Pseudo‐chilblain lesions and COVID‐19: a controversial relationship

Dear Editor,

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has been associated with different cutaneous manifestations, including acral lesions similar to chilblains. ¹ News of the possible association between chilblains and COVID‐19 in the media and on social networks generated consternation among the general public in Spain and a considerable increase in medical consultations. A direct association between pseudo‐chilblains and COVID‐19, however, has not been unequivocally demonstrated, as microbiologically confirmed SARS‐CoV‐2 infection has been reported in very few cases. ² , ³

We had the opportunity to study 14 patients with pseudo‐chilblain lesions during the state of emergency declared in Spain on March 14, 2020 (Fig. 1). Their mean age was 13.28 years (range, 7–20 years). The clinical and analytical data are summarized in Table 1.

Figure 1.

Pseudo‐chilblain lesions. Erythema and swelling on the third left toe (a); purpuric macules on the second and third right toes (b)

Table 1.

Clinical features and laboratory tests

Case	Sex	Age (years)	Comorbidities	Family background	Site of lesions	COVID‐19 symptoms	COVID‐19 PCR	IgA + IgM SARS‐CoV‐2	IgG SARS‐CoV‐2	ANA	ANCA	D‐dimer	ACL	Cryoglobulins	Cryoagglutinins	IgG/M PB19	IgG/M Enterovirus	Treatment
1	M	12	ADHD	No	Feet	No	Negative	Negative	Negative	Negative	Negative	High	Negative	Negative	Negative	IgG positive	Negative	Topical corticosteroids, pentoxifylline
2	F	12	Adenoidectomy	No	Left foot	Malaise, low‐grade fever	Negative	Negative	Negative	1/80 speckled pattern	Negative	Normal	Negative	Positive, cryocyte <1%	Negative	IgG positive	Negative	No
3	M	14	No	No	Feet	Malaise, low‐grade fever	Negative	Negative	Negative	Negative	Negative	Normal	Negative	Negative	Negative	IgG/M negative	Negative	No
4	F	7	No	No	Feet	No	Negative	Negative	Positive	Negative	Negative	Normal	Negative	Negative	Negative	IgG positive	Negative	Topical corticosteroids
5	F	12	No	No	Feet	No	Negative	Negative	Negative	Negative	Negative	High	Negative	Negative	Negative	IgG positive	Negative	Topical corticosteroids and antibiotic
6	F	13	No	Father SARS‐CoV‐2+	Hands	No	Negative	Negative	Negative	Negative	Negative	Normal	Negative	Negative	Negative	IgG positive	Negative	No
7	M	17	ADHD	No	Feet >>>hands	No	Negative	Positive	Negative	Negative	Negative	High	Negative	Positive, cryocyte <1%	Negative	IgG positive	Negative	Pentoxifylline
8	F	20	Raynaud's disease	No	Hands	No	Negative	Negative	Negative	1/80 speckled pattern	Negative	Normal	Negative	Negative	Negative	IgG positive	Negative	No
9	F	13	No	No	Heels	No	Negative	Negative	Negative	Negative	Negative	Normal	Negative	Positive, cryocyte <1%	Negative	IgG/M negative	Negative	Topical corticosteroids and antibiotic
10	M	15	No	No	Hands and feet	No	Negative	Negative	Negative	1/40 speckled pattern	Negative	Normal	Negative	Negative	Negative	IgG positive	Negative	Topical corticosteroids
11	F	17	No	No	Hands and feet	No	Negative	Negative	Negative	Negative	Negative	Normal	Negative	Negative	Negative	IgG positive	Negative	Topical corticosteroids
12	M	12	Hypothyroidism, GHD	No	Feet >>>hands	Low‐grade fever	Negative	Negative	Negative	Negative	Negative	Normal	Negative	Negative	Negative	IgG/M negative	Negative	No
13	M	11	Atopic dermatitis	No	Heels	No	Negative	Negative	Negative	Negative	Negative	Normal	Negative	Negative	Negative	IgG positive	Negative	No
14	M	11	No	Mother SARS‐CoV‐2+	Feet	No	Negative	Negative	Negative	Negative	Negative	Normal	Negative	Negative	Negative	IgG/M negative	Negative	No

ADHD, attention deficit hyperactivity disorder; ACL, anticardiolipin antibodies; ANA, antinuclear antibodies; ANCA, antineutrophil cytoplasmic antibodies; F, female; GHD, growth hormone deficiency; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; M, male.

PCR for SARS‐CoV‐2 was negative in 100% of patients. Serological testing (chemiluminescent immunoassay, Vircell, Spain, and enzyme‐linked immune assay, Euroimmun, Germany) revealed two positive cases: a 13‐year‐old girl with a positive result for SARS‐CoV‐2 IgG antibodies and a 17‐year‐old boy with a positive result for SARS‐CoV‐2 IgA and IgM antibodies. Additional tests were performed to rule out other possible causes of acrocyanosis (Table 1). The only significant pathological finding was cryoglobulinemia in three patients, including the 17‐year‐old boy with SARS‐CoV‐2 IgA and IgM antibodies. All the patients progressed favorably.

Chilblains represent an inflammatory skin reaction resulting from a maladaptive vascular response to very cold weather. ⁴ The accumulation of cases several weeks after the peak in COVID‐19 cases in Spain raised questions about a possible association with SARS‐CoV‐2. Pseudo‐chilblain lesions have been reported as a late manifestation of COVID‐19 and have been mostly observed in young patients with mild symptoms. ¹ , ⁴ However, a causative link between pseudo‐chilblain lesions and SARS‐CoV‐2 infection has not been proven. It has been suggested that immune‐mediated inflammation or microthrombosis might have a role in their pathogenesis. ⁴ Another theory is that SARS‐CoV‐2 infection might induce the expression of type 1 interferon, leading to microangiopathic changes. ⁵ Hubiche et al ³ demonstrated a significantly higher INF‐alpha response in patients with pseudo‐chilblain lesions. They suggested that the type of immune response is a key factor explaining the different clinical manifestations of SARS‐CoV‐2 infection. ³

The patient in our series who tested positive for SARS‐CoV‐2 IgM antibodies also tested positive for cryoglobulins, which could also have a pathogenic role, as has been observed in patients with hepatitis C virus infection. ⁶ Three months later, serological test was repeated again in this patient showing the same result as previously with no seroconversion for SARS‐CoV‐2 IgG. It is probably that SARS‐CoV‐2 IgM and IgA antibodies detected were a false positive result possibly associated with cryoglobulins.

Nonetheless, it is striking that molecular and serological tests were positive for SARS‐CoV‐2 in just two (14.2%) of the 14 patients in our series. ¹ , ² , ⁴ In a review of the literature, Docampo‐Simón et al ² found a similar rate (14.8%) for patients with chilblain‐like lesions and a positive PCR for SARS‐CoV‐2. On the other hand, the rate observed by Galván‐Casas et al ¹ was considerably higher at 41%; although, in this survey participating dermatologists relocated to the care of patients diagnosed with COVID‐19. These studies have very different inclusion criteria, which could justify the discrepancy in the percentage of positives. It is important to note that very few patients with pseudo‐chilblain lesions have undergone serological testing for SARS‐CoV‐2, and, similarly to in our study, most of the results have been negative. ² , ³ This raises several hypotheses. First, the low sensitivity of the rapid IgG/IgM tests performed at the start of the pandemic may have resulted in high false‐negative rates, and second, circulating antibody levels may drop rapidly, impeding their detection. ⁴ It has also been hypothesized that pseudo‐chilblain lesions may not be an exclusive marker of SARS‐CoV‐2 infection and may actually be because of other factors, such as trauma, other viral infections (mainly B19 parvovirus infection), and, in particular, a sedentary lifestyle, which would reduce acral blood flow, favoring the development of chilblain‐like lesions in certain patients. ¹ Finally, Hubiche et al ³ explained that patients with pseudo‐chilblain could clear SARS‐CoV‐2 infection before humoral immunity occurs because of an exaggerated type I interferon response. This could justify the low rate of seropositivity in these patients. ³

Considering the information available to date, we believe that further research is needed to investigate the causes and pathogenic mechanisms underlying pseudo‐chilblain lesions to confirm a definitive association with SARS‐CoV‐2 infection.