Non-Multisystem Inﬂammatory Syndrome in Children—Postacute Sequelae of Paediatric COVID-19: Autoimmune or Autoinﬂammatory? A Systematic Review of the Reported Cases

: Three years after its emergence, coronavirus disease 2019 (COVID-19) continues to be a leading cause of worldwide morbidity and mortality. This systematic review comprises relevant case reports that discuss non-multisystem inﬂammatory syndrome in children (non-MIS-C) and postacute sequalae of COVID-19 (PASC) in the paediatric population, also known as long COVID syndrome. The study aims to highlight the prevalent time interval between COVID-19 and the development of non-MIS-C post-infectious sequalae (PIS). Databases were searched for studies that met our inclusion and exclusion criteria. The ﬁnal screening revealed an equal sex distribution where the commonest age intervals were school-age and adolescence, with 38% of the patients being older than six years. Interestingly, hospital admission during the course of COVID-19 was not a predictor of the subsequent PASC; forty-nine patients (44.9%) were hospitalized while sixty patients (55.1%) were not hospitalized. Moreover, the most predominant time interval between COVID-19 and the developing PASC was within 14 days from the start of COVID-19 infection (61%). These ﬁndings suggest a crucial link between COVID-19 and immune PIS in the paediatric population, especially those older than six years. Accordingly, follow-up and management are encouraged in case of unusual symptoms and signs following COVID-19 infection, regardless of the COVID-19 infection severity.


Introduction
Acute infections are typically defined as self-limiting infections usually lasting less than six months and that usually lead to either complete resolution or death. While many

Exclusion Criteria
-Any case with a multi-inflammatory syndrome of children (MIS-C) or Kawasaki disease was excluded, and any flare-up of a pre-existing autoinflammatory condition was excluded. -Any case not addressing the outcome parameters was excluded.

Outcome Parameters
The main outcome parameters were the age, sex of the included cases, the interval between COVID-19 and the subsequent autoimmune sequelae, and the need for hospitalization during COVID-19 infection that preceded the resultant autoimmune sequelae.
Patients were categorized according to the aforementioned age ranges and time intervals as well as the need for hospital admission during COVID-19 and sex. The number and percentage of patients in each category of each outcome parameter were determined, and a comparison between different categories of each outcome parameter was implemented using a chi-square test and illustrated as a pie chart.
Age categories were numbered as follows: Category 1: infancy (<2 y), Category 2: preschool children (3-5 y), Category 3: school children (6-12 y), Category 4: adolescents (13-18 y). A receiver operating characteristic curve analysis was performed where hospitalization was the classification variable, to measure the age categories predicting hospitalization in the context of non-MIS-C postacute sequelae.

Results
We gathered a total of 78 reports of autoimmune sequelae following COVID-19, comprising a collective total of 109 patients. (References included in individual results). Figure 1 is a preferred reporting item for systemic reviews and meta-analysis (PRISMA) flow charts. Figure 1 is a preferred reporting item for systemic reviews and meta-analysis (PRISMA) flow charts. Figure 2 is a detailed algorithm for the distribution and overlap of reports and the number of patients per diagnosis.
Both of them, indicate that we included a total of 78 reports, comprising 109 patients.     Figure 2 is a detailed algorithm for the distribution and overlap of reports and the number of patients per diagnosis.
Both of them, indicate that we included a total of 78 reports, comprising 109 patients.  Both of them, indicate that we included a total of 78 reports, comprising 109 patients.

Overall Results
The sex distribution in retrieved cases was equal between the two genders. Regarding age, the commonest two age intervals involved were school-aged children and adolescents, with each accounting for 38% of the overall cases. Hospital admission during COVID-19 did not seem to be a good predictor of subsequent autoimmune sequelae as there was no statistically significant difference between the number of cases with hospital admission and those who were not admitted, i.e., 49 and 60, respectively. Finally, yet importantly, most of the observed PIS were observed within 14 days of the COVID-19 infection, accounting for 61% of the total cases. (Tables 1 and 2) illustrate the details of the overall results described in this paragraph. Table 1. Age, sex distribution, hospital admission, and interval to immune sequelae of patients with postacute COVID-19 sequelae.

Reference
Age Sex

Course of COVID-19 Infection and Hospitalization Data
Outcome Notes [14] 14 Female 21 days Congestion and fatigue for three weeks.

•
The patient was restarted on hydrocortisone 50 mg/m 2 /day and weaned down to a maintenance physiologic dose. • Aldosterone was <1 ng/dL and plasma renin was 0.43 ng/mL/h (normal range 0. 25-5.82), and she started on fludrocortisone 0.05 mg daily.
• Due to persistent haemodynamic instability and catecholamine dependence, despite improvement in her inflammatory markers, random cortisol was drawn and was <1 µg/dL. • Hydrocortisone stress dose at 50 mg/m 2 /day was initiated, and this led to improvement in her clinical condition and was able to be weaned off vasopressor support.

•
The baseline ACTH level was elevated to >1250 pg/mL (normal range 9-57 pg/mL), and both baseline and stimulated cortisol was <1 µg/dL, confirming a diagnosis of primary adrenal insufficiency. • 21-hydroxylase anti-adrenal antibodies were positive. • A diagnosis of primary adrenal insufficiency and autoimmune hypothyroidism in addition to MIS-C was made.
Abbreviations: ACTH: adrenocorticotropic hormone; and MIS-C: multisystem inflammatory syndrome in children. Figure 3 is a receiver operating characteristic curve (ROC) demonstrating the sensitivity of age categories in predicting hospitalization in the context of non-MIS-C sequelae of COVID-19. It clearly shows that younger age groups, categories 1 and 2 (infants [0-2 years]) and preschool [3-5 years]), were more likely to require hospitalization, with a sensitivity of 69%. cents, with each accounting for 38% of the overall cases. Hospital admission during COVID-19 did not seem to be a good predictor of subsequent autoimmune sequelae as there was no statistically significant difference between the number of cases with hospital admission and those who were not admitted, i.e., 49 and 60, respectively. Finally, yet importantly, most of the observed PIS were observed within 14 days of the COVID-19 infection, accounting for 61% of the total cases. (Tables 1 and 2) illustrate the details of the overall results described in this paragraph. Figure 3 is a receiver operating characteristic curve (ROC) demonstrating the sensitivity of age categories in predicting hospitalization in the context of non-MIS-C sequelae of COVID-19. It clearly shows that younger age groups, categories 1 and 2 (infants [0-2 years]) and preschool [3-5 years]), were more likely to require hospitalization, with a sensitivity of 69%.
SARS-CoV-2 releases amino acid sequences similar to ACTH, which should rather cause secondary adrenal insufficiency; however, the presence of anti-21-hydroxylase antibodies was not documented, as in other infectious causes of Addison's disease [15]. (Table 3) Acute ANCA-associated vasculitis is a rare but documented condition following SARS-CoV-2 infection in adults and is even rarer in the paediatric population. Here we present to you four case reports of paediatric ANCA-associated vasculitis following an acute SARS-CoV-2 infection. The male-to-female ratio in the reported cases was 1:1, and the mean age among the four patients was approximately 16 years old. All of the patients (100%) acquired acute ANCA-associated vasculitis as an immediate sequela (within 0-4 weeks after COVID-19 infection), and none had delayed nor persistent sequelae. Two patients developed perinuclear anti-neutrophil cytoplasmic antibody (P-ANCA) vasculitis, as seen in Firenzen et al. and Weston et al., while the other two patients developed cytoplasmic anti-neutrophil cytoplasmic antibody (C-ANCA) vasculitis. Two of the patients had preexisting asthma, as seen in Firenzen et al. and Bryant et al. The general prognosis for post-COVID ANCA vasculitis in the previous patients was good with mild to moderate COVID-19 courses. However, the patient reported by Weston et al. was admitted to ICU due to a worsening respiratory status. All patients recovered and were discharged after proper treatment.

Anti-Neutrophil Cytoplasmic Antibody
Molecular mimicry is not the first suggested mechanism for ANCA disorders after COVID-19; T-lymphocyte activation with the subsequent uncontrolled secretion of betainterferon is regarded as the principal theory underlying ANCA disorders following COVID-19 [16].    (Table 4) Concerning the data gathered on post-COVID-19 patients suffering from demyelinating disorders other than Gullain-Barré Syndrome (GBS), we noticed an almost equal ratio of males and females (8 males to 11 females) in the reported cases. The youngest case reported was of a 3-year-old and the oldest was 16 years old. The average age was found to be 11 years.

Central Demyelinating Disorders
The course of the preceding COVID infection was mostly mild. Five cases were asymptomatic, and the most reported symptom was fever. The time frame between infection and the neurological presentation ranged from a week to months, with three cases presenting with neurological manifestation during the course of COVID-19 infection.
Of the 19 reported cases, 7 cases were diagnosed as new-onset acute disseminated encephalomyelitis* (ADEM), 1 case was diagnosed as anti-N-methyl-d-aspartate (anti-NMDA)-receptor encephalitis and one case was that of unspecified encephalitis.
Two cases of optic neuritis were reported, as well as two cases of neuromyelitis optica spectrum disorder. Three of the reported cases were of post-COVID multiple sclerosis and one case exhibited an anti-myelin oligodendrocyte glycoprotein (anti-MOG) demyelinating disorder. One case developed longitudinal extensive transverse myelitis (LETM).
A complete recovery was observed in five cases; meanwhile, the rest of the cases suffered from mild remnants, including increased blind spot, persistent gait, residual diffuse weakness, and unilateral papilledema. Furthermore, one patient experienced relapse post-treatment and was placed on rituximab.
It is suggested that direct CNS infection by SARS-CoV-2 through the olfactory pathway weakens the blood-brain barrier via gliosis, the latter mechanism combined with a dysregulated immune response and a cytokine storm can explain the resulting CNS damage seen with COVID-19 [21].  14 Male During the course of the disease Asymptomatic Rankin Score: 0 and absolute control of epilepsy.
Presence of psychiatric symptoms post discharge.
• Presented with altered behaviour and mental status, seizures, insomnia, and orolingual dyskinesias.  (Table 5) Although the number of adult COVID-19 infections diagnosed with GBS is increasing, the occurrence of cases in the paediatric population remains limited or perhaps underreported.

Guillain-Barré Syndrome
The research entails that reported paediatric cases of SARS-CoV-2 infection associated with GBS had an average age of 16 years. In general, the age group varied drastically, with the youngest reported case being a 2-month-old male infant 15 days after the course of COVID infection, and the oldest reported patient being a 17-year-old female with a short course of COVID infection 8 days prior to the neurological complications. We assume that the severity of the infection is not directly linked to the Guillain-Barré manifestations since seven of the reported cases were asymptomatic, and the rest of the cases demonstrated variable degrees of severity. Sixteen cases showed a mild course, and eight cases were severe and required paediatric intensive care unit (PICU) admission and mechanical ventilation.
All cases showed immediate post-COVID neurological complications ranging from 0 to 4 weeks after acquiring the infection. To elaborate, the time interval between the disease and the sequelae was around 1 week in 7 cases, 2 weeks in 10 cases, 3 weeks in 2 cases, and 1 month in 11 cases. The shortest interval reported was 2 days.
A full recovery was observed in most cases with the use of IVIG and physiotherapy. However, weakness in neck and limb muscles persisted in 8 of the cases (out of 43), regardless of therapy. One case showed complete recovery after intravenous immunoglobulin (IVIG) except for general hyporeflexia, diminished fine touch sensation in limbs, persistent lower limb weakness, and required home ventilation. Four cases even acquired new deficits and two patients died of respiratory muscle paralysis.
The occurrence of GBS within two weeks rather than 2-4 weeks after the infectious agent mimics the picture seen with the Zika virus. This suggests a proinflammatory state leading to direct nerve damage rather than the presence of autoantibodies [34]. Table 5. Guillain-Barré Syndrome (GBS) as a postacute sequela of COVID-19.

Interval between COVID-19
Infection and Autoimmune Disorder

Course of COVID-19 Infection and Hospitalization Data
Outcome Notes [35] 3 Female 2 weeks Not specified

•
The patient was treated with 5 cycles of IVIG 0.5 mL/kg/day and then discharged after spending 1 month in the paediatric unit.
• Presented with progressive and ascending paraesthesia evolving two weeks after respiratory infection. • The patient presented with bilateral lower extremity weakness that progressed to paralysis and the inability to walk, which progressed to upper limbs and dyspnoea later.
[38] 13 Female 1 month Fever • PICU admission and two weeks of ventilation. • Complete neurological recovery and discharge after 6 weeks of hospitalization, IVIG, and plasmapheresis.

•
The patient presented with a high-grade fever, cough, vomiting, and progressive body rash complicated with shock. • After 7 days, no response to painful stimuli or spontaneous eye opening, quadriparesis with facial weakness, weak diaphragmatic excursion, and seizures. • The patient presented with pain, paresthesia, weakness in the lower limbs followed by the upper limbs' involvement, and without respiratory impairment.

•
The patient was admitted to PICU; however, he was extubated accidentally on day five in PICU and died despite resuscitation attempts.
• The patient presented with acute progressive symmetric ascending quadriparesis with bilateral facial paresis.  (Table 6) Hepatic involvement has been widely described as part of the acute setting of SARS-CoV-2 infection, manifesting as a mild increase in liver enzymes without hepatic dysfunction, which eventually subsides as the clinical course of COVID-19 improves. Severe COVID-19 infection in the paediatric population can result in MIS-C and multiorgan failure including hepatic failure. With that being said, here we present five case reports of isolated hepatitis with or without hepatic failure as the main presentation of COVID-19 infection in children. The female-to-male ratio was found to be 3:2 with 150% of females being more susceptible to acquiring the reported complications. The mean age among patients was approximately 6 years old. Ultimately, all patients received all of the needed treatment and were discharged accordingly.
Molecular mimicry with the activation of autoreactive T cells and the secretion of proinflammatory mediators has been proposed as a potential mechanism for the occurrence of hepatitis following COVID-19 [55].  Table 7) Four cases of de novo HLH were reported following COVID-19 infections. It was found that the age of the patients varied from neonates to school age in both diseases, with a predominance of preschool age (mean age = 3). HLH appeared equally in both males and females (1:1). Three cases presented with symptoms of HLH several weeks after COVID, but one had symptoms during the course of COVID. The severity of the preceding COVID infection ranged from unremarkable to severe, with two of the cases having required ICU admission during their COVID infection.
It is worth noting that one case presented with concomitant post-COVID viral encephalitis with cerebral atrophy, and another case was diagnosed as Chédiak-Higashi syndrome.
A triggered immune response could be the mechanism of HLH development in COVID-19 patients. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could activate the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, a potent activator of macrophages, with a significant release of interleukin 1 beta (IL-1b) subsequently leading to the release of interleukin-6 (IL-6) [58]. • Associated with post-COVID viral encephalitis with cerebral atrophy.
[62] 6 weeks female During the course Fever of up to 40 • C and poor feeding. Recovery.

•
The patient was diagnosed with Chédiak-Higashi syndrome and required haematopoietic stem cell transplantation.
Abbreviations: Yrs: years; HUS: haemolytic-uremic syndrome; HLH: haemophagocytic lymphohistiocytosis; and TRAP: TNF receptor-associated periodic syndrome. (Table 8) Eight cases were documented with HUS following COVID-19 in the paediatric age groups. The mean age of the patients was 7 years. All HUS cases were males, with only one case report of COVID related to HUS in a female. Only two cases required ICU admission during the course of the preceding COVID.

Haemolytic-Uremic Syndrome
It is worth noting that all HUS cases were atypical HUS, except for one case of concomitant COVID-19 and Shiga-toxin-associated HUS. In all cases, treatment was given with zero mortality.
Direct endothelial damage by SARS-CoV-2 may be the trigger for the activation of complementary and subsequent HUS in COVID-19 cases [63]. • The patient had a history of prematurity (26 weeks of gestation) and known neurological abnormalities since birth (microcephaly, joint contractures, and axial hypotonia).

months Male During the course of COVID-19 infection
Presented with pyrexia, diarrhoea, and reduced drinking.
• Treated empirically with eculizumab, triple therapy for hypertension, and peritoneal dialysis for acute kidney injury and anuria. • Five months after discharge, the patient still had hypertension and mild persistent proteinuria.

•
The patient was discharged after being treated with Eculizumab and advised to receive it every 3 weeks for aHUS.

•
The patient presented with fever, emesis, and respiratory distress. • Diagnosed as DKA on top of type 1 diabetes mellitus and atypical haemolytic-Uremic syndrome. • Admitted to PICU for DKA management.

•
The patient had a history of prematurity at 34 weeks of gestation, intrauterine growth restriction, severe failure to thrive, microcephaly, pachygyria, agenesis of the corpus callosum, postnatal embolic stroke with residual cranial nerve IV palsy, retinopathy of prematurity, and multiple dysmorphisms without a unifying genetic disorder.  (Table 9) The literature investigated 10 paediatric case reports discussing post-COVID-19 ITP. It was found that ITP in children can be triggered by various viruses, including human immunodeficiency virus (HIV), hepatitis B, hepatitis C, cytomegalovirus (CMV), varicella zoster virus (VZV), and, recently, SARS-CoV-2. Despite ITP being more common in males, the female-to-male ratio among the cases collected from the literature is 3:2. The mean age was 8 years. Results found that only three patients developed ITP during the course of COVID, while the remaining seven developed symptoms an average of 3.7 weeks after being infected with COVID-19. Seven out of ten cases had a mild course of COVID-19 infection prior to ITP, while only one case required ICU admission for 14 days after the infection progressed to acute respiratory distress syndrome (ARDS).
All patients recovered successfully after receiving the proper steroid and IVIG treatment. Several mechanisms have been postulated to induce thrombocytopenia in the context of COVID-19, but not all of them are mediated by autoantibodies. Viral infection and inflammation result in lung damage. Damaged lung tissues and pulmonary endothelial cells may activate platelets in the lungs, resulting in aggregation and the formation of microthrombi, which increases platelet consumption. Most patients with COVID-19 who have thrombocytopenia have elevated D-dimer levels and impaired coagulation time, which further proves the above hypothesis that there is low intravascular coagulation [69]. Table 9. Idiopathic thrombocytopenic purpura (ITP) as postacute sequela of COVID-19. • Presented with fever and ecchymoses over limbs for two weeks.  (Table 10) Most of the published cases in the literature reported exacerbations of pre-existing psoriasis following an attack of COVID. However, two papers reported de novo cases. The first reported nine cases of de novo appearance, consisting of six males and three females. The mean age was 10 years.

Course of COVID-19 Infection and Hospitalization Data
Eight of the nine cases had a mild course of the preceding COVID infection, and only one patient needed hospital admission. The patients developed various variants of psoriasis, with guttate psoriasis being the most common. Six of the patients had a previous family history of psoriasis. The second paper reported a 13-year-old male with a previously mild course of COVID-19 infection that developed psoriasis vulgaris, which responded fully to topical steroids.
Psoriasis is a sustained inflammation led by a T-cell-driven autoimmune response with elevated levels of interleukin (IL)-23, IL-17, and tumour necrosis factor-alpha (TNF-a). Psoriasis has also been associated with higher levels of angiotensin-converting enzyme type 2 (ACE2) than the general population. COVID-19 spike protein has been noted to have a high affinity for ACE2 receptors. This could be a possible causal mechanism of reactivity in the association between psoriasis and COVID-19 infection and vaccination [79].  (Table 11) Only one case of post-COVID development of autoimmune sclerosing cholangitis (AISC) had been reported in the paediatric age groups at the time of data collection. It manifested as a delayed post-COVID autoimmune sequelae 2 months after the setting of a SARS-CoV-2 infection in a 14-year-old male patient. The presence of advanced fibrosis observed in the patient's liver biopsy suggests that the autoimmune process may have Rheumato 2023, 3 152 started before COVID-19, and the infection itself accelerated the progression of the disease. However, the lack of other reported cases makes this theory hard to prove.
The patient had a mild course of the preceding COVID-19 infection. All symptoms of AISC subsided after receiving a two-month course of prednisone as well as azathioprine.
Cholangiopathy following COVID-19 might not only be the result of autoinflammation or autoimmune; a possible confounder is a hypoxic injury. Hypoxia leads to biliary necrosis, and previous reports of influenza cases have demonstrated sclerosing cholangitis as a result of severe hypoxia [82].  (Table 12) As for systemic lupus erythematosus (SLE) triggered by COVID-19, two cases were reported at the time of this paper. Both cases were female patients. The first case was a 13-year-old patient who was hospitalized after developing severe pneumonia during the course of COVID-19 infection. The interval between COVID-19 infection and the development of SLE was 2 months. The patient required plasma exchange to show improvement.

Systemic Lupus Erythematosus
The second patient was an 18-year-old female who had a simultaneous onset of SLE with COVID-19 infection. She was hospitalized and needed mechanical ventilation. She also developed severe attacks of deep venous thrombosis (DVT) with positive antiphospholipid antibodies and lupus anticoagulant, and, unfortunately, went into cardiac arrest after developing cardiac tamponade and could not be resuscitated.
Genome-wide association studies show that there is a genetic component shared between SLE and COVID-19. The locus with the most evidence of shared association is TYK2, a gene critical to the type I interferon pathway, where the local genetic correlation is negative. Another shared locus is CLEC1A [84].  (Table 13) Much like other endocrine post-COVID-19 sequelae, paediatric thyroid complications are not uncommon. Some would even hypothesize that COVID-19 is an endocrine disorder given the number of sites it affects besides the respiratory system. Many papers have attributed this to the fact that the COVID-19 virus utilizes an entry receptor, the ACE-2 receptor. The ACE-2 receptor is expressed in many endocrine tissues, one of which is the thyroid follicular cell, rendering it more susceptible to the relentless virus. Table 13 contains the relevant papers found against our search criteria, describing the most prominent paediatric thyroid complications among the post-intensive care syndrome (PICS), age, sex, course of the COVID-19 infection, and whether or not it was a de novo complication. Accordingly, the female-to-male ratio was found to be 5:4, with the female sex being the most predominant and the mean age being approximately 14 years.
While four patients acquired an immediate post-COVID-19 sequelae ranging between 2-4 weeks after COVID-19 infection and five other patients acquired delayed post-COVID19 sequelae ranging between 4 weeks up to 6 months, no patients were reported with persistent paediatric post-COVID19 thyroid complications lasting for more than 6 months.
Seven out of nine of the patients were previously healthy, while two out of the nine had pre-existing hyperthyroid states at the time of COVID-19 infection. Seven out of nine patients had a rather mild self-limiting course of COVID-19, while two required ICU admission, as seen in Victoria et al. However, all patients recovered and were discharged eventually after adequate treatment.
Three of the nine patients were found to have acquired autoimmune hypothyroidism, one case of which was associated with primary adrenal insufficiency as part of autoimmune polyglandular syndrome type 2 in Flokas et al. (mentioned in Addison's Table). Two patients developed a thyrotoxic storm on top of a pre-existing state of hyperthyroidism, while two others developed de novo Grave's disease, one of which was also associated with a thyrotoxic storm, as seen in Qureshi   Mild course with low-grade fever, congestion, cough, and body aches that resolved in a few days.

•
The patient was started on methimazole 10 mg once daily and propranolol 10 mg twice a day for symptomatic relief.

•
Clinical and biochemical improvement after treatment.

•
The patient was diagnosed with psoriasis vulgaris and was treated with topical steroids resulting in a complete resolution.
• Presented with dizziness, easy fatigability, difficulty in sleeping, a presyncopal episode, heat intolerance, and weight loss (8 lbs during 2 months) despite an increased appetite.  • Patient recovered.
• Presented in shock following one week of fever, lethargy, diarrhoea, vomiting, and worsening anaemia (Hb 6.9 g/dL).

•
The patient was resuscitated with normal saline first, then, a blood transfusion, epinephrine drip, and admitted to ICU. • The family reported she had a history of fatigue, constipation, dry skin, oligomenorrhea, cold intolerance, and a family history of autoimmune hypothyroidism in her grandmothers. • Diagnosed with autoimmune thyroiditis and primary adrenal insufficiency as part of APS2. • Both of them started treatment of levothyroxine sodium 25 µg every day. • They both recovered biochemically and clinically after the last follow-up.
• Presented with easy fatigability, decreased appetite, and hair loss.

•
The thyroid function test results showed a hypothyroid state with thyroid-stimulating hormone (TSH) levels of 16 mIU/mL (up to 4.7 mIU/mL) and a free T4 of 0.5 ng/dL (0.7-1.8 ng/dL).

•
The thyroid antibody profile was positive for anti-thyroglobulin antibodies (Tg) of 252 IU/mL (less than 50 IU/mL) and anti-thyroid peroxidase antibodies (TPO) of 71.2 IU/mL (less than 50 IU/mL  (Table 14) Regarding TRAPS, only a single case report of post-COVID TRAPS was found in a 6-year-old female of delayed onset, 4 months after a COVID infection of unspecified severity.
The patient suffered from three attacks of macrophage activation syndrome (MAS) as a presentation of TRAPS for which she was hospitalized and treated.
She recovered after being admitted to the PICU for 22 days and received methylprednisolone and anakinra.  (Table 15) Similarly, SARS-CoV-2 has proven to manifest itself through catalyzing diabetic ketoacidosis (DKA) and unmasking autoimmune type 1 diabetes mellitus, particularly in children. The mechanism for that is hypothesized to be similar to that of thyroid-related sequelae: through ACE-2 receptors found in the endocrine part of the pancreas. Furthermore, a recent study by Govender et al. reported that COVID-19 can precipitate insulin resistance in some patients causing chronic metabolic disorders that would not have existed otherwise. All in all, the exact relationship between SARS-CoV-2 and type 1 diabetes mellitus remains uncertain and requires further research.
According to the 10 case reports collected, we have concluded a male predominance with a male: female ratio of 7:3, where females are 43% less likely to acquire post-COVID-19 type 1 diabetes mellitus. The mean age for said complication is approximately 9 years old. Moreover, 100% of the patients developed de novo type 1 diabetes mellitus with none having a pre-existing disease.
In nine patients out of ten, post-COVID-19 type 1 diabetes mellitus was immediate (manifesting anytime between the start of COVID-19 infection and 4 weeks after) with only one case being delayed, as reported by Naguib et al. (manifesting 1-6 months after the start of COVID-19 infection), and none reporting persistent (lasting more than 6 months) post-COVID19 complications. Only one patient exhibited mild COVID-19 symptoms, as seen in Lanca et al., while the rest of the patients exhibited high severity.
Eight patients were admitted to the PICU with a median length of stay of approximately 3 days. However, seven of them were eventually discharged after clinical improvement.
Out of the 10 patients, one death was reported in Brothers et al. due to multisystem failure, metabolic acidosis, and fungal urosepsis from Candida glabrata resistance to azoles, despite DKA resolution.

Discussion
Throughout this systematic review of all non-MIS-C postinfectious immune sequelae of COVID-19, the two key findings uncovered were the rapid development of those immune sequelae in less than 14 days from the onset of COVID-19 and the high prevalence of these complications in children older than 6 years old.
It also seems that no age is spared-postacute sequelae have affected the whole spectrum from infancy to adolescence.
The interval between infectious disease and its postacute sequelae is important as it might be suggestive of the underlying mechanism.
Different pathogeneses underlie different types of similar postinfectious disorders, and mechanisms can be predictable from the time interval until the development of such sequelae. For instance, reactive arthritis is known to develop immediately following the related infection, and despite the incomplete understanding of the pathogenesis of reactive arthritis, it is hypothesized that T lymphocytes are induced by bacterial fragments such as lipopolysaccharide and nucleic acids when invasive bacteria reach the systemic circulation. These activated cytotoxic T cells then attack the synovium. It is still unclear whether reactive arthritis involves the production of autoantibodies or not, but the rapid development of this postinfectious complication within days of the initial infection suggests a T-cell-mediated autoinflammatory process rather than a classic autoimmune disorder [103,104].
Another extreme example of postinfectious sequelae is the celiac disease process, which is rarely observed after a rotavirus infection. It differs from reactive arthritis in being a delayed postacute sequelae, which necessitates weeks, up to months, to develop after infection. Surprisingly, it shares similarities to reactive arthritis, a T-cell-mediated mechanism with hypercytokinemia. This occurs because rotaviruses disrupt intestinal immune homeostasis, eventually facilitating T-cell-mediated immunity against dietary antigens. Type I interferon (IFN) and interferon regulatory factor 1 signalling play a central role by blocking regulatory T-cell conversion and promoting helper T-cell immunity.
Rheumatic fever is another classic example of postinfectious sequelae. Rheumatic fever develops within a 2-4 weeks interval after the initial infection. Autoantibodies to myosin, tropomyosin, and collagens have been identified [105].
According to our study, in the case of post-COVID-19 infections, 61% of the PIS occurred within 14 days of the infections, with many occurring during the course of the disease. This rapid onset of PIS to SARS-CoV-2 suggests a rather similar autoinflammatory process to the postinfectious diseases previously mentioned, notably reactive arthritis, with dysregulated immunity leading to widespread activation of T cells and hypercytokinemia.
In COVID-19, next-generation sequencing has revealed activated CD8+, T-helper type 1, Th17, natural killer (NK), and natural killer T (NKT) cells together with other innate immune cells that secrete additional cytokines to target virus-infected cells, and their overstimulation, together with effector innate immune cells, may lead to tissue damage [106].
Moreover, CD8+ T cells expressing high levels of PD-1, CTLA-4, TIGIT, granzyme B, and perforin were increased in the severe group compared with the mild group. This data suggests that SARS-CoV-2 infection may lead to functional impairment in CD4+ T cells and uphold excessive activation of CD8+ T cells [106].
Another interesting finding in our study was the high prevalence of postinfectious sequelae in children and adolescents older than six years. This is thought to be due to a distinct group of lymphocytes known as regulatory T cells (Tregs), which are key inflammatory response regulators and play a pivotal role in immune tolerance and homeostasis. Treg-mediated robust immunosuppression provides self-tolerance and protection against autoimmune diseases. However, once this system fails to operate or poorly operates, it leads to an extreme situation where the immune system reacts against self-antigens and destroys host organs and, consequently, causes autoimmune and autoinflammatory diseases. There is established evidence that Tregs decline with age. An interesting study focused on T-cell differentiation from infancy to childhood, and it was noted that the proinflammatory Th17 cell increases after the age of three years of age. Moreover, the functionality of CD4 cells increased with age; secretion of IL-17 and TNF was positively correlated with increasing age after the age of three years. These findings might explain why postacute sequelae were more prominent after the age of six years [107,108].

Limitations
The biggest challenge and limitation we faced in the construction of this systematic review was the diversity of outcome parameters in the collected reports. The available reports did not always include the same information about the discussed patients. This led to a significant limitation in the retrieved outcome parameters.
Any risk of bias has been illustrated in Figure 4 [109].
Rheumato 2023, 3, FOR PEER REVIEW 34 destroys host organs and, consequently, causes autoimmune and autoinflammatory diseases. There is established evidence that Tregs decline with age. An interesting study focused on T-cell differentiation from infancy to childhood, and it was noted that the proinflammatory Th17 cell increases after the age of three years of age. Moreover, the functionality of CD4 cells increased with age; secretion of IL-17 and TNF was positively correlated with increasing age after the age of three years. These findings might explain why postacute sequelae were more prominent after the age of six years [107,108].

Limitations
The biggest challenge and limitation we faced in the construction of this systematic review was the diversity of outcome parameters in the collected reports. The available reports did not always include the same information about the discussed patients. This led to a significant limitation in the retrieved outcome parameters.
Any risk of bias has been illustrated in Figure 4 [109]. A PRISMA chart has been designed using the updated guidelines for reporting for systematic reviews [110].

Conclusions and Clinical Implications
This is the largest systematic review to date of all non-MIS-C post-infectious immune sequelae (PIS) of COVID-19. The results suggest that PIS commonly occur immediately (within 14 days) after infection with COVID-19, which prompts the conclusion of an autoinflammatory process rather than a classic autoimmune pathology. On that account, more evidence is needed to focus on the underlying mechanisms, as this can contribute to enhancing the management of patients by giving a variety of immune modulators immediately after COVID-19 infection. In addition, equal care should be given to hospitalized and non-hospitalized patients after infection because the severity of COVID-19 did not prove to be a predictor of the occurrence of post-infectious immune sequelae. Close attention should be given to patients above 6 years of age as our data suggest a high predilection for complications in this age group.  A PRISMA chart has been designed using the updated guidelines for reporting for systematic reviews [110].

Conclusions and Clinical Implications
This is the largest systematic review to date of all non-MIS-C post-infectious immune sequelae (PIS) of COVID-19. The results suggest that PIS commonly occur immediately (within 14 days) after infection with COVID-19, which prompts the conclusion of an autoinflammatory process rather than a classic autoimmune pathology. On that account, more evidence is needed to focus on the underlying mechanisms, as this can contribute to enhancing the management of patients by giving a variety of immune modulators immediately after COVID-19 infection. In addition, equal care should be given to hospitalized and non-hospitalized patients after infection because the severity of COVID-19 did not prove to be a predictor of the occurrence of post-infectious immune sequelae. Close attention should be given to patients above 6 years of age as our data suggest a high predilection for complications in this age group. Institutional Review Board Statement: Not applicable as this study is a systematic review of reported cases.
Informed Consent Statement: Not applicable as this study is a systematic review of reported cases. Data Availability Statement: Data is made available upon request to the corresponding author.