Muco-Cutaneous Changes Following COVID-19 in Children

Coronavirus disease 2019 (COVID-19) is an illness caused by the novel coronavirus designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first identified in Wuhan, China, in December 2019, and soon spread all over the world causing a global pandemic. Since the beginning of the pandemic, fewer cases of COVID-19 have been reported in children than in adults. Most cases have been mild and only a small proportion of infected children needed hospitalization. As the pandemic evolved, it was soon evident that immune dysregulation inflicted by the virus, posed children at risk for their lives. It is still hard to predict its effects on children health and well-being. Here are reported a series of cases of muco-cutaneous changes following COVID-19 infection in children. Children ranged from 8 months to ten years. They had a history of a recent COVID-19 infection (1 - 3 months ago), with a RT-PCR for COVID-19 negative, SARS-CoV-2 IgM negative and a positive SARS-Cov-2 IgG. Their presentation was consistent with a late reaction to COVID-19 reaction with muco-cutaneous changes domi-nating the scenery.

Patients with severe diseases have evidence of hiperimmune response with persistent fevers, elevated inflammatory markers and elevated proinflammatory cytokines [5] [6]. Common symptoms in children are cough, fever, shortness of breath, sore throat, diarrhea, myalgia, fatigue, rhinorrhea, vomiting, nasal congestion, abdominal pain, rash [7] [8] [9]. The rate of children with critical illness ranges from 0.4% -9% of confirmed cases but some reports include patients diagnosed in hospital [2] [4] [10] [11]. Factors associated with severe disease in children are neonatal age group, male gender, lower respiratory tract disease and pre-existing medical conditions [4]. Differences between adults and children are as the result of changes in immune function and the angiotensin-converting enzyme (ACE) 2receptors, used by the virus to enter type II pneumocytes in the lung. The immune system of children is highly prepared to novel pathogens, due to high levels of innate IgM antibodies and the ability to rapidly produce natural antibodies with broad reactivity [12]. Other differences are proposed alterations in T cell populations in adults due to continuous antigen stimulation and thymic involution, varied levels of ACE-2 expression in children, and the simultaneous presence of other viruses in the respiratory mucosa of children, competing with SARS-CoV-2 [13]. Besides all these children have fewer comorbidities and a stronger pulmonary regenerative potential.

Method & Material
This is a case-report series. Children were admitted in the General Pediatric Ward at the University Hospital Center "Mother Teresa", Tirana, Albania during October 2020-April 2021. The cases are enlisted according the time of admission.
Case nr.1 A 21 months old female presented at the University Hospital Center of Tirana with a skin rash; palpable, non-pruritic plaques, purple-colored in center, spread over the trunk, extremities and face and mild edema on the extremities ( Figure   1). She had a family history of COVID-19 infection 3 -4 months ago. On physical examination appeared irritable with moderate fever, colored lips and a strawberry tongue.
RT-PCR for COVID-19 was negative. SARS-CoV-2 IgM were negative and    Blood cultures were negative. Radiologic examination of the lungs and heart were normal. After a 7-day course of intra-venous prednisolone and antibiotics, the rash faded and inflammatory parameters were normalized. Case nr.3 An 8 months old male presented at the hospital with a widespread rash on the skin including palms of the hands and soles ( Figure 3). He had a family history of COVID-19 over 2 months ago. On physical examination he appeared ill, irritable with high fever 40˚C, red cracked lips, conjunctivitis and a strawberry tongue. He had a RT-PCR for COVID-19 negative, SARS-CoV-2 IgM were negative and a positive SARS-Cov-2 IgG 6.8 (<0.8).
Blood cultures were negative. Radiologic examination of the lungs and heart revealed no abnormalities. After a 7-day course of intra-venous prednisolone and antibiotics, the rash faded and inflammatory parameters turned to normal.
Case nr.4 A 10 years old male presented at the hospital with an erythematous rash on the face and neck, a three day high fever and cough (Figure 4). He also had a history of family COVID-19 almost 2 months ago. On physical examination he appeared ill, tired with moderate fever and an injected pharynx. He had a RT-PCR for COVID-19 negative, SARS-CoV-2 IgM were negative and a positive SARS-Cov-2 IgG 3.8 (<0.8). Journal of Biosciences and Medicines   Blood cultures were negative. Radiologic examination of the lungs and heart were normal. After a 7-day course of intra-venous prednisolone and antibiotics, the rash faded and inflammatory parameters normalized and the child was play-full again.

Discussion
As the pandemic affected nearly all the world, pediatrician and parents were somehow consoled by the apparent fact that the health of children were in less risk than theirs, but while the pandemic evolved the number of children infected increased too. SARS CoV-2 infection is characterized by an initial cytokine storm that can result in acute respiratory distress syndrome which is characteristic of the severe disease in adults, but cases have been reported in children too.
Children have a stronger innate immune response, higher proportion of total lymphocyte and absolute number of T and B cells, as well as natural killer cells, which play an important role in virus clearance [14] [15]. Children also have a less pro-inflammatory cytokine response, which make them less prone to develop acute respiratory distress syndrome. The initial phase of cytokine storm is then followed by a period of immune dysregulation which is accused for most of COVID-19 complications.
Since May 2020, several highly endemic countries reported a high incidence of multisystem inflammatory syndrome (MIS) in children. Several case definitions were proposed, all include fever, elevated inflammatory markers, and organ   tongue. Leukocytosis with neutrophilia was found in all cases. C Reactive Protein (CRP) was increased in all cases and D-dimer was increased in three of them. Blood cultures were all negative. Platelets were in normal values except two cases where platelets count increased in the second week of the disease. Thrombocytosis is not typical in MISC, otherwise it is companied by thrombocytopenia. Thrombocytosis in children are usually reactive, particularly common during recovery phase of an infection or inflammation and are usually transient and subsides when the primary stimulus ceases. Reactive thrombocytosis is usually mediated by increased release of numerous cytokines in response to infections. A wide range of cytokines may participate in the stimulation of platelet production, IL-3, IL-11, granulocyte-macrophage colony-stimulating factor, erythropoietin but the most imported role is plaid by thrombopoietin and IL-6 which are initially elevated in response to infections [18]. Prednisolone was used in all cases from 3 -5 days. Erythema faded and inflammatory parameters stabilized in 1 week. Considering all the data of the presented cases, it was assumed to be a late inflammatory reaction to COVID-19 infection. Initially it seemed as the children were developing MISC, as some criteria of MISC matched, but somehow the immune dysregulation did not reach the magnitude to cause a full-blown MISC, and skin resulted the only organ involved.

Conclusion
It is now clear that children of any age may be infected with SARS-CoV-2. They suffer a less severe acute infection compared to adults, but the immune dysregulation that follows, pose the children at risk of late inflammatory reactions that sometimes may be life-threatening. Skin rashes may be the presenting feature of a late post COVID-19 immune reaction. As the pandemic continues to evolve, it is still hard to predict the mid and long term effects on children health and well-being.