Dr Evans described the mottling observed in some of the infants as being indicative of air embolism. The closest description of such skin manifestations is observed in parechovirus/enterovirus infection, and is demonstrative of sympathetic nervous system arousal. The mottling occurs due to adrenaline. Adrenaline in the nerve terminals can constrict arteries to change blood flow. This can happen when the brain gets inflamed and is a way to divert oxygen to the brain. The binding of adrenaline to its receptors on arteries results in vasoconstriction and subsequent changes in blood flow patterns. The relative discolouration of the skin is a function of blood flow patterns. Where constriction of arteries occur due to the release of adrenaline, the distal limbs, such as the legs, will exhibit a noticeable pallor, and the local pooling of blood in other areas of the body can make them appear swollen and discoloured.
The medical doctors at CoCH described a fluctuating colour pattern in the neonates. The cause of these changes is the relative saturation of adrenaline binding to receptors on arteries. The colour changes recede because the adrenaline and the receptor complex have a relatively short half-life. Loss of adrenaline activity will cause a return of the normal skin colour.
Adrenaline plays a core role in regulating heart rate and may have been the cause of the increased incidence of tachycardia observed in the neonates, and even the primary factor initiating cardiac arrest. The release of adrenaline from the adrenal gland occurs in response to environmental and physiological stresses. In nearly all the cases at CoCH, the infants first presented with moderate-severe tachycardia. Ultimately, adrenaline is a fast acting hormone, which can rapidly cause changes in blood flow, heart rate, and metabolism. The release of adrenaline is a compensatory mechanism experienced upon contracting infectious disease and through environmental stressors. Adrenaline release in response to invasion by infectious pathogens plays a primary role in dampening the innate immune response (Kox et al., 2014). This serves an important function, as excessive innate immune reactivity due to host infection is associated with cytokine storms. Cytokine storms describe a massive molecular event due to upregulation of proinflammatory cells and the release of pro inflammatory factors. When left unchecked, innate immune reactivity can cause disseminated intravascular coagulation, resulting in internal bleeding and death (Yang et al., 2021).
Skin manifestations due to changes in blood flow, apnoeic events and sudden death are features of Covid-19 infections. The appearance of transient skin manifestations in the context of infectious diseases may reflect an attempt to limit innate immune reactivity through the release of adrenaline, in order to prevent the onset of a lethal cytokine storm. However, adrenaline release must be carefully regulated because it is equally associated with tachycardia, due to increased peripheral vasoconstriction, pulmonary venoconstriction and reduced left ventricular compliance.