The Triad of COVID-19 in Children: Acute COVID-19, Multisystem Inflammatory Syndrome, and Long COVID—Part II
Abstract
Coronavirus disease 2019 (COVID-19), which is now known to be caused by severe acute respiratory syndrome coronavirus 2, has been a public health threat since early 2020 and has affected millions of people worldwide. Many studies have now shown that this virus exhibits a milder infection in children compared to adults. Acute COVID-19 infection, multisystem inflammatory syndrome in children (MIS-C), and long COVID have been recently well-established in the pediatric population with a myriad of systemic manifestations. This section of the review will focus on the following systems—neurology, psychiatry, endocrinology, hematology, and oncology—under three broad lenses, such as acute COVID-19, MIS-C, and long COVID. [Pediatr Ann. 2025;54(1):e40–e44.]
Introduction
The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared to be a pandemic by the World Health Organization in early 2020.1 It has claimed the lives of millions of people across the globe. Interestingly, COVID-19 infection in children has a better prognosis compared to adults, where only a small proportion of children are culprits of severe COVID-19–related complications leading to devastating clinical sequelae.
The clinical spectrum of COVID-19 can be divided into acute COVID-19, multisystem inflammatory syndrome in children (MIS-C), and long COVID. Most children diagnosed with acute COVID-19 are asymptomatic or have a very mild illness. Fever, cough, shortness of breath, diarrhea, abdominal pain, headache, fatigue, and myalgia are some of the commonly reported symptoms in the acute phase.2,3 Soon thereafter, cases of MIS-C were reported, typically occurring 2 to 4 weeks post-acute COVID-19 infection.
MIS-C is a hyperinflammation syndrome mostly presenting with cardiac, gastrointestinal, and mucocutaneous manifestations. MIS-C is postulated to be caused by a postinfectious immune dysregulation leading to a cytokine storm causing multisystemic organ dysfunction. For the most part, the outcomes of children with MIS-C have been favorable, with an approximately 2% mortality rate.4
Although the precise definition of long COVID has not been established, most clinical societies consider long COVID to be symptoms persisting more than 4 weeks after an acute COVID-19 infection. Fatigue and shortness of breath are the most frequently observed symptoms in long COVID. Some of the symptoms in long COVID are known to persist for as long as 6 months.5 Part II of this article will focus on the clinical manifestations of the following systems: neurology, psychiatry, endocrinology, hematology, and oncology under the three categories of acute COVID-19, MIS-C, and long COVID.
Neurology
It is important to know the consequences of both acute and long-term sequelae of COVID-19 on the nervous system, as some of it can lead to permanent neurodevelopmental issues. There is a dearth of data in this area.6 Understanding the pathophysiology can help us better understand the seriousness of these consequences. The spike protein of COVID-19 attaches to the angiotensin-converting enzyme 2 (ACE-2) in the neuron and then spreads through the nervous system, either via the intranasal pathway or the hematogenous pathway. In the intranasal pathway, the human coronavirus (HCoV) virions go across the cribriform plate, thereby reaching the olfactory bulb. It spreads between neurons through exocytosis/endocytosis across synapses.7 In the hematogenous pathway, the HCoV virions are taken up by monocytes, and this leads to increased permeability of the blood brain barrier due to increased expression of cytokines, thereby leading to central nervous system disease.8
The most common neurological symptom of acute COVID-19 was fatigue/myalgia followed by headaches. There have been some case series highlighting meningitis and meningoencephalitis; although, none of them have cerebrospinal fluid studies performed that have isolated the virions.9 Other neurological manifestations include altered encephalopathy with alerted mental status, cerebellar and brain stem ataxia, and seizure.10 Peripheral nervous system side effects of anosmia and ageusia is already well-known.11 There have been several case reports of Guillain-Barré syndrome, which was observed several weeks after the infection and is now thought of as a long-term sequela. It is very important to closely follow-up with these children to make sure that there is no respiratory muscle involvement.12 Other peripheral nervous system manifestations include muscle injury and rhabdomyolysis.13 Most of the studies in children done so far have focused more on the respiratory system, and hence, neurological manifestations are believed to be underreported.
Another area that one needs to focus on is neurodevelopmental outcomes of children with COVID-19 infection, particularly following Guillain-Barré syndrome, such as spastic or flaccid quadriparesis and sphincter control issues.14 The pathogenesis of neurocognitive involvement includes multiple theories. One theory is about an increase in cytokines, such as interleukin 6 (IL-6), that penetrate the blood brain barrier and affect neurocognition. Another theory is that the inflammation associated with the infection can lead to gamma-amino-butyric acid–ergic impairment, thereby leading to apathy and executive deficiencies.15
Psychiatry
It is a well-established fact that the mental health of children and young adults who are affected by emergencies and disasters are often more pronounced compared to adults. Several studies have reported cognitive and memory impairment, along with confusion.16 There are data showing higher possibility of posttraumatic stress disorder in those with a pre-existing diagnosis of major depressive disorder who develop COVID-19 infection.17 A recent large metanalysis showed that 1 in 5 youth experienced increased anxiety, while 1 in 4 experienced increased depression, with female children and older children showing higher tendencies during the latter part of the pandemic.18 We do not have enough data on specific types of anxiety disorders, such as social anxiety, separation anxiety, or panic disorders. Another important study showed an increased association of substance use disorder among adolescents who were infected, with 20% reportedly indulging in substance use at least once a week. These consequences further highlight the need for mental health resources to address this.19
Endocrinology
There have been recent studies showing COVID-19 infection as a trigger for new onset of type 1 diabetes mellitus. The proposed mechanism is COVID-19–induced islet cell damage.20 There is beta cell damage that releases islet cell antigens. This then triggers autoreactive T cells leading to autoimmune destruction and development of type 1 diabetes mellitus. There is decreased glucose mediated insulin release and a delay in conversion of proinsulin to insulin.21 Case reports have also shown that they present in severe form in diabetic ketoacidosis with significant hypokalemia.22 Hypokalemia is perhaps due to the reduced ACE-2 expression, leading to reduced conversion of angiotensin II, which causes increased secretion of aldosterone and leads to hypokalemia.22 COVID-19 infection also affects lipid metabolism, but most of the data are from adults. There is a decrease in total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B and A-1 levels, with variable serum triglyceride levels and an increase in lipoprotein (a) levels.23 An inverse correlation is seen between HDL-C and LDL-C levels with C-reactive protein levels.
COVID-19 infection has also been shown to reduce cortisol response to stress. This is perhaps due to molecular mimicry between COVID-19 and the adrenocorticotropic hormone (ACTH). Hence, there is some antibody cross-reactivity to ACTH with reduction of its levels.24
COVID-19 infection also affects the reproductive system. ACE-2 is expressed in testes, Sertoli cells, Leydig cells, and spermatogonia. There is reported reduction in testosterone levels in young adults. This may also be due to the suppressive effects of the virus on the hypothalamic-pituitary-gonadal axis. There are inadequate data on COVID-19 affecting the hypothalamic-pituitary-gonadal axis or its effects on thyroid function on children.
Hematology
Thrombocytopenia is a well-established finding both in the acute setting and during MIS-C.25 There have been a few reported cases of isolated immune thrombocytopenia (ITP) occurring 2 to 4 weeks post–acute COVID infection,26 which was not associated with MIS-C (no other systemic involvement). The most common presenting symptoms in these reported cases were petechiae, epistaxis, and bruising a few weeks after a COVID-19 infection. Platelet count ranged from 4,000 to 20,000 in these cases, and most of the patients who were symptomatic were treated with intravenous immunoglobulin (IVIG) or steroids.26
Xu et al.27 proposed a few possible mechanisms of COVID-19–associated ITP. These include (1) cytokine storm, which abolishes hematopoiesis and decreases platelet count; (2) the virus directly infecting the hematopoietic stem cells and causing dysfunction; (3) viral-induced autoantibodies causing platelet destruction; and (4) lung injury caused by the virus, which activates platelets and causes microthrombi, and thus, causes thrombocytopenia by increased platelet consumption.27
Anemia is one of the commonly reported hematological manifestations of MIS-C.25 There have now been a few cases of autoimmune hemolytic anemia reported during an acute COVID-19 infection (ie, isolated anemia with or without ITP and no other symptoms of MIS-C).28 Many cases of COVID-19–triggered autoimmune hemolytic anemia have been shown to manifest as cold agglutinin disease, a very rare occurrence in the pediatric population. Presenting symptoms were pallor and jaundice with laboratory findings showing evidence of hemolysis. Some cases have shown only warm antibodies (immunoglobulin G [IgG+]), mixed antibodies (IgG+ and C3d+), and exclusively cold agglutinins (C3d+). Most of the patients responded to steroids (ie, pulse methylprednisolone followed by a steroid taper) as a first-line treatment. Few other cases needed the addition of IVIG as a second-line treatment.28
Evans syndrome has also been reported where anemia and thrombocytopenia have both occurred in the setting of COVID-19 infection. Lymphopenia is one of the most common laboratory findings in children with COVID-19.29 Various mechanisms have been postulated that contribute to COVID-19–induced lymphopenia. COVID-19 brings about a cytokine storm that causes an increase in IL-6 and TNF-α (tumor necrosis factor alpha), which have a cytotoxic effect on the T cells and NK cells. The virus creates an exhaustion of CD4+ and CD8+ T cells, as evidenced by a decrease in cell death protein 1 and T-cell immunoglobulin and mucin domain-containing molecule 3, the two markers of T-cell exhaustion.30 Lastly, some of the genes involved in T cell activation, such as MAP2K7 and SOS1, are downregulated during an acute COVID-19 infection. An interesting point to note is that all the previously mentioned hematological abnormalities are generally seen in adults with moderate to severe COVID-19 infection. However, in children, they appear even with minimal symptoms of COVID-19 infection.
Early in the pandemic, many adult patients had evidence of venous thromboembolism, with laboratory findings suggesting a high D-dimer and fibrinogen, low platelets, and prolongation of PT (prothrombin time).31 A large multicenter study was conducted by Whitworth et al.32 to evaluate the incidence of thrombosis in children hospitalized with COVID-19, which reported the highest incidence in patients with MIS-C, followed by those with acute COVID-19, and lastly, with minimal incidence in asymptomatic patients. This was also the first pediatric study to demonstrate a co-relation in the incidence of thromboembolism and raised D-dimer, a finding well-established in the adult population. In children, deep vein thrombosis was the most reported, followed by superficial thrombosis, pulmonary embolism, and, very rarely, arterial ischemic stroke and cerebral venous sinus thrombosis. All these manifestations are encased under the broad umbrella of COVID-19–associated coagulopathy.33 The International Society on Thrombosis and Haemostasis has recommended that patients who are hospitalized with COVID-19 who have either a high D-dimer or risk factors for the development of venous thromboembolism should be anticoagulated for the duration of hospitalization with low molecular weight heparin (preferred).34
Oncology
Patients with comorbidities have a higher risk of COVID-19 complications as compared to the general population. Hence, children with malignancies form a subset of the most vulnerable pediatric population. Johnston et al.35 performed an observational study that highlighted those older patients with hematological malignancies, and patients who are neutropenic and those with other comorbidities were the ones who were at the highest risk of severe COVID-19 sequelae.
Greaves hypothesis states that there are 2 hits in leukemogenesis: The primary mutations in utero lead to the formation of preleukemic clones, and there must be a secondary mutation usually driven by environmental factors that leads to overt leukemia.36 Interestingly, it was noted that a small cohort of children with acute COVID-19 infection presented a few weeks later with anorexia, bone pain, fatigue, and hematological laborator y abnormalities who later ended up being diagnosed with leukemia. This hypothesizes that COVID-19 infection may be a second hit leading to the development of leukemia.37 There are no published studies about the association of long COVID presenting as hematological/oncologic systemic involvement, as all the previously mentioned manifestations were reported either during an acute COVID-19 infection or as an involvement of MIS-C. There also have been no reported associations to date of any solid tumor malignancies and their link to COVID-19.
Conclusion
Most of the children who are diagnosed with COVID-19 are either asymptomatic or experience very mild symptoms. However, there is a subset of pediatric patients, most with underlying comorbidities, who experience fatal symptoms either during the acute phase or weeks later, manifesting as MIS-C. Long COVID is a relatively newer entity in children with inconsistent data in the pediatric population. Hence, future studies are warranted to better understand this disease process to make treatment recommendations to prevent the morbidity associated with its long-term sequelae.
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