Progressive PNS, ANS, and CNS involvement developed in a child recovering from COVID-19 presenting with a URI. There are several reasons to consider an autoimmune etiopathogenesis related to preceding SARS-CoV-2 infection. First, children with or without multisystem inflammatory syndrome (MIS-C), as in this patient, exhibit similar pathogenic SARS-CoV-2 IgG anti-spike (S) antibody profiles with comparatively lower levels of neutralizing activity and anti-nucleocapsid (N)-specific antibodies associated with a reduced protective serologic response . Second, absence of the acute respiratory distress syndrome (ARDS) in this patient and in children overall is consistent with the lower expression of SARS-CoV-2 viral receptor (angiotensin-converting enzyme 2 (ACE2)) in airway epithelial cells , yet a more robust innate immune response . Third, pediatric T-cell responses to SARS-CoV-2 exceed the adult responses due to an increased number of naïve T-cells available to respond to new pathogens  including those recently acquired T-cell memory cells related to coronavirus strains  and more frequent respiratory illnesses seen in children overall. Fourth, there is mounting interest in the contribution of infection and the host microbiome  and antineuronal antibodies to neuropsychiatric illness  particularly autoantibodies reactive to surface antigens of neurons in the limbic system present in the hippocampus, that are important in mood and cognition.
Central nervous system involvement
There are no reported studies of brain PET/MRI studies in pediatric COVID-19 neurological illness; however, affected adults show hypometabolism in multiple cortical areas in acute  and late COVID-19 illness , likely reflecting impaired neuronal activity . Putative mechanisms of COVID-19 CNS involvement including encephalopathy include a dysregulated neuroinflammatory immune response to the systemic infection as well as the impact of pre-existing medical conditions, rather than virally mediated pathology despite detection of SARS-CoV-2 RNA and proteins in postmortem brain tissues . Although there are no postmortem series of childhood COVID-neurological illness, adult COVID-19 decedents  show elevated levels of circulating interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α, indicative of a cytokine storm associated with focal and diffuse cortical, brainstem, and leptomeningeal T-cell mediated inflammation.
Peripheral nervous system involvement
LaRovere and colleagues  described 4 hospitalized children with COVID-19 manifesting new deficits of Guillain-Barré syndrome (GBS) at discharge; 2 others with painful neuropathy and neurocognitive deficits (2 cases) reminiscent of the present patient. Dalakas  suggested a post-infectious autoimmune mechanism in 11 cases of GBS lacking evidence of SARS-CoV-2 replication in CSF, and associated with GD1b antibodies in another, all with improvement after IVIg. GBS in association with COVID-19 was heralded by fever (74%), cough (67%), interstitial pneumonia (62%), hypoageusia (38%), and hypoanosmia (26%) in a meta-analysis of 42 adults  and in rare instances of childhood affliction  that would qualify for PASC.
Dysautonomia has been reported in COVID-19-related GBS  with frequent association of sphincter dysfunction. The present patient instead manifested dysautonomia as a feature of painful small fiber sensory neuropathy (SFN)  shown respectively by tilt table testing and ENF histology. Similarly affected adults recovering from COVID-19 were successfully treated with IVIg . New-onset postural orthostatic tachycardia syndrome (POTS) was described in a previously healthy adult patient weeks after quarantining from COVID-19 illness suggesting an immune mechanism of onset  but not in pediatric subjects. SARS-CoV-2 tropism for the brainstem due to increased expression of ACE2 and corresponding neuroinflammatory changes associated with COVID-19 neurological illness  may contribute to persistent brainstem dysfunction and latent dysautonomia. There is a potential role for cardiac imaging with 123I-meta-iodobenzylguanidine (MIBG) in suspected cases of sympathetic denervation associated with dysautonomia in PASC to assess the integrity of the cardiac ANS .
Toward a unified concept of PASC
PASC can be described by the acronym, I-Cubed (I3) that posits a multiplier effect of infection, immunity, and inflammation; which conditioned by environmental and genetic predisposing factors, may be the source of host autoimmunity . The underlying basis of PASC, especially in the CNS, may not be fully appreciated until controlled clinical and autopsy cohort studies are performed. IVIg appears to be an effective agent in the management of MIS-C and Kawasaki disease (KD) which it can mimic  as well as adult PASC . It is unlikely that the designations COVID Long Hauler and Long COVID will be appropriate terms for PASC. However, given the need to assemble 20,000 subjects with SARS-CoV-2 infection and 1000 subjects with PASC for the NIH-funded initiatives, their sheer magnitude and reach of social media may make them useful cohorts for future controlled research.