Evaluation of cutaneous symptoms in children infected with COVID-19.

To the Editor,

Severe acute respiratory syndrome causing coronavirus (SARS‐CoV‐2) is a new coronavirus responsible for the pandemic named coronavirus disease 2019(COVID‐19). Although the pathogenesis of the disease has not been completely understood yet, it may cause clinical pictures with various degrees of multisystem involvement. ,

Studies have indicated that coronavirus can also cause cutaneous lesions; however, specific cutaneous symptoms of COVID‐19 infection have not been disclosed yet. The prevalence of cutaneous manifestations in COVID‐19 patients was between 0.2% and 20.4% in the recently published studies , , , , and 3.4% in a review including 28 studies where the patients aged between 0 and 18 years age had COVID‐19. In this respect, we aimed to analyze the incidence and the types of cutaneous manifestations associated with COVID‐19 infections in pediatric patients.

Children who were diagnosed COVID‐19 in Ankara City Hospital, Children's Hospital in Turkey between March 11 and September 30, 2020, were evaluated in this prospective study. The study protocol was approved by the Institutional Ethics Committee of Ankara City Hospital (E1‐20‐546).

Of the 5143 children infected with SARS‐CoV‐2, only 13 (0.25%) developed cutaneous lesions during the period of study. The median age of those children was 80 months (IQR: 19‐118.5 months), and 10 of them were boys (76.90%) (Table 1). Only 2 of the patients had a chronic disease; epilepsy; and undefined immunodeficiency (Tables 1 and 2).

TABLE 1

Characteristics of patients and cutaneous symptoms (n = 13)

Characteristics of patients	% (n)
Age (median, IQR, ‘month’)	80 (19‐118.5) month
Gender (female/male)	3/10 patient
Having chronic disease	15.3% (n:2)
Cutaneous symptoms
Maculopapular exanthem	61.5% (n:8)
Urticaria	23% (n:3)
Palmoplantar eryhtema	7.6% (n:1)
Bullous lesion	7.6% (n:1)
Erythema nodosum	7.6% (n:1)
Associated clinical entities
DRESS a	7.6% (n:1)
SJS a	7.6% (n:1)
MIS‐C disease	15.3% (n:2)
Rash location
Trunk	76.9% (n:10)
Face	69.2% (n:9)
Extremity	38.4% (n:5)
Gluteal legion	15.3% (n:2)
Hand and Foot	15.3% (n:2)

There was drug exposure that also could be cause of the symptoms.

TABLE 2

Characteristics of clinical findings

Patient number	Gender	Age (Month)	Symptoms at admission	Rash type Rash localization Rash onset time	Clinical progress	Concomitant drug use
1. Patient	Male	20	Fever, rash	Maculopapular Face and trunk Rashes developed at the 2nd day of the disease	Rash subsided in 4 days Symptoms resolved completely	No
2. Paitent	Male	43	Rash, fever, and swelling at knee joint	Urticaria, Face, trunk, extremities Rashes developed at the first day of the disease	At the second day fever and swelling at knee joint developed Rash subsided in 4 days Symptoms resolved completely	No
3. Patient	Male	160	Fever, cough, and vertigo	Maculopapular Face and trunk Rash developed at the 4th day of the disease	Rash subsided in 1 day. Symptoms resolved completely	Ampicillin‐sulbactam: 1th day, 1th dose
4. Patient	Male	150	Fever, cough, dyspnea, and weakness	Erythema nodosum Dorsum of the hands and pretibial surface Rash developed at the 14th day of the disease	Developed bilateral rales, hypotension Cold type autoimmune hemolytic anemia was added to the clinical picture Rash subsided in 1 day. Symptoms resolved completely	Ceftriaksone, macrolide, teicoplanin, azithromycin, favipiravir, clexane, and interferon treatments were given. After three dose/week interferon treatment, it was terminated and rash coincided one day after interferon treatment termination but other treatments continued. (He was diagnosed with an undefined immunodeficiency)
5. Patient	Male	80	Fever, rash	Urticaria Face and trunk Rash coincided at the same time of fever	Rash subsided in 1 day. Symptoms resolved completely	No
6. Patient	Female	5	Fever, cough, vomiting, diarrhea, and rash	Maculopapular Face Rash developed at the 2th day of the disease	Rash subsided in 1 day. Symptoms resolved completely	No
7. Patient	Male	13	Fever, vomiting, diarrhea, and rash	Maculopapular Face, trunk, extremities Rash developed at the 10th day of the disease	Rash subsided in 4 days. Symptoms resolved completely	No
8. Patient	Male	18	Fever, diarrhea, and rash	Urticaria Rash developed at the 3rd day of the disease	Rash subsided in 3 days. Symptoms resolved completely	No
9. Patient	Male	133	Fever, dyspnea	Maculopapular Face and trunk Rash developed at the 4th day of the disease	Rash subsided in 15 days. Symptoms resolved completely	Hydroxychloroquine 2th day, 2th dose
10. Patient	Male	92	Fever, cough, and rash	Maculopapular Face, trunk, extremities Rash developed at the first day of the disease and coincided with the other symptoms	Developed DRESS with liver involvement Rash subsided in 18 days. Symptoms resolved completely	Amoxicillin‐clavulanic acid 9th day and Carbamazepinene 19th day (He was diagnosed with epilepsy)
11. Patient	Male	84	Fever, throat pain, cough, rash, and mucosal lesion	Maculopapular and bullous epidermal detachment and mucosal lesions Face, scalp, neck, trunk Mucosa involvement: Oral and anal Rash developed at the 2nd day of the disease	Developed SJS with pulmonary involvement. Rash subsided in 14 days. ‐Unfortunately, he was exitus.	Amoxicillin‐clavulonic acid 2nd day
12. Patient	Female	104	Fever, abdominal pain, diarrhea, weakness, bilateral conjunctivitis, strawberry tongue, and rash	Maculopapular, Bilateral palmoplantar erythema, Face, trunk, and gluteal location Rash developed at the 5th day of the disease	Developed MIS‐C (Myocardial dysfunction) Rash subsided in 4 days. Symptoms resolved completely	Cefixim 2nd day
13. Patient	Female	70	Fever, abdominal pain, vomiting, bilateral conjunctivitis, and rash	Maculopapular trunk, axilla, and gluteal location Rash developed at the 3rd day of the disease	Developed MIS‐C (pleural and pericardial effusion, myocardial dysfunction) Rash subsided in 3 days. Symptoms resolved completely	No

Common cutaneous manifestations of infected children in our hospital were maculopapular exanthema and urticaria: 61.5%(n:8) and 23%(n:3), respectively. One of the patients developed erythema nodosum. Two of them were presented as severe cutaneous adverse reactions (SCARs); drug rash with eosinophilia and systemic symptoms (DRESS); and Stevens‐Johnson syndrome (SJS), respectively, and two patients developed multisystem inflammatory syndrome in children (MIS‐C) (Tables 1 and 2).

Cutaneous symptoms began before the COVID‐19 symptoms (2 days before) only in one patient, and 10 of the patients presented cutaneous manifestations after the COVID‐19 symptoms (median 3 days after). Cutaneous symptoms coincided with the onset of other COVID‐19 symptoms in two of the patients. The mean of the duration time of rashes was 5.6 days. Additionally, all patients had a fever. Cough, dyspnea, vomiting, diarrhea, abdominal pain, and vertigo; 30.8%(n:4), 23.1%(n:3), 23.1%(n:3), 30.8%(n:4), 15.4%(n:2), and 7.7%(n:1), respectively, were also observed at the admission of the patients (Table 2).

In our study, there were six patients with a history of drug usage. We terminated the usage of any suspicious drug due to the rash in combination with the medication history of the patient. The aforementioned patients did not have any reported history of drug allergy. On the second day of the treatment and after 2 hours of the dose, maculopapular exanthema was observed in the trunk, face, and legs of the patient who was treated with hydroxychloroquine. The hydroxychloroquine treatment was terminated in 1 day (patient nine). One of the patients received favipiravir and ampicillin‐sulbactam treatments. Maculopapular exanthema was seen at the trunk of the patient after 1 hour of the first dose of ampicillin‐sulbactam. After termination of the ampicillin‐sulbactam treatment, rashes were revealed in 1 day while favipiravir treatment was continued (patient three) (Table 2). It was observed that one of the patient has developed DRESS. An eight‐year‐old boy having epilepsy disease presented with fever, cough, and rashes in trunk, face, and lower extremities. The patient was on the ninth day of amoxicillin‐clavulanic acid treatment and on the 19th day of carbamazepine treatment when the rash started. In his laboratory findings, serum transaminases and eosinophil level were elevated and viral markers were negative. Hence, the carbamazepine treatment and amoxicillin‐clavulanic acid treatment were terminated. He received levetiracetam treatment for epilepsy (patient ten) (Table 2).

One patient was presented with SJS. The patient was prescribed amoxicillin‐clavulanate for complaints of fever, throat pain, and cough. After 2 days of amoxicillin‐clavulanate usage, he applied to the hospital with fever, maculopapular lesions, mucosal lesions in oral and anal mucosa, blistering cutaneous lesions, vesicles and bullae with desquamation commonly affecting the face, scalp, and neck, and anterior chest wall and back. Nikolsky's sign was positive. Also, severe respiratory distress was examined (patient eleven) (Table 2).

In one patient, COVID‐19 infection was presented with cough and fever. Erythema nodosum developed at the bilateral extensor surface of the hands and pretibial surface of the bilateral lower extremity on the 8th day of his hospitalization (Table 2). He was treated with ceftriaxone, macrolide, teicoplanin, azithromycin, favipiravir, clexane, dexamethasone, and interferon‐alpha treatment. Erythema nodosum was observed one day after the termination of the interferon treatment. The patient showed improvement in one day without termination of any other treatment (patient four).

Two patients with a diagnosis of MIS‐C had rashes. The first MIS‐C patient had high and persistent fever, bilateral non‐purulent conjunctivitis, polymorphic rash in the trunk and gluteal area, strawberry tongue, and palmoplantar erythema. Rashes began after the second day of cefixime and after 3 days of abdominal pain, diarrhea, and fever. We terminated the usage of the drug (patient twelve). The second patient with MIS‐C had fever, vomiting, and abdominal pain on the fourth day. Bilateral conjunctivitis, maculopapular exanthemas on trunk, gluteal region, and bilateral axilla developed after 3 days of the outset of COVID‐19 symptoms. The patient did not have a history of drug usage (Table 2).

The patients were discharged when they were healed, and one of them was deceased (SJS).

Limited studies have investigated the cutaneous manifestations in COVID‐19 only in children.

Erythematous rash and localized or diffuse urticarial and chickenpox‐like lesions are the most common manifestations in COVID‐19. In the literature, there is one case indicating the relationship between coronavirus and DRESS syndrome. Maculopapular rashes such as erythema multiforme‐like or diffuse erythroderma are the commonly observed cutaneous manifestations of MIS‐C. Whitaker and et al reported that 30 of the 58 children patients who were diagnosed as MIS‐C had erythematous rashes. In genetically predisposed individuals, SARS‐CoV‐2 can trigger the development of a rapid autoimmune and/or autoinflammatory dysregulation and lead to severe interstitial pneumonia. A case report reported that a 58‐year‐old female patient developed SJS and TEN overlap syndrome with COVID‐19 positivity. The pathogenesis of cutaneous symptoms is not understood yet. In COVID‐infected patients, cutaneous manifestations may be directly related to coronavirus or caused by another underlying viral infection or due to adverse drug reactions that are newly started. , Adverse drug effects, drug‐drug interactions, and hypersensitivity reactions may develop with drugs used during COVID‐19 therapy. Therefore, COVID‐19 patients should be followed up carefully.

The cutaneous symptoms during COVID‐19 may be mild (maculopapular exanthem and urticarial) or severe (SJS, DRESS, and MIS‐C). In the present study, it was not clear if six of 13 patients presented the symptoms of the drug given or virus. More studies should be conducted to confirm and understand the skin involvement in COVID‐19.

AUTHOR CONTRIBUTIONS

Azize Pınar Metbulut: Data curation (equal); Formal analysis (equal); Investigation (equal); Writing‐original draft (equal); Writing‐review & editing (equal). Aslinur Ozkaya Parlakay: Project administration (equal); Resources (equal); Supervision (equal); Visualization (equal). Gülsüm İclal Bayhan: Methodology (equal); Resources (equal); Supervision (equal); Visualization (equal). Saliha Kanik: Data curation (equal); Investigation (equal); Methodology (equal). Belgin Gülhan: Formal analysis (equal); Methodology (equal); Resources (equal); Supervision (equal). Zeynep Şengül Emeksiz: Data curation (equal); Methodology (equal); Resources (equal). Emrah Şenel: Visualization (equal); Writing‐review & editing (equal). Emine Dibek Misirlioglu: Project administration (equal); Writing‐original draft (equal); Writing‐review & editing (equal).

CONFLICT OF INTEREST

The authors have no conflicts of interest to declare.

PEER REVIEW

The peer review history for this article is available at https://publons.com/publon/10.1111/pai.13467.