When Lara Hawthorne, an illustrator in Bristol, UK, began developing strange symptoms after having COVID-19, she hoped that they weren’t due to the virus. Her initial illness had been mild. “I’ve been triple vaccinated. I felt quite protected,” she says. But months later, she was still sick with a variety of often debilitating symptoms: earaches, tinnitus, congestion, headaches, vertigo, heart palpitations, muscle pain and more. On some days, Hawthorne felt so weak that she could not get out of bed. When she finally saw her physician, the diagnosis was what she had been dreading: long COVID.
Unable to find relief, she became increasingly desperate. After reading an opinion piece in The Guardian newspaper about how blood clots might be to blame for long COVID symptoms, Hawthorne contacted a physician in Germany who is treating people with blood thinners and a procedure to filter the blood. She hasn’t heard back yet — rumour has it that people stay on the waiting list for months — but if she has the opportunity to head there for these unproven treatments, she probably will. “I don’t want to wait on my health when I’m feeling so dreadful,” she says.
Researchers are baffled by long COVID: hundreds of studies have tried to unpick its mechanism, without much success. Now some scientists, and an increasing number of people with the condition, have been lining up behind the as-yet-unproven hypothesis that tiny, persistent clots might be constricting blood flow to vital organs, resulting in the bizarre constellation of symptoms that people experience.
Proponents of the idea (#teamclots, as they sometimes refer to themselves on Twitter) include Etheresia Pretorius, a physiologist at Stellenbosch University in South Africa, and Douglas Kell, a systems biologist at the University of Liverpool, UK, who led the first team to visualize micro-clots in the blood of people with long COVID. They say that the evidence implicating micro-clots is undeniable, and they want trials of the kinds of anticoagulant treatment that Hawthorne is considering. Pretorius penned the Guardian article that caught Hawthorne’s attention.
But many haematologists and COVID-19 researchers worry that enthusiasm for the clot hypothesis has outpaced the data. They want to see larger studies and stronger causal evidence. And they are concerned about people seeking out unproven, potentially risky treatments.
When it comes to long COVID, “we’ve now got little scattered of bits of evidence”, says Danny Altmann, an immunologist at Imperial College London. “We’re all scuttling to try and put it together in some kind of consensus. We’re so far away from that. It’s very unsatisfying.”
Cascade of clots
Pretorius and Kell met about a decade ago. Pretorius had been studying the role of iron in clotting and neglected to cite some of Kell’s research. When he reached out, they began chatting. “We had a Skype meeting and then we decided to work together,” Pretorius says. They observed odd, dense clots that resist breaking down for years in people with a variety of diseases. The research led them to develop the theory that some molecules — including iron, proteins or bits of bacterial cell wall — might trigger these abnormal clots.
Blood clotting is a complex process, but one of the key players is a cigar-shaped, soluble protein called fibrinogen, which flows freely in the bloodstream. When an injury occurs, cells release the enzyme thrombin, which cuts fibrinogen into an insoluble protein called fibrin. Strands of fibrin loop and criss-cross, creating a web that helps to form a clot and stop the bleeding.
Under a microscope, this web typically resembles “a nice plate of spaghetti”, Kell says. But the clots that the team has identified in many inflammatory conditions look different. They’re “horrible, gunky, dark”, Kell says, “such as you might get if you half-boiled the spaghetti and let it all stick together.” Research by Kell, Pretorius and their colleagues suggests that the fibrin has misfolded1, creating a gluey, ‘amyloid’ version of itself. It doesn’t take much misfolding to seed disaster, says Kell. “If the first one changes its conformation, all the others have to follow suit”, much like prions, the infectious misfolded proteins that cause conditions such as Creutzfeldt–Jakob disease.
Pretorius first saw these strange, densely matted clots in the blood of people with a clotting disorder2, but she and Kell have since observed the phenomenon in a range of conditions1 — diabetes, Alzheimer’s disease and Parkinson’s disease, to name a few. But the idea never gained much traction, until now.
When the pandemic hit in 2020, Kell and Pretorius applied their methods almost immediately to people who had been infected with SARS-CoV-2. “We thought to look at clotting in COVID, because that is what we do,” Pretorius says. Their assay uses a special dye that fluoresces when it binds to amyloid proteins, including misfolded fibrin. Researchers can then visualize the glow under a microscope. The team compared plasma samples from 13 healthy volunteers, 15 people with COVID-19, 10 people with diabetes and 11 people with long COVID3. For both long COVID and acute COVID-19, Pretorius says, the clotting “was much more than we have previously found in diabetes or any other inflammatory disease”. In another study4, they looked at the blood of 80 people with long COVID and found micro-clots in all of the samples.
So far, Pretorius, Kell and their colleagues are the only group that has published results on micro-clots in people with long COVID.
But in unpublished work, Caroline Dalton, a neuroscientist at Sheffield Hallam University’s Biomolecular Sciences Research Centre, UK, has replicated the results. She and her colleagues used a slightly different method, involving an automated microscopy imaging scanner, to count the number of clots in blood. The team compared 3 groups of about 25 individuals: people who had never knowingly had COVID-19, those who had had COVID-19 and recovered, and people with long COVID. All three groups had micro-clots, but those who had never had COVID-19 tended to have fewer, smaller clots, and people with long COVID had a greater number of larger clots. The previously infected group fell in the middle. The team’s hypothesis is that SARS-CoV-2 infection creates a burst of micro-clots that go away over time. In individuals with long COVID, however, they seem to persist.
Dalton has also found that fatigue scores seem to correlate with micro-clot counts, at least in a few people. That, says Dalton, “increases confidence that we are measuring something that is mechanistically linked to the condition”.
In many ways, long COVID resembles another disease that has defied explanation: chronic fatigue syndrome, also known as myalgic encephalomyelitis (ME/CFS). Maureen Hanson, who directs the US National Institutes of Health (NIH) ME/CFS Collaborative Research Center at Cornell University in Ithaca, New York, says that Pretorius and Kell’s research has renewed interest in a 1980s-era hypothesis about abnormal clots contributing to symptoms. Pretorius, Kell and colleagues found amyloid clots in the blood of people with ME/CFS, but the amount was much lower than what they’ve found in people with long COVID5. So clotting is probably only a partial explanation for ME/CFS, Pretorius says.
Where these micro-clots come from isn’t entirely clear. But Pretorius and Kell think that the spike protein, which SARS-CoV-2 uses to enter cells, might be the trigger in people with long COVID. When they added the spike protein to plasma from healthy volunteers in the laboratory, that alone was enough to prompt formation of these abnormal clots6.
Bits of evidence hint that the protein might be involved. In a preprint7 posted in June, researchers from Harvard University in Boston, Massachusetts, reported finding the spike protein in the blood of people with long COVID. Another paper8 from a Swedish group showed that certain peptides in the spike can form amyloid strands on their own, at least in a test tube. It’s possible that these misfolded strands provide a kind of template, says Sofie Nyström, a protein chemist at Linköping University in Sweden and an author of the paper.
A California-based group found that fibrin can actually bind to the spike. In a 2021 preprint9, it reported that when the two proteins bind, fibrin ramps up inflammation and forms clots that are harder to degrade. But how all these puzzle pieces fit together isn’t yet clear.
If the spike protein is the trigger for abnormal clots, that raises the question of whether COVID-19 vaccines, which contain the spike or instructions for making it, can induce them as well. There’s currently no direct evidence implicating spike from vaccines in forming clots, but Pretorius and Kell have received a grant from the South African Medical Research Council to study the issue. (Rare clotting events associated with the Oxford–AstraZeneca vaccine are thought to happen through a different mechanism (Nature596, 479–481; 2021).)
Raising safety concerns about the vaccines can be uncomfortable, says Per Hammarström, a protein chemist at Linköping University and Nyström’s co-author. “We don’t want to be over-alarmist, but at the same time, if this is a medical issue, at least in certain people, we have to address that.” Gregory Poland, director of the Mayo Clinic’s vaccine research group in Rochester, Minnesota, agrees that it’s an important discussion. “My guess is that spike and the virus will turn out to have a pretty impressive list of pathophysiologies,” he says. “How much of that may or may not be true for the vaccine, I don’t know.”
Dearth of data
Many researchers find it plausible and intriguing that micro-clots could be contributing to long COVID. And the hypothesis does seem to fit with other data that have emerged on clotting. Researchers already know that people with COVID-19, especially severe disease, are more likely to develop clots. The virus can infect cells lining the body’s 100,000 kilometres of blood vessels, causing inflammation and damage that triggers clotting.
Those clots can have physiological effects. Danny Jonigk, a pathologist at Hanover Medical School in Germany, and his colleagues looked at tissue samples from people who died of COVID-19. They found micro-clots and saw that the capillaries had split, forming new branches to try to keep oxygen-rich blood flowing10. The downside was that the branching introduces turbulence into the flow that can give rise to fresh clots.
Several other labs have found signs that, in some people, this tendency towards clotting persists months after the initial infection. James O’Donnell, a haematologist and clotting specialist at Trinity College Dublin, and his colleagues found11 that about 25% of people who are recovering from COVID-19 have signs of increased clotting that are “quite marked and unusual”, he says.
What is less clear is whether this abnormal clotting response is actually to blame for any of the symptoms of long COVID, “or is it just, you know, another unusual phenomenon associated with COVID?” O’Donnell says.
Alex Spyropoulos, a haematologist at the Feinstein Institutes for Medical Research in New York City, says the micro-clot hypothesis presents “a very elegant mechanism”. But he argues that much more work is needed to tie the lab markers to clinical symptoms. “What’s a little bit disturbing is that these authors and others make huge leaps of faith,” Spyropoulos says.
Jeffrey Weitz, a haematologist and clotting specialist at McMaster University in Hamilton, Canada, points out that the method Pretorius’s team is using to identify micro-clots “isn’t a standard technique at all”. He adds: “I’d like to see confirmation from other investigators.” Micro-clots are difficult to detect. Pathologists can spot them in tissue samples, but haematologists tend to look for markers of abnormal clotting rather than the clots themselves.
Other, larger studies of long COVID have failed to find signs of clotting. Michael Sneller, an infectious-disease specialist, and his colleagues at the NIH in Bethesda, Maryland, thoroughly examined 189 people who had been infected with SARS-CoV-2, some with lingering symptoms and some without, and 120 controls12. They did not specifically look for micro-clots. But if micro-clots had been clogging the capillaries, Sneller says, they should have seen some evidence — tissue damage in capillary-rich organs such as the lungs and kidneys, for example. Micro-clots might also damage red blood cells, leading to anaemia. But Sneller and his colleagues found no signs of this in any of the lab tests.
Kell and Pretorius argue that just because this study didn’t find any evidence of micro-clots doesn’t mean they aren’t there. One of the key issues with long COVID is that “every single test comes back within the normal ranges”, Pretorius says. “You have desperately ill patients with no diagnostic method.” She hopes that other researchers will read their papers and attempt to replicate their results. “Then we can have a discussion,” she says. The ultimate causal proof, she adds, would be people with long COVID feeling better after receiving anticoagulant therapies.
There is some limited evidence of this. In an early version of a preprint, posted in December 2021, Kell, Pretorius and other researchers, including physician Gert Jacobus Laubscher at Stellenbosch University, reported that 24 people who had long COVID and were treated with a combination of two antiplatelet therapies and an anticoagulant experienced some relief13. Participants reported that their main symptoms resolved and that they became less fatigued. They also had fewer micro-clots. Pretorius and Kell are working to gather more data before they try to formally publish these results. But other physicians are already using these medications to treat people with long COVID. Some are even offering a dialysis-like procedure that filters fibrinogen and other inflammatory molecules from the blood. To O’Donnell, such treatment feels premature. He accepts that some people with long COVID are prone to clots, but leaping from a single small study to treating a vast number of people is “just not going to wash in 2022 in my book”, he says. Sneller agrees. “Anticoagulating somebody is not a benign thing. You basically are interfering with the blood’s ability to clot,” he says, which could make even minor injuries life-threatening.
Kell says he’s tired of waiting for a consensus on how to treat long COVID. “These people are in terrible pain. They are desperately unwell,” he says. Altmann understands that frustration. He gets e-mails almost daily, asking: “Where are the drug trials? Why does it take so long?” But even in the midst of a pandemic, he argues, researchers have to follow the process. “I’m not rubbishing anybody’s data. I’m just saying we’re not there yet,” he says. “Let’s join up the dots and do this properly.”
A proportion of patients surviving acute coronavirus disease 2019 (COVID-19) infection develop post-acute COVID syndrome (long COVID (LC)) lasting longer than 12 weeks. Here, we studied individuals with LC compared to age- and gender-matched recovered individuals without LC, unexposed donors and individuals infected with other coronaviruses. Patients with LC had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1) that remained persistently high at 8 months after infection. Using a log-linear classification model, we defined an optimal set of analytes that had the strongest association with LC among the 28 analytes measured. Combinations of the inflammatory mediators IFN-β, PTX3, IFN-γ, IFN-λ2/3 and IL-6 associated with LC with 78.5–81.6% accuracy. This work defines immunological parameters associated with LC and suggests future opportunities for prevention and treatment.
Acute COVID-19, caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by a broad spectrum of clinical severity, from asymptomatic to fatal1,2. The immune response during acute illness contributes to both host defense and pathogenesis of severe COVID-19 (ref. 3). Pronounced immune dysregulation with lymphopenia and increased expression of inflammatory mediators3,4 have been described in the acute phase. Following acute COVID-19 infection, a proportion of patients develop physical and neuropsychiatric symptoms lasting longer than 12 weeks (known as Long COVID, chronic COVID syndrome or post-acute sequelae of COVID-19 (ref. 5)), henceforth denoted as LC. Although similar syndromes have been described following infection with SARS-CoV-1 (ref. 6) and Middle East respiratory syndrome–related coronavirus7, LC often develops after mild-to-moderate COVID-19 (refs. 8,9). Symptoms persisting 6 months were observed in 76% of hospitalized patients, with muscle weakness and fatigue being most frequently reported10,11. LC affects between 10% and 30% of community-managed COVID-19 cases 2 to 3 months after infection12,13 and can persist >8 months after infection14. LC symptoms include severe relapsing fatigue, dyspnea, chest tightness, cough, brain fog and headache15. The underlying pathophysiology of LC is poorly understood.
Here, we analyzed a cohort of individuals followed systematically for 8 months after COVID-19 infection according to a predefined schedule, comparing them to healthy donors unexposed to SARS-CoV-2 (unexposed healthy controls (UHCs)) before December 2019, and individuals who had been infected with prevalent human coronaviruses (HCoVs; HCoV-NL63, O229E, OC43 or HKU1), but not SARS-CoV-2. The ADAPT study9 enrolled adults with SARS-CoV-2 infections confirmed by PCR at St Vincent’s Hospital community-based testing clinics in Sydney (Australia). For the majority of participants, their first visit occurred between months 2 and 3 after infection (median of 79 days after the date of initial diagnosis)9,14, with 93.6% and 84.5% of participants completing subsequent month 4 (median, 128 days) and month 8 (median, 232 days) visits (Table 1). Of the 147 patients recruited (70.5% through ADAPT sites and 29.5% externally), 31 participants (21.08%) were designated as LC based on the occurrence of one of three major symptoms (fatigue, dyspnea or chest pain) at month 4 (Supplementary Table 1). These participants were age and gender matched with 31 asymptomatic matched controls (MCs) from the same cohort who did not report symptoms at month 4 after infection but were symptomatic during the acute phase of the infection (Supplementary Table 2). There was a 10% trend toward some improvement of symptoms over time in LC, but this trend was not statistically significant (Fisher’s exact P = 0.44).Table 1 Patient characteristics
To examine biomarkers associated with LC, we assessed 28 analytes in the serum of patients from the LC, MC, HCoV and UHC groups at month 4 after infection using a bead-based assay. Six proinflammatory cytokines (interferon β (IFN-β), IFN-λ1, IFN-γ, CXCL9, CXCL10, interleukin-8 (IL-8) and soluble T cell immunoglobulin mucin domain 3 (sTIM-3)) were elevated in the LC and MC groups compared to the HCoV and UHC groups (Fig. 1), with no difference observed in the 22 other analytes, including IL-6 and IL-33 (Extended Data Fig. 1). There was no difference between LC and MCs for any individual analyte at this time point (Extended Data Fig. 1a, b). IFN-β was 7.92-fold and 7.39-fold higher in the LC and MC groups compared to the HCoV group and 7.32- and 6.83-fold higher compared to UHCs (Fig. 1a). IFN-λ1 was increased 2.44-fold and 3.24-fold in the LC and MC groups compared to the HCoV group and 2.42- and 3.21-fold compared to UHCs. IL-8 was higher in the LC (3.43-fold) and MC (3.56-fold) groups compared to the HCoV and UHC groups (Fig. 1a). CXCL10 was elevated in the LC group compared to the HCoV (2.15-fold) and UHC (3.2-fold) groups and in the MC group compared to the HCoV (1.7-fold) and UHC (3.06-fold) groups. CXCL9 was 1.69-fold higher in the LC group than in the UHC group, and sTIM-3 was elevated in the LC group, but not the MC group, when compared to the HCoV group (1.46-fold) (Fig. 1a and Extended Data Fig. 1c).
IFN-β and IFN-λ1 decreased 4.4-fold and 1.8-fold, respectively, in the MC group at month 8 compared to month 4 (Fig. 1b). In the LC group, IFN-β decreased by 1.5-fold, and IFN-λ1 increased by 1.05-fold at month 8 compared to month 4, which was not statistically significant (Fig. 1b). At month 8, IFN-β and IFN-λ1 remained significantly elevated in the LC group compared to the MC, HCoV and UHC groups (Extended Data Fig. 2a). Reductions in CXCL9, CXCL10, IL-8 and sTIM-3 were observed in the LC and MC groups at month 8 compared to month 4 (Fig. 1b). At month 8, there was also decreased expression of some of the 22 analytes that were not significantly different among the four groups at month 4 (Extended Data Fig. 2b,c).
Because plasma ACE2 activity has been reported to be elevated 114 days after SARS-CoV-2 infection16, we investigated whether this occurred in our cohort at months 3, 4 and 8 after infection. Median plasma ACE2 activity was significantly higher in both LC and MC groups compared to the HCoV group at month 3 (LC, 1.92-fold; MC, 2.47-fold) and month 4 (LC, 1.75-fold; MC, 2.62-fold) after infection (Fig. 1c). At month 8, plasma ACE2 activity in the LC and MC groups decreased to levels observed in the HCoV and UHC groups (Fig. 1c). No difference was observed within LC and MC groups at months 3, 4 or 8, but both groups had higher activity compared to the HCoV group, suggesting that this parameter is specific to SARS-CoV-2 infection and is not a common feature of other coronaviruses.
Next, we used a classification model to determine an optimal set of analytes most strongly associated with LC. This linear classifier was trained on log-transformed analyte data to reduce the bias observed in each of the analytes and improve model accuracy. This log-linear classification model was used to develop a metric for feature importance17. To identify analytes that were associated with LC and not MC, we used the analyte data at month 8, the time point with the greatest difference between the LC and MC groups. The performance of each of the log-linear models was quantified by an accuracy estimate and an F1 score evaluated by taking averages after bootstrapping, which randomly sampled from the original population to create a new population. By considering every possible pair of the 28 serum analytes and plasma ACE2 activity, a classification model including two analytes (IFN-β and pentraxin 3 (PTX3)) had an LC prognostic accuracy of 78.54% and an F1 score of 0.77. Three analytes (IFN-β, PTX3 and IFN-γ) achieved an accuracy of 79.68%, with an F1 score of 0.79. Four analytes (IFN-β, PTX3, IFN-λ2/3 and IL-6) achieved an accuracy of 81.59% and an F1 score of 0.81. When all 29 analytes were featured, the calculated accuracy was 77.4%, with an F1 score of 0.76 (Table 2).Table 2 Accuracy and F1 score (with confidence intervals) for the top two, three and four features and all features identified by machine learning utilizing a log-linear classification model
After generating 1,000 randomly sampled populations, we counted the number of times each feature appeared in the best performing set of features, combining sets if several sets achieved the same accuracy. This revealed that IFN-β was the most important feature, appearing in 89%, 93% and 94% of the best sets of two, three and four features, respectively (Fig. 2a). Linear classifiers defined a decision boundary. Each patient analyte concentration at month 8 lied on either side of the boundary, and its positioning relative to the boundary determined whether the patient was predicted to experience LC or asymptomatic COVID (Fig. 2b). Although the decision boundary of the four featured analytes at month 8 is four dimensional, the boundary can be visualized with two-dimensional projections of IFN-β against the other highly associated analytes (PTX3, IFN-γ, IFN-λ2/3 and IL-6 (Fig. 2b). Longitudinal levels of these key feature cytokines indicate the advantage of log-linear models in differentiating LC from MCs (Fig. 2c).
To investigate differences in immune cell profiles between LC and MCs, we developed a 19-parameter flow cytometry panel and phenotyped peripheral blood mononuclear cells (PBMCs) from LC and MC donors at months 3 and 8 after infection. Dimensional reduction via TriMap coupled with Phenograph clustering (n = 14; LC = 7, MC = 7) identified 24 distinct cell clusters at month 3 and 21 clusters at month 8 (Extended Data Fig. 3a) including T, B, NK and myeloid cell clusters (Extended Data Fig. 3b,c). Concatenated phenotype data from each of the 7 LC or MC and 7 UHC contributed to every population cluster (Extended Data Fig. 4a–d). Of the 24 subsets identified at month 3, five were absent in LC donors: naive CD127lowGzmB−CCR7+CD45RA+CD27+CD8+ T cells, CD57+GPR56+GzmB+CD8+ T cells, naive CD127loTIM-3−CCR7+CD45RA+CD27+CD4+ T cells, innate-like CD3+CD4−CD8− T cells (may comprise natural killer T cells and γδ-T cells), and naive CD127loTIM-3−CD38lowCD27−IgD+ B cells (Fig. 3a). Three clusters remained absent at month 8 in LC donors (naive CD127lowGzmB−CCR7+CD45RA+CD27+CD8+ T cells, naive CD127lowTIM-3−CCR7+CD45 RA+CD27+CD4+ T cells, and naive CD127lowTIM-3−CD38lowCD27−IgD+ B cells) (Fig. 3b), indicating perturbations at month 8 in LC donors. Naive T and B cells expressing low levels of CD127 and TIM-3 were detected in the MC and UHC groups but were absent in the LC group at months 3 and 8 (Extended Data Fig. 4e,f).
The frequency of highly activated CD38+HLA-DR+ myeloid cells was elevated at month 8 in the LC group compared to MCs (Fig. 3c). Frequencies of activated CD14+CD16+ monocytes were higher in the LC group compared to MCs at months 3 and 8. The percentages of plasmacytoid dendritic cells (pDCs) expressing the activation markers CD86 and CD38 were also higher in the LC group at both time points compared to MCs (Fig. 3c). There was no difference in the frequencies of activated CD11c+ myeloid dendritic cells between month 3 and month 8 (Extended Data Fig. 5a). The T cell activation and exhaustion markers PD-1 and TIM-3 were more highly expressed on CD8+ T cells in the LC group compared to MCs at month 3 (PD-1, 3.04-fold; TIM-3, 1.6-fold) and month 8 (PD-1 2.86-fold) (Fig. 3d). However, PD-1 and TIM-3 coexpression was similar on CD4+ and CD8+ T cells in the LC and MC groups (Extended Data Fig. 5b).
Here, we show that convalescent immune profiles after COVID-19 are different from those following infection with other coronaviruses. Several cytokines (mostly type I and III IFN, but also chemokines downstream of IFN-γ) were highly elevated in individuals following the resolution of active SARS-CoV-2 infection compared to HCoVs and UHCs at month 4 after infection. IFN-β and IFN-λ1 remained elevated in the LC group at month 8 after initial infection, while their levels began to resolve in MCs. Elevated plasma ACE2 activity was noted in the LC and MC groups at month 4 but trended toward normal by month 8 after infection. We identified a set of analytes (IFN-β, PTX3, IFN-γ, IFN-λ2/3 and IL-6) that highly associated with LC at month 8, indicating that components of the acute inflammatory response and activation of fibroblast or epithelial cells, T cells and myeloid cells are associated with LC. Immune cell phenotyping indicated chronic activation of a subset of CD8+ T cells, with expansion of PD-1+ and TIM-3+ subsets and pDCs and monocytes persisting from month 3 to month 8 in the LC group. These changes were accompanied by an absence of naive T and B cell subsets expressing low levels of CD127 and TIM-3 in peripheral blood of patients with LC. These findings suggest that SARS-CoV-2 infection exerts unique prolonged residual effects on the innate and adaptive immune systems and that this may be driving the symptomology known as LC.
IFN-β and IFN-λ1 were highly elevated in convalescent COVID-19 samples compared to HCoV and UHC samples. Although these levels decreased over time in patients who recovered, they remained high in patients with LC. The morbidity of acute COVID-19 infection appears to correlate with high expression of type I and III IFN in the lungs of patients18. IFN-λ produced by murine lung dendritic cells in response to synthetic viral RNA is associated with damage to lung epithelium19, and IFN-λ signaling hampers lung repair during influenza infection in mice20. Severe acute COVID-19 has been associated with diminished type I IFN and enhanced IL-6 and tumor necrosis factor (TNF) responses19. Although our cohort of individuals with LC consisted mostly of patients with mild or moderate initial illness, elevated type I and III IFN levels were maintained to month 8 after infection and are consistent with the observed prolonged activation of pDCs, indicating a chronic inflammatory response.
Patients with COVID-19 who are admitted to the intensive care unit have high plasma levels of sTIM-3 (ref. 21). We found elevated levels of sTIM-3 in the LC group, but not in the MC or HCoV groups, which is consistent with the expanded subsets of memory CD8+ T cells expressing TIM-3 and PD-1 and indicates chronic T cell activation and potentially exhaustion. Similarly, shedding of membrane-bound protein ACE-2 during acute infection22 resulting in increased activity in plasma16 continues into convalescence, regardless of symptom severity at month 4, and normalizes at month 8 in most patients.
We employed a log-linear classification model to assess all combinations of analytes to determine the subset of analytes most strongly associated with LC. IFN-β, together with PTX3, IFN-λ2/3, IFN-γ and IL-6, differentiated LC from MCs with high accuracy at month 8. IFN-λ2/3 are secreted by pDCs following viral RNA sensing by TLR7, TLR9 and RIG-123,24. PTX3 increased in lung epithelia and plasma of patients with severe COVID-19 and can serve as an independent strong prognostic indicator of short-term mortality25,26,27. IL-6 is a pleiotropic mediator that drives inflammation and immune activation28. A high IL-6/IFN-γ ratio is associated with severe acute COVID-19 infection29. The observation that the best correlate for LC is an eclectic combination of biomarkers reinforces the breadth of host response pathways that are activated during LC.
T cell activation (indicated by CD38 and HLA-DR), T cell exhaustion and increases in B cell plasmablasts occur during severe COVID-19 (refs. 30,31,32). These markers identified highly activated monocytes and pDCs, the frequencies of which decreased over time in MCs, but not in patients with LC. Type I and type III IFN upregulate major histocompatibility complex expression, including HLA-DR33. An unbiased large-scale dimensional reduction approach identified the depletion of three clusters of naive B and T cell subsets present in the LC group at month 8 after infection. Altogether, these observations suggest persistent conversion of naive T cells into activated states, potentially due to bystander activation secondary to underlying inflammation and/or antigen presentation by activated pDCs or monocytes. The ultimate result of this chronic stimulation may be expansion of PD-1+ or TIM-3+ CD8+ memory T cells. Bystander activation of unactivated naive subsets into more activated phenotypes is consistent with observations in acute severe COVID-19 (refs. 34,35).
Although individuals with LC and MCs were matched for age and gender, it is possible that the differences observed reflect differences in unrecognized factors between these groups. Although more LC donors had severe acute disease (eight LC donors and two MCs), sensitivity analyses excluding these patients did not alter the statistical significance of the major associations described here. Because of the timing of ethics approval and cohort setup, samples were not collected during acute infection. We were therefore unable to determine whether elevations in biomarkers during convalescence correlate with levels during acute infection. Although some perturbations observed here are potentially consistent with a hypothesis that the major drivers of the expression of biomarkers in convalescence are those in the acute infection, others are not. Our results require validation in other LC cohorts. Finally, our definition of LC was set internally given the lack of international consensus. Nevertheless, the inclusion of three of the most common persisting symptoms and blinding of cases and controls helped ensure the validity of our findings.
In summary, our data indicate an ongoing, sustained inflammatory response following even mild-to-moderate acute COVID-19, which is not found following prevalent coronavirus infection. The drivers of this activation require further investigation, but possibilities include persistence of antigen, autoimmunity driven by antigenic cross-reactivity or a reflection of damage repair. These observations describe an abnormal immune profile in patients with COVID-19 at extended time points after infection and provide clear support for the existence of a syndrome of LC. Our observations provide an important foundation for understanding the pathophysiology of this syndrome and potential therapeutic avenues for intervention.
The ADAPT study is a prospective cohort study of post–COVID-19 recovery established in April 2020 (ref. 14). A total of 147 participants with confirmed SARS-CoV-2 infection were enrolled, the majority following testing in community-based clinics run by St Vincent’s Hospital Sydney, with some patients also enrolled with confirmed infection at external sites. Initial study follow-up was planned for 12 months after COVID-19 and subsequently extended to 2 years. Extensive clinical data and a biorepository was systematically collected prospectively. The aims of ADAPT are to evaluate a number of outcomes after COVID-19 relating to pathophysiology, immunology and clinical sequalae. Laboratory testing for SARS-CoV-2 was performed using nucleic acid detection from respiratory specimens with the EasyScreen Respiratory Detection kit (Genetic Signatures) and the EasyScreen SARS-CoV-2 detection kit. Two ADAPT cohort subpopulations were defined based on initial severity of COVID-19 illness: (1) patients managed in the community and (2) patients admitted to the hospital for acute infection (including those requiring intensive care support for acute respiratory distress syndrome). Patients were defined as having LC at 4 months based on the presence of one or more of the following symptoms: fatigue, dyspnea or chest pain14. These patients were gender and age (±10 years) matched with ADAPT participants without LC (matched ADAPT controls) (Table 1). Samples for these analyses were collected at the 3-, 4- and 8-month assessments. Our cohort consisted of 62 participants (31 with LC and 31 MCs); enrollment visits were performed at a median of 76 (IQR, 64–93) days after initial infection. Their 4-month assessments were performed at a median of 128 (IQR, 115–142) days after initial infection (4.2 months). Their 8-month assessments were performed at a median of 232 (IQR, 226–253) days after initial infection (7.7 months). The dropout rate has been very low to date (approximately 9.4% at 12 months). Four participants did not complete the 8-month assessment after the 4-month assessment. The reasons for this include ‘did not attend’ (n = 2) and ‘lost to follow-up’ (n = 2). A further population of patients presenting to St Vincent’s Hospital clinics for COVID-19 testing on the multiplex respiratory panel who were PCR positive for any of the four human common cold coronaviruses (HCoV-NL63, O229E, OC43 or HKU1) and PCR negative for SARS-CoV-2 were recruited into the ADAPT-C substudy and used as a comparator group.
The ADAPT study was approved by the St Vincent’s Hospital Research Ethics Committee (2020/ETH00964) and is a registered trial (ACTRN12620000554965). The ADAPT-C substudy was approved by the same committee (2020/ETH01429). All data were stored using REDCap (v11.0.3) electronic data capture tools. Unexposed healthy donors were recruited through St Vincent’s Hospital and approved by St Vincent’s Hospital Research Ethics Committee (HREC/13/SVH/145). The University of Melbourne unexposed donors were approved by Medicine and Dentistry HESC study ID 2056689. All participants gave written informed consent, and patients were not compensated.
Sample processing and flow cytometry
Blood was collected for biomarker analysis (serum separating tube (SST) 8.5 ml x1 (serum) and EDTA 10 ml x1 (plasma)), and 36 ml was collected for PBMCs (ACD (citric acid, trisodium citrate and dextrose) 9 ml x4). Phenotyping of PBMCs was performed as described previously36. Briefly, cryopreserved PBMCs were thawed using RPMI (+L-glutamine) medium (ThermoFisher Scientific) supplemented with penicillin/streptomycin (Sigma-Aldrich) and subsequently stained with antibodies binding to extracellular markers for 20 min. Extracellular panel included Live/Dead dye Near InfraRed, CXCR5 (MU5UBEE) and CD38 (HIT2) (ThermoFisher Scientific); CD3 (UCHT1), CD8 (HIL-72021), PD-1 (EH12.1), TIM-3 (TD3), CD27 (L128), CD45RA (HI100), CD86 (BU63), CD14 (HCD14), CD16 (GB11), IgD (IA6-2), CD25 (2A3) and CD19 (HIB19) (BioLegend); and CD4 (OKT4), CD127 (A019D5), HLA-DR (L234), GRP56 (191B8), CCR7 (G043H7) and CD57 (QA17A04) (BD Biosciences). Perm Buffer II (BD Pharmingen) was used for intracellular staining of granzyme B (GB11, BD Biosciences). Samples were acquired on an Cytek Aurora (BioLegend) using Spectroflo software. Before each run, all samples were fixed in 0.5% paraformaldehyde.
The LEGENDplex Human Anti-Virus Response Panel (IL-1β, IL-6, IL-8, IL-10, IL-12p70, IFN-α2, IFN-β, IFN-λ1, IFN-λ2/3, IFN-γ, TNF-α, IP-10 and GM-CSF) and a custom-made panel (IL-5, IL-9, IL-13, IL-33, PD-1, sTIM-3, sCD25, CCL2 (MCP-1), PTX3, transforming growth factor β1, CXCL9 (MIG-1), myeloperoxidase, PECAM-1, ICAM-1 and VCAM-1) were purchased from BioLegend, and assays were performed as per the manufacturer’s instructions. Beads were acquired and analyzed on a BD Fortessa X20 SORP (BD Biosciences). Samples were run in duplicate, and 4,000 beads were acquired per sample. Data analysis was performed using Qognit LEGENDplex software (BioLegend). Lower limit of detection values were used for all analytes at the lower limit.
Catalytic ACE2 detection in plasma
Plasma ACE2 activity was measured using a validated, sensitive quenched fluorescent substrate-based assay as previously described37. Briefly, plasma (0.25 ml) was diluted into low-ionic-strength buffer (20 mmol l−1 Tris-HCl, pH 6.5) and added to 200 ml ANXSepharose 4 Fast-Flow resin (Amersham Biosciences, GE Healthcare) that removed a previously characterized endogenous inhibitor of ACE2 activity. After binding and washing, the resulting eluate was assayed for ACE2 catalytic activity. Duplicate samples were incubated with the ACE2-specific quenched fluorescent substrate, with or without 100 mM ethylenediaminetetraacetic acid. The rate of substrate cleavage was determined by comparison to a standard curve of the free fluorophore 4-amino-methoxycoumarin (Sigma-Aldrich) and expressed as picomoles of substrate cleaved per milliliter of plasma per minute. The intra- and interassay coefficients of variation were 5.6% and 11.8%, respectively. Samples below the limit of detection were designated 0.02 (half the lower limit of detection; i.e., 50% × 0.04).
The analytes most associated with LC were identified via log-linear classification. For an arbitrary set of four analytes, let the concentration of the ith analyte at 8 months be denoted wi. Log-linear classification assigns a weight ai to the logarithm of each analyte concentration. A linear function of these logged concentrations and weights takes the form f(a⃗ )f(a→) is a threshold parameter. The weights wi and the intercept w0 are selected to maximize the predictive power of the linear classifier by training on the analyte data, where f(a⃗ )>0f(a→)>0 results in the classifier predicting that the participant with analyte concentration a⃗ a→ has LC and does not have LC otherwise.
Because of the modest small sample size of 58 participants at month 8, we performed bootstrapping to randomly sample new populations of size 58 from our population with replacement. The sampled population was then split 29:29 into test and train datasets. The training dataset was used to train a log-linear classifier using Python3 v3.8.10 and the Scikit-learn machine learning package v0.24.1. From the test set, the number of true positives (TPs; both the classifier and data indicate the participant had LC), true negatives (TNs; both the classifier and data indicate the participant had asymptomatic COVID), false positives (FPs; classifier predicts the participant will have LC, but the data disagree) and false negatives (FNs; classifier predicts the participant will have asymptomatic COVID, but the data disagree) were identified. Then, two subsequent scores were calculated. The accuracy is defined as (TP + TN)/(TP + TN + FP + FN) and measures the proportion of test participants that had their COVID status correctly predicted. The second measure is the F1 score and is defined as TP/(TP + 0.5 × (FP + FN)), which is a measure that combines recall, how many LC cases were correctly predicted and precision (of all the participants predicted to have LC, how many were correct). This process is repeated for 1,000 different bootstrapped sample populations. The average accuracy of a model of N analytes is then calculated and used to assess which combination of N analytes performs the best.
Dimensional reduction and clustering analysis
FCS 3.0 files were compensated manually using acquisition-defined matrix as a guide, and the gating strategy was based on unstained or endogenous controls. Live singlets were gated from patients with LC and asymptomatic MCs using FlowJo v.10.7.2, samples were decoded and statistical analysis between groups and unsupervised analysis was performed, with matched asymptomatic controls as the primary comparator group. For unsupervised analysis, the following FlowJo plugins were used: DownSample (v.3), TriMap (v.0.2), Phenograph (v.3.0) and ClusterExplorer (v.1.5.9) (all FlowJo LLC). First, 100,000 events per sample were downsampled from the total live singlet gate (Extended Data Fig. 6). The newly generated FCS files were labeled according to control or patient group (LC or MCs) and concatenated per group. Subsequently, 20,000 events were taken from each grouped sample by downsampling. The two new FCS files corresponding to LC and MCs were then concatenated for dimensionality reduction analysis using TriMap (40,000 events in total). TriMap was conducted using the following parameters to include the markers CD25, CD38, CCR7, CD19, IgD, CD45RA, PD-1, TIM-3, CD4, CD57, CD127, CD27, HLA-DR, CD8, CXCR5, GPR56 and granzyme B and using the following conditions: metric = Euclidean, nearest neighbors = 15 and minimum distance = 0.5. The phenograph plugin was then used to determine clusters of phenotypically related cells. The same markers as TriMap and parameters k = 152 and Run ID = auto were used for analysis. Finally, the ClusterExplorer plugin was used to identify the phenotype of the clusters generated by phenograph.
All column graphs are presented as medians with IQRs. One-way analysis of variance with Kruskal–Wallis and Dunn’s correction for multiple comparisons was used for serum analyte analysis. A Wilcoxon paired t test was used to analyze statistical data with Prism v9.0 (GraphPad) software. For unpaired samples, a Mann–Whitney U test was used. Two-tailed P values less than 0.05 were considered significant (*P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001).
To protect patient privacy, underlying electronic health records may be accessed via a remote server pending a material transfer agreement and approval from study steering committee. As data within this manuscript are from an ongoing clinical trial, further data will be provide by the corresponding author upon request and will require approval from study steering committee.
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For many Covid-19 patients, the end of the acute stage of infection is only the beginning of another difficult experience: Long Covid. Defined by the persistence of physical and neuropsychiatric symptoms over a period of 12 weeks or longer, the exact causes of long Covid remain largely elusive. A recent analysis by researchers at the University of New South Wales’ Kirby institute and St Vincent’s Hospital Sydney sheds some light on the topic. In long Covid patients they have uncovered evidence of sustained inflammation and activation of the immune response for at least 8 months after initial infection. These findings provide a framework through which to define more accurately and diagnose long Covid.
Phetsouphanh et al. were given a chance to look for “biomarkers” underlying long Covid with help from data gathered as part of St Vincent’s Hospital’s ADAPT study. The study collected blood samples from unvaccinated Australians during the height of the country’s first pandemic wave.
Immune biomarkers are measurable indicators that act as a kind of map key, letting researchers know what processes and responses characterize a certain disease. This study represents the first laboratory analysis of long Covid’s impact on the immune system.
To pin down exactly what’s happening to Covid “long-haulers,” as they’ve come to be known, Phetsouphanh et al. compared the blood samples from the ADAPT study with those derived from healthy donors unexposed to SARS-CoV-2. The ADAPT cohort was made up of individuals with PCR-confirmed Covid-19 infections, tracked over a period of eight months. Blood samples were drawn two months, four months, and eight months after the initial infection. After four months, 31 of a total 147 participants were classified as having long Covid based on the persistence of one of three major symptoms: fatigue, labored breathing, or chest pain. Those exhibiting long Covid symptoms were matched with 31 symptom-free participants of the same trial, used as an additional control cohort.
The team of researchers also compared the blood samples with those of individuals infected with other, non-SARS-CoV-2 human coronaviruses.
“As immunologists we’re almost like detectives at a crime scene. We have thousands of potential biomarkers – or leads – to investigate, but only a handful of them will reveal something useful. We can use some of our knowledge of what’s been measured in acute COVID and other post-viral fatigue syndromes to narrow the investigation down a little bit, but because long COVID is still a new syndrome, we have to take a broad examination of the evidence and look almost everywhere,” says Dr. Phetsouphanh.
Of the 28 potential markers the researchers analyzed, six were noticeably elevated in both the long Covid cohort and the asymptomatic control cohort four months after initial infection. All six were proinflammatory cytokines, signaling proteins that help boost inflammation as part of the innate immune response. Two proinflammatory cytokines stood out as particularly elevated in the Covid cohorts vis-à-vis the other two cohorts: interferon β (IFN-β), and interferon λ1 (IFN-λ1).
The remaining 22 analytes were the same across all four cohorts.
Inflammation is a critical part of recovery, helping the body get rid of the source of damage and helping it repair injured tissue, but too much of it can have unwanted effects. Especially when the inflammation persists beyond any actual outside threat.
Professor Gail Matthews, the study’s senior researcher, mentioned: “But what we’re seeing with long COVID is that even when the virus has completely left the body, the immune system remains switched on. If you measure the same thing after a standard cough or cold, which we did in this study through one of our control groups, this signal is not there. It’s unique to sufferers of long COVID.”
The long Covid cohort and the asymptomatic matched control cohort may have had the same readings four months in, but at eight months the two began to come apart. The levels of proinflammatory cytokines in the asymptomatic cohort dropped off, whereas those in the long Covid cohort remained more or less steady, with only a statistically insignificant decrease.
Four of the markers, analyzed via a data model, proved to be especially accurate in predicting long Covid: IFN-β, PTX3, IFN-λ2/3 and IL-6. Of these, IFN-β was the single most important indicator of long Covid, present 94% of the time when modeled in a set of four markers.
As exciting as this data is, the researchers are already looking ahead: how does the rate of long Covid incidence and distribution of biomarkers change depending on vaccination status, the variant with which one was infected, and the severity of one’s infection?
The plight of long haulers was dismissed early on in the pandemic, often leaving sufferers to deal with life-altering symptoms on their own, without clinical or institutional support. This analysis by Phetsouphanh et al. helps firmly ground their experiences in biology. Long Covid is a medical condition, often debilitating, and has to be treated as such.
The same expert panel will meet again on Wednesday to discuss shots from Moderna and Pfizer for the kids under 5.
According to the CDC data, the incidence of heart inflammation was 4.41 excess per 100,000 who received the Pfizer/BioNTech for males aged 18-39 versus 6.27 excess cases per 100,000 for Moderna, Reuters reported.
The overall incidence is relatively rare and the vast majority who suffer the side effect fully recover, but a comparison showed the risk of myocarditis and pericarditis in young males aged 18-39 was 1.1 to 1.5 times higher after the Moderna shot, the FDA said in its presentation, citing data from three U.S. vaccine safety databases.
Some countries in Europe have limited use of Moderna’s vaccine for younger age groups after surveillance suggested it was tied to a higher risk of heart inflammation, and the FDA delayed its review of the Moderna shot to assess the myocarditis risk.
The FDA said data from European and Canadian regulators showed that the risk was 1.7 to 7.3 times higher for Moderna’s vaccine than Pfizer’s in adolescents and young men.
Outside experts are considering the data before deciding whether to recommend Moderna’s vaccine for children and teens aged 6-17 years of age. The Pfizer vaccine is already authorized for children 5 and older.
An FDA official claimed that the findings on myocarditis and pericarditis linked to both the mRNA shots “were not consistent across all of the U.S. vaccine safety monitoring systems.”
The CDC also claimed that recent data suggests that most people with myocarditis after mRNA COVID-19 vaccination recover over time.
Daniel Horowitz, the senior editor at The Blaze, tweeted on Monday regarding the side effects of the Moderna vaccine.
“Holy Moly! one-quarter of the kids in Moderna’s trial reported Grade 3 side effects, meaning they couldn’t go to school https://fda.gov/media/159189/download… So many had flu-like symptoms! Even the original strain of covid mainly did this to kids. Yet, we are giving them these symptoms upfront,” Horowitz tweeted.
Robert F. Kennedy also weighed in and said, “FDA’s risk-benefit document in connection with the Moderna mRNA shot in kids is dishonest, and evidence that the public health establishment has abandoned science, logic, reason, rationality, empathy, health and medicine.”
Moderna’s vaccine efficacy was 36.8% at ages 2-5 years during for omicron
The headline : “Briefing data… also support Moderna’s vaccine for kids up to age 17” is challenging, as an understatement.
The Food and Drug Administration previously said on Friday night that Moderna’s coronavirus vaccine for children under 6 is effective in preventing symptomatic infection without causing worrisome side effects.
Despite all the evidence and data showing the risks of myocarditis and pericarditis, FDA advisers consider Moderna’s COVID shots for children 6 through 17 years of age.
The FDA held up Moderna’s teen vaccine for months while it investigated a rare side effect, heart inflammation. That’s mostly a risk for teen boys and young men, and also can occur with the Pfizer vaccine. Moderna got extra scrutiny because its shots are a far higher dose..
In their review, FDA scientists said there were no confirmed cases of the heart inflammation in Moderna’s kid studies. But experts say the studies may have had too few participants for a rare side effect like that to appear.
“It’s just not enough people in the clinical trials to detect” the problem if it’s occurring, said Dr. Jesse Goodman of Georgetown University, a former FDA vaccine chief, in a call with reporters earlier this week.
The FDA analysis concluded that two doses of Moderna are effective in preventing symptomatic COVID-19 illness in teens and younger kids, with the levels of virus-fighting antibodies comparable to those developed in young adults.
Vaccine effectiveness was estimated at 93% for the 12-17 group, and 77% for the younger group. However, the research was done when earlier versions of the coronavirus were causing most U.S. infections, and it’s not clear how well they work against more recent variants.
The FDA review said it was likely a booster shot would be needed, as is now recommended for children vaccinated with Pfizer’s shots, as well as for all adults.
If the FDA authorizes Moderna shots for teens and schoolchildren, the matter moves next to the CDC, which makes recommendations about vaccinations to doctors and the public. A CDC spokesperson said the agency is not expected to take up the question until later this month.
For some individuals, the road to recovery from COVID-19 is long. While most people recover from mild COVID-19 symptoms over the course of one to two weeks, “long-haul” patients can suffer from lingering symptoms for months on end. This syndrome, called post-acute COVID-19 or “long COVID,” can have devastating effects on the daily lives of millions of patients.
To discuss what we know about long COVID, Jodie Guest, PhD, professor and vice chair of the department of epidemiology at Emory’s Rollins School of Public Health, teamed up with Alex Truong, MD, co-director of the post-COVID clinic at Emory’s Executive Park. Truong is also an assistant professor in the Division of Pulmonary and Critical Care Medicine at Emory University School of Medicine.
A: “A lot of our patients come in with very, very similar symptoms of brain fog, fatigue and shortness of breath,” says Truong. “It’s almost as if I can cut and paste one patient’s story to the next patient.”
“It’s very rare that someone comes in with a singular issue,” he continues. “It’s always a host of issues. Most of the time, patients are complaining that their brain fog and fatigue are the biggest limiters of their activities of daily living — their ability to get back to work, the ability to go back to school or take care of their kids. There’s a smaller population of patients who have had chronic pain syndromes and chronic shortness of breath syndromes that are often very challenging to figure out.”
Q: How many people who have COVID-19 will develop long COVID?
A: “That’s a really hard question to answer, because I think we are lacking the data,” Truong says. “I think, unfortunately, we aren’t at a place yet where we really know who’s at risk, and so we don’t know what the proportions are.”
Guest notes that current estimates for the risk of long-term symptoms range broadly from 15% to 80% of COVID-19 patients.
“That span of statistics, being all over the board, includes patients who are severely sick in the hospital and those who are not severely sick,” Truong adds. “If I had to guess, I would have to say it’s probably closer to the 15 to 20% range, depending on the population you’re looking at.”
Q: Is hospitalization due to severe COVID-19 associated with an increased risk of long COVID?
A: “A lot happens in the hospital and in the ICU that puts patients at risk for long-term outcomes, regardless of whether they have COVID or not,” Truong says, noting that survivors of any critical illness are prone to develop symptoms such as cognitive dysfunction, chronic fatigue and chronic pain.
“We have a syndrome called post-ICU syndrome that actually captures this collection of conditions that patients suffer from,” he says. “I think it’s difficult to separate what is post-COVID syndrome versus what is post-ICU syndrome. As we move forward in this diagnosis, this category of post-COVID folks will have to be better defined so that we can better separate it from the post-ICU folks.”
One key difference Truong does see between the two syndromes is that post-acute COVID patients generally report issues with attention, concentration and brain fog, while individuals with post-ICU syndrome often experience more memory loss.
Q: Is long COVID associated with damage to cells in the body caused by COVID-19?
A: “Initially, we thought of COVID as a lung infection virus. We do see a lot of patients in our post-COVID populations who have persistent lung inflammation, and some patients progress to scarring, representing that there is direct lung parenchyma damage,” Truong says.
“We’re also realizing that COVID is possibly a vascular problem,” he continues. “It will affect the blood vessels and can cause a whole cohort of symptoms that may be explained by decreased blood flow, such as brain fog and some of the cardiomyopathies that we may be having.”
Some of these symptoms, such as lung and heart inflammation, may be reversed with medication. Unfortunately, symptoms like brain fog are more difficult to resolve.
“We’re only at the very beginning steps of understanding how COVID affects the brain,” Truong says. “There are some data that suggest there are proinflammatory changes within the brain and movements of proinflammatory cells past the blood-brain barrier that may affect the limbic system, or the core systems of your brain that are responsible for things like mood, attention and memory.”
“We’re still in the process of trying to figure out what the importance of these different pathologies are,” he adds, noting that further research is needed to better understand these symptoms.
Q: Can people who fully recover from COVID-19 develop long COVID symptoms later?
A: “It was originally assumed that long COVID was associated with severe symptoms during your original infection, but now there seems to be some data that people are developing new issues after fully recovering from COVID-19,” Guest says. “Even people who didn’t have symptoms can experience some of these post-COVID-related health issues, which can present as a lot of different types and combinations of health problems and seem to range for a long period of time.”
Truong says the causes of post-COVID syndrome among this category of seemingly recovered patients are particularly frustrating to trace.
“We do get a population of patients who have very mild symptoms or in some cases don’t have any symptoms and just incidentally were found to have COVID, and then months later developed a syndrome of brain fog, fatigue and shortness of breath that isn’t explained by some pathology and the lung,” he says.
“I think that initially, there was a lot of conversation as to whether inflammation was playing a role in why patients are having post-COVID syndrome,” he continues. “The thought was the more severely sick you initially were, the more likely you are to have post-COVID. That has totally been blown out of the water. We do not see that signal whatsoever.”
Truong adds that post-COVID symptoms among these patients may potentially be explained by preliminary research regarding COVID-19 and autoimmunity.
“Patients who get infected with COVID may recover from the initial illness easily, but subsequently develop some sort of auto-antibody or auto-protein that the body does react to, and then manifests a lot of these other symptoms,” he says.
Q: How do you know whether a patient has long COVID or another condition?
A: “That’s been the big challenge in our clinic,” Truong says. “When patients come in with what sounds like post-COVID syndrome, the first step is always to make sure that there were confirmed COVID tests.” Patients can’t be diagnosed with post-COVID syndrome without having had a confirmed positive COVID-19 test.
Next, the clinic conducts several tests to rule out other diagnoses for patients who struggle with symptoms such as brain fog and fatigue.
“We do a whole slew of lab work that checks for thyroid levels, vitamin D deficiency, vitamin B12 deficiency, anemia and a bunch of other abnormalities,” he explains.
Easily treatable conditions like hypothyroidism and significant anemia are rarely diagnosed at the post-COVID clinic, and while vitamin deficiencies are common, Truong says patients often continue to experience symptoms even after those vitamins have been repleted.
“I think, unfortunately, we’re at the stage where if you have a COVID diagnosis and I can’t figure out other causes for your symptoms, then I’m blaming it on post-COVID syndrome,” he says. “That’s not very sexy or scientific, but at this point in the evolution of this syndrome, this is where we’re at.”
Q: When should people seek care for long-term symptoms after having COVID-19?
A: “I think that what patients should expect is that after their acute illness, in the next two to four weeks after they’ve been infected, they’re not going to feel well,” Truong says. “They’re going feel like they have brain fog, they’re probably going to have fevers and chills, body aches and fatigue.”
“If those symptoms last beyond four to six weeks from their initial infection and it’s affecting their lives and the ways that they do their job, or affecting how they’re functioning and activities of daily living, then I think that’s when it’s really important for them to come see us,” he continues.
“There is a population of patients who do have lingering symptoms past those four to six weeks after infection, and it’s just getting better on its own, but slowly,” Truong adds. “To those patients, I would say, wait and watch. But if it’s really affecting you, and it’s not improving at all, then please don’t wait too long to come see us.”
Q: Is the post-COVID clinic at Emory’s Executive Park still busy?
A: “Yes, we are very busy,” Truong says. “Interestingly, I was expecting a much bigger wave of new patients with the Omicron wave. I think that we’re still seeing patients who were of the previous waves right now.”
“I feel like we’re so much better at taking care of patients,” he adds, highlighting the progress the clinic has made since last year. “I think we have a little bit more data on our side, we have a lot more experience on our side, and I think we’re able to approach patients in a way that is much more systematic.”
Q: Where else can long COVID patients turn for support?
A: Many individuals with long COVID find support through social media. Online communities for people suffering from post-COVID symptoms have formed over platforms such as Facebook, Reddit and Twitter.
“There are several communities that actually have been really helpful,” Truong says. “Patients are passing information around, both for the good and bad. But I think right now, patients are finding the Internet is a really good resource for finding information on how to take care of themselves, as well as finding professionals who may be able to help them along with their journey.”
“That support system can be so good if the information is accurate,” Guest adds.
Q: Can children experience long COVID?
A: “Children can definitely get the long-haul or post-COVID syndrome. I think they tend to be less likely to have symptoms of shortness of breath and respiratory issues, and more likely to have a lot of the brain fog and fatigue issues that we’re seeing,” Truong says.
While Truong only treats adult patients at the post-COVID clinic, he says he hears about teenagers who have experienced long-haul symptoms for more than a year after initial infection. “They can’t get back to school and do the things that they need to do — most of which, again, centers around the brain fog and fatigue.”
Q: Does long COVID impact women more than men?
A: At the Emory post-COVID clinic, Truong sees about twice as many female patients as he does male patients.
“I think the data we have is that more women are showing up to the clinic than men are,” he says. “I have no idea whether that is because post-COVID syndrome is affecting women more than men, or if it is that they’re just seeking care and men are being stubborn and not seeking care.”
“I think in part it has to do with a selection bias, but I wouldn’t be surprised if the rates are truly a little bit higher in women than men,” he adds. “In similar syndromes such as chronic fatigue syndrome, we do see that those rates are slightly higher in women than men.”
Q: Does vaccination impact the risk of developing long COVID?
A: “The data we have so far have suggested that yes, indeed, it is helping protect you from having post-COVID syndrome if you get a breakthrough infection after you’ve had all three of your shots, which includes the booster,” Truong says. “I do have a small population of patients who have had post-COVID syndrome after they’ve been vaccinated, but it seems like those folks tend to have rather mild disease and tend to resolve a lot faster than my folks who have not been vaccinated and got COVID, and thus post-COVID syndrome, after.”“The safest way to keep from getting long COVID, or post-COVID syndrome, is certainly to make sure you keep from getting COVID-19,” Guest says. “The best way to do that is by getting vaccinated, getting a booster, making sure you protect those people who are around you, and when cases are still high out in the community, please wear a mask when you’re indoors in public spaces.”
Some people suffering with severe cases of COVID-19 will show signs of kidney damage, even those who had no underlying kidney problems before they were infected with the coronavirus. Signs of kidney problems in patients with COVID-19 include high levels of protein or blood in the urine and abnormal blood work.
Studies indicate more than 30% of patients hospitalized with COVID-19 develop kidney injury, and more than 50% of patients in the intensive care unit with kidney injury may require dialysis. Sperati says early in the pandemic, some hospitals were running short on machines and sterile fluids needed to perform dialysis.
“As general treatments for patients with COVID-19 have improved, the rates of dialysis have decreased. This has helped to alleviate shortages, although intermittent supply chain disruptions remain a concern.
“Many patients with severe COVID-19 are those with co-existing, chronic conditions, including high blood pressure and diabetes. Both of these increase the risk of kidney disease,” he says.
But Sperati and other doctors are also seeing kidney damage in people who did not have kidney problems before they got infected with the virus.
How does COVID-19 damage the kidneys?
The impact of COVID-19 on the kidneys is complex. Here are some possibilities doctors and researchers are exploring:
Coronavirus might target kidney cells
The virus itself infects the cells of the kidney. Kidney cells have receptors that enable the new coronavirus to attach to them, invade, and make copies of itself, potentially damaging those tissues. Similar receptors are found on cells of the lungs and heart, where the new coronavirus has been shown to cause injury.
Too little oxygen can cause kidneys to malfunction
Another possibility is that kidney problems in patients with the coronavirus are due to abnormally low levels of oxygen in the blood, a result of the pneumonia commonly seen in severe cases of the disease.
Cytokine storms can destroy kidney tissue
The body’s reaction to the infection may be responsible as well. The immune response to the new coronavirus can be extreme in some people, leading to what is called a cytokine storm.
When that happens, the immune system sends a rush of cytokines into the body. Cytokines are small proteins that help the cells communicate as the immune system fights an infection. But this sudden, large influx of cytokines can cause severe inflammation. In trying to kill the invading virus, this inflammatory reaction can destroy healthy tissue, including that of the kidneys.
COVID-19 causes blood clots that might clog the kidneys
The kidneys are like filters that screen out toxins, extra water and waste products from the body. COVID-19 can cause tiny clots to form in the bloodstream, which can clog the smallest blood vessels in the kidney and impair its function.
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.
“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.
“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.
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.
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).
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
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).
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.
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.
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
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.
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
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).
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).
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.
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.
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.
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.
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.
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.1, 2 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.
2.1 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.).
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),7–26 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.
TABLE 1. Management and response of patients with urticaria and/or angioedema during COVID-19 infection
Asymptomatic. 2 weeks after COVID-19 confirmed by RT-PCR
Not 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)
62-year-old current smoker man with diagnosed T4N2M1b G3 stage IV squamous cell lung carcinoma with pleuro-pulmonary involvement
Urticarial papular lesions, with marked itching and minimal erythema
Lower dorsal, lumbar and gluteal region
2 days after first reportingCOVID-19 symptoms. Two days before COVID-19 confirmed by RT-PCR
Vasculitis 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/day
Within 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 evident
46-year-old female nurse with history of hay fever and mild asthma
Widespread urticarial eruption; red-raised blanching and itchy rash with angioedema of lips and hands
Face, arms, torso, legs, and loins
48 hours before developing COVID-19 symptoms.2 days before COVID-19 confirmed by RT-PCR
Not carried out
No prescribed regular medications no over-the-counter medications
Started 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 recovery
Generalized urticaria with angioedema of face and neck
At same time as COVID-19 symptoms
Initial 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.
Elderly woman admitted to the hospital with bilateral pneumonia testing positive for COVID-19
Painful erythematous patches which left residual purpura when fading
Trunk, buttocks, and hips
> 5 days after first reporting COVID-19 symptoms
Histologic 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 debris
Treatment with hydroxychloroquine, lopinavir/ritonavir, and azithromycin for 5 days
A sudden worsening of respiratory condition led to the patient’s death, and therefore, no treatment could be prescribed.
Middle-aged man with a 14-day history of fever, cough and anosmia
Erythematous and edematous plaques with active border and purpuric center
14 days after first reporting COVID-19 symptoms
Evidence of small-vessel damage: preserved epidermis with moderate perivascular neutrophilic inflammation and blood extravasation in the dermis. Endothelial swelling, necrosis and fibrin deposition
Therapy with hydroxychloroquine and azithromycin was started as treatment for COVID-19.Prednisone and antihistamines were administered for his skin condition.
51-year-old otherwise healthy woman with a 3-day history of dry cough and arthralgias
Widespread pruritic evanescent skin lesions (lasting <24 hours).Multiple well-demarcated erythematous edematous papules and plaques with diffuse underlying erythema
Trunk, thighs, upper limbs, and predominantly on the facial area and dorsal aspects of bilateral hands
3 days after first reported COVID-19 symptoms and confirmation of COVID-19 by RT-PCR
The 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 hours
Early 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.
12 days after admission, first reported COVID-19 symptoms and confirmation of COVID-19 by RT-PCR
Not carried out
Treatment 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?)
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.
1 day after admission
Not carried out
CT 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.
Metformin 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 day
55-year-old woman admitted for pyrexia, dry cough, and dyspnea
Urticarial skin rash characterized by erythematous, smooth, slightly elevated papules and wheals, associated to severe pruritus.
3 days before admission and confirmation of COVID-19 by RT-PCR
No 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 pneumonia
In the following days urticaria improved gradually.Twenty-five days after admission, patient was discharged.
64-year-old patient with acute respiratory distress syndrome (PaO2/FiO2 ≤ 100 mm Hg) caused by COVID-19
Skin rash was already present at the time of hospital admission
Treatment 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 drugs
Blood 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.
First episode: Painful erythematous-edematous plaques.Some lesions evolved into bruises.Second episode: Exuberant urticarial lesions. Light erythema and edema with intense itching
First episode: Flexor face of forearms and leg extensors|.Second episode: Exuberant urticarial lesions on shoulders. and inguinal region. Light erythema and edema on palms
First 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 symptoms
First 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 betamethasone
On day 3 of hospitalization, after presenting with COVID-19 symptoms
History 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.
Rapidly 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 limbs
On day +11 of disease evolution, after resolution of previous COVID-19 symptoms
No 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.
37-year-old Caucasian woman, in her 10th postpartum day
Craniocaudal cutaneous manifestation characterized by erythematous maculopapular lesions
Trunk, neck, and face
3 days after first reporting COVID-19 symptoms
No 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.
Erythematous, rash, edematous nonpruritic annular fixed plaques of various diameters
Upper limbs, chest, neck, abdomen and palms, sparing the face, and mucous membranes
At same time as COVID-19 symptoms
Histological 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 symptoms
Oral hydroxychloroquine sulfate 200 mg three times per day for 10 days
No pulmonary symptoms developed.Rash fully recovered on day 6 of treatment
12 hours of slightly asymmetric, and nonpitting edema of cheeks and lips
Lip and facial swelling.He had no other sites of swelling and had no rash.
12 days before COVID-19 symptoms
Leukocytosis 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.
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.
4.1 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 severity33, 29 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.26, 33 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-19.46, 47 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
All included articles were case. Only three case reports detailed pathological study results.9, 13, 28 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
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.
Coronavirus disease-19 (COVID-19) is an ongoing global pandemic caused by the “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2), which was isolated for the first time in Wuhan (China) in December 2019. Common symptoms include fever, cough, fatigue, dyspnea and hypogeusia/hyposmia. Among extrapulmonary signs associated with COVID-19, dermatological manifestations have been increasingly reported in the last few months.
The polymorphic nature of COVID-19-associated cutaneous manifestations led our group to propose a classification, which distinguishes the following six main clinical patterns: (i) urticarial rash, (ii) confluent erythematous/maculopapular/morbilliform rash, (iii) papulovesicular exanthem, (iv) chilblain-like acral pattern, (v) livedo reticularis/racemosa-like pattern, (vi) purpuric “vasculitic” pattern. This review summarizes the current knowledge on COVID-19-associated cutaneous manifestations, focusing on clinical features and therapeutic management of each category and attempting to give an overview of the hypothesized pathophysiological mechanisms of these conditions.Keywords: COVID-19, Cutaneous manifestations, SARS-CoV-2Go to:
In December 2019, a novel zoonotic RNA virus named “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2) was isolated in patients with pneumonia in Wuhan, China. Since then, the disease caused by this virus, called “coronavirus disease-19” (COVID-19), has spread throughout the world at a staggering speed becoming a pandemic emergency . Although COVID-19 is best known for causing fever and respiratory symptoms, it has been reported to be associated also with different extrapulmonary manifestations, including dermatological signs . Whilst the COVID-19-associated cutaneous manifestations have been increasingly reported, their exact incidence has yet to be estimated, their pathophysiological mechanisms are largely unknown, and the role, direct or indirect, of SARS-CoV-2 in their pathogenesis is still debated. Furthermore, evidence is accumulating that skin manifestations associated with COVID-19 are extremely polymorphic . In this regard, our group proposed the following six main clinical patterns of COVID-19-associated cutaneous manifestations in a recently published review article: (i) urticarial rash, (ii) confluent erythematous/maculopapular/morbilliform rash, (iii) papulovesicular exanthem, (iv) chilblain-like acral pattern, (v) livedo reticularis/racemosa-like pattern, (vi) purpuric “vasculitic” pattern (shown in Fig. Fig.1)1) . Other authors have attempted to bring clarity in this field, suggesting possible classifications of COVID-19-associated cutaneous manifestations [4, 5, 6]. Finally, distinguishing nosological entities “truly” associated with COVID-19 from cutaneous drug reactions or exanthems due to viruses other than SARS-CoV-2 remains a frequent open problem.
Clinical features of COVID-19-associated cutaneous manifestations.
Herein, we have striven to provide a comprehensive overview of the cutaneous manifestations associated with COVID-19 subdivided according to the classification by Marzano et al. , focusing on clinical features, histopathological features, hypothesized pathophysiological mechanisms and therapeutic management.Go to:
Clinical Features and Association with COVID-19 Severity
It is well known that urticaria and angioedema can be triggered by viral and bacterial agents, such as cytomegalovirus, herpesvirus, and Epstein-Barr virus and mycoplasma. However, establishing a cause-effect relationship may be difficult in single cases [7, 8]. Urticarial eruptions associated with COVID-19 have been first reported by Recalcati  in his cohort of hospitalized patients, accounting for 16.7% of total skin manifestations. Urticaria-like eruptions have been subsequently described in other cohort studies. Galván Casas et al.  stated that urticarial rash occurred in 19% of their cohort, tended to appear simultaneously with systemic symptoms, lasted approximately 1 week and was associated with medium-high severity of COVID-19. Moreover, itch was almost always present . Freeman et al.  found a similar prevalence of urticaria (16%) in their series of 716 cases, in which urticarial lesions predominantly involved the trunk and limbs, relatively sparing the acral sites. As shown in Table Table1,1, urticaria-like signs accounted for 11.9% of cutaneous manifestations seen in an Italian multicentric cohort study on 159 patients [unpubl. data]. Urticarial lesions associated with fever were reported to be early or even prodromal signs of COVID-19, in the absence of respiratory symptoms, in 3 patients [11, 12, 13]. Therefore, the authors of the reports suggested that isolation is needed for patients developing such skin symptoms if COVID-19 infection is suspected in order to prevent possible SARS-CoV-2 transmission [11, 12, 13]. COVID-19-related urticaria occurred also in a familial cluster, involving 2 patients belonging to a Mexican family of 5 people, all infected by SARS-CoV-2 and suffering also from anosmia, ageusia, chills and dizziness . Angioedema may accompany COVID-19-related urticaria, as evidenced by the case published in June 2020 of an elderly man presenting with urticaria, angioedema, general malaise, fatigue, fever and pharyngodynia . Urticarial vasculitis has also been described in association with COVID-19 in 2 patients .
Prevalence of different clinical patterns in the main studies on COVID-19-associated cutaneous manifestations
First author (total size of study population)
Number of patients with urticarial rash (%)
Number of patients with confluent erythematous/maculopapular/morbilliform rash (%)
Number of patients with papulo-vesicular exanthem (%)
Number of patients with chilblain-like acral pattern (%)
Number of patients with livedo reticularis/racemosa-like pattern (%)
Number of patients with purpuric “vasculitic” pattern (%)
Histopathological studies of urticarial rashes are scant. In a 60-year-old woman with persistent urticarial eruption and interstitial pneumonia who was not under any medication, Rodriguez-Jiménez et al.  found on histopathology slight vacuolar interface dermatitis with occasional necrotic keratinocytes curiously compatible with an erythema multiforme-like pattern. Amatore et al.  documented also the presence of lichenoid and vacuolar interface dermatitis, associated with mild spongiosis, dyskeratotic basal keratinocytes and superficial perivascular lymphocytic infiltrate, in a biopsy of urticarial eruption associated with COVID-19 (Fig. (Fig.22).
Histopathological features of the main cutaneous patterns associated with COVID-19. a Urticarial rash. b Confluent erythematous maculopapular/morbilliform rash. c Chilblain-like acral lesions. d Purpuric “vasculitic” pattern.
Shanshal  suggested low-dose systemic corticosteroids as a therapeutic option for COVID-19-associated urticarial rash. Indeed, the author hypothesized that low-dose systemic corticosteroids, combined with nonsedating antihistamines, can help in managing the hyperactivity of the immune system in COVID-19, not only to control urticaria, but also to improve possibly the survival rate in COVID-19.Go to:
Clinical Features and Association with COVID-19 Severity
Maculopapular eruptions accounted for 47% of all cutaneous manifestations in the cohort of Galván Casas et al. , for 44% of the skin manifestations included in the study by Freeman et al. , who further subdivided this group of cutaneous lesions into macular erythema (13%), morbilliform exanthems (22%) and papulosquamous lesions (9%), and for 30.2% of the cutaneous manifestations included in the unpublished Italian multicentric study shown in Table Table1.1. The prevalence of erythematous rash was higher in other studies, like that published by De Giorgi et al.  in May 2020, in which erythematous rashes accounted for 70% of total skin manifestations. In the series by Freeman et al. , macular erythema, morbilliform exanthems and papulosquamous lesions were predominantly localized on the trunk and limbs, being associated with pruritus in most cases. In the same series, these lesions occurred more frequently after COVID-19 systemic symptoms’ onset . The clinical picture of the eruptions belonging to this group may range from erythematous confluent rashes to maculopapular eruptions and morbilliform exanthems. Erythematous lesions may show a purpuric evolution  or coexist from the beginning with purpuric lesions . Erythematous papules may also be arranged in a morbilliform pattern . In a subanalysis of the COVID-Piel Study  on maculopapular eruptions including also purpuric, erythema multiforme-like, pityriasis rosea-like, erythema elevatum diutinum-like and perifollicular eruptions, morbilliform exanthems were the most frequent maculopapular pattern (n = 80/176, 45.5%) . This study showed that in most cases lesions were generalized, symmetrical and started on the trunk with centrifugal progression. In the same subanalysis, hospital admission due to pneumonia was very frequent (80%) in patients with a morbilliform pattern . In this group, the main differential diagnoses are represented by exanthems due to viruses other than SARS-CoV-2 and drug-induced cutaneous reactions.
Histopathology of erythematous eruptions was described by Gianotti et al. , who found vascular damage in all the 3 cases examined. A clinicopathological characterization of late-onset maculopapular eruptions related to COVID-19 was provided also by Reymundo et al. , who observed a mild superficial perivascular lymphocytic infiltrate on the histology of 4 patients. In contrast, Herrero-Moyano et al.  observed dense neutrophilic infiltrates in 8 patients with late maculopapular eruptions. The authors of the former study postulated that this discrepancy could be attributable to the history of new drug assumptions in the series of Herrero-Moyano et al.  (Fig. (Fig.22).
The management of confluent erythematous/maculopapular/morbilliform rash varies according to the severity of the clinical picture. Topical corticosteroids can be sufficient in most cases , systemic corticosteroids deserving to be administered just in more severe and widespread presentations.Go to:
Clinical Features and Association with COVID-19 Severity
COVID-19-associated papulovesicular exanthem was first extensively reported in a multicenter Italian case series of 22 patients published in April 2020 . In this article, it was originally described as “varicella-like” due to resemblance of its elementary lesions to those of varicella. However, the authors themselves underlined that the main clinical features of COVID-19-associated papulovesicular exanthem, namely trunk involvement, scattered distribution and mild/absent pruritus, differentiated it from “true” varicella. In this study, skin lesions appeared on average 3 days after systemic symptoms’ onset and healed after 8 days, without scarring sequelae . The exact prevalence of papulovesicular exanthems is variable. Indeed, in a cohort of 375 patients with COVID-19-associated cutaneous manifestations , patients with papulovesicular exanthem were 34 (9%), while they were 3 out of 52 (5.8%), 1 out of 18 (5.5%) and 2 out of 53 (4%) in the cohorts published by Askin et al. , Recalcati  and De Giorgi et al. , respectively. In the Italian multicentric study shown in Table Table1,1, papulovesicular rash accounted for 18.2% of skin manifestations. Furthermore, even if papulovesicular exanthem tends to involve more frequently the adult population, with a median age of 60 years in the study by Marzano et al. , also children may be affected . Galván Casas et al.  reported that vesicular lesions generally involved middle-aged patients, before systemic symptoms’ onset in 15% of cases, and were associated with intermediate COVID-19 severity. Fernandez-Nieto et al.  conducted a prospective study on 24 patients diagnosed with COVID-19-associated vesicular rash. In this cohort, the median age (40.5 years) was lower than that reported by Marzano et al. , and COVID-19 severity was mostly mild or intermediate, with only 1 patient requiring intensive unit care support. In our cohort of 22 patients, a patient was hospitalized in the intensive care unit and 3 patients died . Vesicular rash, which was generally pruritic, appeared after COVID-19 diagnosis in most patients (n = 19; 79.2%), with a median latency time of 14 days . Two different morphological patterns were found: a widespread polymorphic pattern, more common and consisting of small papules, vesicles and pustules of different sizes, and a localized pattern, less frequent and consisting of monomorphic lesions, usually involving the mid chest/upper abdominal region or the back .
Mahé et al.  reported on 3 patients with typical COVID-19-associated papulovesicular rash, in which the histological pattern of skin lesions showed prominent acantholysis and dyskeratosis associated with the presence of an unilocular intraepidermal vesicle in a suprabasal location. Based on these histopathological findings, the authors refused the term “varicella-like rash” and proposed a term which was more suitable in their view: “COVID-19-associated acantholytic rash.” Histopathological findings of another case of papulovesicular eruption revealed extensive epidermal necrosis with acantholysis and swelling of keratinocytes, ballooning degeneration of keratinocytes and signs of endotheliitis in the dermal vessels . Acantholysis and ballooned keratinocytes were found also by Fernandez-Nieto et al.  in 2 patients.
The differential diagnosis with infections caused by members of the Herpesviridae family has been much debated. Tammaro et al.  described the onset of numerous, isolated vesicles on the back 8 days after COVID-19 diagnosis in a Barcelonan woman and reported on 2 patients from Rome presenting with isolated, mildly pruritic erythematous-vesicular lesions on their trunk, speculating that these manifestations might be due to viruses belonging to the Herpesviridae family. On the other hand, classic herpes zoster has been reported to complicate the course of COVID-19 .
The controversy regarding the role of herpesvirus in the etiology of papulovesicular exanthems fuelled an intense scientific debate. Indeed, some authors raised the question whether papulovesicular exanthem associated with COVID-19 could be diagnosed without ruling out varicella zoster virus and herpes simplex virus with Tzanck smear or polymerase chain reaction (PCR) for the Herpesviridae family in the vesicle fluid or on the skin [36, 37]. In our opinion, even if seeking DNA of Herpesviridae family members is ideally advisable, clinical diagnosis may be reliable in most cases, and the role of herpes viruses as mere superinfection in patients with dysfunctional immune response associated with COVID-19 needs to be considered . To our knowledge, SARS-CoV-2 has not been hitherto isolated by means of reverse transcriptase PCR in the vesicle fluid of papulovesicular rash [33, 31].
No standardized treatments for COVID-19-related papulovesicular exanthem are available, also given that it is self-healing within a short time frame. Thus, a “wait-and-see” strategy may be recommended.Go to:
Chilblain-Like Acral Pattern
Clinical Features and Association with COVID-19 Severity
COVID-19-related chilblain-like acral lesions have been first described in a 13-year-old boy by Italian authors in early March . Since then, several “outbreaks” of chilblain-like acral lesions chiefly involving young adults and children from different countries worldwide have been posted on social media and published in the scientific literature [40, 41, 42, 43, 44, 45, 46]. Caucasians seem to be significantly more affected than other ethnic groups [47, 48]. Chilblain-like acral lesions were the second most frequent cutaneous manifestation (n = 46/159; 28.9%) in the multicenter Italian study shown in Table Table1.1. Different pathogenetic hypotheses, including increased interferon release induced by COVID-19 and consequent cytokine-mediated inflammatory response, have been suggested . Furthermore, virus-induced endothelial damage as well as an obliterative microangiopathy and coagulation abnormalities could be mechanisms involved in the pathogenesis of these lesions . Chilblain-like acral lesions associated with COVID-19 were depicted as erythematous-violaceous patches or plaques predominantly involving the feet and, to a lesser extent, hands [40, 51]. Rare cases of chilblain-like lesions involving other acral sites, such as the auricular region, were also reported . The occurrence of blistering lesions varied according to the case series analyzed; Piccolo et al. , indeed, reported the presence of blistering lesions in 23 out of 54 patients, while other authors did not describe bullous lesions in their series [40, 47]. Dermoscopy of these lesions revealed the presence of an indicative pattern represented by a red background area with purpuric globules . Pain/burning sensation as well as pruritus were commonly reported symptoms, even if a small proportion of patients presented with asymptomatic lesions [40, 44, 47]. Unlike other COVID-19-related cutaneous findings, chilblain-like acral lesions tended to mostly involve patients without systemic symptoms.
The frequent occurrence of chilblain-like lesions in the absence of cold exposure and the involvement of patients without evident COVID-19-related symptoms raised the question whether these manifestations were actually associated with SARS-CoV-2 infection.
Histopathological and Pathophysiological Findings
Chilblain-like lesions share many histopathological features with idiopathic and autoimmunity-related chilblains, including epidermal necrotic keratinocytes, dermal edema, perivascular and perieccrine sweat gland lymphocytic inflammation. Vascular changes such as endotheliitis and microthrombi may be found [40, 45, 54, 55] (Fig. (Fig.22).
Data on the real association between chilblain-like acral lesions and COVID-19 are controversial.
The first case series failed to perform SARS-CoV-2 testing in all patients, also due to logistic problems and economic restrictions, and diagnosed COVID-19 only in a minority of patients with chilblain-like acral lesions [40, 44, 47]. Subsequently, some authors systematically sought SARS-CoV-2 with serology and/or nasopharyngeal swab in patients with chilblain-like acral lesions. In their cohort of 38 children with pseudo-chilblain, Caselli et al.  showed no evidence of SARS-CoV-2 infection by PCR or serology. Chilblain-like acral lesions appeared not to be directly associated with COVID-19 also in the case series by Herman et al. . These authors failed to detect SARS-CoV-2 in nasopharyngeal swabs and skin biopsies and demonstrated no specific anti-SARS-CoV-2 immunoglobulin IgM or IgG antibodies in blood samples. Therefore, they concluded that lifestyle changes associated with lockdown measures might be a possible explanation for these lesions . Similar results were obtained also by other authors [58, 59, 60, 61, 62, 63] weakening the hypothesis of a direct etiological link between SARS-CoV-2 and chilblain-like acral lesions.
Opposite conclusions have been drawn by Colmenero et al. , who demonstrated by immunohistochemistry and electron microscopy the presence of SARS-CoV-2 in endothelial cells of skin biopsies of 7 children with chilblain-like acral lesions, suggesting that virus-induced vascular damage and secondary ischemia could explain the pathophysiology of these lesions.
In the absence of definitive data on chilblain-like acral lesions’ pathogenesis, the occurrence of such lesions should prompt self-isolation and confirmatory testing for SARS-CoV-2 infection .
In the absence of significant therapeutic options for chilblain-like acral lesions associated with COVID-19 and given their tendency to spontaneously heal, a “wait-and-see” strategy may be suggested.Go to:
Livedo Reticularis/Racemosa-Like Pattern
Clinical Features and Association with COVID-19 Severity
Livedo describes a reticulate pattern of slow blood flow, with consequent desaturation of blood and bluish cutaneous discoloration. It has been divided into: (i) livedo reticularis, which develops as tight, symmetrical, lace-like, dusky patches forming complete rings surrounding a pale center, generally associated with cold-induced cutaneous vasoconstriction or vascular flow disturbances such as seen in polycythemia and (ii) livedo racemosa, characterized by larger, irregular and asymmetrical rings than seen in livedo reticularis, more frequently associated with focal impairment of blood flow, as it can be seen in Sneddon’s syndrome .
In our classification, the livedo reticularis/racemosa-like pattern has been distinguished by the purpuric “vasculitic” pattern because the former likely recognizes a occlusive/microthrombotic vasculopathic etiology, while the latter can be more likely considered the expression of a “true” vasculitic process . Instead, the classification by Galván Casas et al.  merged these two patterns into the category “livedo/necrosis”.
In a French study on vascular lesions associated with COVID-19, livedo was observed in 1 out of 7 patients . In the large cases series of 716 patients by Freeman et al. , livedo reticularis-like lesions, retiform purpura and livedo racemosa-like lesions accounted for 3.5, 2.6 and 0.6% of all cutaneous manifestations, respectively. In the multicentric Italian study, livedo reticularis/racemosa-like lesions accounted for 2.5% of cutaneous manifestations (Table (Table11).
The pathogenic mechanisms at the basis of small blood vessel occlusion are yet unknown, even if neurogenic, microthrombotic or immune complex-mediated etiologies have been postulated .
Livedo reticularis-like lesions are frequently mild, transient and not associated with thromboembolic complications [68, 69]. On the contrary, livedo racemosa-like lesions and retiform purpura have often been described in patients with severe coagulopathy [60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72].
Histopathological and Pathophysiological Findings
The histopathology of livedoid lesions associated with COVID-19 has been described by Magro et al. , who observed in 3 patients pauci-inflammatory microthrombotic vasculopathy. The same group demonstrated that in the thrombotic retiform purpura of patients with severe COVID-19, the vascular thrombosis in the skin and internal organs is associated with a minimal interferon response permitting increased viral replication with release of viral proteins that localize to the endothelium inducing widespread complement activation , which is frequent in COVID-19 patients and probably involved in the pathophysiology of its clinical complications .
In view of the absence of significant therapeutic options for livedo reticularis/racemosa-like lesions associated with COVID-19, a “wait-and-see” strategy may be suggested.Go to:
Purpuric “Vasculitic” Pattern
Clinical Features and Association with COVID-19 Severity
The first COVID-19-associated cutaneous manifestation with purpuric features was reported by Joob et al. , who described a petechial rash misdiagnosed as dengue in a COVID-19 patient. Purpuric lesions have been suggested to occur more frequently in elderly patients with severe COVID-19, likely representing the cutaneous manifestations associated with the highest rate of COVID-19-related mortality . This hypothesis is corroborated by the unfavorable prognosis observed in several cases reported in the literature [77, 78].
The purpuric pattern reflects the presence of vasculitic changes probably due to the direct damage of endothelial cells by the virus or dysregulated host inflammatory responses induced by COVID-19.
These lesions are likely to be very rare, representing 8.2% of skin manifestations included in the Italian multicentric study shown in Table Table1.1. In their case series of 7 patients with vascular skin lesions related to COVID-19, Bouaziz et al.  reported 2 patients with purpuric lesions with (n = 1) and without (n = 1) necrosis. In the series by Freeman et al. , 12/716 (1.8%) and 11/716 (1.6%) cases of patients with palpable purpura and dengue-like eruption, respectively, have been reported. Galván Casas et al.  reported 21 patients with “livedo/necrosis,” most of whom presenting cutaneous signs in concomitance with systemic symptoms’ onset.
Purpuric lesions may be generalized , localized in the intertriginous regions  or arranged in an acral distribution . Vasculitic lesions may evolve into hemorrhagic blisters . In most severe cases, extensive acute necrosis and association with severe coagulopathy may be seen . Dermoscopy of purpuric lesions revealed the presence of papules with incomplete violaceous rim and a central yellow globule .
When performed, histopathology of skin lesions showed leukocytoclastic vasculitis [77, 79], severe neutrophilic infiltrate within the small vessel walls and in their proximity , intense lymphocytic perivascular infiltrates , presence of fibrin [79, 81] and endothelial swelling  (Fig. (Fig.22).
Topical corticosteroids have been successfully used for treating mild cases of purpuric lesions . Cases with necrotic-ulcerative lesions and widespread presentation may be treated with systemic corticosteroids.Go to:
Other COVID-19-Associated Cutaneous Manifestations
Other peculiar rare COVID-19-related cutaneous manifestations that cannot be pigeonholed in the classification proposed by our group  include, among others, the erythema multiforme-like eruption , pityriasis rosea-like rash , multi-system inflammatory syndrome in children , anagen effluvium  and a pseudoherpetic variant of Grover disease . However, the spectrum of possible COVID-19-associated skin manifestations is likely to be still incomplete, and it is expected that new entities associated with this infection will be described.Go to:
COVID-19-associated cutaneous manifestations have been increasingly reported in the last few months, garnering attention both from the international scientific community and from the media. A few months after the outbreak of the pandemic, many narrative and systematic reviews concerning the dermatological manifestations of COVID-19 have been published [2, 3, 6, 88, 89, 90, 91]. A summary of clinical features, histopathological findings, severity of COVID-19 systemic symptoms and therapeutic options of COVID-19-related skin manifestations has been provided in Table Table22.
Summary of clinical features, histopathological findings, severity of COVID-19 systemic symptoms and therapeutic options of COVID-19-related skin manifestations
Itching urticarial rash predominantly involving the trunk and limbs; angioedema may also rarely occur
Vacuolar interface dermatitis associated with superficial perivascular lymphocytic infiltrate
Low-dose systemic corticosteroids combined with nonsedating antihistamines
Topical corticosteroids for mild cases; systemic corticosteroids for severe cases
(i) Widespread polymorphic pattern consisting of small papules, vesicles and pustules of different sizes; (ii) localized pattern consisting of papulovesicular lesions, usually involving the mid chest/upper abdominal region or the back
Prominent acantholysis and dyskeratosis associated with unilocular intraepidermal vesicles in a suprabasal location
Wait and see
Chilblain-like acral pattern
Erythematous-violaceous patches or plaques predominantly involving the feet or, to a lesser extent, hands. Pain/burning sensation as well as pruritus were commonly reported symptoms
Perivascular and periadnexal dermal lymphocytic infiltrates
Wait and see
Livedo reticularis/racemosa-like pattern
Livedo reticularis-like lesions: mild, transient, symmetrical, lace-like, dusky patches forming complete rings surrounding a pale center. Livedo racemosa-like lesions: large, irregular and asymmetrical violaceous annular lesions frequently described in patients with severe coagulopathy
Livedo reticularis-like lesions: intermediate severity; livedo racemosa-like lesions: high severity
Pauci-inflammatory microthrombotic vasculopathy
Wait and see
Purpuric “vasculitic” pattern
Purpuric lesions may be generalized, arranged in an acral distribution or localized in the intertriginous regions. Purpuric elements may evolve into hemorrhagic blisters, possibly leading to necrotic-ulcerative lesions
Leukocytoclastic vasculitis, severe perivascular neutrophilic and lymphocytic infiltrate, presence of fibrin and endothelial swelling
Topical corticosteroids for mild cases; systemic corticosteroids for severe cases
The correlation between severity of COVID-19 systemic symptoms and skin manifestations has been inferred mainly from the study by Freeman et al. .
Albeit several hypotheses on pathophysiological mechanisms at the basis of these skin findings are present in the literature [50, 92, 93], none of them is substantiated by strong evidence, and this field needs to be largely elucidated. Moreover, cutaneous eruptions due to viruses other than SARS-CoV-2 [35, 37] or drugs prescribed for the management of this infection [94, 95] always need to be ruled out.
Experimental pathophysiological studies and clinical data derived from large case series are still needed for shedding light onto this novel, underexplored and fascinating topic.
Although COVID-19-associated cutaneous manifestations have been increasingly reported, their pathophysiological mechanisms need to be extensively explored. The conditions may be distinguished in six clinical phenotypes, each showing different histopathological patterns.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.:
This paper did not receive any funding.
Giovanni Genovese wrote the paper with the contribution of Chiara Moltrasio. Angelo Valerio Marzano and Emilio Berti supervised the work and revised the paper for critical revision of important intellectual content.Go to:
We would like to thank Dr. Cosimo Misciali, Dr. Paolo Sena and Prof. Pietro Quaglino for kindly providing us with histopathological pictures.Go to:
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