COVID-19 and EBV Co-Infection in a Child

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), reported first in December 2019 in Wuhan, China. The virus soon spread all over the world and the World Health Organization (WHO) declared a global pandemic on March 11, 2020. At the beginning of the outbreak, infections were more common in adults then in children; however, in the following months, the number of pediatric infection cases increased significantly. The disease in children is less severe, but occasionally it may be complicated with Multisystem Inflammatory Syndrome. Some of the symptoms and signs may be overlapped with other infectious diseases of the childhood and confound the appropriate diagnosis. A high index of suspicion must be maintained in children while making a diagnosis. We report the case of a 5 years old presented with COVOD-19 and EBV co-infection.


Introduction
China on January 20, 2020. At the beginning of the outbreak, COVID-19 infections were more common in adults then in children; however, in the following months, the number of pediatric infection cases increased significantly. Most cases in children are mild and treatment consists in supportive care; only a small number need hospitalization and mortality rate is low < 0.1% of diagnosed children [1] [2] [3] [4]. As we are discovering each day more about SARS-CoV-2 infection, differences between adults and pediatric disease are probably due to changes within both immune function and the angiotensin-converting enzyme (ACE) 2 receptor, 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 with broad reactivity, in addition to the production of the anti-inflammatory interleukin (IL)-10 by neonatal B cells [5].
Other probable explanations are alternations 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 [6]. Besides, all this children have fewer comorbidities and a stronger pulmonary regenerative potential than adults. Thrombocytosis was assumed to be of reactive origin due to excessive inflammation generated by the combination of two infectious agents COVID-19 and EBV. Once the combined diagnosis was confirmed therapeutic approach was symptomatic. Fever subsided gradually, lymphadenitis was reduced and the child appeared playful. Thrombocytosis subsided after a couple of weeks too (Table 1).

Discussion
As SARS-CoV-2 disease is emerging and the world is in the middle of the pandemic, it is not easy for the pediatrician, to differ between COVID-19 infection and other potential viruses of childhood. Almost all medical resources are directed towards COVID-19 infections and still it's challenging to make a diagnosis or predicts its complications in children.
It is already known that fewer cases of COVID-19 disease have been diagnosed in children than in adults. The majority of the pediatric cases have been mild, but severe illness has been reported in 2.5% of pediatric cases in China, according to the World Health Organization [7]. The most reported signs and symptoms in children are cough, pharyngeal erythema and fever. Other less common signs and symptoms include diarrhea, fatigue, rhinorrhea, vomiting and nasal congestion. A small percent presents with severe disease, dyspnea, persistent high fever, lethargy, increased levels of enzymes [4]. Since May 2020, several highly endemic countries reported a high incidence of multisystem inflammatory syndrome (MIS) in children [8] [9] [10] [11]. All include fever, elevated inflammatory markers, and organ dysfunction not attributed to another infectious cause. The median interval from COVID-19 symptom onset to MIS onset is 25 days [12]. The higher rate of positive serologic tests compared with nasopharyngeal reverse transcription-polymerase chain reaction (RT-PCR) is  Figure 1) [16]. Some patients meet the criteria for macrophage activation syndrome (MAS).
As the presenting child had a negative reverse transcriptase protein chain reaction (RT-PCR) for COVID-19 but a positive serology for COVID-19 (increased IgM levels, which are higher during weeks 2 -3 of illness), prolonged fever > 10 days, cough, diarrhea, fatigue, cervical lymphadenopathy, pharyngeal erythema Table 2. CDC case definition for multisystem inflammatory syndrome in children (MIS-C). headache, fatigue, and fever [20]. Both CD4 and CD8 T cells make a robust response to EBV antigens, the massive lymphocytosis in the blood that characterizes infectious mononucleosis is thought to consist largely of CD8 T cells specific for EBV lytic antigens [21]. Both agents EBV and COVID-19 modulate the immune system.
Thrombocytosis is not typical in EBV or COVID-19 infection otherwise they are companied by mild 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 [22]. In this case thrombocytosis is an exaggerated physiologic response to the combined infections. Despite the strikingly high platelet count, sometimes exceeding 1,000,000 cells/mm 3 , thrombotic and/or hemorrhagic complications are highly exceptional.

Conclusion
COVID-19 has inflicted all the world population. The number of infected children is progressively increasing. The disease in children is less severe, but sometimes it may be complicated with Multisystem Inflammatory Syndrome. Some of the symptoms and signs may be overlapped with other infectious diseases of the childhood, such as EBV and respiratory viruses, and confound the appropriate diagnosis. So a high index of suspicion must be maintained in children while making a diagnosis.