema multiforme-like, pityriasis rosea-like, erythema elevatum diutinum-like and perifollicular eruptions, morbilliform exanthems were the most frequent maculopapular pattern (n = 80/176, 45.5%) . This study showed that in most cases lesions were generalized, symmetrical and started on the trunk with centrifugal progression. In the same subanalysis, hospital admission due to pneumonia was very frequent (80%) in patients with a morbilliform pattern . In this group, the main differential diagnoses are represented by exanthems due to viruses other than SARS-CoV-2 and drug-induced cutaneous reactions.
Histopathology of erythematous eruptions was described by Gianotti et al. , who found vascular damage in all the 3 cases examined. A clinicopathological characterization of late-onset maculopapular eruptions related to COVID-19 was provided also by Reymundo et al. , who observed a mild superficial perivascular lymphocytic infiltrate on the histology of 4 patients. In contrast, Herrero-Moyano et al.  observed dense neutrophilic infiltrates in 8 patients with late maculopapular eruptions. The authors of the former study postulated that this discrepancy could be attributable to the history of new drug assumptions in the series of Herrero-Moyano et al.  (Fig. (Fig.22).
The management of confluent erythematous/maculopapular/morbilliform rash varies according to the severity of the clinical picture. Topical corticosteroids can be sufficient in most cases , systemic corticosteroids deserving to be administered just in more severe and widespread presentations.Go to:
Clinical Features and Association with COVID-19 Severity
COVID-19-associated papulovesicular exanthem was first extensively reported in a multicenter Italian case series of 22 patients published in April 2020 . In this article, it was originally described as “varicella-like” due to resemblance of its elementary lesions to those of varicella. However, the authors themselves underlined that the main clinical features of COVID-19-associated papulovesicular exanthem, namely trunk involvement, scattered distribution and mild/absent pruritus, differentiated it from “true” varicella. In this study, skin lesions appeared on average 3 days after systemic symptoms’ onset and healed after 8 days, without scarring sequelae . The exact prevalence of papulovesicular exanthems is variable. Indeed, in a cohort of 375 patients with COVID-19-associated cutaneous manifestations , patients with papulovesicular exanthem were 34 (9%), while they were 3 out of 52 (5.8%), 1 out of 18 (5.5%) and 2 out of 53 (4%) in the cohorts published by Askin et al. , Recalcati  and De Giorgi et al. , respectively. In the Italian multicentric study shown in Table Table1,1, papulovesicular rash accounted for 18.2% of skin manifestations. Furthermore, even if papulovesicular exanthem tends to involve more frequently the adult population, with a median age of 60 years in the study by Marzano et al. , also children may be affected . Galván Casas et al.  reported that vesicular lesions generally involved middle-aged patients, before systemic symptoms’ onset in 15% of cases, and were associated with intermediate COVID-19 severity. Fernandez-Nieto et al.  conducted a prospective study on 24 patients diagnosed with COVID-19-associated vesicular rash. In this cohort, the median age (40.5 years) was lower than that reported by Marzano et al. , and COVID-19 severity was mostly mild or intermediate, with only 1 patient requiring intensive unit care support. In our cohort of 22 patients, a patient was hospitalized in the intensive care unit and 3 patients died . Vesicular rash, which was generally pruritic, appeared after COVID-19 diagnosis in most patients (n = 19; 79.2%), with a median latency time of 14 days . Two different morphological patterns were found: a widespread polymorphic pattern, more common and consisting of small papules, vesicles and pustules of different sizes, and a localized pattern, less frequent and consisting of monomorphic lesions, usually involving the mid chest/upper abdominal region or the back .
Mahé et al.  reported on 3 patients with typical COVID-19-associated papulovesicular rash, in which the histological pattern of skin lesions showed prominent acantholysis and dyskeratosis associated with the presence of an unilocular intraepidermal vesicle in a suprabasal location. Based on these histopathological findings, the authors refused the term “varicella-like rash” and proposed a term which was more suitable in their view: “COVID-19-associated acantholytic rash.” Histopathological findings of another case of papulovesicular eruption revealed extensive epidermal necrosis with acantholysis and swelling of keratinocytes, ballooning degeneration of keratinocytes and signs of endotheliitis in the dermal vessels . Acantholysis and ballooned keratinocytes were found also by Fernandez-Nieto et al.  in 2 patients.
The differential diagnosis with infections caused by members of the Herpesviridae family has been much debated. Tammaro et al.  described the onset of numerous, isolated vesicles on the back 8 days after COVID-19 diagnosis in a Barcelonan woman and reported on 2 patients from Rome presenting with isolated, mildly pruritic erythematous-vesicular lesions on their trunk, speculating that these manifestations might be due to viruses belonging to the Herpesviridae family. On the other hand, classic herpes zoster has been reported to complicate the course of COVID-19 .
The controversy regarding the role of herpesvirus in the etiology of papulovesicular exanthems fuelled an intense scientific debate. Indeed, some authors raised the question whether papulovesicular exanthem associated with COVID-19 could be diagnosed without ruling out varicella zoster virus and herpes simplex virus with Tzanck smear or polymerase chain reaction (PCR) for the Herpesviridae family in the vesicle fluid or on the skin [36, 37]. In our opinion, even if seeking DNA of Herpesviridae family members is ideally advisable, clinical diagnosis may be reliable in most cases, and the role of herpes viruses as mere superinfection in patients with dysfunctional immune response associated with COVID-19 needs to be considered . To our knowledge, SARS-CoV-2 has not been hitherto isolated by means of reverse transcriptase PCR in the vesicle fluid of papulovesicular rash [33, 31].
No standardized treatments for COVID-19-related papulovesicular exanthem are available, also given that it is self-healing within a short time frame. Thus, a “wait-and-see” strategy may be recommended.Go to:
Chilblain-Like Acral Pattern
Clinical Features and Association with COVID-19 Severity
COVID-19-related chilblain-like acral lesions have been first described in a 13-year-old boy by Italian authors in early March . Since then, several “outbreaks” of chilblain-like acral lesions chiefly involving young adults and children from different countries worldwide have been posted on social media and published in the scientific literature [40, 41, 42, 43, 44, 45, 46]. Caucasians seem to be significantly more affected than other ethnic groups [47, 48]. Chilblain-like acral lesions were the second most frequent cutaneous manifestation (n = 46/159; 28.9%) in the multicenter Italian study shown in Table Table1.1. Different pathogenetic hypotheses, including increased interferon release induced by COVID-19 and consequent cytokine-mediated inflammatory response, have been suggested . Furthermore, virus-induced endothelial damage as well as an obliterative microangiopathy and coagulation abnormalities could be mechanisms involved in the pathogenesis of these lesions . Chilblain-like acral lesions associated with COVID-19 were depicted as erythematous-violaceous patches or plaques predominantly involving the feet and, to a lesser extent, hands [40, 51]. Rare cases of chilblain-like lesions involving other acral sites, such as the auricular region, were also reported . The occurrence of blistering lesions varied according to the case series analyzed; Piccolo et al. , indeed, reported the presence of blistering lesions in 23 out of 54 patients, while other authors did not describe bullous lesions in their series [40, 47]. Dermoscopy of these lesions revealed the presence of an indicative pattern represented by a red background area with purpuric globules . Pain/burning sensation as well as pruritus were commonly reported symptoms, even if a small proportion of patients presented with asymptomatic lesions [40, 44, 47]. Unlike other COVID-19-related cutaneous findings, chilblain-like acral lesions tended to mostly involve patients without systemic symptoms.
The frequent occurrence of chilblain-like lesions in the absence of cold exposure and the involvement of patients without evident COVID-19-related symptoms raised the question whether these manifestations were actually associated with SARS-CoV-2 infection.
Histopathological and Pathophysiological Findings
Chilblain-like lesions share many histopathological features with idiopathic and autoimmunity-related chilblains, including epidermal necrotic keratinocytes, dermal edema, perivascular and perieccrine sweat gland lymphocytic inflammation. Vascular changes such as endotheliitis and microthrombi may be found [40, 45, 54, 55] (Fig. (Fig.22).
Data on the real association between chilblain-like acral lesions and COVID-19 are controversial.
The first case series failed to perform SARS-CoV-2 testing in all patients, also due to logistic problems and economic restrictions, and diagnosed COVID-19 only in a minority of patients with chilblain-like acral lesions [40, 44, 47]. Subsequently, some authors systematically sought SARS-CoV-2 with serology and/or nasopharyngeal swab in patients with chilblain-like acral lesions. In their cohort of 38 children with pseudo-chilblain, Caselli et al.  showed no evidence of SARS-CoV-2 infection by PCR or serology. Chilblain-like acral lesions appeared not to be directly associated with COVID-19 also in the case series by Herman et al. . These authors failed to detect SARS-CoV-2 in nasopharyngeal swabs and skin biopsies and demonstrated no specific anti-SARS-CoV-2 immunoglobulin IgM or IgG antibodies in blood samples. Therefore, they concluded that lifestyle changes associated with lockdown measures might be a possible explanation for these lesions . Similar results were obtained also by other authors [58, 59, 60, 61, 62, 63] weakening the hypothesis of a direct etiological link between SARS-CoV-2 and chilblain-like acral lesions.
Opposite conclusions have been drawn by Colmenero et al. , who demonstrated by immunohistochemistry and electron microscopy the presence of SARS-CoV-2 in endothelial cells of skin biopsies of 7 children with chilblain-like acral lesions, suggesting that virus-induced vascular damage and secondary ischemia could explain the pathophysiology of these lesions.
In the absence of definitive data on chilblain-like acral lesions’ pathogenesis, the occurrence of such lesions should prompt self-isolation and confirmatory testing for SARS-CoV-2 infection .
In the absence of significant therapeutic options for chilblain-like acral lesions associated with COVID-19 and given their tendency to spontaneously heal, a “wait-and-see” strategy may be suggested.Go to:
Livedo Reticularis/Racemosa-Like Pattern
Clinical Features and Association with COVID-19 Severity
Livedo describes a reticulate pattern of slow blood flow, with consequent desaturation of blood and bluish cutaneous discoloration. It has been divided into: (i) livedo reticularis, which develops as tight, symmetrical, lace-like, dusky patches forming complete rings surrounding a pale center, generally associated with cold-induced cutaneous vasoconstriction or vascular flow disturbances such as seen in polycythemia and (ii) livedo racemosa, characterized by larger, irregular and asymmetrical rings than seen in livedo reticularis, more frequently associated with focal impairment of blood flow, as it can be seen in Sneddon’s syndrome .
In our classification, the livedo reticularis/racemosa-like pattern has been distinguished by the purpuric “vasculitic” pattern because the former likely recognizes a occlusive/microthrombotic vasculopathic etiology, while the latter can be more likely considered the expression of a “true” vasculitic process . Instead, the classification by Galván Casas et al.  merged these two patterns into the category “livedo/necrosis”.
In a French study on vascular lesions associated with COVID-19, livedo was observed in 1 out of 7 patients . In the large cases series of 716 patients by Freeman et al. , livedo reticularis-like lesions, retiform purpura and livedo racemosa-like lesions accounted for 3.5, 2.6 and 0.6% of all cutaneous manifestations, respectively. In the multicentric Italian study, livedo reticularis/racemosa-like lesions accounted for 2.5% of cutaneous manifestations (Table (Table11).
The pathogenic mechanisms at the basis of small blood vessel occlusion are yet unknown, even if neurogenic, microthrombotic or immune complex-mediated etiologies have been postulated .
Livedo reticularis-like lesions are frequently mild, transient and not associated with thromboembolic complications [68, 69]. On the contrary, livedo racemosa-like lesions and retiform purpura have often been described in patients with severe coagulopathy [60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72].
Histopathological and Pathophysiological Findings
The histopathology of livedoid lesions associated with COVID-19 has been described by Magro et al. , who observed in 3 patients pauci-inflammatory microthrombotic vasculopathy. The same group demonstrated that in the thrombotic retiform purpura of patients with severe COVID-19, the vascular thrombosis in the skin and internal organs is associated with a minimal interferon response permitting increased viral replication with release of viral proteins that localize to the endothelium inducing widespread complement activation , which is frequent in COVID-19 patients and probably involved in the pathophysiology of its clinical complications .
In view of the absence of significant therapeutic options for livedo reticularis/racemosa-like lesions associated with COVID-19, a “wait-and-see” strategy may be suggested.Go to:
Purpuric “Vasculitic” Pattern
Clinical Features and Association with COVID-19 Severity
The first COVID-19-associated cutaneous manifestation with purpuric features was reported by Joob et al. , who described a petechial rash misdiagnosed as dengue in a COVID-19 patient. Purpuric lesions have been suggested to occur more frequently in elderly patients with severe COVID-19, likely representing the cutaneous manifestations associated with the highest rate of COVID-19-related mortality . This hypothesis is corroborated by the unfavorable prognosis observed in several cases reported in the literature [77, 78].
The purpuric pattern reflects the presence of vasculitic changes probably due to the direct damage of endothelial cells by the virus or dysregulated host inflammatory responses induced by COVID-19.
These lesions are likely to be very rare, representing 8.2% of skin manifestations included in the Italian multicentric study shown in Table Table1.1. In their case series of 7 patients with vascular skin lesions related to COVID-19, Bouaziz et al.  reported 2 patients with purpuric lesions with (n = 1) and without (n = 1) necrosis. In the series by Freeman et al. , 12/716 (1.8%) and 11/716 (1.6%) cases of patients with palpable purpura and dengue-like eruption, respectively, have been reported. Galván Casas et al.  reported 21 patients with “livedo/necrosis,” most of whom presenting cutaneous signs in concomitance with systemic symptoms’ onset.
Purpuric lesions may be generalized , localized in the intertriginous regions  or arranged in an acral distribution . Vasculitic lesions may evolve into hemorrhagic blisters . In most severe cases, extensive acute necrosis and association with severe coagulopathy may be seen . Dermoscopy of purpuric lesions revealed the presence of papules with incomplete violaceous rim and a central yellow globule .
When performed, histopathology of skin lesions showed leukocytoclastic vasculitis [77, 79], severe neutrophilic infiltrate within the small vessel walls and in their proximity , intense lymphocytic perivascular infiltrates , presence of fibrin [79, 81] and endothelial swelling  (Fig. (Fig.22).
Topical corticosteroids have been successfully used for treating mild cases of purpuric lesions . Cases with necrotic-ulcerative lesions and widespread presentation may be treated with systemic corticosteroids.Go to:
Other COVID-19-Associated Cutaneous Manifestations
Other peculiar rare COVID-19-related cutaneous manifestations that cannot be pigeonholed in the classification proposed by our group  include, among others, the erythema multiforme-like eruption , pityriasis rosea-like rash , multi-system inflammatory syndrome in children , anagen effluvium  and a pseudoherpetic variant of Grover disease . However, the spectrum of possible COVID-19-associated skin manifestations is likely to be still incomplete, and it is expected that new entities associated with this infection will be described.Go to:
COVID-19-associated cutaneous manifestations have been increasingly reported in the last few months, garnering attention both from the international scientific community and from the media. A few months after the outbreak of the pandemic, many narrative and systematic reviews concerning the dermatological manifestations of COVID-19 have been published [2, 3, 6, 88, 89, 90, 91]. A summary of clinical features, histopathological findings, severity of COVID-19 systemic symptoms and therapeutic options of COVID-19-related skin manifestations has been provided in Table Table22.
Summary of clinical features, histopathological findings, severity of COVID-19 systemic symptoms and therapeutic options of COVID-19-related skin manifestations
Itching urticarial rash predominantly involving the trunk and limbs; angioedema may also rarely occur
Vacuolar interface dermatitis associated with superficial perivascular lymphocytic infiltrate
Low-dose systemic corticosteroids combined with nonsedating antihistamines
Topical corticosteroids for mild cases; systemic corticosteroids for severe cases
(i) Widespread polymorphic pattern consisting of small papules, vesicles and pustules of different sizes; (ii) localized pattern consisting of papulovesicular lesions, usually involving the mid chest/upper abdominal region or the back
Prominent acantholysis and dyskeratosis associated with unilocular intraepidermal vesicles in a suprabasal location
Wait and see
Chilblain-like acral pattern
Erythematous-violaceous patches or plaques predominantly involving the feet or, to a lesser extent, hands. Pain/burning sensation as well as pruritus were commonly reported symptoms
Perivascular and periadnexal dermal lymphocytic infiltrates
Wait and see
Livedo reticularis/racemosa-like pattern
Livedo reticularis-like lesions: mild, transient, symmetrical, lace-like, dusky patches forming complete rings surrounding a pale center. Livedo racemosa-like lesions: large, irregular and asymmetrical violaceous annular lesions frequently described in patients with severe coagulopathy
Livedo reticularis-like lesions: intermediate severity; livedo racemosa-like lesions: high severity
Pauci-inflammatory microthrombotic vasculopathy
Wait and see
Purpuric “vasculitic” pattern
Purpuric lesions may be generalized, arranged in an acral distribution or localized in the intertriginous regions. Purpuric elements may evolve into hemorrhagic blisters, possibly leading to necrotic-ulcerative lesions
Leukocytoclastic vasculitis, severe perivascular neutrophilic and lymphocytic infiltrate, presence of fibrin and endothelial swelling
Topical corticosteroids for mild cases; systemic corticosteroids for severe cases
The correlation between severity of COVID-19 systemic symptoms and skin manifestations has been inferred mainly from the study by Freeman et al. .
Albeit several hypotheses on pathophysiological mechanisms at the basis of these skin findings are present in the literature [50, 92, 93], none of them is substantiated by strong evidence, and this field needs to be largely elucidated. Moreover, cutaneous eruptions due to viruses other than SARS-CoV-2 [35, 37] or drugs prescribed for the management of this infection [94, 95] always need to be ruled out.
Experimental pathophysiological studies and clinical data derived from large case series are still needed for shedding light onto this novel, underexplored and fascinating topic.
Although COVID-19-associated cutaneous manifestations have been increasingly reported, their pathophysiological mechanisms need to be extensively explored. The conditions may be distinguished in six clinical phenotypes, each showing different histopathological patterns.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.:
This paper did not receive any funding.
Giovanni Genovese wrote the paper with the contribution of Chiara Moltrasio. Angelo Valerio Marzano and Emilio Berti supervised the work and revised the paper for critical revision of important intellectual content.Go to:
We would like to thank Dr. Cosimo Misciali, Dr. Paolo Sena and Prof. Pietro Quaglino for kindly providing us with histopathological pictures.Go to:
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The coronavirus disease 2019 (COVID -19) pandemic caused by the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has affected almost every country in the world, resulting in severe morbidity, mortality and economic hardship, and altering the landscape of healthcare forever. Although primarily a pulmonary illness, it can affect multiple organ systems throughout the body, sometimes with devastating complications and long-term sequelae. As we move into the second year of this pandemic, a better understanding of the pathophysiology of the virus and the varied imaging findings of COVID-19 in the involved organs is crucial to better manage this complex multi-organ disease and to help improve overall survival. This manuscript provides a comprehensive overview of the pathophysiology of the virus along with a detailed and systematic imaging review of the extra-thoracic manifestation of COVID-19 with the exception of unique cardiothoracic features associated with multisystem inflammatory syndrome in children (MIS-C). In Part I, extra-thoracic manifestations of COVID-19 in the abdomen in adults and features of MIS-C will be reviewed. In Part II, manifestations of COVID-19 in the musculoskeletal, central nervous and vascular systems will be reviewed.
The coronavirus 2019 disease (COVID-19), which originated in Wuhan, China, has quickly become a global pandemic, bringing normal life to a standstill in almost all countries around the world. The severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a novel virus preceded by two other recent coronavirus infections, the severe acute respiratory syndrome coronavirus (SARS-CoV-1) and the Middle Eastern respiratory syndrome coronavirus (MERS–CoV), but it has more far-reaching and devastating consequences. As of March 2021, the COVID-19 pandemic has resulted in over 29 million cases in the United States and over 121 million cases globally. As of April 2021, it is responsible for the deaths of over half a million people in the United States and more than 2 ½ million worldwide . As the disease has evolved over the past year, so has our understanding of the virus, including its pathophysiology, clinical presentation and imaging manifestations. Although COVID-19 is predominately a pulmonary illness, it is now established to have widespread extra-pulmonary involvement affecting multiple organ systems. The SARS-CoV-2 has a highly virulent spike protein which binds efficiently to the angiotensin converting enzyme 2 (ACE2) receptors which are expressed in many organs, including the airways, lung parenchyma, several organs in the abdomen, particularly the kidneys and GI system, central nervous system and the smooth and skeletal muscles of the body . The virus initially induces a specific adaptive immune response, and when this response is ineffective, it results in uncontrolled inflammation, which ultimately results in tissue injury .
This article provides a comprehensive review of the pathophysiology and imaging findings of the extra-thoracic manifestations of COVID-19 with the exception of unique cardiothoracic features associated with multisystem inflammatory syndrome in children (MIS-C). In Part I, extra-thoracic manifestations of COVID-19 in the abdomen in adults and the varying features of multisystem inflammatory syndrome in children will be reviewed, with imaging findings summarized in Table 1, Table 2 . In Part II, manifestations of COVID-19 in the musculoskeletal system, the central nervous system and central and peripheral vascular systems will be reviewed.
Summary of abdominal imaging findings in COVID-19 in adults.
• Increased or coarsened echogenicity on US
• Hypoattenuation on non-contrast or contrast enhanced CT
• Periportal edema and heterogeneous enhancement on CT
• Loss of signal on opposed-phase sequences on MRI
• Portal vein thrombus
• Features of acute interstitial pancreatitis
• Biliary ductal dilatation
• Increased or heterogeneous parenchymal echogenicity on US
• Loss of corticomedullary differentiation on US
• Preserved cortical thickness
• Perinephric fat stranding and thickening of Gerota’s fascia on CT
• Wedge shaped perfusion defects on CT or MRI
• Thrombus in the renal artery or vein
• Mural edema
• Acalculous cholecystitis
• Bladder wall thickening
• Mural hyperenhancement
• Perivesicular stranding
• Mural thickening
• Fluid-filled colon
• Pneumatosis intestinalis
• Portal vein gas
• Acute mesenteric ischemia
• Vascular occlusion (superior mesenteric artery, superior mesenteric vein, or portal vein)
• Mesenteric fat stranding, ascites
• Active gastrointestinal bleeding (duodenal or gastric ulcer) on CTA
Varying derangements of the liver, biliary system, gallbladder, portal vein and pancreas may occur in COVID-19 with hepatic parenchymal injury and biliary stasis reported with highest frequency. The mechanism of involvement of these structures appears to be multifactorial. The most direct form of injury results from SARS CoV-2 entry into host cells by binding to ACE2 receptors detected in several locations in the hepatobiliary system, including biliary epithelial cells (cholangiocytes), gallbladder endothelial cells and both pancreatic islet cells and exocrine glands [, , , ].
2.1.1. Hepatic injury
Direct SARS CoV-2 entry into cholangiocytes may cause liver damage by disrupting bile acid transportation or by triggering acid accumulation resulting in liver injury . Systemic inflammation, hypoxia inducing hepatitis and adverse drug reactions may incite liver injury . Several drugs commonly used to treat COVID-19 patients, including acetaminophen, lopinavir and ritonavir can be hepatotoxic . One study excluding COVID-19 patients receiving hepatotoxic drugs, still found patients with liver injury. Therefore, liver damage in COVID-19 patients is likely not entirely drug-induced but may also be due to acute infection [8,9]. Furthermore, since patients with chronic liver disease such as cirrhosis, autoimmune liver disease and prior liver transplantation are more susceptible to COVID-19 infection , underlying conditions may also contribute to liver injury.
The most frequent hepatic derangement is abnormal liver function tests reported in 16–53% of patients [10,11] and including raised levels of alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transferase with mild elevation of bilirubin. The majority of cases are mild and self-limited, with severe liver damage rare . Liver injury is most prevalent in the second week of COVID-19 infection, and has a higher incidence in those with gastrointestinal symptoms and more severe infection . Based on a meta-analysis of hepatic autopsy findings of deceased COVID-19 patients in 7 countries, hepatic steatosis (55%), hepatic sinus congestion (35%) and vascular thrombosis (29%) were the most common . In a retrospective study of abdominal imaging findings of 37 COVID-19 patients, 27% who underwent ultrasound had increased hepatic echogenicity considered to represent fatty liver with elevated liver enzymes being the most frequent indication for ultrasound . It should be noted that since obesity is a major risk factor for severe COVID-19 infection, it might contribute to the frequency of steatosis identified on imaging. In another retrospective abdominal sonographic study of 30 ICU patients with COVID-19, the most common finding was hepatomegaly (56%), with most cases having increased hepatic echogenicity and elevated liver function tests . In the only retrospective case-control study of 204 COVID-19 patients who underwent non-contrast chest CT scan, steatosis was found in 31.9% of cases and only 7.1% of controls . Steatosis was based on a single ROI measurement in the right lobe with an attenuation value ≤ 40 HU. However, underlying risk factors for steatosis such as diabetes, obesity, hypertension and abnormal lipid profile, were not available to exclude preexisting conditions leading to steatosis. Finally, unlike in the spleen and kidney where infarcts are reported in COVID-19, hepatic infarction is not a distinct feature. This is likely due to the liver’s unique dual blood supply.
On imaging the liver may be enlarged. On ultrasound, the liver of patients with abnormal liver function tests may be coarsened and/or increased in echogenicity (Fig. 1, Fig. 2 ). On CT scan, the liver may be hypoattenuated on non-contrast or contrast-enhanced exam due to steatosis (Fig. 3 ). Periportal edema and heterogeneity of hepatic enhancement may be seen on contrast-enhanced CT or MRI due to parenchymal inflammation. On MRI, loss of signal on opposed-phase sequences (Fig. 4 ) may be seen due to steatosis and periportal edema may be conspicuous on T2-weighted images or on contrast-enhanced images [7,8,14]. Periportal lymphadenopathy, typical of chronic liver disease, is not reported in COVID-19 . In patients with severe COVID-19 infection, ancillary manifestations of hepatic inflammation and injury, such as parenchymal attenuation changes and abscesses may be seen (Fig. 5 ).
This Article Presents a Detailed Overview with Imaging. To View the Rest of This Analysis Click Here:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged as a highly virulent respiratory pathogen that is known as the causative agent of coronavirus disease 2019 (COVID-19). Diarrhea is a common early symptom in a significant proportion of patients with SARS-CoV-2 infection. SARS-CoV-2 can infect and replicate in esophageal cells and enterocytes, leading to direct damage to the intestinal epithelium. The infection decreases the level of angiotensin-converting enzyme 2 receptors, thereby altering the composition of the gut microbiota. SARS-CoV-2 elicits a cytokine storm, which contributes to gastrointestinal inflammation. The direct cytopathic effects of SARS-CoV-2, gut dysbiosis, and aberrant immune response result in increased intestinal permeability, which may exacerbate existing symptoms and worsen the prognosis. By exploring the elements of pathogenesis, several therapeutic options have emerged for the treatment of COVID-19 patients, such as biologics and biotherapeutic agents. However, the presence of SARS-CoV-2 in the feces may facilitate the spread of COVID-19 through fecal-oral transmission and contaminate the environment. Thus gastrointestinal SARS-CoV-2 infection has important epidemiological significance. The development of new therapeutic and preventive options is necessary to treat and restrict the spread of this severe and widespread infection more effectively. Therefore, we summarize the key elements involved in the pathogenesis and the epidemiology of COVID-19-associated diarrhea.
Authors: Lena F. Schimkea,5, Alexandre H.C. Marquesa, Gabriela Crispim Baiocchia, Caroline Aliane de Souza Pradob Dennyson Leandro M. Fonsecab , Paula Paccielli Freirea , Desirée Rodrigues Plaçab , Igor Salerno Filgueirasa ,Ranieri Coelho Salgadoa, Gabriel Jansen-Marquesc, Antonio Edson Rocha liveirab , Jean PierreSchatzmann Perona, José Alexandre Marzagão Barbutoa,d, Niels Olsen Saraiva Camaraa , Vera Lúcia Garcia Calicha , Hans D. Ochse, Antonio Condino-Netoa, Katherine A. Overmyerf,g, Joshua J. Coonh,i, JosephBalnisj,k, Ariel Jaitovichj,k, Jonas Schulte-Schreppingl, Thomas Ulasm, Joachim L. Schultzel,m, Helder I.Nakayab, Igor Jurisican,o,p, Otavio Cabral-Marquesa,b,q
ABSTRACT Clinical and hyperinflammatory overlap between COVID-19 and hemophagocytic lymphohistiocytosis (HLH) has been reported. However, the underlying mechanisms are unclear. Here we show that COVID-19 and HLH have an overlap of signaling pathways and gene signatures commonly dysregulated, which were defined by investigating the transcriptomes of 1253 subjects (controls, COVID-19, and HLH patients) using microarray, bulk RNA-sequencing (RNAseq), and single-cell RNAseq (scRNAseq). COVID-19 and HLH share pathways involved in cytokine and chemokine signaling as well as neutrophil-mediated immune responses that associate with COVID-19 severity. These genes are dysregulated at protein level across several COVID-19 studies and form an interconnected network with differentially expressed plasma proteins which converge to neutrophil hyperactivation in COVID-19 patients admitted to the intensive care unit. scRNAseq analysis indicated that these genes are specifically upregulated across different leukocyte populations, including lymphocyte subsets and immature neutrophils.
Artificial intelligence modeling confirmed the strong association of these genes with COVID-19 severity. Thus, our work indicates putative therapeutic pathways for intervention.
INTRODUCTION More than one year of Coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome Coronavirus (SARS-CoV)-2, more than 197 million cases and 4,2 million deaths have been reported worldwide (July 30th 2021, WHO COVID-19 Dashboard). The clinical presentation ranges from asymptomatic to severe disease manifesting as pneumonia, acute respiratory distress syndrome (ARDS), and a life-threatening hyperinflammatory syndrome associated with excessive cytokine release (hypercytokinaemia)1–3 . Risk factors for severe manifestation and higher mortality include old age as well as hypertension, obesity, and diabetes4. Currently, COVID-19 continues to spread, new variants of SARS-CoV-2 have been reported and the number of infections resulting in death of young individuals with no comorbidities has increased the mortality rates among the young population 5,6. In addition, some novel SARS-CoV-2 variants of concern appear to escape neutralization by vaccine-induced humoral immunity7 . Thus, the need for a better understanding of the immunopathologic mechanisms associated with severe SARS-CoV-2 infection.
Patients with severe COVID-19 have systemically dysregulated innate and adaptive immune responses, which are reflected in elevated plasma levels of numerous cytokines and chemokines including granulocyte colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF), interleukin (IL)-6, IL-6R, IL18, CC chemokine ligand 2 (CCL2) and CXC chemokine ligand 10 (CXCL10)8–10 , and hyperactivation of lymphoid and myeloid cells11. Notably, the hyperinflammation in COVID-19 shares similarities with cytokine storm syndromes such as those triggered by sepsis, autoinflammatory disorders, metabolic conditions and malignancies12–14 ,often resembling a hematopathologic condition called hemophagocytic lymphohistiocytosis (HLH)15. HLH is a life-threatening progressive systemic hyperinflammatory disorder characterized by multi-organ involvement, fever flares, hepatosplenomegaly, and cytopenia due to hemophagocytic activity in the bone marrow15–17 or within peripheral lymphoid organs such as pulmonary lymph nodes and spleen. HLH is marked by aberrant activation of B and T lymphocytes and monocytes/macrophages, coagulopathy, hypotension, and ARDS. Recently, neutrophil hyperactivation has been shown to also play a critical role in HLH development18,19. This is in agreement with the observation that the HLH-like phenotype observed in severe COVID-19 patients is due to an innate neutrophilic hyperinflammatory response associated with available under aCC-BY-NC-ND 4.0 International license. (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
It is made bioRxiv preprint doi: ttps://doi.org/10.1101/2021.07.30.454529; this version posted August 1, 2021. The copyright holder for this preprint virus-induced hypercytokinaemia which is dominant in patients with an unfavorable clinical course17 . Thus, HLH has been proposed as an underlying etiologic factor of severe COVID191,3,20. HLH usually develops during the acute phase of COVID-191,20–27 . However, a case of HLH that occurred two weeks after recovery from COVID-19 has recently been reported as the cause of death during post-acute COVID-19 syndrome28 . The familial form of HLH (fHLH) is caused by inborn errors of immunity (IEI) in different genes encoding proteins involved in granule-dependent cytotoxic activity of leukocytes such as AP3B1, LYST, PRF1, RAB27A, STXBP2, STX11, UNC13D29–31. In contrast, the secondary form (sHLH) usually manifests in adults following a viral infection (e.g., adenovirus, EBV, enterovirus, hepatitis viruses, parvovirus B19, and HIV)32,33, or in association with autoimmune /rheumatologic, malignant, or metabolic conditions that lead to defects in T/NK cell functions and excessive inflammation16,31. fHLH and sHLH affect both children and adults, however, the clinical and genetic distinction of HLH forms is not clear since immunocompetent children can develop sHLH 34,35, while adult patients with sHLH may also have germline mutations in HLH genes36. Of note, germline variants in UNC13D and AP3B1 have also been identified in some COVID-19 patients with HLH phenotype37, thus, indicating that both HLH forms may be associated with COVID-19.
Here, we characterized the signaling pathways and gene signatures commonly dysregulated in both COVID-19 and HLH patients by investigating the transcriptomes of 1253 subjects (controls, COVID-19, and HLH patients) assessed by microarray, bulk RNA-sequencing (RNAseq), and single-cell RNAseq (scRNAseq) (Table 1). We found shared gene signatures and cellular signaling pathways involved in cytokine and chemokine signaling as well as neutrophilmediated immune responses that associate with COVID-19 severity.