Vaccinated Up to 15X MORE LIKELY Than Unvaxxed to Develop Heart Inflammation Requiring Hospitalization: Peer Reviewed Study

Authors:  Julian Conradson Published April 25, 2022 at 4:14pm

A new study out of Europe has revealed that cases of heart inflammation that required hospitalization were much more common among vaccinated individuals compared to the unvaccinated.

A team of researchers from health agencies in Finland, Denmark, Sweden, and Norway found that rates of myocarditis and pericarditis, two forms of potentially life-threatening heart inflammation, were higher in those who had received one or two doses of either mRNA-based vaccine – Pfizer’s or Moderna’s.

In all, researchers studied a total of 23.1 million records on individuals aged 12 or older between December 2020 and October 2021. In addition to the increased rate overall, the massive study confirmed the chances of developing the heart condition increased with a second dose, which mirrors other data that has been uncovered in recent months.

From the *peer-reviewed study, which was published by the Journal of the American Medical Association (JAMA):

“Results of this large cohort study indicated that both first and second doses of mRNA vaccines were associated with increased risk of myocarditis and pericarditis. For individuals receiving 2 doses of the same vaccine, risk of myocarditis was highest among young males (aged 16-24 years) after the second dose. These findings are compatible with between 4 and 7 excess events in 28 days per 100 000 vaccinees after BNT162b2, and between 9 and 28 excess events per 100 000 vaccinees after mRNA-1273.

The risks of myocarditis and pericarditis were highest within the first 7 days of being vaccinated, were increased for all combinations of mRNA vaccines, and were more pronounced after the second dose.”

Also mirroring other data, the study confirmed that young people, especially young males, are the ones who are suffering the worst effects of the experimental jab. Young men, aged 16-24 were an astounding 5-15X more likely to be hospitalized with heart inflammation than their unvaccinated peers.

But it isn’t just young men, all age groups across both sexes – except for men over 40 and girls aged 12-15 – experienced a higher rate of heart inflammation post-vaccination when compared to the unvaxxed.

From The Epoch Times, who spoke with one of the study’s main researchers, Dr. Rickard Ljung:

“‘These extra cases among men aged 16–24 correspond to a 5 times increased risk after Comirnaty and 15 times increased risk after Spikevax compared to unvaccinated,’ Dr. Rickard Ljung, a professor and physician at the Swedish Medical Products Agency and one of the principal investigators of the study, told The Epoch Times in an email.

Comirnaty is the brand name for Pfizer’s vaccine while Spikevax is the brand name for Moderna’s jab.

Rates were also higher among the age group for those who received any dose of the Pfizer or Moderna vaccines, both of which utilize mRNA technology. And rates were elevated among vaccinated males of all ages after the first or second dose, except for the first dose of Moderna’s shot for those 40 or older, and females 12- to 15-years-old.”

Although the peer-reviewed study found a direct link between mRNA based vaccines and increased incident rate of heart inflammation, the researchers claimed that the “benefits” of the experimental vaccines still “outweigh the risks of side effects,” because cases of heart inflammation are “very rare,” in a press conference about their findings earlier this month.

However, while overall case numbers may be low in comparison to the raw numbers and thus technically “very rare,” the rate at which individuals are developing this serious condition has increased by a whopping amount. When considering the fact that 5-15X more, otherwise healthy, young men will come down with the condition – especially since the chances of Covid-19 killing them at that age are effectively zero (99.995% recovery rate) – it’s downright criminal for governments across the world to continue pushing mass vaccinations for everyone.

Dr. Peter McCullough, a world-renowned Cardiologist who has been warning about the long-term horror show that is vaccine-induced myocarditis in young people, certainly thinks so. In his expert opinion, the study does anything but give confidence that the benefits of the vaccine outweigh the risks. In “no way” is that the case, he says. Actually, it’s quite the opposite.

From McCullough, via The Epoch Times:

“In cardiology we spend our entire career trying to save every bit of heart muscle. We put in stents, we do heart catheterization, we do stress tests, we do CT angiograms. The whole game of cardiology is to preserve heart muscle. Under no circumstances would we accept a vaccine that causes even one person to stay sustain heart damage. Not one. And this idea that ‘oh, we’re going to ask a large number of people to sustain heart damage for some other theoretical benefit for a viral infection,’ which for most is less than a common cold, is untenable. The benefits of the vaccines in no way outweigh the risks.”

It’s also worth pointing out that the new study’s findings could be an indicator as to what is driving the massive spike in the excess death rates in the United States and across the world. Correlating exactly with the rollout of the experimental mRNA Covid-19 vaccines, people have been dying at record-breaking rates, especially millennials, who experienced a jaw-dropping 84% increase in excess deaths (compared to pre-pandemic) in the final four months of 2021.

With all the data that has been made available up to this point, there is no denying that the vaccine is at least partially to blame for the spike in severe illness and death, if not entirely. Nevertheless, the CDC, Fauci, Biden, and the rest of the corrupt establishment continue to push mass vaccines, just approved another booster jab (with plans for another already in the works), and are licking their chops to unleash another round of Covid hysteria and crippling restrictions come this fall.

Colchicine: A Possible COVID-19 Long haul Cardiac Therapy

Last Updated: December 16, 2021

Last Updated: December 16, 2021

Colchicine is an anti-inflammatory drug that is used to treat a variety of conditions, including gout, recurrent pericarditis, and familial Mediterranean fever.1 Recently, the drug has been shown to potentially reduce the risk of cardiovascular events in those with coronary artery disease.2 Colchicine has several potential mechanisms of action, including reducing the chemotaxis of neutrophils, inhibiting inflammasome signaling, and decreasing the production of cytokines, such as interleukin-1 beta.3 When colchicine is administered early in the course of COVID-19, these mechanisms could potentially mitigate or prevent inflammation-associated manifestations of the disease. These anti-inflammatory properties coupled with the drug’s limited immunosuppressive potential, favorable safety profile, and widespread availability have prompted investigation of colchicine for the treatment of COVID-19.

Recommendations

  • The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of colchicine for the treatment of nonhospitalized patients with COVID-19, except in a clinical trial (BIIa).
  • The Panel recommends against the use of colchicine for the treatment of hospitalized patients with COVID-19 (AI).

Rationale

For Nonhospitalized Patients With COVID-19

COLCORONA, a large randomized placebo-controlled trial that evaluated colchicine in outpatients with COVID-19, did not reach its primary efficacy endpoint of reducing hospitalizations and death.4 However, in the subset of patients whose diagnosis was confirmed by a positive SARS-CoV-2 polymerase chain reaction (PCR) result from a nasopharyngeal (NP) swab, a slight reduction in hospitalizations was observed among those who received colchicine.

PRINCIPLE, another randomized, open-label, adaptive-platform trial that evaluated colchicine versus usual care, was stopped for futility when no significant difference in time to first self-reported recovery from COVID-19 between the colchicine and usual care recipients was found.5

The PRINCIPLE trial showed no benefit of colchicine, and the larger COLCORONA trial failed to reach its primary endpoint, found only a very modest effect of colchicine in the subgroup of patients with positive SARS-CoV-2 PCR results, and reported more gastrointestinal adverse events in those receiving colchicine. Therefore, the Panel recommends against the use of colchicine for the treatment of COVID-19 in nonhospitalized patients, except in a clinical trial (BIIa).

For Hospitalized Patients With COVID-19

In the RECOVERY trial, a large randomized trial in hospitalized patients with COVID-19, colchicine demonstrated no benefit with regard to 28-day mortality or any secondary outcomes.6 Based on the results from this large trial, the Panel recommends against the use of colchicine for the treatment of COVID-19 in hospitalized patients (AI).

Clinical Data for COVID-19

Colchicine in Nonhospitalized Patients With COVID-19

The COLCORONA Trial

The COLCORONA trial was a contactless, double-blind, placebo-controlled, randomized trial in outpatients who received a diagnosis of COVID-19 within 24 hours of enrollment. Participants were aged ≥70 years or aged ≥40 years with at least 1 of the following risk factors for COVID-19 complications: body mass index ≥30, diabetes mellitus, uncontrolled hypertension, known respiratory disease, heart failure or coronary disease, fever ≥38.4°C within the last 48 hours, dyspnea at presentation, bicytopenia, pancytopenia, or the combination of high neutrophil count and low lymphocyte count. Participants were randomized 1:1 to receive colchicine 0.5 mg twice daily for 3 days and then once daily for 27 days or placebo. The primary endpoint was a composite of death or hospitalization by Day 30; secondary endpoints included components of the primary endpoint, as well as the need for mechanical ventilation by Day 30. Participants reported by telephone the occurrence of any study endpoints at 15 and 30 days after randomization; in some cases, clinical data were confirmed or obtained by medical chart reviews.4

Results

  • The study enrolled 4,488 participants.
  • The primary endpoint occurred in 104 of 2,235 participants (4.7%) in the colchicine arm and 131 of 2,253 participants (5.8%) in the placebo arm (OR 0.79; 95% CI, 0.61–1.03; P = 0.08).
  • There were no statistically significant differences in the secondary outcomes between the arms.
  • In a prespecified analysis of 4,159 participants who had a SARS-CoV-2 diagnosis confirmed by PCR testing of an NP specimen (93% of those enrolled), those in the colchicine arm were less likely to reach the primary endpoint (96 of 2,075 participants [4.6%]) than those in the placebo arm (126 of 2,084 participants [6.0%]; OR 0.75; 95% CI, 0.57–0.99; P = 0.04). In this subgroup of patients with PCR-confirmed SARS-CoV-2 infection, there were fewer hospitalizations (a secondary outcome) in the colchicine arm (4.5% of patients) than in the placebo arm (5.9% of patients; OR 0.75; 95% CI, 0.57–0.99).
  • More participants in the colchicine arm experienced gastrointestinal adverse events, including diarrhea which occurred in 13.7% of colchicine recipients versus 7.3% of placebo recipients (P < 0.0001). Unexpectedly, more pulmonary emboli were reported in the colchicine arm than in the placebo arm (11 events [0.5% of patients] vs. 2 events [0.1% of patients]; P= 0.01).

Limitations

  • Due to logistical difficulties with staffing, the trial was stopped at approximately 75% of the target enrollment, which may have limited the study’s power to detect differences for the primary outcome.
  • There was uncertainty as to the accuracy of COVID-19 diagnoses in presumptive cases.
  • Some patient-reported clinical outcomes were potentially misclassified.

The PRINCIPLE Trial

PRINCIPLE is a randomized, open-label, platform trial that evaluated colchicine in symptomatic, nonhospitalized patients with COVID-19 who were aged ≥65 years or aged ≥18 years with comorbidities or shortness of breath, and who had symptoms for ≤14 days. Participants were randomized to receive colchicine 0.5 mg daily for 14 days or usual care. The coprimary endpoints, which included time to first self-reported recovery or hospitalization or death due to COVID-19 by Day 28, were analyzed using a Bayesian model. Participants were followed through symptom diaries that they completed online daily; those who did not complete the diaries were contacted by telephone on Days 7, 14, and 29. The investigators developed a prespecified criterion for futility, specifying a clinically meaningful benefit in time to first self-reported recovery as a hazard ratio ≥1.2, corresponding to about 1.5 days of faster recovery in the colchicine arm.

Results

  • The study enrolled 4,997 participants: 212 participants were randomized to receive colchicine; 2,081 to receive usual care alone; and 2,704 to receive other treatments.
  • The prespecified primary analysis included participants with SARS-CoV-2 positive test results (156 in the colchicine arm; 1,145 in the usual care arm; and 1,454 in the other treatments arm).
  • The trial was stopped early because the criterion for futility was met; the median time to self-reported recovery was similar in the colchicine arm and the usual care arm (HR 0.92; 95% CrI, 0.72–1.16).
  • Analyses of self-reported time to recovery and hospitalizations or death due to COVID-19 among concurrent controls also showed no significant differences between the colchicine and usual care arms.
  • There were no statistically significant differences in the secondary outcomes between the colchicine and usual care arms in both the primary analysis population and in subgroups, including subgroups based on symptom duration, baseline disease severity, age, or comorbidities.
  • The occurrence of adverse events was similar in the colchicine and usual care arms.

Limitations

  • The design of the study was open-label treatment.
  • The sample size of the colchicine arm was small.

Colchicine in Hospitalized Patients With COVID-19

The RECOVERY Trial

In the RECOVERY trial, hospitalized patients with COVID-19 were randomized to receive colchicine (1 mg loading dose, followed by 0.5 mg 12 hours later, and then 0.5 mg twice daily for 10 days or until discharge) or usual care.6

Results

  • The study enrolled 11,340 participants.
  • At randomization, 10,603 patients (94%) were receiving corticosteroids.
  • The primary endpoint of all-cause mortality at Day 28 occurred in 1,173 of 5,610 participants (21%) in the colchicine arm and 1,190 of 5,730 participants (21%) in the placebo arm (rate ratio 1.01; 95% CI, 0.93–1.10; P = 0.77).
  • There were no statistically significant differences between the arms for the secondary outcomes of median time to being discharged alive, discharge from the hospital within 28 days, and receipt of mechanical ventilation or death.
  • The incidence of new cardiac arrhythmias, bleeding events, and thrombotic events was similar in the 2 arms. Two serious adverse events were attributed to colchicine: 1 case of severe acute kidney injury and one case of rhabdomyolysis.

Limitations

  • The trial’s open-label design may have introduced bias for assessing some of the secondary endpoints.

The GRECCO-19 Trial

GRECCO-19 was a small, prospective, open-label randomized clinical trial in 105 patients hospitalized with COVID-19 across 16 hospitals in Greece. Patients were assigned 1:1 to receive standard of care with colchicine (1.5 mg loading dose, followed by 0.5 mg after 60 minutes and then 0.5 mg twice daily until hospital discharge or for up to 3 weeks) or standard of care alone.7

Results

  • Fewer patients in the colchicine arm (1 of 55 patients) than in the standard of care arm (7 of 50 patients) reached the primary clinical endpoint of deterioration in clinical status from baseline by 2 points on a 7-point clinical status scale (OR 0.11; 95% CI, 0.01–0.96).
  • Participants in the colchicine group were significantly more likely to experience diarrhea (occurred in 45.5% of participants in the colchicine arm vs. 18.0% in the standard of care arm; P = 0.003).

Limitations

  • The overall sample size and the number of clinical events reported were small.
  • The study design was open-label treatment assignment.

The results of several small randomized trials and retrospective cohort studies that have evaluated various doses and durations of colchicine in hospitalized patients with COVID-19 have been published in peer-reviewed journals or made available as preliminary, non-peer-reviewed reports.8-11 Some have shown benefits of colchicine use, including less need for supplemental oxygen, improvements in clinical status on an ordinal clinical scale, and reductions in certain inflammatory markers. In addition, some studies have reported higher discharge rates or fewer deaths among patients who received colchicine than among those who received comparator drugs or placebo. However, the findings of these studies are difficult to interpret due to significant design or methodological limitations, including small sample sizes, open-label designs, and differences in the clinical and demographic characteristics of participants and permitted use of various cotreatments (e.g., remdesivir, corticosteroids) in the treatment arms.

Adverse Effects, Monitoring, and Drug-Drug Interactions

Common adverse effects of colchicine include diarrhea, nausea, vomiting, abdominal cramping and pain, bloating, and loss of appetite. In rare cases, colchicine is associated with serious adverse events, such as neuromyotoxicity and blood dyscrasias. Use of colchicine should be avoided in patients with severe renal insufficiency, and patients with moderate renal insufficiency who receive the drug should be monitored for adverse effects. Caution should be used when colchicine is coadministered with drugs that inhibit cytochrome P450 (CYP) 3A4 and/or P-glycoprotein (P-gp) because such use may increase the risk of colchicine-induced adverse effects due to significant increases in colchicine plasma levels. The risk of myopathy may be increased with the concomitant use of certain HMG-CoA reductase inhibitors (e.g., atorvastatin, lovastatin, simvastatin) due to potential competitive interactions mediated by CYP3A4 and P-gp pathways.12,13 Fatal colchicine toxicity has been reported in individuals with renal or hepatic impairment who received colchicine in conjunction with P-gp inhibitors or strong CYP3A4 inhibitors.

Considerations in Pregnancy

There are limited data on the use of colchicine in pregnancy. Fetal risk cannot be ruled out based on data from animal studies and the drug’s mechanism of action. Colchicine crosses the placenta and has antimitotic properties, which raises a theoretical concern for teratogenicity. However, a recent meta-analysis did not find that colchicine exposure during pregnancy increased the rates of miscarriage or major fetal malformations. There are no data for colchicine use in pregnant women with acute COVID-19. Risks of use should be balanced against potential benefits.12,14

Considerations in Children

Colchicine is most commonly used in children to treat periodic fever syndromes and autoinflammatory conditions. Although colchicine is generally considered safe and well tolerated in children, there are no data on the use of the drug to treat pediatric acute COVID-19 or multisystem inflammatory syndrome in children (MIS-C).

References

  1. van Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R, Aletaha D. Colchicine for acute gout. Cochrane Database Syst Rev. 2014(8):CD006190. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25123076.
  2. Xia M, Yang X, Qian C. Meta-analysis evaluating the utility of colchicine in secondary prevention of coronary artery disease. Am J Cardiol. 2021;140:33-38. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33137319.
  3. Reyes AZ, Hu KA, Teperman J, et al. Anti-inflammatory therapy for COVID-19 infection: the case for colchicine. Ann Rheum Dis. 2021 May;80(5):550-557. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33293273.
  4. Tardif JC, Bouabdallaoui N, L’Allier PL, et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respir Med. 2021;9(8):924-932. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34051877.
  5. PRINCIPLE Trial Collaborative Group, Dorward J, Yu L, et al. Colchicine for COVID-19 in adults in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.09.20.21263828v1.
  6. RECOVERY Collaborative Group. Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet Respir Med. 2021;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34672950.
  7. Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial. JAMA Netw Open. 2020;3(6):e2013136. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32579195.
  8. Brunetti L, Diawara O, Tsai A, et al. Colchicine to weather the cytokine storm in hospitalized patients with COVID-19. J Clin Med. 2020;9(9). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32937800.
  9. Sandhu T, Tieng A, Chilimuri S, Franchin G. A case control study to evaluate the impact of colchicine on patients admitted to the hospital with moderate to severe COVID-19 infection. Can J Infect Dis Med Microbiol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33133323.
  10. Lopes MI, Bonjorno LP, Giannini MC, et al. Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial. RMD Open. 2021;7(1). Available at: https://www.ncbi.nlm.nih.gov/pubmed/33542047.
  11. Salehzadeh F, Pourfarzi F, Ataei S. The impact of colchicine on the COVID-19 patients; a clinical trial. Research Square. 2020;Preprint. Available at: https://www.researchsquare.com/article/rs-69374/v1.
  12. Colchicine (Colcrys) [package insert]. Food and Drug Administration. 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf.
  13. American College of Cardiology. AHA statement on drug-drug interactions with statins. 2016. Available at: https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2016/10/20/21/53/recommendations-for-management-of-clinically-significant-drug. Accessed November 2, 2021.
  14. Indraratna PL, Virk S, Gurram D, Day RO. Use of colchicine in pregnancy: a systematic review and meta-analysis. Rheumatology (Oxford). 2018;57(2):382-387. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29029311.

www.covid19treatmentguidelines.nih.govAn official website of the National Institutes of Health

Management of urticaria in COVID-19 patients: A systematic review

Authors: Eyad Abuelgasim,Ann Christine Modaragamage Dona,Rajan Singh Sondh,Amer Harky

First published: 28 September 2020 https://doi.org/10.1111/dth.14328

Abstract

The global pandemic COVID-19 has resulted in significant global morbidity, mortality and increased healthcare demands. There is now emerging evidence of patients experiencing urticaria. We sought to systematically review current evidence, critique the literature, and present our findings. Allowing PRISMA guidelines, a comprehensive literature search was carried out with Medline, EMBASE, Scopus, Cochrane, and Google Scholar, using key MeSH words, which include “COVID-19,” “Coronavirus,” “SARS-Cov-2,” “Urticaria,” “Angioedema,” and “Skin rash” up to 01 August 2020. The key inclusion criteria were articles that reported on urticaria and/or angioedema due to COVID-19 infection and reported management and outcome. Studies were excluded if no case or cohort outcomes were observed. Our search returned 169 articles, 25 of which met inclusion criteria. All studies were case reports, reporting 26 patients with urticaria and/or angioedema, COVID-19 infection and their management and/or response. ajority of patients (n = 16, 69%) were over 50 years old. However, urticaria in the younger ages was not uncommon, with reported case of 2 months old infant. Skin lesions resolved from less than 24 hours to up to 2 weeks following treatment with antihistamines and/or steroids. There have been no cases of recurrent urticaria or cases nonresponsive to steroids. Management of urticarial in COVID-19 patients should involve antihistamines. Low dose prednisolone should be considered on an individualized basis. Further research is required in understanding urticarial pathogenesis in COVID-19. This will aid early diagnostic assessment in patients with high index of suspicion and subsequent management in the acute phase.

1 INTRODUCTION

The global pandemic COVID-19 is caused by severe acute respiratory syndrome coronavirus-2 (SARS-COV2). It has resulted in global morbidity, mortality and significantly increased healthcare demands.12 It was originally reported that the main symptoms of COVID-19 to be a cough and fever. However, as the pandemic progressed, our understanding of COVID-19 increased, leading to anosmia and/or hyposmia established as a third symptom. As our understanding of this disease increases, it is reported that SARS-COV2 can present with clinical manifestations beyond the respiratory system. We are now aware that neurological manifestation can develop which encompasses acute skeletal muscle injury as well as an impaired consciousness.3 Additionally, severe infections can have an impact on renal and cardiac function.4

More recently, there has been a growing interest regarding the dermatological manifestations in patients with COVID-19. Skin manifestations during the course of a COVID-19 infection was first reported in China, however the prevalence was low at 0.2% cases out of 1099 cases.5 There is now emerging evidence in literature making reference to some patients experiencing urticaria. Urticaria manifests itself as urticarial plaques that affect the upper dermis which can cover the skin and mucous membranes. It is described as erythematous and pruritic, and can sometimes present with angioedema, a type of swelling of the dermis subcutaneous tissue, the mucosa, and submucosal tissues.6

The objective of this systematic review is to review the current literature on urticaria in COVID-19 patients. Furthermore, we aim to provide insight into urticarial pathogenesis and management in such patients.

2 METHODS

2.1 Literature search

This study was done according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method identifying published literature on urticaria and/or angioedema due to COVID-19 infection and its management and outcomes. The comprehensive literature search was carried out with Medline, EMBASE, Scopus, Cochrane database, and Google Scholar, using key MeSH words, which include “COVID-19,” “Coronavirus,” “SARS-Cov-2,” “Urticaria,” “Angioedema,” and “Skin rash.” Manual cross checking of reference lists of relevant articles was performed. All published articles have been reviewed, and the findings have been included in this study. The relevant articles have been cited and referenced within this study. The limits included studies in English and articles published after December 2019 until 01 August 2020. All the relevant articles identified were analyzed by two authors, and the results were appropriately summarized and reported.

2.2 Inclusion and exclusion criteria

The key inclusion criteria were articles that reported on urticaria and/or angioedema due to COVID-19 infection and reported management and outcome, and studies were excluded if no case or cohort outcomes were observed. Other exclusion criteria were consensus documents, editorials, commentaries, and narrative reviews.

2.3 Data extraction

All studies were screened by two authors independently (E.A. and A.D); disagreement was resolved by consensus or involvement of other authors (R.S. and A.H.). The extracted data then were crosschecked by a third author to validate their accuracy (A.H.).

3 RESULTS

Following an extensive database search, 169 articles were identified. Of these, 34 were selected for full text review based on their title and abstract. Full text screening resulted in the final selection of 25 articles (Figure 1),726 reporting 26 patients with urticaria and/or angioedema and COVID-19 infection and their management plan and/or response to management. Table 1 includes the summarized key findings of the studies included in this review. All included articles were case reports.

Details are in the caption following the image
FIGURE 1Open in figure viewerPowerPointArticle selection flowchart (PRISMA)

TABLE 1. Management and response of patients with urticaria and/or angioedema during COVID-19 infection

StudyCase characteristicCutaneous manifestationInvolvement siteAccompanied by COVID-19 symptomsSkin biopsyMedical and drug HistoryManagementResponse to managementDuration of skin lesions
Proietti et al76-month-old, male infantGiant urticaria, with multiple lesionMainly affecting the trunk and limbsAsymptomatic. 2 weeks after COVID-19 confirmed by RT-PCRNot reportedNot correlated with drugs (topical or systemic), bacterial or parasitic infections, inhalant exposure, or insect bites.Allergies such as allergic rhinitis, atopic dermatitis, and food allergy were not reported.Laboratory findings were within the normal ranges.Betamethasone (soluble tablets, 0.5 mg/day for 7 days)Clinical improvement following treatment<7 days
Sousa Gonçalves et al857-year-old Caucasian manUrticarial rash (an erythematous papular rash with irregular contoursElbows6 days after first reporting COVID-19 symptomsNot reportedNo newly initiated drugs, patient did not have atopy or a clinical history of allergy or other conditionsNot reportedNot reportedNot reported
Rolfo et al962-year-old current smoker man with diagnosed T4N2M1b G3 stage IV squamous cell lung carcinoma with pleuro-pulmonary involvementUrticarial papular lesions, with marked itching and minimal erythemaLower dorsal, lumbar and gluteal region2 days after first reportingCOVID-19 symptoms. Two days before COVID-19 confirmed by RT-PCRVasculitis involving the superficial and deep dermis, with signs of microangiothrombosis, showing fibrinoid changes of vessel wall with some granulomas, neutrophilic infiltrate, and nuclear debris.2 days after the last immunotherapy dose—ipilimumab (1 mg/kg every 6 weeks) plus nivolumab (3 mg/kg every 2 weeks)Serial ferritin, D-Dimer (DD), and IL6 in addition to ANAS and C4, to discard differential diagnoses, were evaluated.Elevation of ferritin (940 ng/mL) and DD (2.600 ng/dL) was documented.Hydroxychloroquine (400 mg BID on day 1200 mg BID for 14 days).Azithromycin (500 mg day 1250 mg days 2–5)Methylprednisolone 1 mg/.kgEnoxaparin 40 mg SC/dayWithin 14 days, dominant skin lesions disappeared, cough and chest CT-scan normalized.ANAS and complement C4 normalized, as were clotting times and fibrinogen. Serial evaluation of IL6 levels by ELISA only had a slightly elevated value of 246 pg/mL (range 6.25-200 pg/mL,) and throughout the 18-day follow-up period there was lymphopenia that became less evident14 days
Shanshal1031-year-old lady with a 5-year history of well-controlled chronic urticariaExtensive, severely itching urticarial lesionsMainly concentrated on the trunk and extremities and sparing of the face, palm, and sole5 days after first reporting COVID-19 symptoms.3 days before COVID-19 confirmed by RT-PCRNot reportedNonsedating antihistaminesLow-dose systemic steroid and nonsedating antihistamineRash controlled within 5 days5 days
Hassan1146-year-old female nurse with history of hay fever and mild asthmaWidespread urticarial eruption; red-raised blanching and itchy rash with angioedema of lips and handsFace, arms, torso, legs, and loins48 hours before developing COVID-19 symptoms.2 days before COVID-19 confirmed by RT-PCRNot carried outNo prescribed regular medications no over-the-counter medicationsStarted fexofenadine hydrochloride 180 mg, two to four times per day.Rash worsened following day and was associated with angioedema.Advised to continue taking fexofenadine hydrochloride 180 mg four times per day and she was commenced on prednisolone 40 mg once daily for 3 days.Prednisolone helped lip and hand swelling, but rash remained itchy.Chlorphenamine maleate 4 mg four times/day was subsequently added.The rash resolved completely over next few days. The patient made a full clinical recoveryAround 14 days
Najafzadeh et al12Elderly manPruritic hives 1.5-8.0 cm in diameterGeneralized urticaria with angioedema of face and neckAt same time as COVID-19 symptomsNot reportedNot reportedInitial biochemical tests showed low numbers of white blood cells (WBC) (WBC = 2.75 × 103). Lymphopenia was detected (lymphocytes = 852).RT-PCR for COVID-19 was not performed. CT chest was carried out, which showed pneumonia with bilateral and subpleural areas of ground-glass opacification, consolidation affecting the lower lobes and confirming the diagnosis of COVID-19.Not reportedNot reported
de Perosanz-Lobo et al13Elderly woman admitted to the hospital with bilateral pneumonia testing positive for COVID-19Painful erythematous patches which left residual purpura when fadingTrunk, buttocks, and hips> 5 days after first reporting COVID-19 symptomsHistologic changes characteristic of small-vessel urticarial.Vasculitis: blood extravasation and neutrophilic perivascular inflammation with prominent karyorrhexis. There are some macrophages with a cytoplasm full of nuclear debrisTreatment with hydroxychloroquine, lopinavir/ritonavir, and azithromycin for 5 daysA sudden worsening of respiratory condition led to the patient’s death, and therefore, no treatment could be prescribed.MortalityN/A
Middle-aged man with a 14-day history of fever, cough and anosmiaErythematous and edematous plaques with active border and purpuric centerButtocks14 days after first reporting COVID-19 symptomsEvidence of small-vessel damage: preserved epidermis with moderate perivascular neutrophilic inflammation and blood extravasation in the dermis. Endothelial swelling, necrosis and fibrin depositionNot reportedTherapy with hydroxychloroquine and azithromycin was started as treatment for COVID-19.Prednisone and antihistamines were administered for his skin condition.14 days later, the patient was asymptomatic.14 days
Falkenhain-López et al1451-year-old otherwise healthy woman with a 3-day history of dry cough and arthralgiasWidespread pruritic evanescent skin lesions (lasting <24 hours).Multiple well-demarcated erythematous edematous papules and plaques with diffuse underlying erythemaTrunk, thighs, upper limbs, and predominantly on the facial area and dorsal aspects of bilateral hands3 days after first reported COVID-19 symptoms and confirmation of COVID-19 by RT-PCRThe patient had not taken any medication before the onset of the symptoms.No recent contact with plants, chemicals, or topical products. No urticarial lesions before, and no precipitating factors were found.Review of systems was negative for diarrhea, dysphagia, or other suggestive symptoms of anaphylaxis.Blood test showed lymphopenia and elevated C-reactive protein (5.4 mg/L) and LDH (388 U/L). Chest radiography revealed bilateral pulmonary infiltrates.Treatment with loratadine 10 mg every 12 hoursEarly improvement of pruritus and resolution of skin lesions within 2 days.The patient did not experience recurrent episodes of urticaria after 7 days of antihistaminic treatment.7 days
Goldust et al1574-year-old Wuhan man presented with fever (100.4 F), dry cough and fatigueDiffuse, irregular shaped, partially confluent urticarial whealsGeneralized12 days after admission, first reported COVID-19 symptoms and confirmation of COVID-19 by RT-PCRNot carried outTreatment included hydroxychloroquine, lopinavir/ritonavir, thymosin, and methylprednisolone.A CT scan of the lung showed ground-glass changes.Treatment included hydroxychloroquine, lopinavir/ritonavir, thymosin, and methylprednisolone. (unclear which medications were started before/after development of urticaria—possible reaction to medication?)Not reportedNot reported
65-year-old subfebrile (98.6 F) Wuhan woman had dry cough, fatigue and diarrhea (four times a day)Disseminated, variable size, erythematous patches, which fade on pressure. Few patches were confluent.Generalized1 day after admissionNot carried outRuxolitinibCT scan showed bilateral ground-glass changes.RT-PCR swabs did not detect SAR-Cov-2.Symptoms considered as unspecific viral rash due to COVID-19 and included as differential diagnosis a drug eruption due to the antineoplastic drug ruxolitinib.Not reportedNot reported
Aktaş et al1664-year-old femaleSevere pink urticarial plaquesGeneralizedDuring course of COVID-19Not reportedMetformin and a combination of irbesartan and hydrochlorothiazide treatment for years due to diabetes mellitus and hypertension.No atopy in dermatological examination. Similar reaction occurred 9 years ago lasting a few weeks.Detailed investigation including thorax computed tomography and testing coronavirus.Treated with hydroxychloroquine, azithromycin, and oseltamivir in intensive care unit for 7 days.As etiology of her diffuse urticaria, viral infection itself, drugs she received, and psychological stress of the clinical condition were considered.Cetirizine 10 mg twice a day.Urticarial reaction was partially controlled on Cetirizine 10 mg twice a dayNot reported
Diotallevi et al1755-year-old woman admitted for pyrexia, dry cough, and dyspneaUrticarial skin rash characterized by erythematous, smooth, slightly elevated papules and wheals, associated to severe pruritus.Generalized3 days before admission and confirmation of COVID-19 by RT-PCRNot reportedNo new medication before the rash appeared.The patient did not report neither similar episodes in the past, nor allergies to drugs or foods.High-resolution computed tomography scan of the chest revealed a diffuse bilateral ground-glass opacity.Blood test revealed normal blood count (no lymphopenia or lymphocytosis or eosinophilia), slight increase of procalcitonin serum level (0.14 ng/mL), C-reactive protein (CRP, 12.1 mg/dL), and liver enzymes (GOT, GPT, LDH, GGT fourfold levels).A systemic treatment with intravenous daily administration of betamethasone sodium phosphate 4 mg and chlorphenamine maleate 10 mg, in addition to antiviral therapy with lopinavir/ritonavir for pneumoniaIn the following days urticaria improved gradually.Twenty-five days after admission, patient was discharged.Not reported
64-year-old patient with acute respiratory distress syndrome (PaO2/FiO2 ≤ 100 mm Hg) caused by COVID-19Urticarial rashGeneralizedSkin rash was already present at the time of hospital admissionNot reportedTreatment with lopinavir/ritonavir and hydroxychloroquine from 1 week, and no new drug introduction had been made in the last 3 weeks before skin rash development.No history of allergy to drugs or foods, nor recent intake of new drugsBlood test revealed abnormal blood count with neutrophil leukocytosis (neutrophil granulocytes 8.600/mm3), and mild lymphopenia (lymphocytes 700/mm3), moderate increase of pro-calcitonin serum levels (0.87 ng/mL), marked increase of CRP (10.2 mg/dL), and liver enzymes (GOT, GPT, LDH, GGT fourfold levels) serum levels.Mechanical ventilation for respiratory failure.Intravenous administration of methylprednisolone 40 mg/die and bilastine 20 mg/die.Skin rash is slightly improved after 48 hours from the beginning of the treatment.Patient in stable condition.Not reported
de Medeiros et al1855 years old female, intensive care physicianFirst episode: Painful erythematous-edematous plaques.Some lesions evolved into bruises.Second episode: Exuberant urticarial lesions. Light erythema and edema with intense itchingFirst episode: Flexor face of forearms and leg extensors|.Second episode: Exuberant urticarial lesions on shoulders. and inguinal region. Light erythema and edema on palmsFirst episode: 5 days after contact with COVID-19 ICU patient.Second episode: 2 days after second exposure with COVID-19 ICU patient. At same time as COVID-19 symptomsNot reportedNot reportedFirst episode: Betamethasone cream 0.1% once a day.Second episode: Bilastine 20 mg one tablet a day for 15 days.Betamethasone ointment 0.1% cream once a day for 2 daysConfirmation of COVID-19 by RT-PCR.First episode: lesion resolution in 3 days.Second episode: Within 48 hours, there were no more wheals and erythematous-edematous plaques appeared without itching in the antecubital and popliteal fossae.Lesions regressed after the use of betamethasoneFirst episode: 3 days.Second episode: 4 days
Cepeda-Valdes et al19Patient 1 was a 50-year-old woman, and Patient 2 was a 20-year-old woman, who was the daughter of Patient 1Bilateral disseminated rash characterized by erythematous annular and irregular wheals on the skin that appeared suddenly and disappeared within <24 hoursShoulders, elbows, knees, and buttocksAfter developing COVID-19 symptomsNot reportedNeither patient had any history of similar lesions, and no trigger factors other than the viral context were identifiedAntihistamines and moisturizers48 hours after treatment was started the urticaria resolved2 days
Naziroğlu et al2053-year-old malePruritic edematous plaquesGeneralizedNo respiratory or systemic symptomsNot reportedNo previous history of atopic conditions including drug or food allergy, chronic urticaria.Treatment was started with diagnosis of COVID-19On the fourth day of his admission, his skin lesions regressed and he was discharged on the fifth day of his admission4 days
Gunawan et al2151-years-old malePruritic urticariaOn day 3 of hospitalization, after presenting with COVID-19 symptomsNot reportedHistory of hypertension, diabetes, dyslipidemia and hyperuricemia on therapy.No urticaria triggers other than viral infection were found, as there was no history of food allergy, drug allergy, chronic urticaria, or other allergies. There was no history of consuming new medicine in 15 days prior besides COVID-19 treatment in hospital.Patient was treated with azithromycin, hydroxychloroquine, cefoperazone-sulbactam, omeprazole, and medicines for his comorbidities.Oral antihistamine loratadine was added to his treatment with improvement of symptom on the next day. The suspicion of urticaria caused by the medicines given in hospital could be eliminated by the fact his urticaria improved even the medicines continued to be given.Improvement of symptom on the next day24 hours
Adeliño et al2230-year-old female physicianRapidly spreading wheals.In a few hours, face wheals promptly converted to facial angioedema, with preferential involvement of periocular region and mild edema of the lips, without compromise of the tongue, uvula, vocal cords, or the airway.Face, trunk, abdomen, and limbsOn day +11 of disease evolution, after resolution of previous COVID-19 symptomsNot reportedNo relevant past medical history except for pine seeds allergy, following a strict nut-free diet since she was diagnosed.Family history of hereditary angioedema.Not on any medication.She had not taken nonsteroidal inflammatory drugs or angiotensin-converting enzyme inhibitors the previous 15 days.She had not exercised, had not drunk alcohol, nor was on menstrual period.Oral antihistamine (ebastine 10 mg ter in die)24 hours after the onset of the cutaneous symptoms, both the wheals and angioedema started to fade off, turning into erythematous macules until complete resolution.24 hours
Paolino et al2337-year-old Caucasian woman, in her 10th postpartum dayCraniocaudal cutaneous manifestation characterized by erythematous maculopapular lesionsTrunk, neck, and face3 days after first reporting COVID-19 symptomsNot reportedAcetaminophenNo signs of dyspnea, and the vital signs (including saturation) were all in normal range.A symptomatic treatment with only acetaminophen was prescribed seventh postpartum day prior development of rash.Breastfeeding has not been suspended.After 8 days, the cutaneous lesions clearly improved along with improvement of the general symptoms and absence of fever and dry cough.The newborn did not show any symptom of the disease and did not develop any cutaneous lesion.8 days
Ahouach et al2457-year-old womanDiffuse fixed erythematous blanching maculopapular lesionsAsymptomatic over the limbs and trunk, with burning sensation over the palms48 hours before COVID-19 symptomsSlight spongiosis, basal cell vacuolation and mild perivascular lymphocytic infiltrateNo drug intake, except paracetamol for feverNo treatmentFever and rash resolved within 9 days, dry cough within 2 weeks.9 days
Quintana-Castanedo et al2561-year-old male physicianProgressive, mildly itchy urticarial rash consisting of confluent, edematous and erythematous papulesThighs, arms and forearms. Palms and soles were spared.Not reportedNot reportedNo drug during last 2 monthsOral antihistaminesRemained afebrile during the next week. Cutaneous rash resolved in 7 days.7 days
Rivera-Oyola et al2660-year-old womanSudden-onset mild hemi-facial atrophy and scoliosis, generalized, pruritic rash, large, disseminated, and urticarial plaquesTrunk, head, upper, and lower extremities9 days after first reporting COVID-19 symptomsNot reportedEstradiol, for many months and allergy to propofol.No recent changes to her medications.FexofenadineThe patient recovered from her infection without sequelae and did not require hospitalization.Urticarial lesions did not recur on her discontinuation of the fexofenadine 1 week after starting.1 day
Morey-Olivé et al272-month-old girlAcute urticaria, apparently pruriticFace and upper extremities which spread in a few hours to trunk and lower extremities. The palms and soles were not affected.4 days after low fever, at the same time with COVID-19 symptomsNot reportedNot reportedOral symptomatic treatmentMost lesions healed within 24 hours, and the cutaneous manifestations resolved in 5 days in the absence of any other signs and symptoms5 days
Amatore et al2839-year-old maleErythematous, rash, edematous nonpruritic annular fixed plaques of various diametersUpper limbs, chest, neck, abdomen and palms, sparing the face, and mucous membranesAt same time as COVID-19 symptomsHistological findings were unspecific, consistent with viral exanthemata: superficial perivascular lymphocytic infiltrate, papillary dermal edema, mild spongiosis, lichenoid and vacuolar interface dermatitis, dyskeratotic basilar eratinocytes, occasional neutrophils but no eosinophils within the dermal infiltrate.No relevant medical history.Taken no medications in the days and weeks prior to onset of symptomsOral hydroxychloroquine sulfate 200 mg three times per day for 10 daysNo pulmonary symptoms developed.Rash fully recovered on day 6 of treatment6 days
van Damme et al2939-year-old female nursePruritic urticarial rashGeneralizedAt same time as COVID-19 symptomsNot reportedNo change in her daily habits or drugsBilastineGradual improvement of rashNot reported
Henry et al3027-year-old womanPruritic rash, large, disseminated, and urticarial plaquesParticular face and acral involvement48 hours before COVID-19 symptomsNot reportedNo triggers except for the viral context were found, and common viral serology was negative.Paracetamol and oral antihistaminesSlow improvement symptomsNot reported
Cohen et al3162-year-old man with a history of hypertension12 hours of slightly asymmetric, and nonpitting edema of cheeks and lipsLip and facial swelling.He had no other sites of swelling and had no rash.12 days before COVID-19 symptomsN/ALisinoprilLeukocytosis with relative lymphopenia and elevated high-sensitivity C-reactive protein and D-dimer. Functional C1 inhibitor levels (59.7 mg/dL), C3 levels (206 mg/dL), and C4 levels (46 mg/dL) were all elevated.Intravenous methylprednisolone, famotidine, and diphenhydramine. His lisinopril was held.By hospital day 2, swelling markedly improved.Discharged home in stable condition.2 days

The majority of patients (n = 16, 69%) were over 50 years old. However, urticaria in the younger ages was not uncommon, with reported case of 2 months old girl. Skin lesions were reported resolve from less than 24 hours to up to 2 weeks following treatment with antihistamines and/or steroids. There have been no cases of recurrent urticaria or cases nonresponsive to steroids.

4 DISCUSSION

4.1 Demographic of COVID-19 patients with urticaria development

The review population revealed that the majority of patients (18 patients) affected by urticaria were over 50 years old. However, urticaria in the younger ages was not uncommon. Typically, urticaria has a peak onset of 20-40 years and affects females more than males, which was found to be the case in this review. Lifetime incidence of urticaria is reported to be 15%.32 It has been reported that urticaria may be a rare manifestation of COVID-19, which has been observed in just under 4% of COVID-19 patients.33

Of note, most case reports have found skin manifestations to not be associated with disease severity3329 Conversely, a prospective Spanish cohort study reported that the presentation of urticaria and maculopapular skin lesions were associated with higher morbidity (severe COVID-19 illness) and higher mortality rate (2%).34 Further observational studies will aid further understanding of the association of COVID-19 disease progression and dermatological manifestations.

4.2 Pathophysiology of urticaria in COVID-19

The pathophysiology was previously hypothesized to be attributed to drug-induced urticaria. Urticaria is a well-known cutaneous manifestation of a drug eruption,35 however, urticaria has been debated in COVID-19 patients as to whether the virus directly results in urticaria, or if urticaria is caused by a drug eruption. There have been reports of COVID-19 positive cases with urticaria, where there had been no changes in their medication regime.2633 This may suggest that urticaria could be directly related to the pathogenesis of the SARS-CoV2. However, individual case reports have reported urticaria manifestation prior to commencement of therapy for COVID-19 as well as reports of remission from urticaria despite continuation of drug therapy.29 This suggests that urticaria in COVID-19 is likely multifactorial and drug-associated skin manifestations to not account for all cases.

SARS-CoV-2 entry into a cell is mediated through binding to angiotensin-converting enzyme-2 (ACE2) protein and subsequent endocytosis in epithelial targets in the lung.36 Of note, systemic response may be owed to the presentation of ACE2 on other tissues, including kidney, brain and importantly, the vasculature. Angiotensin (Ang) I and Ang II are deactivated by ACE2 Ang I and Ang II are associated with inflammation, oxidative stress and fibrotic scarring.37 In the instance of coronavirus infection, the binding of SARS-CoV-2 with ACE2 disrupts normal ACE2 activity. This may result in increased activity of Ang II, leading to formation of reactive oxygen species, disrupt antioxidant and vasodilatory molecules, and result in complement activation.38 Such disrupted physiological processes were observed in a rat model with aberrant expression of Ang II.39

COVID-19 associated skin manifestations may be mediated by the systemic inflammatory response that follows the human body’s response to an acute infection.40 This includes activation of the complement system and adjustment of the cytokine-chemokine milieu.10 Consequently, this progresses to aberrant activation and sequential degranulation of mast cells. It is hypothesized that mast cell degranulation is the principal pathophysiology associated with subsequent systemic organ damage in COVID-19.41 Of note, most patients with COVID-19 were reported to have elevated levels of circulating interleukin-6 (IL-6).42 Furthermore, colocalization of SARS-CoV-2 glycoproteins and respective complement mediators have been reported in peripheral cutaneous blood vessels.43 Therefore, it is possible that these mediators may be attributed to urticarial pathogenesis.

Urticaria has sometimes been associated with eosinophilia (>500 eosinophils/mm3), which has been observed in a number of COVID-19 cases.44 Moreover, eosinophilia seems to have a protective mechanism and has been associated with a better prognosis.45 There have also been some cases where patients initially presented with urticaria only before experiencing the typical COVID-19 symptoms and testing positive. What was evident in these cases was that they had been taking some form of prescribed medication prior to testing positive to COVID-19.4647 Despite some patients having no medication changes, they still were taking medication at the time of onset of urticaria, suggesting that COVID-19 may cause eosinophilia, resulting in drug hypersensitivity and thus urticaria. However, more research is needed to formally establish this relation.

4.3 Diagnosis assessment

It is important to ensure that urticaria is correctly diagnosed so that appropriate treatment can be administered. A diagnostic characteristic of urticaria is that the cutaneous lesions must be evanescent. Multiple case reports have not detailed this characteristic in their studies, so it is important this is taken into consideration. Furthermore, some case reports have mentioned how a skin biopsy for histopathological studies may aid in a diagnosis of urticaria.48 One case report has discussed that a skin biopsy of a COVID-19 patient with urticaria revealed perivascular infiltrate of lymphocytes, some eosinophils and upper dermal oedema.49 A skin biopsy and awareness of evanescent lesions may allow for the differentiation to be made between urticaria and other cutaneous manifestations, limiting the chance of a misdiagnosis.

On clinical assessment clinicians should consider the possibility of glucose-6-pyruvate dehydrogenase (G6PD) deficiency in COVID-19 patients as this group of patients may have a dominance of high-producing IL-6 allele. In one study group, this correlation has been reported in 71% of patients.50

4.4 Patient management

Classically, the recommended algorithm for treating urticaria includes the use of second-generation antihistamines, and if inadequate control within 2-4 weeks, the dose can be increased up to four times the original dose. If this is still inadequate control after a further 2-4 weeks, specialist referral should be considered, where specialists can consider prescribing omalizumab and ciclosporin to help alleviate symptoms.51 However, in most patients, second generation oral antihistamines provide adequate control of urticaria.52 The pathophysiology of COVID-19 related urticaria demonstrates that antihistamines alone will not stop mast cell histamine degranulation but will only act to reduce the severity of urticaria.

Low systemic steroids, on the other hand, target the COVID-19 inflammatory storm, which prevents mast cell activation, and thus histamine release. Therefore, low dose systemic steroids may be able to effectively manage urticaria in COVID-19 through their proposed mechanism of action. Combining this with antihistamines can improve patients’ clinical response to urticaria10. A further benefit of low dose steroids, shown through a randomized control trial, has demonstrated an increase in survival rate in COVID-19 patients (Randomized Evaluation of COVID-19 Therapy [RECOVERY], ClinicalTrials.gov Identifier: NCT04381936). Although corticosteroids are promising, it may increase the risk of prolonged viral replication, so it may be best to use them for the shortest duration possible until symptoms are controlled. After this, consideration should be made to promptly switch to omalizumab. Ciclosporin is currently not recommended in COVID-19 patients.52

4.5 Limitations

All included articles were case. Only three case reports detailed pathological study results.91328 A diagnostic characteristic of urticaria is that the cutaneous lesions must be evanescent (no one lesion should last more than 24 hours), however this was only noted by Falkenhain-López et al.14

5 CONCLUSION

Urticaria is a significant manifestation of COVID-19, notably affecting patient morbidity. As such the clinical presentation of urticaria can aid diagnostic assessment, while considering risk factors, such as G6PD deficiency and aberrant IL-6 expression. Management of COVID-19 patients should involve antihistamines. Low dose prednisolone should be considered on an individualized basis. Further research is required in understanding urticarial pathogenesis in COVID-19. This will aid early diagnostic assessment in patients with high index of suspicion and subsequent management in the acute phase.

Skin Manifestations Associated with COVID-19: Current Knowledge and Future Perspectives

Authors: Giovanni Genovese,a,bChiara Moltrasio,a,cEmilio Berti,a,b and Angelo Valerio Marzanoa,b,*

Dermatology. 2020 Nov 24 : 1–12.Published online 2020 Nov 24. doi: 10.1159/000512932PMCID: PMC7801998PMID: 33232965

Abstract

Background

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.

Summary

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:

Introduction

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 [1]. 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 [2]. 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 [3]. 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) [2]. Other authors have attempted to bring clarity in this field, suggesting possible classifications of COVID-19-associated cutaneous manifestations [456]. 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.

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Fig. 1

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. [2], focusing on clinical features, histopathological features, hypothesized pathophysiological mechanisms and therapeutic management.Go to:

Urticarial Rash

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 [78]. Urticarial eruptions associated with COVID-19 have been first reported by Recalcati [9] 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. [4] 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 [4]. Freeman et al. [10] 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 [111213]. 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 [111213]. 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 [14]. 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 [15]. Urticarial vasculitis has also been described in association with COVID-19 in 2 patients [16].

Table 1

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 (%)
Galván Casas [4] (375)73 (19)176 (47)34 (9)71 (19)21 (6)
Freeman [10] (716)55 (8.1)115 (16.1)49 (7.2)422 (62)46 (6.4)51 (7.1)
Askin [29] (52)7 (13.5)29 (55.8)3 (5.8)1 (1.9)08 (15.4)
De Giorgi [20] (53)14 (26)37 (70)2 (4)000
Unpublished data from an Italian multicentric study (159)19 (11.9)48 (30.2)29 (18.2)46 (28.9)4 (2.5)13 (8.2)

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Histopathological Findings

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. [17] found on histopathology slight vacuolar interface dermatitis with occasional necrotic keratinocytes curiously compatible with an erythema multiforme-like pattern. Amatore et al. [18] 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).

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Fig. 2

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.

Therapeutic Options

Shanshal [19] 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:

Confluent Erythematous/Maculopapular/Morbilliform Rash

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. [4], for 44% of the skin manifestations included in the study by Freeman et al. [10], 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. [20] in May 2020, in which erythematous rashes accounted for 70% of total skin manifestations. In the series by Freeman et al. [10], 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 [21]. 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 [21] or coexist from the beginning with purpuric lesions [22]. Erythematous papules may also be arranged in a morbilliform pattern [23]. In a subanalysis of the COVID-Piel Study [4] 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%) [24]. 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 [24]. In this group, the main differential diagnoses are represented by exanthems due to viruses other than SARS-CoV-2 and drug-induced cutaneous reactions.

Histopathological Findings

Histopathology of erythematous eruptions was described by Gianotti et al. [25], 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. [26], who observed a mild superficial perivascular lymphocytic infiltrate on the histology of 4 patients. In contrast, Herrero-Moyano et al. [27] 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. [26] (Fig. ​(Fig.22).

Therapeutic Options

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 [23], systemic corticosteroids deserving to be administered just in more severe and widespread presentations.Go to:

Papulovesicular Exanthem

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 [28]. 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 [28]. The exact prevalence of papulovesicular exanthems is variable. Indeed, in a cohort of 375 patients with COVID-19-associated cutaneous manifestations [4], 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. [29], Recalcati [9] and De Giorgi et al. [20], 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. [28], also children may be affected [30]. Galván Casas et al. [4] 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. [31] 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. [28], 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 [28]. 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 [31]. 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 [31].

Histopathological Findings

Mahé et al. [32] 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 [33]. Acantholysis and ballooned keratinocytes were found also by Fernandez-Nieto et al. [31] in 2 patients.

The differential diagnosis with infections caused by members of the Herpesviridae family has been much debated. Tammaro et al. [34] 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 [35].

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 [3637]. 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 [38]. To our knowledge, SARS-CoV-2 has not been hitherto isolated by means of reverse transcriptase PCR in the vesicle fluid of papulovesicular rash [3331].

Therapeutic Options

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 [39]. 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 [40414243444546]. Caucasians seem to be significantly more affected than other ethnic groups [4748]. 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 [49]. Furthermore, virus-induced endothelial damage as well as an obliterative microangiopathy and coagulation abnormalities could be mechanisms involved in the pathogenesis of these lesions [50]. 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 [4051]. Rare cases of chilblain-like lesions involving other acral sites, such as the auricular region, were also reported [52]. The occurrence of blistering lesions varied according to the case series analyzed; Piccolo et al. [51], indeed, reported the presence of blistering lesions in 23 out of 54 patients, while other authors did not describe bullous lesions in their series [4047]. Dermoscopy of these lesions revealed the presence of an indicative pattern represented by a red background area with purpuric globules [53]. Pain/burning sensation as well as pruritus were commonly reported symptoms, even if a small proportion of patients presented with asymptomatic lesions [404447]. 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 [40455455] (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 [404447]. 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. [56] 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. [57]. 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 [57]. Similar results were obtained also by other authors [585960616263] 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. [64], 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 [65].

Therapeutic Options

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 [66].

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 [2]. Instead, the classification by Galván Casas et al. [4] 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 [43]. In the large cases series of 716 patients by Freeman et al. [10], 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 [67].

Livedo reticularis-like lesions are frequently mild, transient and not associated with thromboembolic complications [6869]. On the contrary, livedo racemosa-like lesions and retiform purpura have often been described in patients with severe coagulopathy [60616263646566676869707172].

Histopathological and Pathophysiological Findings

The histopathology of livedoid lesions associated with COVID-19 has been described by Magro et al. [73], 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 [74], which is frequent in COVID-19 patients and probably involved in the pathophysiology of its clinical complications [75].

Therapeutic Options

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. [76], 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 [4]. This hypothesis is corroborated by the unfavorable prognosis observed in several cases reported in the literature [7778].

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. [43] reported 2 patients with purpuric lesions with (n = 1) and without (n = 1) necrosis. In the series by Freeman et al. [10], 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. [4] reported 21 patients with “livedo/necrosis,” most of whom presenting cutaneous signs in concomitance with systemic symptoms’ onset.

Purpuric lesions may be generalized [79], localized in the intertriginous regions [80] or arranged in an acral distribution [81]. Vasculitic lesions may evolve into hemorrhagic blisters [77]. In most severe cases, extensive acute necrosis and association with severe coagulopathy may be seen [78]. Dermoscopy of purpuric lesions revealed the presence of papules with incomplete violaceous rim and a central yellow globule [82].

Histopathological Findings

When performed, histopathology of skin lesions showed leukocytoclastic vasculitis [7779], severe neutrophilic infiltrate within the small vessel walls and in their proximity [77], intense lymphocytic perivascular infiltrates [81], presence of fibrin [7981] and endothelial swelling [82] (Fig. ​(Fig.22).

Therapeutic Options

Topical corticosteroids have been successfully used for treating mild cases of purpuric lesions [80]. 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 [2] include, among others, the erythema multiforme-like eruption [83], pityriasis rosea-like rash [84], multi-system inflammatory syndrome in children [85], anagen effluvium [86] and a pseudoherpetic variant of Grover disease [87]. 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:

Conclusion

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 [23688899091]. 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.

Table 2

Summary of clinical features, histopathological findings, severity of COVID-19 systemic symptoms and therapeutic options of COVID-19-related skin manifestations

Clinical featuresCOVID-19 severityHistopathological findingsTherapeutic options
Urticarial rashItching urticarial rash predominantly involving the trunk and limbs; angioedema may also rarely occurIntermediate severityVacuolar interface dermatitis associated with superficial perivascular lymphocytic infiltrateLow-dose systemic corticosteroids combined with nonsedating antihistamines
Confluent erythematous/maculopapular/morbilliform rashGeneralized, symmetrical lesions starting from the trunk with centrifugal progression; purpuric lesions may coexist from the onset or develop during the course of the skin eruptionIntermediate severitySuperficial perivascular lymphocytic and/or neutrophilic infiltrateTopical corticosteroids for mild cases; systemic corticosteroids for severe cases
Papulovesicular exanthem(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 backIntermediate severityProminent acantholysis and dyskeratosis associated with unilocular intraepidermal vesicles in a suprabasal locationWait and see
Chilblain-like acral patternErythematous-violaceous patches or plaques predominantly involving the feet or, to a lesser extent, hands. Pain/burning sensation as well as pruritus were commonly reported symptomsAsymptomatic statusPerivascular and periadnexal dermal lymphocytic infiltratesWait and see
Livedo reticularis/racemosa-like patternLivedo 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 coagulopathyLivedo reticularis-like lesions: intermediate severity; livedo racemosa-like lesions: high severityPauci-inflammatory microthrombotic vasculopathyWait and see
Purpuric “vasculitic” patternPurpuric 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 lesionsHigh severityLeukocytoclastic vasculitis, severe perivascular neutrophilic and lymphocytic infiltrate, presence of fibrin and endothelial swellingTopical corticosteroids for mild cases; systemic corticosteroids for severe cases

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The correlation between severity of COVID-19 systemic symptoms and skin manifestations has been inferred mainly from the study by Freeman et al. [10].

Albeit several hypotheses on pathophysiological mechanisms at the basis of these skin findings are present in the literature [509293], 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 [3537] or drugs prescribed for the management of this infection [9495] 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.

Key Message

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.:

Funding Sources

This paper did not receive any funding.

Author Contributions

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:

Acknowledgment

We would like to thank Dr. Cosimo Misciali, Dr. Paolo Sena and Prof. Pietro Quaglino for kindly providing us with histopathological pictures.Go to:

References

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COVID-19 and chronic kidney disease: a comprehensive review

Authors: Inah Maria D. Pecly,1Rafael B. Azevedo,1Elizabeth S. Muxfeldt,1,2Bruna G. Botelho,1Gabriela G. Albuquerque,1Pedro Henrique P. Diniz,1Rodrigo Silva,1 and Cibele I. S. Rodrigues3

J Bras Nefrol. 2021 Jul-Sep; 43(3): 383–399.Published online 2021 Apr 9. doi: 10.1590/2175-8239-JBN-2020-0203PMCID: PMC8428633PMID: 33836039

Abstract

Kidney impairment in hospitalized patients with SARS-CoV-2 infection is associated with increased in-hospital mortality and worse clinical evolution, raising concerns towards patients with chronic kidney disease (CKD). From a pathophysiological perspective, COVID-19 is characterized by an overproduction of inflammatory cytokines (IL-6, TNF-alpha), causing systemic inflammation and hypercoagulability, and multiple organ dysfunction syndrome. Emerging data postulate that CKD under conservative treatment or renal replacement therapy (RRT) is an important risk factor for disease severity and higher in-hospital mortality amongst patients with COVID-19. Regarding RAAS blockers therapy during the pandemic, the initial assumption of a potential increase and deleterious impact in infectivity, disease severity, and mortality was not evidenced in medical literature. Moreover, the challenge of implementing social distancing in patients requiring dialysis during the pandemic prompted national and international societies to publish recommendations regarding the adoption of safety measures to reduce transmission risk and optimize dialysis treatment during the COVID-19 pandemic. Current data convey that kidney transplant recipients are more vulnerable to more severe infection. Thus, we provide a comprehensive review of the clinical outcomes and prognosis of patients with CKD under conservative treatment and dialysis, and kidney transplant recipients and COVID-19 infection.

Keywords: Renal Insufficiency, Chronic; Renal Dialysis; Peritoneal Dialysis; Mortality; Morbidity:

Introduction

In December 2019, cases of atypical pneumonia began to rise in the city of Wuhan, located in the providence of Hubei, China1. In March 2020, amid initiation of global spread, the World Health Organization (WHO) declared the outbreak a pandemic, caused by SARS-CoV-2, a new positive-strand RNA virus from the coronoviridae family, being from the same family of the viruses responsible for the severe acute respiratory syndrome (SARS) in 2002 and the middle east respiratory syndrome (MERS) in 20122  4. In Brazil, until mid-September, the country surpassed 4,100,000 confirmed cases and 130,000 deaths due to the disease2 , 3. The etiological agent of COVID-19 is more infectious than SARS and MERS, with a basic number of reproductions (R0) ranging from 2-3.55  7. Moreover, besides a high transmission rate, authors postulate that a crucial factor regarding the transmission of COVID-19 infection is the high level of SARS-CoV-2 present in the upper respiratory tract, even among pre-symptomatic patients, contributing to the global spread of the disease5  8.

From a pathophysiological perspective, COVID-19, especially in severe forms, is characterized by an overproduction of inflammatory cytokines due to cytokine storm triggered by viral infection, leading to systemic inflammation and a prothrombotic state9 , 10. Thus, besides lung involvement, other organ complications are observed in patients with SARS-CoV-2 infection such as kidney damage leading to acute kidney injury (AKI)11, raising concerns regarding the clinical outcomes and prognosis of patients with preexisting comorbidities such as chronic kidney disease (CKD), end-stage kidney disease (ESKD), and kidney transplant recipients under immunosuppression therapy.

A meta-analysis including 73 studies evaluating the association between multi-organ dysfunction and COVID-19 development revealed that patients with CKD were more likely to develop severe SARS-CoV-2 infection (OR 1.84 [95%CI 1.47-2.30])12. Hence, besides disease severity, it is imperative to evaluate the clinical outcomes, prognosis, and mortality associated with COVID-19 infection in patients with history of CKD, CKD on maintenance dialysis, and kidney transplant recipients (Figure 1).

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Figure 1COVID-19 in patients with Chronic Kidney Disease. Brief summary of the key points regarding SARS-CoV-2 infection in patients with prior CKD undergoing conservative or dialytic therapy.

Methodology

A thorough scoping review based on the PubMed electronic bibliographic database was performed between April and September 2020, using the following Mesh terms: “Renal” OR “Kidney”, OR “Hemodialysis”, OR “Peritoneal Dialysis”, OR AND “Chronic Kidney Disease” AND “Kidney Transplant Recipients” AND “COVID-19”, with adoption of the PICO strategy and classification of the level of evidence.

The guiding question to construct the review was: what is the latest scientific evidence regarding SARS-CoV-2 in patients with COVID-19 and chronic kidney disease? Articles diverging from the central theme were excluded from the review. After exclusion, 90 articles were selected and cited directly or via cross-reference in the present review.Go to:

Integrated Discussion

Patients with ckd under conservative treatment and covid-19

In 2017, CKD affected around 10.0% of the global population. In Brazil, more than 10 million presented the disease in its different stages, with 139,691 undergoing dialysis of which 93.2% in hemodialysis in 201913  15. In addition to the high prevalence, CKD remarkably increases morbimortality and is associated with higher infection risk, mainly respiratory, and a more precise comprehension of the prognosis and the clinical evolution of CKD patients infected by COVID-19 is crucial16. In a study evaluating the early predictors of clinical outcomes of COVID-19 outbreak in Milan, Italy, the prevalence of CKD amongst hospitalized patients with COVID-19 was 11.8%17.

De Lusignan et al. in a recent cross-sectional study describing the risk factors for SARS-CoV-2 infection among 3,802 patients in the Oxford Royal College of General Practitioners Research and Surveillance Centre primary care network found that individuals with CKD were more likely to test positive for COVID-19 (68 [32.9%] of 207 with CKD vs. 519 [14.4%] of 3595 without CKD; OR 1.91 [CI95% 1.31-2.78])18.

The high incidence of kidney involvement observed in hospitalized patients with COVID-19 might be also due to the presence of previous chronic kidney impairment. Cheng et al., in a prospective analysis of 701 patients with COVID-19, demonstrated that in comparison with patients with normal serum creatinine (SCr), patients admitted with elevated SCr presented higher leukocyte count (9.5±8.0 vs. 7.2±7.4 x 109/L, p=0.005), lower lymphocyte count (0.8±0.5 vs. 0.9±0.5 x 109/L, p=0.015), lower platelet count (191±94 vs. 216±84 x 109/L, p=0.014), prolonged partial thromboplastin time >42s (54.2 vs. 40.4%, p=0.029), higher D-dimer levels (>0.5mg/L) (89.8 vs. 75.3%, p=0.002), increased procalcitonin (≥0.5ng/mL) (29.3 vs. 6.9%, p<0.001), increased lactose dehydrogenase (LDH) (458±254 vs. 364±180, p=0.001), and the incidence of AKI was significantly higher in patients with elevated baseline SCr (11.9 vs. 4.0%, p=0.001). Furthermore, patients with COVID-19 and elevated baseline SCr presented higher prevalence of intensive care unit (ICU) admission (12.8 vs. 10.0%, p=0.382) and mechanical ventilation (21.8 vs. 12.8%, p=0.012). After univariate Cox regression analysis, elevated baseline SCr increased the risk of in-hospital death by almost three-fold (HR 2.99 [CI95% 2.00-4.47], p<0.001). CKD per se is associated with a proinflammatory state, inferring that patients with chronic kidney impairment and COVID-19 might evolve with a more pronounced cytokinetic storm, resulting in more severe systemic inflammation and hypercoagulability, being an important risk factor for acute kidney injury, severe illness, and mortality19.

The prospective analysis performed by Cheng et al. conjectures that previous chronic kidney impairment might have a negative impact on the clinical evolution and fatality risk of COVID-1919. Moreover, an analysis of the international Health Outcome Predictive Evaluation for COVID-19 registry (HOPE-COVID-19) evaluating the impact of renal function on admission and mortality in 758 patients with SARS-CoV-2 infection revealed a CKD prevalence of 8.5% amongst infected patients, and 30.0% had kidney dysfunction upon admission (eGFR <60mL/min/1.73m2)20. Patients were allocated into three groups according to the eGFR upon admission: absence of significant renal failure (eGFR >60mL/min/1.73m2), moderate renal failure (eGFR 30-60mL/min/1.73m2), and severe renal failure (eGFR <30mL/min/1.73m2). Patients with kidney dysfunction upon hospital admission presented a higher incidence of complications such as sepsis (11.9 vs. 26.4 vs. 40.8%, p<0.001) and respiratory failure (35.4 vs. 72.2 vs. 62.0%, p<0.001). Moreover, the incidence of AKI during admission was 19.7%, and patients with more severe kidney dysfunction upon admission were more susceptible for kidney function worsening during hospitalization (eGFR> 60mL/min/1.73m2 = 5.2% vs. eGFR 30-60mL/min/1.73m2= 31.8% vs. eGFR<30mL/min/1.73m2= 56.0%, p<0.001). Kaplan-Meier survival landmark analysis according to GFR demonstrated that the survival probability after 20 days was remarkably lower in patients with eGFR<30mL/min/1.73m2 (22.8%) and eGFR 30-60mL/min/1.73m2 (27.2%) compared to patients with absence of significant renal failure during hospital admission (71.7%). After Cox multivariate regression analysis, worse kidney function during hospital admission was an independent factor for in-hospital mortality as eGFR 30-60mL/min/1.73m2 increased in two-fold the risk of death (HR 2.205 [95%CI 1.573-3.091], p<0.001) and eGFR<30mL/min/1.73m2 increased almost five-fold the risk for in-hospital death amongst COVID-19 patients (HR 4.925 [95%CI 2.152-5.244], p<0.001)20.

Another prospective cohort study including 1,821 patients admitted to a University reference hospital in Spain revealed that 43.5% of patients with elevated SCr levels on hospital arrival had previous history of CKD and that the raw in-hospital mortality rate was higher in patients with increased SCr (32.4%), patients with previous CKD (41.1%), and patients who developed AKI during hospitalization (15.9%) compared to patients with normal SCr (5.8%). Additionally, the Kaplan-Meier analysis of cumulative incidence for in-hospital death revealed that patients with previous history of CKD and patients with elevated SCr levels on admission presented higher 20 day-mortality than patients with normal baseline creatinine. Elevated SCr on hospital admission (HR 4.07 [95%CI 3.07-5.39]) and previous history of CKD (HR 4.17 [95%CI 3.08-5.66]) were also associated with higher in-hospital death in the univariate Cox regression analysis. Thus, these studies accentuate that history of previous kidney impairment during hospital admission seems to be an independent risk factor for worse prognostic, urging that CKD history and kidney function must be screened during triage in patients with confirmed or suspected COVID-1919  21.

In an initial meta-analysis by Henry and Lippi published in March including four studies involving a total of 1,389 patients infected by SARS-CoV-2, the presence of CKD tripled the risk of patients developing severe disease [OR 3.03 (95%CI 1.09-8.47)]. Despite the low heterogeneity between the studies, none specifically evaluated and considered CKD as a pre-existing disease or obtained statistical significance, creating uncertainties about this association22. Nonetheless, the association between CKD and more severe COVID-19 was strengthened and clarified by subsequent studies.

Abrishami et al. in a single-center study evaluating the clinical and radiological characteristics of 43 adult CKD patients with confirmed COVID-19 in Iran, described that patients with CKD are vulnerable to a more severe form of COVID-19 and are predisposed to a higher mortality rate than the general population. The mean age of patients was 60.65±14.36 years and the most frequent CKD stage was IIIa (44.2%) and the least common was stage IV (4.7%), highlighting that amongst the total 43 CKD patients with COVID-19, 38 (88.4%) were discharged and 5 (11.6%) died on follow-up. The most prevalent symptoms were dyspnea (65.1%) and cough (60.5%). Laboratory evaluation revealed that leukopenia, leukocytosis, and thrombocytopenia were observed in 7 (16.3%), 4 (9.3%), and 12 (27.9%) patients, respectively. Moreover, LDH serum levels were significantly higher in CKD patients who died (740.2 ± 452.9 vs. 355 ± 127.5 IU/L). No significant laboratory alteration was observed across the CKD stages (p>0.05). Regarding CT scan findings, bilateral lung involvement was observed in 93.0% of the patients, the most common pattern of lung involvement was ground glass opacification (35.9%) and reticular pattern (16.3%), and the prevalence of pleural and pericardial effusion were 20.0 and 14.0%, respectively. Moreover, ground glass opacification was significantly higher in patients who died in comparison to survivors (60.0% vs. 31.5%). Regarding the analysis by CKD groups, the extent of lung involvement evaluated by total lung score significantly differ (p>0.05). On admission, 58.1% of CKD patients had severe COVID-19 and the mean duration of hospitalization was 11.65± 6.67 days, being more prolonged in patients with stage V CKD (15.4±6.4 days) and patients who died (16.6. ±8.38 days), despite lack of statistical significance (p>0.05)23. Thus, despite a high prevalence of severe disease and high mortality, higher CKD stage was not significantly associated to a worse prognosis23.

HOPE-COVID-19 investigators also demonstrated that from the 758 patients included in the study, patients with poorer kidney function (GFR 30-60mL/min/1.73m2 and GFR <30mL/min/1.73m2) on hospital admission had more adverse clinical manifestations and laboratory findings compared to patients with absence of significant renal failure (GFR >60mL/min/1.73m2)19. Shortness of breath (55.8 vs. 59.8 vs. 67.2%), tachypnea (19.0 vs. 28.1 vs. 39.9%) and, oxygen saturation on admission <92% (30.5 vs. 59.8 vs. 52.8%) were more frequent in patients with lower GFR during hospital admission. Furthermore, regarding laboratory profile, patients with poorer kidney function evolved with more significant D-dimer elevation (61.% vs. 79.% vs. 65.8%), and procalcitonin elevation (19.5 vs. 26.5 vs. 48.7%). More impaired kidney function during hospital admission was associated with a notably higher incidence of AKI (6.7 vs. 43.4 vs. 86.3%) and acute respiratory distress syndrome (ARDS) (35.4 vs. 72.2 vs. 62.0%). The prospective analysis from Spain corroborates these findings as patients with CKD presented increased inflammatory biomarker values such as CRP (113.7 vs. 65.6 mg/L, p=0.009) and ferritin (1132 vs 8721ng/mL, p=0.04), and altered coagulation markers as elevated D-dimer (>1.7mg/dL (%) (56.5 vs. 34.7%, p<0.001) and prolonged activated partial thromboplastin time (46.1 vs. 38.5 s, p<0.001) than non-CKD patients with COVID-1920 , 21.

A nationwide retrospective case-control study including 2,019,961 individuals evaluating the effect of underlying comorbidities on the severity of COVID-19 in Korea reported that CKD and ESKD were associated with severe COVID-19 (OR 2.052-2.178)24. Furthermore, a meta-analysis and systematic review including 34 studies also demonstrated that CKD (OR 3.02 [95%CI 2.23-4.08]) was associated with more severe and fatal outcomes among patients with COVID-1925. Fried et al. in an observational cohort study assessing clinical characteristics and outcomes of 11,271 patients with COVID-19 hospitalized in 245 hospitals across 38 different states in the United States revealed that CKD was associated with a higher need for mechanical ventilation (OR 1.22 [95%CI 1.05-1.43])26. Moreover, a cross-sectional study of 212,802 confirmed COVID-19 cases from Mexico demonstrated that comorbidities such as previous history of CKD increased the severity of COVID-19. The study found a correlation between CKD and a higher risk of hospitalization (OR 2.54 [95%CI 2.36–2.73]), ICU admission (OR 1.12 [95%CI 0.97-1.29]), and endotracheal intubation (OR 1.30 [1.15-1.48])27.

Besides more adverse clinical outcomes and heightened severity, CKD also seems to be associated with a higher mortality in patients with SARS-CoV-2 infection. Williamson et al. recently described the factors associated with COVID-19-related death using primary records of 17,278,392 adults pseudonymously linked to 10,926 COVID-19 related deaths with a secure health analytics platform from NHS England called OpenSAFELY28. The study emphasizes the significance of CKD as an important risk factor for COVID-19 mortality, as estimated hazard ratios from a multi-variable model associated CKD with eGFR 30-60 (HR 1.33 [95%CI 1.28-1.40]) and eGFR <30 (HR 2.52 [95%CI 2.33-2.72]) as a risk factor for mortality in patients with COVID-1928.

A retrospective observational cohort study evaluating the risk factors associated with mortality among 3,988 critically ill patients with laboratory-confirmed COVID-19 referred for ICU admission in the region of Lombardy in Italy revealed a high mortality in patients with CKD. Among the first 1,715 patients, the prevalence of CKD was 3.1% and of 52 patients with CKD admitted to the ICU, 41 died (78.8%) and 11 were discharged from ICU (21.2%). Regarding mortality in the hospital setting, 44 patients with CKD died (84.6%) and 7 were discharged from the hospital (13.5%). Analyzing the full cohort of 3,988 patients, 87 patients had previous history of CKD (2.2%) and 71 with CKD died (81.6%). After univariate analysis, CKD was associated with higher mortality (HR 2.78 [2.19-3.53], p<0.001) in patients with COVID-19 admitted to the ICU29.

An analysis of 3,391 patients positive for COVID-19 in the Mount Sinai hospital in New York demonstrated that without adjusting for age groups, patients with CKD had a higher risk of mortality (RR 2.51 [95%CI 1.82-3.47], p<0.001) and intubation (RR 2.05 [1.40-3.01], p<0.001). Moreover, amongst CKD patients, a significantly higher rate of death was observed in patients with atrial fibrillation (OR 2.13 [95%CI 1.03-4.43]), heart failure (OR 2.09 [1.16-3.77]), and ischemic heart disease (IHD) (OR 2.87 [1.04-3.36])30. Fang et al. in a meta-analysis and systematic review including 61 studies also associated CKD with higher mortality (RR 7.10 [3.14-16.02], p<0.001), increasing by seven-fold the risk of death in patients with SARS-CoV-2 infection31. Thus, CKD seems to be an important risk factor for disease severity and higher in-hospital mortality27  34.

The interaction between SARS-CoV-2 and the RAAS system raised concerns regarding the use of RAAS inhibitors during the COVID-19 pandemic, due to the possibility of enhanced virulence and infectivity, worsening the prognosis of these patients. Nonetheless, despite ACE-2 being later identified as a receptor for SARS-CoV-2 cell invasion, evidence initially suggesting that the use of RAAS blockers might increase the expression of ACE-2 in the heart and kidneys were not confirmed35.

In a retrospective study with 12,594 individuals who underwent COVID-19 tests, the use of RAAS inhibitors was not associated with a higher risk of contamination nor a worse evolution of the disease among patients infected by SARS-CoV-236. In another case-control study, Mancia et al. evaluated the impact of RAAS inhibitors in the severity of the disease in 6,272 patients who tested positive for COVID-19, in comparison with the control group of the target population37. Analogously, no association between the use of these anti-hypertensive agents and a more severe evolution of COVID-19 was demonstrated36 , 37.

Correspondingly, a meta-analysis of the effects of RAAS blockers (ACE inhibitors and angiotensin 2 AT1 receptor blockers) in patients with COVID-19 compared 308 individuals using RAAS blockers and 1,172 individuals undergoing treatment with other antihypertensive drugs38. Severity of disease, risk of hospitalization, and death were the main outcomes of interest assessed. Patients with COVID-19 who were taking RAAS blockers had a lower risk of developing severe illness (44.0%), lower risk of death (62.0%), and reduced hospitalization (19.0%), although reduced hospitalization did not obtain statistical significance38  41.

Therefore, the initial assumption of a potential increase in infectivity and morbimortality in patients with CKD, hypertension, and/or heart failure undergoing treatment with RAAS blockers during the COVID-19 pandemic and the lack of robust scientific data evidencing a deleterious impact, prompted national and international societies to issue positions urging RAAS inhibitors maintenance in patients with formal indication. Additionally, a non-deleterious impact of RAAS blockers in SARS-CoV-2 clinical evolution has been proven by subsequent papers37 , 38 , 42  46.

The BRACE CORONA trial, the first multi-center randomized controlled study evaluating the safety of ACE inhibitors and ARBs on hospitalized patients with mild to moderate COVID-19 in 659 enrolled patients from 29 distinct sites in Brazil, revealed that among patients with COVID-19 infection undergoing chronic ACEi/ARB therapy, suspending ACEi/ARB did not improve the number of days alive and hospital discharge in 30 days (21.9 vs. 22.9, p=0.009), and a similar 30-day mortality rate was observed in COVID-19 patients who continued or suspended ACEi/ARB therapy (2.8 vs. 2.7%, p=0.95), highlighting that there is no clinical benefit from ACEi inhibitor/ARB treatment interruption in hospitalized patients with mild to moderate COVID-1947.

Studies are still required for a better comprehension of the peculiarities, clinical outcomes, and prognosis of non-dialytic CKD patients with COVID-19, elucidating questions about comorbidities as confounding factors and their immunological profile, to obtain the best possible outcomes for these patients. The main findings of studies involving individuals with CKD under conservative treatment are summarized in Table 1.

Table 1

Summary of the major studies regarding CKD under conservative treatment and COVID-19

AuthorNDesignAge (years)ComorbiditiesMajor findings
Uribarri et al.758Cohort  1.Mortality risk:
  (Kaplan-Meier survival curve):
  -eGFR > 60mL/ min/1.73 m2 = 71.7%
  – eGFR 30-60 mL/ min/1.73 m2 = 27.2%
 HTN (48.9%)– eGFR < 30mL/ min/1.73 m2 = 22.8%
66.0DLP (38.7%)2. Risk factors on admission associated with in-hospital death (multivariate regression):
±18.0DM (21.9%)– Age: (HR 1.034 [CI95%1.021-1.048]; p<0.001)
 CKD (8.5%)– SatO2 <92.0%: (HR 3.310 [2.362-4.369]; p<0.001)
  – eGFR 30-60: (HR 2.205 [1.473-3.091]; p<0.001)
  – eGFR < 30 (HR 4.925 [2.152-5.244]; p<0.001)
Ji et al.219,961Retrospective HTN (22.2%) 
47.05DM (14.2%)1. Severe COVID-19: (multivariate analysis)
±18.0CAD (4.2%)-CKD/ESKD: (OR 2.052-2.178)
 CKD (1.0%) 
Fried et al.11,721Retrospective  1. Severe COVID-19:
 HTN (46.7%)-Mechanical ventilation
> 60DM (27.8 %)(15.2% vs. 11.6%; p<0.001)
(67.3%)CVD (22.6 %)(OR 1.22 [CI95% 1.05-1.43]).
 CKD (4.3%)2.Mortality:
  -CKD (OR 1.66 [CI95% 1.45-1.91]).
Hernández-Galdamez et al.212,802Cross-sectional  1. Severe COVID-19:
  Hospitalization:
 HTN (20.12%)i. CKD (OR 2.54).
45.7DM (16.44%)ii. ICU admission:
±16.3CVD (2.35%)CKD (OR 1.12).
 CKD (2.17%)iii. Intubation:
  CKD (OR 1.30).
  2. Mortality:
  – CKD (OR 2.31).
Williamson et al.17,278,392Cohort18-39 (34.2%)  
40-49 (16.5%) 1.Mortality:
50-59 (17.7%)HTN (34.3%)Kidney function:
60-69 (13.8%)CVD (6.8%)i). eGFR 30-60 (HR 1.33 [1.28-1.40]).
70-79 (11.2%) ii) eGFR <30 (HR 2.52 [2.33-2.72]).
>80 (6.5%)  
Grasselli et al.3,988RetrospectiveHTN (41.2%)1.Mortality:
DM (12.9%)– CKD (OR 2.78 [95%CI 2.19-3.53];p<0.001).
CVD (13.4%)

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DM, diabetes mellitus; HTN, hypertension; CVD, cardiovascular disease; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease; DLP, dyslipidemia; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; ICU, intensive care unit.

Patients with ckd in dialytic therapy and covid-19

Evidence concerning management of CKD patients on dialysis therapy infected with SARS-CoV-2 is still scarce. While these are high-risk patients due to the presence of comorbidities, especially hypertension, cardiopathies, left ventricular hypertrophy, diabetes mellitus, among others, it is not yet clear if dialysis therapy per se is associated with a worse prognosis in patients infected with SARS-CoV-2, although infections in general can decompensate underlying CKD48  52.

In a recent analysis of 37,852 patients in hemodialysis (HD) in Brazil, 1,291 patients were positive for SARS-CoV-2 infection and 357 patients died. Authors postulate that the incidence, mortality, and fatality rates in HD patients were 341/10,000 patients, 94/10,000 patients, and 27.7%, respectively, raising concerns regarding the vulnerability of this group amid the COVID-19 pandemic53.

Implementing social distancing in patients requiring dialysis is difficult due to need of frequent visits to dialysis clinics and direct contact with special care teams of clinics and hospitals, increasing the risk of COVID-19 dissemination and consequently the vulnerability of this group50 , 51.

Initial Chinese case report studies revealed that patients with CKD on dialysis, presented moderate clinical manifestations, with fever as the most prevalent symptom, whilst only a small group of CKD patients developed cough. A study carried out in Zhongnan hospital, Wuhan, described diarrhea as the most frequent manifestation in these patients52. Another study reported gastrointestinal manifestation as the most important initial complaint among patients on dialysis treatment, and due to the atypical symptomatology, the authors emphasized the importance of individualized patient approach to optimize COVID-19 diagnostic accuracy in this peculiar group with uncertain prognosis52  54.

Authors initially hypothesized that the presence of atypical clinical manifestations and a possible less severe evolution of COVID-19 in CKD patients undergoing dialysis was due to the immunodepression status of these patients, inferring that this group of patients might not develop the usual severe immune dysregulation and consequent cytokinetic storm of critical SARS-CoV-2 infection. This could be due to these patients evolving with more significant lymphopenia and lower serum cytokines when compared to infected patients without history of kidney disease55. Nevertheless, recent retrospective and observational studies with more robust epidemiological and clinical data of COVID-19 patients undergoing dialysis demonstrated an increased risk for adverse clinical outcomes and higher mortality in this group of patients.

Xiong et al., in a retrospective multicenter study evaluating the clinical characteristics of 131 patients undergoing hemodialysis with SARS-CoV-2 infection, revealed that the most common symptoms were fever (51.9%), fatigue (45.0%), cough (37.4%), sputum production (29.0%), and dyspnea (26%). Furthermore, 40 (30.5%) patients evolved with acute organ injury and dysfunction, including 24 (28.2%) with cardiac injury, 16 (15.5%) with liver dysfunction, 16 (13.8%) with ARDS, and 9 (9.6%) with cerebrovascular event. Regarding radiologic findings, the most common abnormalities revealed in CT scans were ground-glass or patchy opacities (82.1%) with bilateral lung involvement (86.7%), but foci of consolidation was uncommon (4.3%). Laboratory data revealed that the median levels of hemoglobin and lymphocytes were 105 x 109 cells/L (IQR 91.0-118.0) and 0.7 x 109 cells/L (IQR 0.5-1.1), respectively, and the majority of the patients had normal white cell and platelet counts56.

ESKD on chronic hemodialysis is also associated with higher short-term mortality, worse clinical evolution, and increased severity. A retrospective cohort study with 114 hospitalized patients on chronic hemodialysis with COVID-19 in New York demonstrated that 13.0% required ICU admission, 17.0% required mechanical ventilation, and in-hospital death occurred in 28.0% of these patients, being 87.0% of those who required ICU care57. Likewise, Valeri et al. retrospectively analyzing the clinical presentation and outcomes of 59 hospitalized patients with ESKD and COVID-19 revealed that 18 patients (31%) died in a median of 6 days after hospital admission, including 75.0% of patients who required mechanical ventilation. Moreover, patients who died presented higher initial median values of white blood cell count (7.5 vs. 5.7 x 1000/µL; p=0.04), lactate dehydrogenase (507 vs. 312 U/L; p=0.04), and C-reactive protein (CRP) (163 vs. 30.3 mg/L; p=0.01) in comparison to survivors58.

Tortonese et al. in a retrospective cohort study describing the demographics and clinical course of 44 patients on maintenance dialysis with COVID-19 in the Paris region also showed a correlation with worse outcomes and higher SARS-CoV-2 infection severity. The main coexisting comorbidities were hypertension (97.7%), dyslipidemia (59.1%), diabetes mellitus (50.0%), and obesity (34.1%), whilst the most prevalent symptoms were fever and chills (79.5%) and cough and shortness of breath (29.5%). Diarrhea, a frequent symptom in preliminary case reports, was present in 13.6% of patients59.

Laboratory evaluation revealed that most dialyzed ESKD patients with COVID-19 during hospitalization presented anemia (77.3%), hyperfibrinogenemia (77.3%), hyperferritinemia (70.5%), increased D-dimer levels (56.8%), lymphopenia (54.5%), and increased CRP levels (52.3%), depicting a more profound inflammatory and thrombotic profile. Moreover, aggravation of hematological and inflammatory markers was more remarkable in patients requiring oxygen therapy. Chest computed tomography scan performed in all 41 patients demonstrated a high prevalence of bilateral ground-glass opacities with or without consolidations (80.5%) and severe radiological findings were present in 31.7% of the cases59.

The retrospective analysis also demonstrated that COVID-19 in dialyzed patients was associated with a higher mortality rate, complications, and prolonged hospitalization. The median duration of hospitalization was 12 days (IQR 7-18) and the median length of stay in ICU was 10 days (IQR 7-21). Concerning severe adverse events, 27.3% of ESKD dialytic patients required mechanical ventilation, 27.3% evolved with ARDS, and 22.7%, with hemodynamic instability. In comparison with non-dialyzed patients, ESKD dialyzed patients presented higher mortality (27.3 vs. 12.9%, p=0.006), increased need for intensive care (34.1 vs. 22.7%, p=0.04) and remarkably higher in-ICU mortality (60.0 vs. 20.7%, p=0.002). After univariate Cox survival analysis, ARDS (HR 4.44 [95%CI 1.40-14.03], p=0.01), neutrophil count ≥10g/L (HR 4.49 [1.34-14.93], p=0.01), thrombocytopenia (HR 6.06 [1.64-22.49], p=0.003), metabolic acidosis (HR 11.18 [1.43-87.51], p=0.02), LDH levels ≥ 2 times the upper normal limit (HR 3.99 [1.26-12.63], p=0.016), blood CRP level ≥ 175mg/L (HR 13.06 [1.68-101.41], p<0.001), and D-dimer level > 4000 U/I (HR 4.44 [1.11-11.03], p=0.03) were associated with higher risk of death, being potential prognostic factors for mortality in hospitalized ESKD dialytic patients with COVID-1959.

A report from the Brescia renal COVID task force on the clinical characteristics and short-term outcomes of hemodialysis patients with SARS-CoV-2 infection also revealed a significant association with disease severity and in-hospital mortality. From a total of 94 patients, 57 (60.0%) required hospitalization after a median time from symptom onset of 4 days (IQR, 1-7) and from positive RT-PCR test results of 4 days (IQR, 1-3). Furthermore, 45 patients (79.0%) developed ARDS and 24 patients (42.0%) died after a median of 9 days (IQR, 7-10) from symptom onset. Among patients who died, the most frequent cause of death was respiratory failure secondary to ARDS (63.05%). Among survivors, 11 patients (19.0%) were discharged after a median of 8 days from admission (IQR, 6.5-13) and 15 days (IQR, 12.5-17.5) from onset of symptoms. After univariate logistic regression analysis, heart failure (OR 6.22 [CI95% 1.85-28.6]; p=0.007), ischemic heart disease (OR 5.61 [1.65-25.9]; p=0.01), fever at disease diagnosis (OR 18.2 [5.6-82.44]; p= 0.000013), shortness of breath at diagnosis (OR 18.17 [4.8-119.5]; p = 0.0002), myalgia or fatigue at diagnosis (OR 5.6 [1.65-25.9]; p = 0.01), infiltrates at the baseline chest X-ray (OR 4.4 [1.67-13]; p = 0.004), higher aspartate aminotransferase levels (OR 2.81 [1.08-7.6]; p= 0.04), and higher C-reactive protein levels (OR 4.68 [1.83-12.7]; p = 0.002) were associated with higher chance of developing ARDS during hospitalization. Additionally, ischemic heart disease (OR 3.11 [1.02-9.6]; p= 0.05), fever at disease diagnosis (OR 18.7 [3.62-343]; p = 0.005), cough at disease diagnosis (OR 3.5 [1.28-9.7]; p= 0.01), shortness of breath at disease diagnosis (OR 5.3 [2-15]; p= 0.001), and higher C-reactive protein level at disease diagnosis (OR 6.0 [2.1-19]; p = 0.001) were associated with higher mortality among hospitalized patients60.

Wang et al. in a retrospective single-center case series study in Zhongnan Hospital of Wuhan University evaluated the clinical outcomes of maintenance hemodialysis patients with COVID-19 and the impact of proactive chest CT scans. From 202 HD patients, 7 (3.5%) were diagnosed with SARS-CoV-2 infection, being 5 patients by RT-PCR and 2 patients diagnosed by RT-PCR as a result of screening 197 asymptomatic HD patients by chest CT scan. Regarding chest CT findings, 13 patients presented ground-glass opacity, but only 2 patients (15.0%) were confirmed to have COVID-19 by RT-PCR. Among the 7 patients with confirmed infection, all of them presented bilateral lung involvement. Lymphocytopenia (86%), elevated LDH (75%), elevated D-dimer (83%), elevated CRP (100%), and elevated procalcitonin (100%) were the most prevalent laboratory findings in infected HD patients. Moreover, 4 patients (57.0%) received oxygen therapy, 1 patient received noninvasive and invasive mechanical ventilation (14.0%), 1 patient developed ARDS (14.0%), and 3 patients died61. Additionally, another retrospective analysis of 31 hemodialysis patients with COVID-19 revealed an association with more severe illness and more adverse outcomes as 58.1% of patients presented organ dysfunction including ARDS (25.8%), acute heart failure (22.6%), and septic shock (16.1%)62. Besides worse clinical outcomes, a retrospective analysis of 14 consecutive patients on HD or with advanced CKD who initiated HD after COVID-19 diagnosis in South Korea demonstrated a prolonged median length of hospital and ICU stay in these patients, being 22.0 days and 6.0 days, respectively63.

The clinical outcomes of patients requiring chronic peritoneal dialysis (PD) associated with SARS-CoV-2 infection is also a concern for nephrologists. Sachdeva et al. in a case series study including 419 hospitalized patients with ESKD, 11 patients were on chronic PD (2.6%). Regarding clinical manifestations, the most prevalent symptoms were fever (64.0%), diarrhea (55.0%), shortness of breath (45.0%), cough (45.0%), and myalgias (36.0%). Majority of the patients presented bilateral opacities (82.0%) during initial chest imaging. Moreover, 3 patients (27.0%) were admitted to the ICU requiring mechanical ventilation. The length of hospital stay ranged from 2 to 23 days with a median of 9 days. Two patients died (18.0%) and 9 were discharged from the hospital (82.0%). Further studies with longer follow-up and a larger population are required for a more precise analysis concerning the clinical outcomes of chronic PD patients with COVID-1964.

Hence, SARS-CoV-2 infection in ESKD patients on maintenance dialysis seems to be associated with worse clinical outcomes, more profound inflammatory and thrombotic profile, more severe radiological findings, prolonged hospitalization, and higher fatality rate57  61 , 63.

Considering the hazardous context of SARS-CoV-2 infection, in order to attenuate the spread of the virus in CKD patients undergoing dialysis, a series of safety measures were adopted by hemodialysis centers and clinics to efficiently operate throughout the pandemic (Table 2)65  72. Nonetheless, Corbett et al. in a cohort study evaluating the epidemiology of COVID-19 in dialysis centers in the United Kingdom revealed that COVID-19 caused an abrupt epidemic in patients and healthcare workers. From the cohort of 1,530 patients with established kidney failure treated with dialysis in satellite units, 300 patients (19.6%) developed COVID-1973. In contrast, a study analyzing the incidence, clinical outcomes, and risk factors for mortality of COVID-19 in the French national cohort of dialysis patients demonstrated that the prevalence of COVID-19 varied from less than 1.0 to 10.0%74. Nevertheless, among 1,621 infected patients, 344 died (20.0%) and 9.0% were admitted to the ICU, highlighting that the mortality of ICU patients was higher compared to patients that did not require intensive care (35.0 vs. 15.5%). Risk factors for infection in dialysis patients were male sex (OR 1.2 [95%CI 1.1-1.4]), diabetes (OR 1.3 [1.1-1.4]), patients in need of assistance for transfer (OR 1.5 [1.3-1.8]), and patients treated in a self-care unit (OR 1.3 [1.0-1.6]). Moreover, at-home dialysis was associated with a lower SARS-CoV-2 infection probability (OR 0.6 [0.4-0.8])74. Despite lower incidence of SARS-CoV-2 infection compared with data from Corbett et al., patients on maintenance dialysis with COVID-19 presented high mortality, being imperative to reinforce health team protection and feasible logistics to secure patient safety and access to this indispensable treatment during this critical period65 , 70  74. High-risk of SARS-CoV-2 transmission, increased rates of hospitalization, and heightened morbimortality associated with ESKD patients on hemodialysis increased the support for home-based dialysis during the COVID-19 pandemic, particularly for PD modality75. The main findings of studies involving individuals with CKD under dialysis treatment are summarized in Table 3.

Table 2

Safety measures for dialysis centers during COVID-19 pandemic

GroupMain recommendations
Hemodialysis patients1. Education
 ✓ Patients should call dialysis clinics beforehand, optimizing specific individualized arrival logistics mitigating COVID-19 risk.
 ✓ Patients should inform healthcare team of the presence of suspected COVID-19 symptoms before arrival.
 ✓ Patients should be instructed on the proper use of PPE.
 ✓ Patients should be instructed to safely self-isolate.
 2. Screening
 ✓ Temperature screening for all patients upon arrival in dialysis clinics, being mandatory before and after sessions.
 ✓ All patients should perform hand hygiene upon arrival in dialysis clinics.
 ✓ All patients should wear personal protective equipment at all times during dialysis sessions.
 ✓ Single use dialyzers of confirmed and/or suspected patients should be disposed.
 ✓ All symptomatic dialytic patients must undergo rt-PCR screening test for COVID-19.
 ✓ Symptomatic patients must be kept in isolation during dialysis sessions (6 ft of separation).
 ✓ Patients with signs of critical infection must be immediately referred to a hospital.
Healthcare team3. Education
 ✓ PPE training for appropriate use.
 ✓ PPE use at all times (isolation gown, gloves, mask, and eye protection).
 ✓ Be vigilant towards COVID-19 symptoms.
 ✓ Implementation of disinfection routine of all dialysis stations.
 ✓ Emphasize and enhance dialytic patient’s knowledge regarding SARS-CoV-2 risks and infectivity.
 ✓ Staying home if symptomatic.
 4. Screening
 ✓ Body temperature measurement and symptom triage before contacting and assisting patients.
 ✓ Symptomatic employees must be isolated and submitted to specific protocol.
 ✓ All symptomatic healthcare workers should undergo rt-PCR screening test before patient assistance.

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PPE: personal protective equipment.

Table 3

Summary of the major studies regarding CKD under dialysis and COVID-19

AuthorNDesignAge (years)ComorbiditiesMajor findings
Xiong et al.7,154Retrospective  1. Clinical Manifestations:
 CVD (68.7%)-Fever (51.9%), fatigue (45.0%), cough (37.4%), sputum (29.0%), and dyspnea (26.0%).
63.1DM (22.9%)2. Clinical Evolution:
(13.4)COPD (3.8%)-Acute organ dysfunction (30.5%),
 Cancer (1.5%)– Cardiac injury (28.2%),
  – Liver dysfunction (15.5%),
  – ARDS (13.8%).
Fisher et al.114Cohort  1. Severe COVID-19:
 HTN (90.0%)-ICU admission (13.0%).
64.5DM (67.0%)-Mechanical ventilation (17.0%).
(55.0-73.0)CVD (55.0%)2. Mortality:
 Cancer (12.0%)-In-hospital death (28.0%):
  -ICU (87.0%).
  – General floor (19.0%).
Valeri et al.59Retrospective  1.Severe COVID-19:
  – Mechanical ventilation (14.0%).
 HTN (98.0%)2. Mortality:
63.0DM (69.0%)– In-hospital death: (31.0%).
(56-70)CAD (46.0%)– Laboratory profile of patients who died compared to survivors:
 PD (17.0%)– WBC (507 vs. 312 U/L; p=0.04).
  – CRP (163.0 vs. 80.3 mg/L; p=0.01).
  – LDH (507 vs. 312 U/L; p=0.04).
Tortonese et al.44Retrospective  1. Mortality
 HTN (97.7%)Dialyzed x non-dialyzed:
61.0DM (50.0%)1.1 Fatality Rate:
(51.5-72.5)DLP (59.1%)-Patients requiring oxygen therapy: (36.4%); ICU patients: (60.0%); Non-dialyzed patients: (12.9%); Dialyzed patients: (27.3%).
 Obesity (34.1%)1.2 Risk factors for mortality (Multivariate Cox analysis):
  – Cough (HR 5.18); thrombopenia ≤120g/L (HR 10.22); LDH ≥2N (HR 5.97); CRP ≥175mg/L (HR 19.53).
Alberici et al.94Retrospective  1. Risk factors for ARDS:
 HTN (93.0%)-History of IHD (OR 7.5); fever at diagnosis (OR 17.0); Dyspnea at disease onset (OR 20).
72.0DM (43.0%)2. Risk factors for mortality:
(62.0-79.0)CAD (17.0%)– Fever (OR 18.7); cough (OR 4.0); Increased CRP (OR 5.6).
 Cancer (12.0%)
Cécile et al.1,621Cohort  1. Severe COVID-19:
 DM (50.8%)-ICU admission (9.0%).
71.9CAD (27.2%)-Mechanical ventilation (51.0%).
(60.8-81.0)COPD (15.5%)2. Mortality:
 Cancer (9.3%)-Outpatients (8.5%):
  -Hospitalized (22.4%).
  – ICU (34.0% vs. 15.5%).

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DM: diabetes mellitus; HTN: hypertension; CVD: cardiovascular disease; CAD: coronary artery disease; COPD: chronic obstructive pulmonary disease; PD: pulmonary disease; DLP: dyslipidemia; IHD: ischemic heart disease; ICU: intensive care unit.

Kidney transplant recipients and covid-19

Evidence on the management and prognosis of kidney transplant recipients with COVID-19 is limited to case reports. In the vast majority of cases, the withdrawal or reduction of immunosuppressive therapy and the maintenance or introduction of corticosteroids were advocated, due to their immunomodulatory, anti-inflammatory, and vascular properties, which provide immunological protection to the renal allograft. However, while the ideal time for the reintroduction of immunosuppressive agents is quite uncertain, a prolonged reduction in immunosuppression increases the risk of graft rejection76  84.

Moreover, a significant part of preliminary reports show that kidney transplant recipients with COVID-19 have typical clinical symptoms, with fever and cough being quite recurrent76 , 78 , 84. There are also reports that, in addition to fever and cough, patients presented diarrhea and viral conjunctivitis77 , 85. Another important aspect observed in early case reports concerns radiographic alterations with unilateral or bilateral infiltrates during admission of these patients, of which most require ventilatory support, given the rapid decompensation observed among patients who develop ARDS77  84. Pulmonary complications, infectious or otherwise, are known to be an important cause of morbidity in patients undergoing immunosuppression86.( )It is also important to note that almost all patients in these reports presented comorbidities such as hypertension, diabetes, cancer, obesity, chronic respiratory diseases, and cardiovascular diseases, and some described the development of acute kidney injuries after hospital admission.

Devresse et al. described the clinical outcomes and mortality in a single center case series of 22 cases of COVID-19 in a cohort of 1,200 kidney transplant recipients in Belgium. From a total of 22 patients, 18 (82.0%) required hospitalization, and chest CT scan during admission performed in 15 patients revealed mild involvement in 3 patients (20.0%), moderate involvement in 8 patients (53.0%), severe involvement in 2 patients (13.0%), extensive involvement in 1 patient (7.0%), and critical involvement in 1 patient (7.0%). During hospital admission, the median baseline GFR was 45 (15-95) mL/min/1.73m2, median CRP was 56 (1.5-314) mg/L, and median lymphocyte count was 730 (50-1440)/µL. Moreover, 11 patients required supplemental oxygen therapy and 2 were admitted to the ICU requiring mechanical ventilation. Despite a small number of patients and a short follow-up period, after a period of 18 days, 13 (72.0%) of the 18 patients who required hospitalization were discharged from the hospital after a median of 10 days, however 3 (17.0%) patients were still hospitalized and 2 patients died (11.1%)87.

In another case series study with 12 patients evaluating the clinical course, imaging features, and clinical outcomes of COVID-19 infection in kidney transplant recipients, the most common symptoms were fever (75.0%), cough (75.0%), and dyspnea (41.7%), and only 1 patient had gastrointestinal symptoms. Leukopenia was observed in 4 patients (33.3%), leukocytosis in 1 patient (8.3%), CRP was elevated in 10 patients (83.3%), and creatine phosphokinase was elevated in five patients (55.0%). During hospital admission, mean BUN was 82.9±55.2 mg/dL and creatinine was 2.30±1.09 mg/dL. Initial CT scan on hospital admission revealed bilateral lung involvement in eight patients and unilateral involvement in four patients, the lower lobes were compromised in 11 patients, and a combination of consolidation and ground glass opacities (GGO) was the most prevalent pattern on the chest CT scan (75.05%). The authors postulate that interlobular septal thickening, multilobular patterns, consolidative lesions, and a high score for lung involvement were more prevalent among patients with more adverse outcomes and ARDS. Regarding clinical outcomes, 10 patients were admitted to the ICU, 9 were intubated, and 8 died of severe COVID-19 pneumonia and ARDS. The median length of hospital stay was 15 days (IQR 8.0-1.5) being longer in patients who died (18.0 days, IQR 12.3-21.5)88.

A prospective study assessing the clinical outcomes and the incidence of SARS-CoV-2 infection among 1,216 kidney transplant recipients revealed that patients with kidney transplant have a high risk of severe COVID-19. The most frequent symptoms were fever (77.0%) and cough (58.0%), and 60 patients (91.0%) required hospitalization. Furthermore, 15 patients (22.0%) required mechanical ventilation being transferred to the ICU. Notably, dyspnea was the most frequent symptom in patients admitted to the ICU, being observed in 12 of 15 (80.0%) patients in the invasive mechanical ventilation group compared with 27.0% in the non-invasive group. Also, the majority of patients requiring invasive mechanical ventilation had bilateral and multifocal lung opacities on chest x-ray or CT scan. The mortality rate related to COVID-19 disease in the cohort of kidney transplant population was 1.0%, nonetheless 16 of 66 (24.05%) kidney transplant recipients positive for COVID-19 died. After univariate logistic regression analysis, non-white ethnicity (OR 2.17 [95%CI 1.23-3.78], p=0.007), obesity (OR 2.19 [1.19-4.05, p=0.01), asthma and chronic pulmonary disease (OR 3.09 [1.49-6.41], p=0.002), and diabetes (OR 3.33 [1.92 to 5.77], p<0.001) were independently associated with COVID-19 in kidney transplant recipients89. Caillard et al. in a registry-based observational study including 279 transplant recipient patients with COVID-19 in France demonstrated a high 30-day mortality rate among this patient population (22.8%). Moreover, multivariable analysis identified age >60 years, cardiovascular disease, and dyspnea as independent risk factors for mortality in hospitalized patients90.

Studies are controversial due to their heterogeneity and a large number of confounders that influence the outcome of each case, such as the age of patients, time of transplantation, medications, and comorbidities. The future challenge is to identify the main clinical markers of poor prognosis in patients with kidney transplant, with additional studies with longer follow-up periods and more robust populations of immunosuppressed kidney transplant recipients. Table 4 summarizes the main findings of studies involving kidney transplant recipients.

Table 4

Summary of the major studies regarding kidney transplant recipients and COVID-19

AuthorNDesignAge (years)ComorbiditiesMajor findings
Devresse et al.22Cohort  1. Clinical manifestations: .
 HTN (78.0%)-Fever (78.0%), cough (67.0%), dyspnea (39.0%), digestive symptoms (28.0%), neurologic symptoms (16.0%)
57.0DM (22.0%)2. Radiological presentation on CT:
(41.0-73.0)CVD (22.0%)-Mild (20.0%), moderate (53.0%), severe (13.0%), extensive (7.0%), critical (7.0%).
 Obesity (22.0%)
Abrishami et al.12Case series 0 (14.0%)1. Clinical manifestations:
66.01 (22.0%)
(57.0-76.0)2 (25.0%)-Fever (75.0%), cough (12.0%), dyspnea (41.7%).
 3 (13.0%)2. Radiological presentation on CT:
 >4 (21.0%)– Bilateral involvement (66.7%), GGO (100.0%), consolidation (75.0%), interlobular septal thickening (41.7%).
Elias et al.1216Prospective56.4 ±13.4DM (16.0%)1. Factors associated with COVID-19 in patients with KT (multivariate analysis):
– Non-White ethnicity (OR 2.17 [CI95% 1.23-3.78]; p=0.007), obesity (OR 2.19 [CI95% 1.19-4.05];p=0.01), asthma and COPD (OR 3.09 [CI95% 1.49-6.41; p=0.002), diabetes (OR 3.33 [CI95% 1.92-5.77];p<0.001).
Caillard et al279Observational  1.Clinical manifestations:
  -Symptoms: Fever (80.0%), cough (63.6%), diarrhea (43.5%), dyspnea (40.3%), and anosmia (14.1%).
  2.Laboratory profile:
  -CRP, mg/L (62 [27-144]); procalcitonin, ng/mL (0.20 [0.14-0.48]); lymphocyte count, x109 (0.66 [0.40-0.96]); platelet count, x109/L (178 [145-238); thrombocytopenia, <150 x109/L (54 [29%]); creatinine, µmol/L (176 [131-244]).
  3.Radiographic profile:
 HTN (90.1%)-Lung infiltrates on chest CT were detected in 87.0% of patients.
61.6DM (41.3%)4.Clinical outcomes:
(50.8-69.0)CVD (36.2%)-Complications: Acute kidney injury (43.6%), bacterial coinfection (23.5%), renal replacement therapy (11.1%), viral coinfection (2.1%), fungal coinfection (2.5%).
 Cancer (15.5%)5.Severe COVID-19:
  -Oxygen therapy (72.4%), mechanical ventilation (29.6%), vasopressor support (11.1%).
  -ICU (36.0%); median interval between hospitalization and ICU admission was 4 days [1-25 days].
  Risk factors: >60yr (HR 1.63), BMI>25 kg/m2 (HR 1.80), diabetes (HR 1.73), dyspnea (HR 2.28), fever (HR 1.77), procalcitonin >0.2 (HR 3.19), SatO2 <95.0% (HR 2.47).
  6.Mortality: -30-day mortality rate: 22.8%
  Risk factors: age >60yr (HR 3.81), History of CVD (HR 2.04), dyspnea on hospital admission (HR 2.35).

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DM, diabetes mellitus; HTN, hypertension; CVD, cardiovascular disease; BMI, body mass index; COPD, chronic obstructive pulmonary disease; ICU: intensive care unit.Go to:

Conclusion

CKD under conservative treatment or maintenance dialysis seems to be associated with more adverse clinical outcomes, more severe disease, higher mortality, and poorer prognosis in patients with COVID-19 infection. Further studies are still required to elucidate the prognosis and clinical evolution of transplant kidney recipients. History of CKD must be taken into consideration during risk stratification of patients with confirmed or suspected COVID-19. Early detection of kidney abnormalities, optimal hemodynamic support when indicated, and avoiding nephrotoxic drugs with a risk-benefit judgement are essential steps to ensure a better evolution of these patients during hospitalization.Go to:

Acknowledgements

This study was supported by research grants from the Conselho Brasileiro de Desenvolvimento Científico e Tecnológico (CNPq, Distrito Federal, Brazil) and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ, Brazil). The sponsors have no role in study design, data collection and analysis, results interpretation or in preparation, review and approval of the manuscript.Go to:

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Gastrointestinal perforation secondary to COVID-19

Authors: Case reports and literature review Reem J. Al Argan, MBBS, SB-Med, SF-Endo, FACE, ECNU,Safi G. Alqatari, MBBS, MRCPI, MMedSc, CFP (Rheum), Abir H. Al Said, MBBS, SB-Med, CFP (Pulmo.), Raed M. Alsulaiman, MBBS, SB-Med, Abdulsalam Noor, MBBS, SB-Med, ArBIM, SF-Nephro, Lameyaa A. Al Sheekh, MD, SB-med, and Feda’a H. Al Beladi, MD

Introduction:

Corona virus disease-2019 (COVID-19) presents primarily with respiratory symptoms. However, extra respiratory manifestations are being frequently recognized including gastrointestinal involvement. The most common gastrointestinal symptoms are nausea, vomiting, diarrhea and abdominal pain. Gastrointestinal perforation in association with COVID-19 is rarely reported in the literature.

Patient concerns and diagnosis:

In this series, we are reporting 3 cases with different presentations of gastrointestinal perforation in the setting of COVID-19. Two patients were admitted with critical COVID-19 pneumonia, both required intensive care, intubation and mechanical ventilation. The first one was an elderly gentleman who had difficult weaning from mechanical ventilation and required tracheostomy. During his stay in intensive care unit, he developed Candidemia without clear source. After transfer to the ward, he developed lower gastrointestinal bleeding and found by imaging to have sealed perforated cecal mass with radiological signs of peritonitis. The second one was an obese young gentleman who was found incidentally to have air under diaphragm. Computed tomography showed severe pneumoperitoneum with cecal and gastric wall perforation. The third case was an elderly gentleman who presented with severe COVID-19 pneumonia along with symptoms and signs of acute abdomen who was confirmed by imaging to have sigmoid diverticulitis with perforation and abscess collection.

Interventions:

The first 2 cases were treated conservatively. The third one was treated surgically.

Outcome:

Our cases had a variable hospital course but fortunately all were discharged in a good clinical condition.

Conclusion:

Our aim from this series is to highlight this fatal complication to clinicians in order to enrich our understanding of this pandemic and as a result improve patients’ outcome.

Keywords: acute abdomen, acute diverticulitis, cecal mass, corona virus disease-2019, gastrointestinal perforation. 

Introduction

Corona virus disease-2019 (COVID-19) had been declared pandemic in March 2020.[1] It presents most commonly with fever in more than 80% of cases followed by respiratory symptoms which could progress to adult respiratory distress syndrome in critical cases.[2] However, extra respiratory manifestations are being frequently recognized in association with COVID-19.[3] The gastrointestinal (GI) manifestations have been reported in descriptive studies from China.[2] The most frequently reported GI symptoms are nausea, vomiting, diarrhoea, and abdominal pain.[2,4,5] However, it is rarely reported for COVID-19 to present with GI perforation. To the date of writing this report, there have been only 13 reported of GI perforation in association with COVID-19.

In this series, we are reporting 3 cases who developed GI perforation in association with COVID-19. The first 2 cases developed this fatal complication after presenting with critical COVID-19 pneumonia which required intensive care unit (ICU) admission and mechanical ventilation. The third case presented with severe COVID-19 pneumonia and was diagnosed to have GI perforation at the time of presentation. The first 2 cases were managed conservatively, and the third case was managed surgically. All of the 3 cases recovered and were discharged in good condition. We are reporting this series in order to highlight this rare but fatal complication of COVID-19. This will enhance awareness of clinicians to such complication where early diagnosis and management is crucial in order to improve the patients’ outcome.

2. Case reports

2.1. The patients provided informed consent for publication of their cases

2.1.1. First case

A 70-year old male patient known to have type 2 diabetes mellitus (T2DM), presented to our emergency department (ED) on 1st of June 2020 complaining of 3-day history of dry cough and fever. On examination: Vital signs were remarkable for tachypnea with respiratory rate (RR): 28/min and desaturation with oxygen saturation (O2 sat):81% on room air (RA) but maintained >94% on 15 litres of oxygen via a non-rebreather mask. Nasopharyngeal swab tested positive for SARS-CoV-2 polymerase chain reaction (PCR). Chest X-ray (CXR) showed bilateral lower lung fields air apace opacities (Fig. ​(Fig.1A)1A) consistent with COVID-19 pneumonia. Laboratory investigations were remarkable for high Lactate dehydrogenase (LDH), inflammatory markers, D-dimer and markedly elevated Ferritin (Table ​(Table1).1). He was started on Methylprednisolone 40 mg IV BID, Hydroxychloroquine, Ceftriaxone, Azithromycin, Oseltamivir, and Enoxaparin. After 5 days of hospital admission, he deteriorated and could not maintain saturation on non-rebreather mask, so he was shifted to ICU, intubated and mechanically ventilated. Ceftriaxone was upgraded to Meropenem in addition to same previous therapy. COVID-19 therapy was stopped after completing 10 days, but he was continued on steroids. Figure 1

The chest X-ray (CXR) of the 3 cases at the time of presentation. (A): CXR of the 1st case showing bilateral lower lung fields air apace opacities. (B): CXR of the 2nd case showing bilateral scattered air space consolidative patches throughout the lung fields predominantly over peripheral and basal lungs. (C): CXR of the 3rd case showing bilateral middle and lower zones peripheral ground glass opacities.

Table 1

The laboratory investigations of the 3 cases on presentation.

TestFirst caseSecond caseThird caseNormal range
Complete Blood Count
 White Blood cells6.44.25.7(4.0–11.0) K/uI
 Hemoglobin15.112.113.4(11.6–14.5) g/dL
 Platelets147232283(140–450) K/uI
Renal Profile
 Blood urea nitrogen101411(8.4–21) mg/dL
 Creatinine0.920.820.82(0.6–1.3) mg/dL
Liver Profile
 Total Bilirubin0.50.51.0(0.2–1.2) mg/dL
 Direct Bilirubin0.30.20.3(0.1–0.5) mg/dL
 Alanine Transferase (ALT)265241(7–55) U/L
 Aspartate transferase (AST)425052(5–34) U/L
 Alkaline phosphatase (ALP)745574(40–150) U/L
 Gamma-glutamyl transpeptidase (GGTP)532139(12–64) U/L
 Lactate dehydrogenase (LDH)434442617(81–234) U/L
Inflammatory Markers
 Erythrocyte Sedimentation rate (ESR)63101490–10 mm/h
 C-Reactive Protein (CRP)7.9218.3210.780–5 mg/dL
Others
 Ferritin1114.72565.86654.87(21.81–274.66) ng/mL
 D-Dimer0.60.411.66<=0.5 ug/mL

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Multiple trials of weaning from mechanical ventilation failed. So, tracheostomy was carried out on 20th day of ICU admission and then he was successfully extubated. During his stay in ICU, urine analysis was persistently positive for urinary tract infection secondary to Candida Abican. So, he was started on Caspofungin. At that time, blood culture was negative. After 4 days of Caspofungin, urine analysis and culture became negative. On 32nd day of hospital admission, he was stable clinically, requiring 40% FiO2 through tracheostomy mask, so he was transferred to COVID-19 isolation ward. Meropenem was stopped after 20 days of treatment. Steroid was tapered after transfer to the ward till it was discontinued after 28 days of therapy.

After 14 days of treatment with Caspofungin, follow up C-reactive protein was persistently high. Thus, full septic workup was requested and revealed Candida Albican bacteremia. At that time, urine analysis and culture were negative, Caspofungin was continued for additional 14 days. However, Candidemia persisted, so he was shifted to Anidulafungin for another 14 days. Patient at that time did not have any GI symptoms or signs. For work up of Candidemia, echocardiogram could not be done due to the hospital policy of isolation rooms. Bed side ophthalmology examination was unremarkable.

On 44th day of hospital admission, he developed fresh bleeding per rectum. Hemodynamics were stable. The bleeding resulted in acute drop of 2 g/dL of hemoglobin over 24 hours. He denied abdominal pain, abdominal examination was negative for signs of peritonitis and per rectum examination was unremarkable. Therefore, computed tomography (CT) scan of the abdomen with contrast was carried out. It showed a well-defined mass within the posterior wall of the cecum measuring 3.1 × 3.2 cm associated with discontinuous enhancement and extra-luminal air foci suggestive of complicated perforated sealed cecal mass. This is in addition to radiological findings of peritonitis (Fig. ​(Fig.22A).Figure 2

The contrast enhanced computed tomography (CT) of the abdomen of the 3 cases. (A): CT scan abdomen of the 1st case (Coronal image) showing a well-defined rounded heterogeneous enhanced soft tissue mass lesion within the posterior wall of the cecum measuring (3.1 × 3.2 cm) in anteroposterior and transverse diameter associated with discontinuous enhancement of posterior cecum wall and extra-luminal air foci suggestive of complicated perforated sealed cecum mass. This is in addition to adjacent fat stranding with free fluid as well as enhancement of peritoneal reflection suggestive of peritonitis. (B &C): CT scan abdomen of the 2nd case (Axial & Coronal images). (2B): Axial image showing moderate to severe pneumoperitoneum with air seen more tracking along the ascending colon suggestive of a wall defect in the anterior aspect of the cecum. (2C): Coronal image showing a second defect in the stomach wall. (D): CT scan abdomen of the 3rd case (Coronal image) showing severe sigmoid diverticulosis with circumferential bowel wall thickening compatible with acute diverticulitis, small amount of free air compatible with bowel perforation likely arising from the sigmoid colon and a well-defined 3.3 × 1.5 cm abscess collection adjacent to the sigmoid colon.

In consideration of his stable clinical status, absent signs of peritonitis clinically and being a sealed perforation, he was managed conservatively. So, Meropenem was resumed and Clindamycin was started. 2 days later, bleeding stopped, and he stayed stable clinically without clinical signs of peritonitis. Feeding through nasogastric tube was introduced gradually as tolerated. Antibiotics were continued for a total of 8 days. Trial of weaning from oxygen was attempted gradually which he tolerated till he was maintained on RA. After closure of tracheostomy, on 70th day of hospital admission, the patient was discharged in a good condition with a plan of follow up of cecal mass progression. However, the patient did not follow up in outpatient clinics after discharge.

2.1.2. Second case

A 37-year old male patient, morbidly obese, negative past history, presented to our ED on 11th June 2020. He reported 3-day history of shortness of breath. Vital signs were remarkable for Temperature (Temp.): 38.5 C, pulse rate (PR): 111/min, RR: 30/min and O2 sat: 80% on RA. Laboratory investigations showed high LDH, inflammatory markers and Ferritin (Table ​(Table1).1). He had positive SARS-CoV-2 PCR and CXR showed bilateral air space consolidative patches scattered throughout the lung predominantly over peripheral and basal lungs (Fig. ​(Fig.1B).1B). He was admitted to COVID-19 isolation ward as a case of COVID-19 pneumonia and started on: Triple therapy in the form of: Interferon B1, Lopinavir/Ritonavir and Ribavirin, in addition to Hydroxychloroquine, Ceftriaxone, Azithromycin, Oseltamivir, Dexamethasone 6 mg IV OD and Enoxaparin.

On the 3rd day of admission, his condition deteriorated so, he was shifted to ICU and intubated because of respiratory failure. He was maintained on same treatment for COVID-19. On 2nd day postintubation, clinically he was vitally stable without active clinical GI signs but a routine follow-up CXR showed air under the diaphragm. Therefore, abdomen CT scan with contrast was carried out and showed moderate to severe pneumoperitoneum with air tracking along the ascending colon suggestive of wall defect at the cecum, in addition to another defect noted in the stomach wall (Fig. ​(Fig.2B2B & 2C). Ceftriaxone was upgraded to Piperacillin-Tazobactam and Caspofungin was added to cover for possibility of peritonitis. Again, the patient was managed conservatively, since he was asymptomatic. He remained vitally stable without signs of peritonitis. Enteral feeding was started gradually 3 days later and on the 10th day of hospital admission, he was extubated and shifted to COVID-19 isolation ward. COVID-19 therapy was continued for 12 days.

He tolerated feeding very well. Gradual weaning of oxygen supplementation was carried out till it was discontinued. After 14 days of antibiotics, a follow up CT scan of abdomen showed interval resolution of previously seen pneumoperitoneum. He was discharged on 30th day of hospitalization in a good condition.

2.1.3. Third case

A 74-year old male patient known case of T2DM presented to our ED on 17th July 2020. He gave 3-day history of dry cough, shortness of breath and generalized colicky abdominal pain. No other pulmonary or GI symptoms. He had negative past surgical history. Vital signs were remarkable for Temp: 38.4 C, PR: 105/min, RR: 22/min and O2 sat: 90% on RA, required 3 L/min O2 through nasal cannula. Chest examination was remarkable for reduced breath sound intensity bilaterally without added sounds. Abdomen was distended with generalized tenderness and guarding. Blood tests were remarkable for high LDH, inflammatory markers, Ferritin and D-dimer (Table ​(Table1).1). PCR for SARS-COV-2 was positive and CXR showed bilateral peripheral ground glass opacities at middle and lower lung lobes (Fig. ​(Fig.1C).1C). Due to the presence of abdominal pain along with signs of acute abdomen on examination, a CT scan of the abdomen was done. It showed severe sigmoid diverticulosis with radiological findings of acute diverticulitis, free air compatible with bowel perforation likely at the sigmoid colon with 3.3 cm adjacent abscess collection (Fig. ​(Fig.22D).

Therefore, the patient was started on Piperacillin-Tazobactam, Metronidazole in addition to COVID-19 therapy. He underwent emergency exploratory laparotomy. Intra-operatively, pus and fecal peritonitis along with perforation of 0.5 cm at the distal sigmoid colon were found. So, a Hartmann’s procedure was performed. Pathology result of resected sigmoid colon revealed diverticular disease with surrounding fibrosis, moderate mucosal inflammation with mixed acute and chronic inflammatory cells, negative for malignancy.

He had smooth postoperative course. Enteral feeding was started on 3rd day postoperation and he improved clinically. After a total of 10 days of hospitalization, supplemental oxygen and antibiotics were discontinued. He was discharged on 11th day of hospitalization in a good condition.

3. Discussion

The GI manifestations are the most frequently reported extra-pulmonary manifestations of COVID-19[2] with a prevalence of 10% to 50%.[4,5] The most commonly reported GI symptoms are nausea, vomiting, diarrhoea and abdominal pain.[2,4,5] However, there have been case reports of COVID-19 cases presenting with other GI manifestations. Those include acute surgical abdomen,[6] lower GI bleeding[7] and nonbiliary pancreatitis.[8] In fact, the GI manifestations could be the presenting symptoms of COVID-19 as was reported in a case report by Siegel et al where the patient presented with abdominal pain and upon abdominal imaging, the patient was found to have pulmonary manifestations of COVID-19 in the CT scan of the lung bases.[9]

GI perforation is a surgical emergency, carries a significant mortality rate that could reach up to 90% due to peritonitis especially if complicated by multiple organ failure.[10] It can be caused by many reasons. Those include foreign body perforation, extrinsic bowel obstruction like in cases of GI tumors, intrinsic bowel obstruction like in cases of diverticulitis/appendicitis, loss of GI wall integrity such as peptic ulcer and inflammatory bowel disease in addition to GI ischemia and infections.[11] Several infections have been reported to result in GI perforation like Clostridium difficile, Mycobacterium tuberculosis, Cytomegalovirus and others.[1214] COVID-19 have been rarely reported to result in GI perforation. Till the date of writing this report only 13 cases[1523] have been reported in the literature (Table ​(Table2).2). In addition, Meini et al reported a case of pneumatosis intestinalis in association with COVID-19 but without perforation.[25]

Table 2

Summary of the previously published cases of gastrointestinal perforation in association with COVID-19.

First Author [Reference]Age/ SexCo-morbid ConditionsPresenting symptomsSeverity of COVID-19 pneumoniaCOVID-19 TherapySymptoms prompted investigations for GI perforationSite of PerforationTiming of Perforation post admissionManagement of PerforationOutcome
1Gonzalvez Guardiola et al [15]66 Y/ MMetabolic syndromeNot mentionedCriticalMethylprednisoloneTocilizumab Hydroxychloroquine AzithromycinLopinavir/RitonavirAbdominal painIncreased WBC and CRP.CecumNot mentionedRight colectomyNot mentioned
2De Nardi et al [16]53 Y/MHypertension Supra-ventricular tachycardiaFeverCoughDyspneaCriticalAnakinra Lopinavir/Ritonavir Hydroxychloroquine + AntibioticsAbdominal pain Abdominal distentionSigns of PeritonitisCecum11th day of admissionRight colectomy & ileo-transverse anastomosisDischarged Home
3Kangas-Dick et al [17]74 Y/MNegativeFeverDyspneaDry coughCriticalHydroxychloroquine +AntibioticsIncreased Oxygen requirementMarkedly distended abdomenNot specified (CT scan: Not done)5th day of admissionConservativeDied
4Galvez et al [18]59 Y/MStatus post laparoscopic Roux-en-Y gastric bypass surgeryFeverDry coughMyalgiaHeadacheDyspneaModerateMethylprednisolone + COVID-19 protocol (Not specified)Acute abdominal painWorsening dyspneaGastro-jejunal anastomosis5th day of admissionLaparoscopy& Graham Patch RepairDischarged Home
5Poggiali et al [19]54 Y/ F§HypertensionFeverDry coughGERD symptomsSevereCOVID-19 therapy (Not specified) +AntibioticsAcute chest pain Painful abdomenDiaphragm StomachAt presentationSurgical RepairNot mentioned
6Corrêa Neto et al [20]80 Y/FHypertensionCoronary artery diseaseDry coughFeverDyspneaCriticalCOVID-19 therapy(Not specified) +AntibioticsDiffuse abdominal pain & stiffnessSigmoidAt PresentationLaparotomy with recto-sigmoidectomy & terminal colostomyDied
7Rojo et al [21]54 Y/FHypertensionObesityDyslipidemiaEpilepsyCough,MyalgiaCostal painCriticalHydroxychloroquine Lopinavir/Ritonavir MethylprednisoloneTocilizumabFeverHemodynamic instabilityAnemiaCecum15th day of admissionLaparotomy with right colectomy and ileostomyDied
8Kühn et al [22]59 Y/MNot mentionedFeverNauseaAbdominal pain Fatigue, HeadacheNot specifiedNot mentionedAbdominal painJejunal diverticulumAt presentationOpen small bowel segmental resection & anastomosisDischarged Home
9Seeliger et al [23]31Y/MNot mentionedDyspneaSevereNot mentionedNot mentionedLeft colonAt presentationLeft HemicolectomyDischarged Home
1082 Y/FDyspnea, DiarrhoeaCriticalSigmoidAt presentationOpen drainage of peritonitisDied
1171 Y/FFeverSevereGangrenous appendixAt presentationLaparoscopic appendectomyDischarged Home
1280Y/MNot mentionedSevereSigmoiditisAt presentationHartmann procedureDischarged Home
1377 Y/MDyspneaCriticalDuodenal ulcer23rd day of admissionOpen duodenal exclusion, omega gastro-enteric anastomosisDied
14This Report70Y/MT2DMFeverCoughCriticalMethylprednisolone HydroxychloroquineOseltamivir Enoxaparin+AntibioticsBleeding per rectumHemoglobin DropCecal mass44th day of admissionConservativeDischarged Home
1537Y/MMorbid obesityDyspneaCriticalInterferon B1Lopinavir/RitonavirRibavirinHydroxychloroquineOseltamivirDexamethasone+AntibioticsAir under diaphragm was found incidentally in a follow up CXRCecum4th day of admissionConservativeDischarged Home
1674Y/MT2DMCoughDyspnea Abdominal pain.SevereLopinavir/RitonavirRibavirinMethylprednisolone+AntibioticsAbdominal painSigns of peritonitisSigmoid diverticulosis/diverticulitisAt presentationExploratory laparotomy with Hartmann’s procedureDischarged Home

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Severity of COVID-19 pneumonia is based on classification of severity by Ministry of Health-Saudi Arabia.[24]†Y = Year.M = Male.§F = Female.

Most of the previously reported cases presented initially with respiratory symptoms, 4 cases had also GI symptoms at presentation in the form of abdominal pain, stiffness, nausea and diarrhoea[19,20,22,23] [Table ​[Table2].2]. Eleven out of the 13 cases had severe-critical pneumonia that required either high flow oxygen, intubation or mechanical ventilation which is similar to our first 2 cases. This may indicate that GI perforation is more common in severe and critically ill COVID-19 cases. The most common symptoms which prompted investigations for bowel perforation were abdominal pain and distention [Table ​[Table2].2]. Other indications were signs of peritonitis,[16] worsening hemodynamics[17,18,21] and rising inflammatory markers.[15]

Only one of our cases had abdominal pain and tenderness at presentation. Another developed anemia due to active lower GI bleeding which is similar to the case published by Rojo et al[21] where the patient developed anemia and found to have hemoperitoneum with pericecal hematoma. This is probably explained by the site of perforation since both had cecal perforation. Our other case was diagnosed incidentally after demonstration of air under diaphragm in routine CXR. GI perforation was diagnosed from first day up to 23rd day of presentation with COVID-19 [Table ​[Table2].2]. Our patients had similar variable timing of GI perforation in relation to presentation with COVID-19. It ranged from the first day of diagnosis up to 40 days after presentation with COVID-19 pneumonia. This may tell us that GI perforation could happen at any time during the course of the infection. Our report demonstrates different presentation of GI perforation with COVID-19 since in 2 of the 3 cases, the infection predisposed to having perforation of an underlying GI lesions (cecal mass and diverticulosis). Only Kuhn et al reported similar presentation where the patient had perforation of jejunal diverticulum.[22] This may tell us that having COVID-19 predispose patients with underlying GI lesions to perforation. In addition, in our first case, we think that the source of Candidemia was most probably the bowel since it was persistent even after clearance of Candida Albican from the urine, but it was overlooked due to the absence of GI symptoms at the time of developing the Candidemia. In a study of 62 cases with peritonitis secondary to gastric perforation, Candida species was isolated in 23 cases in peritoneal fluid culture.[26] Therefore, in presence of Candidemia especially in absence of clear source, evaluation of the bowel as a potential source should always be kept in mind.

The effect of SARS-COV-2 virus on the GI system can be explained by different mechanisms. First, the virus uses the same access to enter respiratory and GI tract epithelium which are Angiotensin converting enzyme 2 receptors giving the virus the chance to replicate inside GI cells.[27] In addition, faecal-oral transmission has also been postulated, due to the presence of viral RNA in stool samples.[28] Perforation could result from altered colonic motility due to neuronal damage by the virus[29] in addition to local ischemia resulting from hypercoagulable state caused by the virus especially in critically ill patients.[30] Corrêa Neto et al reported finding ischemia of the entire GI tract during exploratory laparotomy for sigmoid perforation with COVID-19.[20] In addition, Rojo et al reported presence of microthrombi and wall necrosis in the pathology examination of his COVID-19 case with bowel perforation.[21] Other possible implicating factors are the use of Tocilizumab and high dose steroids.[21,31] Both are indicated in severe and critically ill COVID-19 cases. Steroids were used in all of our 3 cases since it is indicated in severe COVID-19 pneumonia according Saudi Arabian Ministry of health guidelines[24] but none of our patients received Tocilizumab. Some of these mechanisms could explain the higher risk of GI perforation in severe and critically ill COVID-19 patients.

The diagnosis of GI perforation is based mainly on radiological findings on CT scan. The most specific findings are segmental bowel wall thickening, focal bowel wall defect, or bubbles of extraluminal gas concentrated in close proximity to the bowel wall.[32] Treatment of GI perforation is mainly surgical in order to improve survival.[33] This is in line with the previously published cases where all were managed surgically except the one reported by Kangas-Dick et al due to the patient’s critical condition, so he was managed conservatively but unfortunately, he died.[17] However, in selected cases where there are no active signs of peritonitis, abdominal sepsis or having sealed perforation, conservative treatment is an acceptable management strategy.[34,35] This was the case in 2 of our cases who were managed conservatively. Fortunately, they did very well and had good outcome.

4. Conclusion

GI manifestations are common in patients with COVID-19. However, GI perforation is rarely reported in the literature. Severe and critically ill COVID-19 patients seem to be at a higher risk of this complication. It has a variable presentation in patients with COVID-19 ranging from incidental finding discovered only radiographically to acute abdomen. The presence of underlying GI lesion predisposes patients with COVID-19 to perforation. High index of suspicion is required in order to manage those patients further and thus, improve their outcome.

Author contributions

Conceptualization: Reem J. Al Argan, Safi G. Alqatari

Data curation: Reem J. Al Argan, Abdulsalam Noor, Lameyaa A. Al Sheekh

Writing – original draft: Reem J. Al Argan, Lameyaa A. Al Sheekh, Feda’a H. Al Beladi

Writing – review & editing: Reem J. Al Argan, Safi G. Alqatari, Abir H. Al Said, Raed M. AlsulaimanGo to:

Footnotes

Abbreviations: COVID-19 = corona virus disease-2019, CT = computed tomography, CXR = chest X-ray, ED = emergency department, GI = gastrointestinal, ICU = intensive care unit, LDH = lactate dehydrogenase, O2 sat = oxygen saturation, PCR = polymerase chain reaction, PR = Pulse rate, RA = room air, RR = respiratory rate, Temp = Temperature, T2DM = Type 2 diabetes mellitus.

How to cite this article: Al Argan RJ, Alqatari SG, Al Said AH, Alsulaiman RM, Noor A, Al Sheekh LA, Al Beladi FH. Gastrointestinal perforation secondary to COVID-19: Case reports and literature review. Medicine. 2021;100:19(e25771).

The authors have no funding and conflicts of interests to disclose.

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

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Study Finds Teenage Boys Six Times More Likely To Suffer Heart Problems From Vaccine Than Be Hospitalized by COVID

Authors; Paul Joseph Watson via Summit News,

Research conducted by the University of California has found that teenage boys are six times more likely to suffer from heart problems caused by the COVID-19 vaccine than to be hospitalized as a result of COVID-19 itself.

“A team led by Dr Tracy Hoeg at the University of California investigated the rate of cardiac myocarditis – heart inflammation – and chest pain in children aged 12-17 following their second dose of the vaccine,” reports the Telegraph.

“They then compared this with the likelihood of children needing hospital treatment owing to Covid-19, at times of low, moderate and high rates of hospitalisation.”

Researchers found that the risk of heart complications for boys aged 12-15 following the vaccine was 162.2 per million, which was the highest out of all the groups they looked at.

This compares to the risk of a healthy boy being hospitalized as a result of a COVID infection, which is around 26.7 per million, meaning the risk they face from the vaccine is 6.1 times higher.

Even during high risk rates of COVID, such as in January this year, the threat posed by the vaccine is 4.3 times higher, while during low risk rates, the risk of teenage boys suffering a “cardiac adverse event” from the vaccine is a whopping 22.8 times higher.

The research data was based on a study of adverse reactions suffered by teens between January and June this year.

In a sane world, such data should represent the nail in the coffin for the argument that teenagers and children should be mandated to take the coronavirus vaccine, but it obviously won’t.

In the UK, the government is pushing to vaccinate 12-15-year-olds, even without parental consent, despite the Joint Committee on Vaccination and Immunisation (JCVI) advising against it.

Meanwhile, in America, Los Angeles County school officials voted unanimously to mandate COVID shots for all

Meningoencephalitis associated with COVID-19: a systematic review

Authors: Ritwick Mondal 1Upasana Ganguly 1Shramana Deb 2Gourav Shome 3Subhasish Pramanik 1Deebya Bandyopadhyay 1Durjoy Lahiri 4

Abstract

With the growing number of COVID-19 cases in recent times. significant set of patients with extra pulmonary symptoms has been reported worldwide. Here we venture out to summarize the clinical profile, investigations, and radiological findings among patients with SARS-CoV-2-associated meningoencephalitis in the form of a systemic review. This review was carried out based on the existing PRISMA (Preferred Report for Systematic Review and Meta analyses) consensus statement. The data for this review was collected from four databases: Pubmed/Medline, NIH Litcovid, Embase, and Cochrane library and Preprint servers up till 30 June 2020. Search strategy comprised of a range of keywords from relevant medical subject headings which includes “SARS-COV-2,” “COVID-19,” and “meningoencephalitis.” All peer reviewed, case-control, case report, pre print articles satisfying our inclusion criteria were involved in the study. Quantitative data was expressed in mean ± SD, while the qualitative date in percentages. Paired t test was used for analyzing the data based on differences between mean and respective values with a p < 0.05 considered to be statistically significant. A total of 61 cases were included from 25 studies after screening from databases and preprint servers, out of which 54 of them had completed investigation profile and were included in the final analysis. Clinical, laboratory findings, neuroimaging abnormalities, and EEG findings were analyzed in detail. This present review summarizes the available evidences related to the occurrence of meningoencephalitis in COVID-19.

For More Information: https://pubmed.ncbi.nlm.nih.gov/33367960/

Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19

Authors: JACC State-of-the-Art ReviewAzita H. Talasaz, PharmD,a,bParham Sadeghipour, MD,cHessam Kakavand, PharmD,a,bMaryam Aghakouchakzadeh, PharmD,aElaheh Kordzadeh-Kermani, PharmD,aBenjamin W. Van Tassell, PharmD,d,eAzin Gheymati, PharmD,aHamid Ariannejad, MD,bSeyed Hossein Hosseini, PharmD,aSepehr Jamalkhani,cMichelle Sholzberg, MDCM, MSc,f,gManuel Monreal, MD, PhD,hDavid Jimenez, MD, PhD,iGregory Piazza, MD, MS,jSahil A. Parikh, MD,k,lAjay J. Kirtane, MD, SM,k,lJohn W. Eikelboom, MBBS,mJean M. Connors, MD,nBeverley J. Hunt, MD,oStavros V. Konstantinides, MD, PhD,p,qMary Cushman, MD, MSc,r,sJeffrey I. Weitz, MD,t,uGregg W. Stone, MD,k,vHarlan M. Krumholz, MD, SM,w,x,yGregory Y.H. Lip, MD,z,aaSamuel Z. Goldhaber, MD,j and Behnood Bikdeli, MD, MSj,k,w,∗

Abstract

Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.

Thromboembolism in Patients With Coronavirus Disease-2019

Microvascular and macrovascular thrombotic complications, including arterial and especially venous thromboembolism (VTE), seem to be common clinical manifestations of coronavirus disease-2019 (COVID-19), particularly among hospitalized and critically ill patients (1234). Pooled analyses have helped in providing aggregate estimates of thrombotic events (4,5). In a recent systematic review and meta-analysis, the overall incidence of VTE among inpatients with COVID-19 was estimated at 17% (95% confidence interval [CI]: 13.4 to 20.9), with variation based on study design and method of ascertainment; there was a four-fold higher incidence rate in patients in the intensive care units (ICUs) compared with non-ICU settings (28% vs. 7%) (6). In addition, postmortem studies show frequent evidence of microvascular thrombosis in patients with COVID-19 (7,8). The influence of these events on mortality rates remains unknown (9).Go to:

Pathophysiology of Thromboembolism in COVID-19: Virchow’s Triad in Action

COVID-19 can potentiate all 3 components of Virchow’s triad and increases the risk of thrombosis (Figure 1 ). First, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection may trigger endothelial dysfunction. Using the angiotensin-converting enzyme 2, which is expressed on the surface of many cells, SARS-CoV-2 enters endothelial cells and may impair their intrinsic antithrombotic properties. It is proposed that viremia, hypoxia, the inflammatory response, increased expression of tissue factor, and elevated levels of neutrophil extracellular traps (NETs) can together disrupt the hemostasis equilibrium and promote endothelial activation (101112). This induction of a procoagulant state along with the reduction in plasminogen activators further results in increased platelet reactivity (131415). Inflammatory cytokines and endothelial activation can lead to downregulation of antithrombin and protein C expression. They can also lead to an increase in the levels of plasminogen activator inhibitor; fibrinogen; factors V, VII, VIII, and X; and von Willebrand factor (16). Increased platelet reactivity, NETosis, and alterations in the aforementioned hemostatic factors result in a hypercoagulable state (171819202122).

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963001/

Hyperglycemia in Acute COVID-19 is Characterized by Adipose Tissue Dysfunction and Insulin Resistance

Authors: Reiterer MRajan MGómez-Banoy NLau JDGomez-Escobar LGGilani AAlvarez-Mulett SSholle ETChandar VBram YHoffman KRubio-Navarro AUhl SShukla APGoyal PtenOever BRAlonso LCSchwartz RESchenck EJSafford MM

Abstract 


COVID-19 has proven to be a metabolic disease resulting in adverse outcomes in individuals with diabetes or obesity. Patients infected with SARS-CoV-2 and hyperglycemia suffer from longer hospital stays, higher risk of developing acute respiratory distress syndrome (ARDS), and increased mortality compared to those who do not develop hyperglycemia. Nevertheless, the pathophysiological mechanism(s) of hyperglycemia in COVID-19 remains poorly characterized. Here we show that insulin resistance rather than pancreatic beta cell failure is the prevalent cause of hyperglycemia in COVID-19 patients with ARDS, independent of glucocorticoid treatment. A screen of protein hormones that regulate glucose homeostasis reveals that the insulin sensitizing adipokine adiponectin is reduced in hyperglycemic COVID-19 patients. Hamsters infected with SARS-CoV-2 also have diminished expression of adiponectin. Together these data suggest that adipose tissue dysfunction may be a driver of insulin resistance and adverse outcomes in acute COVID-19.

The deadly COVID-19 pandemic is underscored by the high morbidity and mortality rates seen in certain vulnerable populations, including patients with diabetes mellitus (DM), obesity, cardiovascular disease, and advanced age, with the latter associated with many chronic cardiometabolic diseases 14 . Hyperglycemia with or without a history of DM is a strong predictor of in-hospital adverse outcomes, portending a 7-fold higher mortality compared to patients with well-controlled blood glucose levels 5 . Hyperglycemia may be seen as a biomarker that predicts poor prognosis. A retrospective study that compared hyperglycemic patients that were treated with insulin against those who were not showed increased mortality in those receiving insulin 6 . However, it remains unclear whether insulin treatment is a surrogate for increased hyperglycemia and overall morbidity, or whether it is an actual causative factor for death. There is thus uncertainty regarding specific treatments for hyperglycemia in acute COVID-19 7 .

Despite our early recognition of the association between hyperglycemia and perilous outcomes, the pathophysiological mechanisms that underlie hyperglycemia in COVID-19 remain undefined 8,9 . Hypotheses have included a broad range of pathologies from direct infection of islets leading to beta cell failure (BCF) and to inflammation and glucocorticoids leading to insulin resistance (IR). Although COVID-19 is primarily a respiratory tract infection, SARS-CoV-2 is known to infect other cell types and often leads to extrapulmonary consequences 10,11 ACE2 and other entry receptors for SARS-CoV-2 can be expressed on pancreatic islet cells and endocrine cells differentiated from human pluripotent stem cells are permissive to infection 12 . Early reports of unexpected diabetic ketoacidosis (DKA) in COVID-19 patients fuelled concerns for a novel form of acute onset beta cell failure. For example, one case described a patient with new onset diabetic ketoacidosis (DKA) who was found to be autoantibody negative for type 1 DM (T1DM) but showed evidence of prior SARS-CoV-2 infection based on serology results, suggesting the possibility of pancreatic beta cell dysfunction or destruction as a result of COVID-19 13 . However, given the high rates of COVID-19 during this pandemic coupled with low background rates of new onset T1DM, the connection between these two events in this case could be “true, true, and unrelated.” Recent studies disagree on whether ACE2 is expressed on pancreatic beta cells or whether the SARS-CoV-2 virus is found in pancreatic beta cells of deceased individuals with COVID-19 1416 . Conversely, the well-known connection between obesity and insulin resistance might lead to impaired immunity and more severe SARS-CoV-2 infection 17 . In fact, population level studies have reported higher risk of complications in obese patients with COVID-19 1820 . Viral infection may lead to systemic insulin resistance and worsened hyperglycemia. In sum, despite much attention, the pathophysiology of hyperglycemia in COVID-19 remains unknown.

Dexamethasone substantially reduces mortality in patients with severe COVID-19 infection requiring oxygen or invasive mechanical ventilation 21 . Glucocorticoids can also provoke hyperglycemia by inducing insulin resistance and beta cell dysfunction. The widespread usage of dexamethasone in severe SARS-CoV-2 infection is sure to exacerbate both the incidence and severity of hyperglycemia in COVID-19.

For More Information: https://europepmc.org/article/PPR/PPR303316