The skin manifestations of the novel coronavirus SARS-CoV-2 were not recognized at the early stages of the pandemic but have received much recent attention in scientific journals and global media outlets. Reported manifestations range from pseudo-chilblains to a morbilliform (measles-like) exanthem, urticaria, vesicular eruptions, a dengue-like petechial rash and ovate scaling macules, and plaques mimicking pityriasis rosea.
The New 'Great Mimicker'
Much like with HIV and syphilis, COVID-associated "rashes" seem to be as numerous as they are hard to pin down. The largest published study to date is a nationwide case series in Spain with 375 cases which identified five clinical patterns. Because of the scarcity and low sensitivity of diagnostic tests available, the investigators accepted patients with confirmed disease as well as those with a clinical diagnosis of COVID in the study. Just under half (41%) of patients with pseudo-chilblains had confirmed infection with positive viral cultures and/or serology.
Observed COVID-associated skin patterns were:
- Acral erythema with vesicles or pustules; so-called "pseudo-chilblains" (19%)
- Vesicular (chicken pox-like) eruptions (9%)
- Maculopapular eruptions (47%)
- Urticaria (19%)
- Livedo or necrosis (6%)
[Editor's note: An atlas with images of COVID-related rashes and other skin changes is available in the Wiley Online Library.]
These investigators found that the vesicular eruptions appeared earliest in the course of COVID-19, prior to any other symptoms in 15% of cases; these developed on the trunk and extremities, were most common in middle-aged adults, and typically lasted around 10 days.
In contrast, the pseudo-chilblains eruption which has received much attention on social media (using the hashtag #COVIDtoes) occurred later. In almost two thirds (59%) of patients, these lesions developed after other symptoms. Despite much concern in the lay press about lesions on toes (which can also, less frequently, present on fingers), pseudo-chilblains acral lesions correlated with a milder disease course and younger patient age. Livedo and necrosis, however, indicated more severe illness and a poor prognosis.
Patients with maculopapular exanthems (47% of reported cases in this series) also had more severe infections and typically manifested skin findings at the same time as other COVID-19 symptoms.
Sounding the Alarm in Kids
In a recent and alarming twist, more than a dozen children—the group once thought to be most immune to severe COVID complications—have presented in the United Kingdom with a multisystem inflammatory condition with features of toxic shock syndrome and atypical Kawasaki disease. Kawasaki-like signs of this "SARS-CoV-2-related inflammatory syndrome" include an erythematous rash, conjunctivitis and glossitis with high fever, abdominal pain and gastrointestinal symptoms, and cardiac inflammation. Another 25 children with similar findings have been identified in France.
Some of these children have tested SARS-CoV-2 positive or had serologic evidence of prior SARS-CoV-2 infection. These findings prompted a warning from the National Health Service and the Paediatric Intensive Care Society.
A similar alert was just issued by the New York City Health Department after 15 children, ages 2-15, were hospitalized in NYC between April 17 and May 1 with illnesses compatible with this syndrome (ie, typical Kawasaki disease, incomplete Kawasaki disease, and/or shock). Polymerase chain reaction (PCR) testing for SARS-CoV-2 was positive in four of the NY children. As of May 6, 2020, the reported number of children affected in New York had risen to 64 and cases in other states were reported.
COVID Toes
Of all the COVID-associated skin manifestations, pseudo-chilblains has drawn the most attention to date. "COVID toes" were first described in China and then in Europe by a network of dermatologists in Italy, Spain, Belgium, and France. These cases typically affect children and young adults, manifesting as acro-located erythematous to violaceous papules and plaques primarily affecting the toes and mimicking chilblains (idiopathic pernio).
Classic cold-induced chilblains is a benign and self-limited condition characterized by acral erythema of the toes (and sometimes fingers) with swelling. In contrast, pseudo-chilblains (COVID toes) often occurs in warmer climates, tends to be more severe and symptomatic (itching, burning, pain), is more likely to ulcerate, and takes longer to resolve.
The earliest case series describing "acro-ischemia presentations" included finger and toe cyanosis, skin bullae, and dry gangrene. This Chinese case series looked at seven critically ill patients with COVID-19 pneumonia, diagnosed and treated in Wuhan in early February. In addition to having fever, cough, and dyspnea, all of the patients developed finger and/or toe cyanosis which progressed to bullae, skin ulceration, and necrosis. All of these individuals also had evidence of a hypercoagulable state with elevated D-dimers and fibrinogen degradation products, and prolonged prothrombin times. Despite treatment with low-molecular-weight heparin, these patients had a poor prognosis; five died with a median time from acro-ischemia onset to death of 12 days.
In contrast, the reported cases of pseudo-chilblains coming out of Europe, the Middle East, and the United States fit more into the benign pattern described by researchers in Spain.
A recent paper described a case involving a 23-year-old man. He presented with sudden-onset "violaceous, infiltrated, and painful plaques on the toes and lateral aspect of the feet," preceded by fever and a dry cough. This patient had no prior history of chilblains, Raynaud's phenomenon, or collagen vascular disease. A nasopharyngeal swab tested PCR-positive for SARS-CoV-2, and coagulation studies were normal with no D-dimers. Histopathology was similar to that of idiopathic pernio, showing a small-vessel lymphocytic vasculitis with variable levels of papillary dermal edema and no intravascular thrombi.
Anecdotally, most young patients with pseudo-chilblains seem to follow this benign course, often remaining otherwise asymptomatic. Adding to the uncertainty, some with clinical features and a history highly suggestive of COVID-related pseudo-chilblains have tested SARS-CoV-2-negative by PCR and/or serologies.
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Discussion
The story of COVID-19 and skin manifestations is changing every day, with dozens of papers still in press. While the spotlight has fallen on pseudo-chilblains ("COVID toes"), the pathophysiology behind this strange manifestation remains mysterious. Some question whether this is a true COVID manifestation or merely an epiphenomenon—so-called "quarantine toes"—brought about by more people walking barefoot during quarantine and an unusually cold spring in parts of the United States.
Some cases may indeed be idiopathic pernio, which is more likely to be reported due to detection bias, given the large amount of recent media coverage about this finding.
Neither detection bias nor a cold spring in the United States can explain the fact that cases are occurring in warm climates in individuals with positive SARS-CoV-2 viral swabs or serologies. A second unrelated infectious trigger causing a surge in pernio, while possible, seems far-fetched.
COVID-associated pernio is treated with the same drugs used for idiopathic pernio. These include high-potency corticosteroids, aspirin, topical calcium channel blockers such as nifedipine, and nitroglycerin paste. All of these uses are off-label.
Decisions in patients with COVID-related skin manifestations plus other characteristic symptoms (eg, cough, fever, shortness of breath, anosmia, loss of taste) or known COVID exposure are easy. They should be tested via nasopharyngeal swab and serologies.
In contrast, those with suspicious skin manifestations who are otherwise asymptomatic, especially with no other risk factors, fall into a gray area. Should such individuals be tested? Should they self-quarantine? To date, there is no clear consensus.
Thanks to coordinated efforts such as the nationwide consensus study in Spainand the American Academy of Dermatology's COVID-19 Dermatology Registry, we can anticipate a better understanding of how and why SARS-CoV-2 affects the skin. Hopefully, these insights will shed light on why this pathogen is so deadly for some and yet mild or asymptomatic in others.
Graeme M. Lipper, MD, is a clinical assistant professor at the University of Vermont Medical College in Burlington, Vermont, and a partner at Advanced DermCare in Danbury, Connecticut.
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An unusually high number of children have been admitted to intensive care in France since April 15 with an inflammatory syndrome very similar to Kawasaki disease.
What do we know about this rare disease? How does the clinical picture of the children currently hospitalized differ from the classic symptomatology? How should they be managed?
Medscape French Edition asked Léa Cacoub, MD, a cardiologist at Lariboisière Hospital, Paris, to take stock.
What is the normal prevalence of Kawasaki syndrome? Are these new cases surprising?
This disease, which is the leading cause of childhood acquired heart disease in industrialized nations, is very rare. It affects around one child in 6000 in France and the United States, and one in 12,000 in the UK. It is more common in Japan, with an incidence of 1 in 1000.
The incidence is 2.5 times higher in patients of Asian origin than in those of Caucasian origin, which suggests a genetic predisposition. It is also surprising that there was no increase in cases of Kawasaki disease since the start of the Asian epidemic in December; at least, this was not reported in the Chinese or Japanese series.
There is an annual seasonal gradient, with winter and spring surges of the disease. But it has become clear over the past 3 weeks that an unusual number of children of all ages have been hospitalized with multisystem inflammation frequently associated with circulatory failure, with elements suggestive of myocarditis.
We are concerned about the epidemic nature of these cases of Kawasaki-like disease in our intensive care units in Île-de-France [the region around Paris], with at least 25 in 3 weeks and 9 in Necker hospital over the past 2 days (as of April 30).
On the other hand, contact with our British, Spanish, Italian, and Belgian colleagues confirms this as an emerging problem.
What is the link between Kawasaki disease and COVID-19?
The pathology of Kawasaki disease is still unknown, and several theories have been proposed, including the possibility of an infection by a microorganism that secretes toxins, and of a process linked to superantigens.
The involvement of the immune system is therefore very strongly suspected, probably mediated by a bacterial or viral agent, and as such the involvement of members of the coronavirus family has already long been suggested (as well as adenoviruses, the herpes virus, Epstein-Barr virus, and others).
Have you been asked to carry out special monitoring in your cardiology departments?
Within the medical community, memos are currently being disseminated in order to look out for the occurrence of this clinical picture in children, as it is predominantly a pediatric pathology. But in can also occur in adults, and cardiac damage linked to COVID-19 has already been widely described in Asian and, more recently, European cohorts.
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Professor Damien Bonnet, MD, from Necker Hospital in Paris, sent us a note to be vigilant over the clinical presentation of our patients admitted to cardiology with COVID-19, and called for communication between doctors of suspicious cases, so as to collate national data and make progress over the association between COVID-19 and vascular diseases, including Kawasaki.
Does the syndrome currently seen in intensive care differ from the classical picture of Kawasaki disease?
The clinical forms are fairly similar to 'classic' Kawasaki disease. But the clinical presentation of recently treated pediatric cases is pleomorphic and may be an incomplete form of Kawasaki disease, especially as some patients have coronary dilatation.
The 20 or so cases identified in the cardiology and intensive care services at Necker Hospital have certain characteristics:
• In the few cases described, the manifestations suggestive of Kawasaki disease are seen between the second and fourth day of fever.
• They initially have a respiratory, hemodynamic, septic, or digestive presentation.
• They have an initial phase that can evoke a cytokine storm, possibly with signs of macrophage activation.
• Collapse is common, while systolic dysfunction of the left ventricle is variable but sometimes profound.
• Moderate troponin elevation.
• Faint changes on ECG.
• Documented coinfection with COVID-19.
Is the treatment the same?
It is. The treatment should be as early as possible. It is based on the the prescription of acetylsalicylic acid (aspirin), at 50 to 80 mg/kg/d during the acute phase, then 3 to 5 mg/kg/d, and on the administration of intravenous immunoglobulins, at 2 g/kg in a single dose.
The response to treatment is usually very good, with apyrexia achieved within a few hours. It has been shown that the prevalence of coronary artery abnormalities depends on the dose of immunoglobulins and not the dose of aspirin, as intravenous immunoglobulin therapy reduces the frequency of coronary aneurysms to less than 5%.
The administration of immunoglobulins should be early, ideally during the first week of the disease; however, if there are persistent signs of inflammation, treatment can continue even after the first week.
In the event of failure after immunoglobulin infusion, defined as the persistence or recurrence of fever 36 hours after the end of the infusion, a second or even a third therapeutic cycle can be performed.
Corticosteroids have long been contraindicated in Kawasaki disease, but recent data shows that corticosteroid therapy can now be recommended in the event of initial failure with immunoglobulins.
Acetylsalicylic acid is given at an anti-inflammatory dose during the acute phase and an anti-platelet dose in the subacute phase. In the absence of cardiac complications, a low dose is maintained until normalization of the sedimentation rate and platelet count.
In children with coronary artery anomalies, treatment is continued until complete regression of the coronary aneurysms, or for life if the aneurysms persist. In the case of giant aneurysm, there is sometimes a need for anticoagulation with vitamin K or heparin and, in selected cases, surgical intervention (bypass surgery, transplantation).
Dr Cacoub has disclosed no relevant financial relationships.
A novel clinical presentation in children involving symptoms seen with atypical Kawasaki disease and toxic shock syndrome may be linked to COVID-19 infection, according to reports from National Health Service England, The Lancet, and the New York City health department.
Fifteen children in New York City hospitals have presented with the condition, provisionally called pediatric multisystem inflammatory syndrome, between April 17 and May 1, according to a health alert from New York City health department deputy commissioner Demetre C. Daskalakis, MD, MPH, on May 4. On May 5, the New York state department of health released a health advisory that 64 suspected cases had been reported in children in New York state hospitals, including New York City.
The New York City reports follow a case study published April 7 in Hospital Pediatrics about the presentation. There also was a statement from the U.K.'s Paediatric Intensive Care Society (PICS) on April 27 that noted "blood parameters consistent with severe COVID-19 in children" as well as abdominal pain, gastrointestinal symptoms, and cardiac inflammation.
"Whilst it is too early to say with confidence, features appear to include high CRP [C-reactive protein], high [erythrocyte sedimentation rate] and high ferritin," the PICS release stated. The cardiac inflammation consists of "myocarditis with raised troponin and [prohormone brain natriuretic peptide]," according to the PICS statement. "Some have an appearance of their coronary arteries in keeping with Kawasaki disease."
The initial 15 New York City patients reportedly all had "subjective or measured fever, and more than half reported rash, abdominal pain, vomiting, or diarrhea," but fewer than half had respiratory symptoms.
The case study described a 6-month-old infant who was admitted and diagnosed with classic Kawasaki disease, who also tested positive for COVID-19 with fever and mild respiratory symptoms, reported Veena G. Jones, MD, a pediatric hospitalist in Palo Alto, Calif., and associates.
While many of the U.K. children presenting with the symptoms had a positive polymerase chain reaction tests for infection from SARS-CoV-2, some also had a negative test. Polymerase chain reaction testing in New York City was positive for 4 children and negative for 11 children, but 6 of the those who tested negative had positive serology tests, potentially pointing to postinfection sequelae.
At press time, more cases were reported from the United Kingdom in The Lancet. In London, eight children with hyperinflammatory shock, showing features similar to atypical Kawasaki disease, Kawasaki disease shock syndrome, or toxic shock syndrome, presented within 10 days to Evelina London Children's Hospital Paediatric ICU, Shelley Riphagen, MBChB, and colleagues revealed.
Clinically, their presentations were similar, with persistent fever, rash, conjunctivitis, peripheral edema, extremity pain, and gastrointestinal symptoms. They all developed warm vasoplegic shock that did not respond to volume resuscitation; noradrenaline and milrinone were administered for hemodynamic support. Seven of the children needed mechanical ventilation for cardiovascular stabilization, although most of them had no significant respiratory involvement.
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Of note was development of small pleural, pericardial, and ascitic effusion — "suggestive of a diffuse inflammatory process," Dr. Riphagen and associates wrote. None of the children initially was positive for SARS-CoV-2; laboratory evidence of infection or inflammation included "elevated concentrations of CRP, procalcitonin, ferritin, triglycerides or d-dimers."
"A common echocardiographic finding was echobright coronary vessels," they wrote. "One child developed arrhythmia with refractory shock, requiring extracorporeal life support, and died from a large cerebrovascular infarct."
As the article went to press, the doctors in that same ICU had seen more than 20 children with similar clinical presentations, Dr. Riphagen and associates reported, and the first 10 tested positive for SARS-CoV-2 antibody, including the 8 described above.
"Most of the children appear to have antibodies to the novel coronavirus, even when they do not have virus detectable in their nose," said Audrey John, MD, PhD, chief of the division of pediatric infectious diseases at Children's Hospital of Philadelphia, where clinicians have seen several cases similar to those described by NHS England and the New York City health department. "This suggests that these symptoms are 'postinfectious,' likely due to an abnormal immune response that happens after viral infection."
She noted at the time of her interview, however, that fewer than 100 U.S. pediatric cases appear to have been reported.
"While our understanding is evolving, given the scope of the COVID-19 pandemic, this suggests that this kind of severe disease in children is very rare indeed," Dr. John said. "Because this syndrome is so newly described, we have to continue to be cautious in attributing this syndrome to COVID-19, as there are many other diseases that look quite similar."
She advised clinicians to be "wary of attributing fever/rash/shock to this syndrome, as the differential is broad, and we do not want to fail to recognize and treat true toxic shock or tick-borne disease."
Dawn Nolt, MD, MPH, an associate professor of pediatrics in infectious diseases at Oregon Health & Science University's Doernbecher Children's Hospital, Portland, also underscored the need to avoid drawing conclusions too quickly.
"At this time, there is no causality established between SARS-COV-2 and these inflammatory syndromes other than a temporal association," said Dr. Nolt, whose hospital has not yet seen any of these cases. "If there is a link, then the symptoms may be from a 'direct hit' of the virus on tissues, or from an overly exuberant immune response."
None of the initial 15 New York City children died, although 5 needed mechanical ventilation and over half needed blood pressure support. The one child in London died from a large cerebrovascular infarct.
If the cases are connected to COVID-19, one explanation for the presentation may be related to the leading hypothesis "that SARS-CoV-2 may stimulate the immune system in such a way to promote vasculitis," Dr. Nolt said in an interview.
"It is unusual that this particular constellation was not reported from the known pediatric cases out of China, where the COVID-19 pandemic originated," Dr. Nolt said. "If there is a link between SARS-CoV-2 and these inflammatory syndromes, this may have resulted from genetic/host differences, changes in the SARS-CoV-2 virus, or other factors yet to be determined."
The New York City bulletin recommended that clinicians immediately refer children presenting with the described symptoms to a specialist in pediatric infectious disease, rheumatology, or critical care.
"Early diagnosis and treatment of patients meeting full or partial criteria for Kawasaki disease is critical to preventing end-organ damage and other long-term complications," the bulletin stated. It recommended aspirin and intravenous immunoglobulin for those who met Kawasaki criteria.
Dr. John said that children with the presentation appear to be responding well to intravenous immunoglobulin and/or steroids. She further emphasized that virtually all pediatric patients recover from COVID-19.
"Physicians should advise families to bring their children and teens back in for evaluation if they develop new fever, rash, or abdominal pain and diarrhea," Dr. John said. "Families should not be afraid to seek care when their kids are sick. Our pediatric hospitals and EDs are open for business and working hard to protect staff and patients."
A Kawasaki syndrome diagnosis requires at least 5 days of a fever at 101-104° F or higher along with four of the following five symptoms: rash over the torso; redness and swelling on palms and soles of the feet with later skin peeling; bloodshot, light-sensitive eyes; swollen lymph glands in the neck; and irritation and inflammation of the mouth, lips and throat, sometimes with "strawberry" tongue, according to the American Heart Association.
A press release from the AHA noted that Kawasaki disease is the most common cause of acquired heart disease in developed countries, but the condition remains rare.
Kawasaki disease's etiology is unknown, but "some evidence suggests an infectious trigger, with winter-spring seasonality of the disease," wrote the case study authors, noting that past research has linked Kawasaki disease with previous or concurrent infections of rhinovirus/enterovirus, parainfluenza, respiratory syncytial virus, influenza, adenovirus, and the four common human coronavirus strains.
"We have to remember that our experience with this pandemic is less than 12 months," Dr. Nolt said. "We are still accumulating information, and any additional manifestations, particularly severe ones, adds to our ability to more quickly detect and treat children."
Dr. Nolt and Dr. John had no disclosures.
Hosp Pediatr. Published online April 7, 2020. Full text
Lancet. Published online May 6, 2020. Full text
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