Wuhan, China notified to WHO in late December 2019 of an unusual cluster of pneumonia cases. The disease later termed COVID 19, spread quickly beyond the borders of China, with the first cases in Europe being recorded on Jan 25, 2020. SARS-CoV2 is the causative agent for COVID 19 infections in humans. This is a positive sense, single-stranded RNA enveloped virus, comprising of glycoprotein spikes on the outer surface, which mediates its entry into the host cell.

ACE2 receptor serves as a molecular target for the novel coronavirus, to enter the target cell, by interacting with the viral glycoprotein spikes. Also, ACE2 has lung-protective effects by limiting angiotensin 2 mediated pulmonary capillary leaks and inflammation. It leads to a cascade of immune responses in the host causing acute respiratory distress syndrome. In this article, it was aimed to discuss the various hypotheses and possible reasons as to why children have milder symptoms as compared to adults.

There are many potential factors protecting children against severe SARS CoV2 infection:

1. Prevention of virus exposure: Probably strict quarantine measures and closing of potential hotspots for pediatric infections like schools and daycare centers. As the movement of children is highly restricted in these times, most of the infections are only spread from infected family members [1].

2. Appropriate infection handling: Children supposedly have trained immunity which means that it is the functional reprogramming of the innate immune cells to a more activated state following initial antigen stimulation (infections or vaccination) through metabolic reprogramming and epigenetic changes (acetylation and demethylation leading to enhanced transcription of Interleukins and tumor necrosis factor) [1-4]. It is known that children uniquely own an active thymus, a lymphatic organ in which the formed T-cells mature, develop and reproduce to fight intracellular pathogens throughout childhood. Thus, there is a greater number of naïve T cells that can be programmed to protect them against the disease [5]. Another hypothesis suggests that these naïve T cells program into memory T cells which play an important role in conferring protection to children against COVID-19 [6].

4. Effects of Lung Development: Lungs gradually have impaired regenerative potential while aging. Since children have greater upper airway resistance, aerosol particles deposit more in the tracheobronchial tree than alveoli, which could lead to less pneumonia and more bronchiolitis-like infections with SARS-CoV2 infection in children [1].

Also, an adult has 500 million alveoli compared to only 3 million alveoli in a newborn which may translate into less severe immune reaction compared to adults as fewer alveoli mean fewer type 2 cells. Studies show that the cellular serine protease TMRRSS2 is also required to allow the entry of coronavirus into host cells and type 2 cells express TMRRSS2 [13].

Androgenic hormones upregulate this gene TMRRSS2, which may show the low incidence of COVID 19 infections in the prepubertal age group [14]. In adults, ventilation of alveoli also occurs via alternate pathways like alveolar pores of Kohn, interbronchiolar Martin’s channels, and bronchioalveolar Lambert’s channels and this is known as collateral ventilation.

In children, these pathways are said to be developed in 5 to 6 years and it can also be speculated that the virus may also spread through these collateral pathways and its absence may prevent the excessive spread of the virus in children [14]. Children also have larger alveolar ventilation and functional residual capacity is smaller which may translate into a higher alveolar clearance in children as compared to adults.

5. ACE 2 regulation: There is a supposedly high ACE 2 expression in the pediatric population which metabolizes angiotensin 2 and inhibits its pro-inflammatory, fibrotic effects. Since there is a downregulation of ACE2 expression, there might be a positive relationship between the concentration of angiotensin 2 in the body and the severity of SARS CoV2 mediated lung injury [1,4]. As per the enzymatic analysis, the levels of ACE2 in children are 13-100 U/L, unlike the levels of adults which is 9-69 U/L [4]. The circulating soluble ACE2 levels aid children and asymptomatic individuals, to counteract the spreading of the virus in the body, by buffering effect, more like neutralizing antibodies.

6. Evolutionary link to disease severity: [3] Bats are known to be the natural reservoir of coronaviruses and they chronically shed these viruses without any major disease in the host animal.

Fig-2: Mild Covid-19 infections in children.

Thus, it has been clear that from evidence, the antioxidant capacity and the antioxidant response potential of the host are two of the key determinants of SARS CoV2 infection outcome. The higher antioxidant capacity of children and young adults combined with their higher ACE2 expression is one of the likely explanations of the low incidence of severe infections in these age groups.

7. Role of HBA1c and blood sugar levels in children: It is known that with advancing age, the tissue sensitivity to insulin decreases which further results in insulin resistance [15,16,17]. There is the robust secretion of insulin from the pancreas and also good sensitivity of tissue to insulin which probably explains the low levels of HBA1c levels in children [18].

Now the two events occurring i.e. the mortality related to COVID 19 increases with age and the average HbA1c of the general population also increases with age, which has been postulated to be causally related to each other [19]. It has been proposed that hyperglycemia in both diabetic and non-diabetic patients may lead to the glycosylation of ACE2 receptors, which may increase the affinity towards SARS CoV2 resulting in severe infection [20].

Since children have better insulin sensitivity, thus lesser HBA1c levels which indicates fewer chances of the hyperglycemic state which may also contribute to protecting children from severe infections of COVID 19.

8. Absence of high-risk factors: There is the absence of any aging-related comorbidities and less degree of smoking, obesity, hypertension.