Abstract
Objective
Although SARS-CoV-2 primarily targets the respiratory system, there is evidence that it can also infect the central nervous system, especially in children, leading to neurological symptoms and long-term consequences. It is imperative to summarize the possible mechanisms, main symptoms, and treatments of neurological symptoms of COVID-19 in children.
Methods
We performed a literature search using the PubMed online database to find studies investigating the mechanisms of COVID-19 infection of the central nervous system and therapies for COVID-19 neurological symptoms in children.
Results
The main mechanisms of action of SARS-CoV-2 virus on the nervous system are direct invasion, systemic inflammation and molecular mimicry. Although the incidence of adverse reactions to intravenous IgG therapy (IVIG) varies greatly and the contraindications are not yet clear, IVIG has been shown to be clearly effective for the neurological symptoms of COVID-19 in children.
Conclusion
However, due to insufficient data, more clinical studies are still needed to confirm its safety and efficacy, further improve the treatment plan, and determine the appropriate dosage to better serve clinical practice.
Significance
The specific regimen of IVIG treatment for COVID-19 in children was explored, which further improved the understanding of COVID-19 and L-C19 neurological diseases in children.
1 Introduction
The coronavirus disease 2019 (COVID-19), which emerged at the end of 2019, rapidly spread among the population and imposed unparalleled challenges on healthcare systems worldwide. Although the SARS-Cov-2 virus mainly targets the respiratory system, as research deepens, increasing evidence shows that it also has a certain impact on the central nervous system environment [1]. Especially in children, although viral infections are usually asymptomatic or mild, COVID-19 and its long-term consequences, known as Long COVID (L-C19), can still cause some distress to the nervous system of some children, and even worsen into long-term organic changes. At present, there is no systematic study of COVID-19 and Long COVID-19 in children; treatment strategies similar to those used in adults are often used clinically. Therefore, this narrative review aims to elucidate the current mechanisms of viral action on the nervous system and provide a comprehensive overview of neurological manifestations and their respective treatments in children since the emergence of the virus. Additionally, it explores in detail the mechanisms, clinical cases, and potential adverse effects of intravenous immune globulin (IVIG), an active and effective treatment option.
2 Mechanisms of COVID-19 and long COVID in the nervous system
So far, there is no clear evidence to support the idea that SARS-Cov-2 invades the nervous system of children, but the highly contagious nature of the virus and the severe infection it causes pose a threat to all children with or without Long COVID-19 [2]. Although crisis situations are rare, the potential impact of COVID-19 on children's neurological systems cannot be ignored. Before delving further into this area, we still need to continue to pay attention and monitor the neurological status of pediatric COVID-19 patients to better understand its pathophysiological mechanisms. There are three hypothesized pathophysiological mechanisms for pediatric neurological diseases, particularly encephalitis, as complications of COVID-19: molecular mimicry, systemic inflammation, and direct invasion. Most of the neurological diseases caused by COVID-19 are related to the long-term interaction between the virus and the immune system (Figs 1–2).
SARS-CoV-2 infection pathways
The virus triggers a “cytokine storm” by infecting immune cells such as lymphocytes, granulocytes, and monocytes, and then infects glial cells. Viral infection leads to the activation of host antibodies and the expansion of lymphocytes, and anti-neuronal autoantibodies cause neurological diseases
Citation: Physiology International 2025; 10.1556/2060.2025.00484
SARS-CoV-2 passes the blood-brain barrier
The virus invades the brain through different pathways such as the vasculature, peripheral nerves, cerebrospinal fluid, and lymphatic system. It passes through the blood-brain barrier through the transneuronal retrograde pathway or hematogenous invasion, and then causes widespread inflammation
Citation: Physiology International 2025; 10.1556/2060.2025.00484
2.1 Direct invasion
Regarding the direct invasion mechanism of SARS-Cov-2, Li Z's research shows that the virus may infiltrate the brain through various pathways, including the vasculature, the peripheral nerves, the cerebrospinal fluid, and the lymphatic system, leading to neurological diseases [3]. Like other viruses, the transneuronal retrograde pathway and hematogenous invasion may be two non-exclusive mechanisms of direct invasion of the nervous system by SARS-CoV-2 [4]. In the former case, the virus may infect peripheral neurons and retrogradely enter the central nervous system via synaptic pathways [4, 5]. For the latter, the current hypothesis suggests that the virus passes through the blood-brain barrier (BBB) by infecting vascular endothelial cells [4]. Once within blood vessels and neuronal cells, the virus will target and bind to ACE2, thereby triggering a pro-inflammatory response in brain endothelial cells and promoting further expression of ACE2 receptors. At the same time, the SARS-CoV-2 spike protein may also induce a pro-inflammatory response in brain endothelial cells [6]. Both of these collectively weaken the BBB barrier function, allowing the virus to invade the central nervous system [7]. In addition, the experimental results of Buzhdygan et al. suggest that ACE2 is not the only target in the interaction between SARS-CoV-2 and brain endothelial cells. There may be reversible activation involving multiple receptors or signalling cascades between the virus and the BBB [7].
2.2 Systemic inflammation
The second pathophysiological mechanism of COVID-19 neurological complications is systemic inflammation caused by excessive activation of the host immune system due to viral infection [8]. After the virus invades the host, it triggers a “cytokine storm” by infecting immune cells such as lymphocytes, granulocytes, and monocytes. A large number of inflammatory factors are released and transported throughout the body to attack various organ systems, including the nervous system [9]. The cytokine storm can also cause endothelial dysfunction, making the BBB more permeable, thus facilitating the virus's crossing of the BBB and its direct invasion into the central nervous system [10]. Serology and laboratory analysis of the cerebrospinal fluid further supported this hypothesis. Studies collected by Siahaan YM et al. show that the most common findings in CSF analysis are elevated protein (42.42%) and lymphocytosis (24.24%), as well as significant increases in pro-inflammatory cytokines represented by interleukin and tumor necrosis factor [11]. Furthermore, there is an increase in pro-inflammatory parameters and inflammatory mediators, such as C-reactive protein and D-dimer [12, 13]. Additionally, EEG performed in patients presenting with altered consciousness, progressive or persistent neurological symptoms (e.g., lethargy, seizures) typically shows a characteristic pattern of global slowing with a diffuse pattern suggestive of widespread inflammation. [11, 12, 14–17]. The pathological mechanism of COVID-19-related neurological disease is believed to involve a step-by-step process of cytokine release, immune response, and inflammation caused by the virus [9, 18], but this hypothesis still requires further research and confirmation.
2.3 Molecular mimicry
The third reasonable mechanism is the molecular mimicry of SARS-CoV-2 infection. Viral infection can lead to the activation of host antibodies and the proliferation of lymphocytes. These immune molecules may cross-react with and attack self-antigens, leading to damage to various systems, including the central nervous system [9, 19]. Several studies have found specific anti-neuronal autoantibodies that may facilitate SARS-CoV-2 infection and invasion of the patients' nervous systems: anti-N-methyl-D-aspartate receptor (NMDAR) antibodies [12, 13, 16, 20], anti-contact protein related protein-like 2 (CASPR2) antibodies [21], anti-myelin oligodendrocyte glycoprotein (MOG) antibodies [17], anti-glutamic acid decarboxylase (GAD) antibodies [22] and anti-GD1a antibodies. The resulting neurological dysfunction can cause autoimmune encephalitis, acute hemorrhagic necrotizing encephalopathy [23], Guillain-Barré syndrome [24], and acute disseminated encephalomyelitis [15], which further supports the pathophysiological hypothesis of molecular mimicry as a mechanism of neurological disease after COVID-19.
2.4 COVID-19 symptoms and related mechanisms
The neurological complications of Long COVID (L-C19) are the following, except that some neurological sequelae may be caused by direct or indirect damage to brain tissue in the acute phase of the virus [19]. What most symptoms have in common is a low-intensity, sustained inflammatory response caused by the interaction between residual viral particles and the immune system after the acute illness phase. In addition, various symptoms have independent mechanisms of action. Aberrant microglial responses to immune signals disrupt neural circuit regulation, function, and plasticity, potentially leading to cognitive impairment and neuropsychiatric disorders [25]. Taste and smell dysfunction is caused by viruses invading the olfactory mucosa [26]. Fatigue symptoms may be caused by a combination of muscle mitochondrial dysfunction, abnormal immune responses, and psychological and environmental factors [27, 28]. Decreased brain metabolic activity caused by trigeminal nerve or nerve root inflammation may be associated with headaches and generalized pain [29, 30]. Elevated pro-inflammatory signalling molecules in L-C19 patients can directly induce myofibrillar proteolysis and reduce protein synthesis, leading to muscle weakness and fatigue; virus-induced cytokines lead to chondrolysis, which may cause joint pain and aggravate osteoarthritis [31].
3 Neurological symptoms of COVID-19 and L-C19 in children
Although respiratory symptoms are primary among COVID-19 patients, more and more studies have proven that multiple organ systems throughout the body may be affected, with nervous system involvement observed in up to 36% of patients [1, 32]. Among children, girls are more likely to develop L-C19 than boys [33], likely attributable to female-related hormonal effects, although both are usually asymptomatic (43%–68% of cases) or cause mild symptoms [34]. There is currently limited empirical evidence on neuropsychiatric symptoms following L-C19 in children and adolescents [35]. Neurological manifestations associated with COVID-19 in pediatric populations encompass a spectrum of conditions including inattention (41.1%), chronic fatigue (39.2%), headache (37.0%), mood changes (24%), memory impairment (13.6%), tremor (13.3%), muscle pain (13.1%), dizziness (11.0%), sleep disorders (10.7%), abnormal sensation (9.7%), abnormal taste and smell (9.4%) and joint pain (9.0%) [36–44]. Table 1 summarizes the neurological symptoms of several pediatric COVID-19 cases.
Summary of neurological symptoms in children with COVID-19 in 9 articles
| Symptoms | Case1 [37] | Case2 [39] | Case3 [43] | Case4 [39] | Case5 [38] | Case6 [41] | Case7 [42] | Case8 [44] | Case9 [36] | Total |
| Number of people | 90 | 129 | 236 | 510 | 89 | 1734 | 518 | 90 | 60 | 3,456 |
| Chronic fatigue | 71.1% | 10.8% | 25.2% | 87.0% | 55.0% | 15.8% | 38.0% | 21.0% | 37.53% | |
| Headache | 28.9% | 16.9% | 38.0% | 62.0% | 4.6% | 15.0% | 5.0% | 35.16% | ||
| Inattention | 8.9% | 10.1% | 60.6% | 45.0% | 10.37% | |||||
| Abnormal taste and smell | 25.6% | 12.3% | 8.7% | 16.0% | 3.23% | |||||
| Sleep disorders | 33.3% | 18.6% | 7.5% | 5.0% | 2.77% | |||||
| Muscle pain | 45.6% | 10.1% | 28.0% | 5.0% | 2.37% | |||||
| Memory impairment | 17.8% | 13.0% | 10.0% | 1.06% | ||||||
| Abnormal sensation | 28.9% | 11.0% | 1.04% | |||||||
| Joint pain | 14.4% | 6.9% | 5.0% | 0.72% | ||||||
| Dizziness | 18.9% | 3.0% | 0.57% |
3.1 Headache
Headache is one of the earliest and most prevalent symptoms of L-C19, often presenting alongside anosmia, myalgia, and cough [45]. The clinical manifestation of long-term COVID headache is similar to that of new-onset persistent headache as outlined in the International Classification of Headache Disorders, 3rd edition (ICHD-3) [46], which is characterized by bilateral pressure headache with frontal or periorbital predominance, throbbing pain, photophobia, phonophobia, nausea and increased pain on movement [47, 48]. Regarding the tension-type headache-like phenotype, primary choices for treatment in the acute phase are simple analgesics (such as paracetamol) and nonsteroidal anti-inflammatory drugs [49]. For preventive treatment, recommendations include tricyclic antidepressants, venlafaxine, or mirtazapine [49]. Studies have shown that glucocorticoids also have some efficacy in the prognosis of long-term COVID headaches [50]. For migraine-like phenotypes, NSAIDs and triptans are deemed appropriate for acute treatment [51], and antidepressants and botulinum toxin A can be used for preventive treatment [47].
3.2 Chronic fatigue
Chronic fatigue is a potential symptom of L-C19 [52], with ongoing investigations into its underlying mechanisms. This fatigue often co-occurs with sleep disorders and depression, causing lasting negative effects on the quality of life of L-C19 patients [53]. Diagnosis of fatigue symptoms necessitates an initial interview, sleepiness assessment, depression screening, fatigue quantification, and laboratory testing for common hematological and metabolic diseases [54]. Exercise therapy usually has no significant effect on chronic fatigue [55], with amantadine being the most commonly prescribed drug for its treatment, constituting approximately 53.8% of fatigue prescriptions [56]. In addition, commonly used drugs include acetyl-L-carnitine, modafinil, glutathione, amitriptyline, and taxifolin.
3.3 Other symptoms
Smell and taste dysfunction often follow fatigue symptoms in patients with mild C-19 [57]. For the vast majority of neurological symptoms, there are currently no studies that show specific drugs, and the treatment options are the same as those for routine neurological complaints.
4 Intravenous immunoglobulin
4.1 The mechanism of action of IVIg
Intravenous immunoglobulin (IVIG) preparations consist of highly purified immunoglobulins obtained from a large pool of healthy donors [58]. As a comprehensive therapeutic tool, they are commonly employed in the treatment of certain neurological diseases associated with systemic inflammation [59]. Currently, IVIG has been used for a variety of neurological diseases linked to COVID-19 and has achieved positive and effective outcomes [60]. Research indicates that IVIG therapy has multiple molecular targets and mechanisms of action. T. L. Vassilev demonstrated that an important target of some IVIg antibodies is a 10-peptide sequence containing the amino acid triplet arginine-glycine-aspartate (RGD) [61]. M. Daëron discovered that IVIg can inhibit the proliferation of B cells by stimulating the inhibitory FcgRIIb receptor found in multiple cell types, including macrophages, B cells, and T cell subsets [62]. IVIg may also interfere with B cell adhesion to fibronectin, platelet aggregation and B cell development by directly neutralizing B cell growth factors [63, 64]. At the cellular level, studies have shown that high-dose IVIg treatment increases the levels of anti-inflammatory cytokines secreted by immature dendritic cells while decreasing the levels of pro-inflammatory cytokines [65]. Paolo Manganotti et al. speculate that IVIg treatment might decrease cytokine production and increase IL-1 receptor antagonist production [60]. In terms of immune regulation, IVIg weakens the ability of complement amplification by stimulating the inactivation of C3 convertase precursor [66], IVIg can also reduce the activation of C3 components and the formation of membrane lytic attack complexes [67]. In patients with SARS-CoV-2, a hypothesized mechanism of action of IVIg therapy is to directly target and neutralize the virus [68, 69].
4.2 Cases of IVIg treatment
IVIG has become an important therapeutic option for various neurological disorders induced by COVID-19. Following COVID-19 infection, patients may develop immune-related neurological complications, including Guillain-Barré syndrome (GBS), acute disseminated encephalomyelitis (ADEM), anti-NMDAR encephalitis, and multisystem inflammatory syndrome in children (MIS-C). IVIG exerts its therapeutic effects by modulating the immune response, reducing inflammation, and mitigating nervous system damage [70]. In COVID-19-related neurological cases, most children treated with IVIG showed improvement and recovered normal physiological functions, except for two children who died due to fulminant cerebral edema and multiple organ failure. A summary of these cases is presented in Table 2.
Summary of cases of IVIG use in children
| Case | Diagnosis | Treatment with medication other than IVIg | IVIg dosage and duration | Outcome |
| 1 [93] | MIS-C | Antibiotics, corticosteroids, glucocorticoids, anakinra, tocilizumab | IVIg (2 g kg−1) 1 dose, specific treatment duration unknown | All patients responded well to these various treatments. |
| 2 [94] | MIS-C | Ceftriaxone, paracetamol, dobutamine, methylprednisolone | Total dose of IVIg 120 g (2 g kg−1) for 72 h | The patient recovered completely without any adverse events. |
| 3 [95] | MIS-C | Unknown | IVIg (1 g kg−1)1dose, specific treatment duration unknown | Discharged after 18 days; encephalopathy subsided and fully ambulatory |
| 4 [96] | MIS-C | Methylprednisolone | IVIg (2 g kg−1)1 dose for 12h | The patient recovered completely without any adverse events. |
| 5 [97] | MIS-C | Methylprednisolone, proton pump inhibitors, broad-spectrum antibiotics (perpecillin/tazobactam), antiplatelet drugs, and enoxaparin are associated. | IVIg (2 g kg−1) 1 dose, specific treatment duration unknown | The patient recovered completely without any adverse events. |
| 6.1 [98] | MIS-C | Broad-spectrum antibiotics, antiviral drugs, acetylsalicylic acid, prednisolone, subcutaneous low-molecular-weight heparin | IVIg (2 g kg−1) 2 dose for 40h | The patient recovered completely without any adverse events. |
| 6.2 [98] | MIS-C | Broad-spectrum antibiotics, antiviral drugs, acetylsalicylic acid, prednisolone, prophylactic subcutaneous low-molecular-weight heparin | IVIg (2 g kg−1) 2 dose for 4 days | The symptoms partially subsided, and short-term fatigue occurred after discharge. |
| 7 [99] | MIS-C? | Treatment was with vancomycin, ceftriaxone, doxycycline, and acetazolamide. | IVIg (2 g kg−1) 1 dose, specific treatment duration unknown | The patient recovered completely without any adverse events. |
| 8 [100] | ADEM | High-dose steroids, rituximab | IVIg (2 g kg−1) 1 dose, specific treatment duration unknown | The patient did not improve with steroids and IVIg, but showed significant improvement with plasma exchange therapy and rituximab infusion. |
| 9 [73] | ADEM | Methylprednisolone, albumin | IVIg (2 g kg−1) 1 dose for 2 days | All symptoms improved significantly, except for a decrease in muscle strength. |
| 10 [77] | ADEM | Methylprednisolone | IVIg for 5 months, specific dosage unknown | The patient recovered completely without any adverse events. |
| 11 [74] | Guillain–Barré syndrome | Albumin, methylprednisolone | IVIg (2 g kg−1) for 24 h, followed by another dose 14 days later | Symptoms partially resolved, with no adverse events. |
| 12 [101] | Guillain–Barré syndrome | Levoracetam, hydralazine, broad-spectrum antibiotics, remdesivir, methylprednisolone, low-dose acetylsalicylic acid | IVIg (0.4 g/kg/day)1 dose for 5 days | The patient recovered completely without any adverse events. |
| 13 [102] | Anti-NMDAR encephalitis | Lorazepam and levetiracetam, methylprednisolone | IVIg (2 g kg−1) 1 dose, specific treatment duration unknown | The patient recovered completely without any adverse events. |
| 14 [16] | Anti-NMDAR encephalitis | Levetiracetam, acyclovir, ceftriaxone, clarithromycin, methylprednisolone, prednisolone, clobazam, and topiramate | IVIg specific treatment regimen is unknown | Symptoms partially resolved, with no adverse events. |
| 15 [103] | Acute necrotizing encephalopathy (ANE) | Glucocorticoids, tocilizumab | IVIg (2 g kg−1) 1 dose, specific treatment duration unknown | One child showed clinical improvement after rescue and medication, and two children died. |
| 16 [104] | Acute necrotizing encephalopathy (ANE) | Remdesivir, tocilizumab, levetiracetam, betamethasone, mannitol, 3% hypertonic saline | IVIg (2 g kg−1) 1 dose, specific treatment duration unknown | Symptoms partially resolved, with no adverse events. |
| 17 [22] | COVID-19-related encephalopathy | Methylprednisolone | IVIg (0.4 g/kg/day)1 dose for 5 days | The patient recovered completely without any adverse events. |
| 18 [105] | Post-infectious COVID-related encephalitis? | Clonazepam, followed by methylprednisolone after clonazepam is stopped | IVIg (0.4 g/kg/day) 1 dose for 5 days | Symptoms partially resolved, with no adverse events. |
IVIG treatment regimens vary depending on the specific neurological disease. For established post-infectious neuroinflammatory diseases such as GBS, ADEM, and anti-NMDAR encephalitis, treatment typically follows current clinical guidelines. These guidelines provide established treatment options for these conditions. Generally, the use of IVIG in GBS and ADEM is similar, with a standard dosage of 0.4 g/kg/day for 5 days [71, 72]. This regimen effectively reduces the inflammatory response in the nervous system and alleviates clinical symptoms. For patients with persistent symptoms, a second course of IVIG may be required after a certain interval [73, 74]. For anti-NMDAR encephalitis, a total dose of 2 g kg−1 is typically administered in divided doses over 3–5 days due to the more intense immune response [75]. In some severe cases, prolonged treatment or combination therapy with other immunosuppressive agents may be necessary. MIS-C is a multisystem inflammatory syndrome associated with COVID-19 infection. IVIG therapy is commonly used as the first-line treatment. The recommended dose of IVIG is 2 g kg−1 (based on ideal body weight if BMI ≥30 kg m−2), with a maximum dose of 100 g. In cases with cardiac dysfunction and concerns about fluid overload, IVIG may be administered at a dose of 1 g kg−1 every 24 h for two doses, with a maximum dose of 50 g [76]. Due to variability in patient conditions, the timing of administration is flexible. Research and clinical practice have shown that IVIG is crucial in treating MIS-C, particularly in reducing damage to the heart and other organs [70]. Although the management of various diseases is guided by treatment protocols, the use of IVIG in clinical practice must be tailored to each patient's specific condition. For example, in Case 11, a more severe immune response may require an extended duration of IVIG therapy or a higher dosage to achieve optimal clinical outcomes [77].
4.3 Summary of the side effects of IVIg
While numerous clinical trials have demonstrated that IVIG is effective and well tolerated in the treatment of post-COVID-19 neurological syndrome, some children may still experience various adverse reactions. We reviewed a large amount of relevant literature and compiled a long table of adverse reactions after IVIG administration in children (Table 3).
Summary of IVIg side effects in children
| Symptoms | Case1 [106] | Case2 [107] | Case3 [108] | Case4 [109] | Case5 [110] | Case6 [111] | Case7 [112] | Case8 [113] | Case9 [114] | Total |
| Number of people | 478 | 1,214 | 12 | 38 | 37 | 305 | 65 | 763 | 20 | 2,932 |
| Headache | 6.7% | 7.9% | 16.7% | 7.9% | 51.4% | 0.66% | 23.1% | 1.3% | 10% | 6.17% |
| fever | 13.6% | 5.7% | 7.9% | 54.1% | 0.66% | 24.6% | 1.3% | 25% | 6.48% | |
| Tachycardia | 6.7% | 0.1% | 1.13% | |||||||
| Nausea/vomiting | 5.9% | 2.7% | 8.3% | 24.6% | 10% | 2.73% | ||||
| Hypertension | 2.7% | 0.33% | 0.3% | 0.10% | ||||||
| Anxiety | 1.0% | 0.2% | 0.27% | |||||||
| Myalgia | 0.4% | 0.9% | 0.44% | |||||||
| Stomach ache | 7.7% | 0.1% | 0.20% | |||||||
| Allergic reactions | 0.6% | 1.0% | 10.8% | 0.98% | 20.0% | 0.5% | 1.33% | |||
| Aseptic meningitis | 8.3% | 0.66% | 0.10% | |||||||
| Cough | 0.2% | 16.2% | 0.31% | |||||||
| Trouble breathing | 0.2% | 2.7% | 0.10% | |||||||
| Cold | 0.3% | 0.33% | 0.9% | 0.41% |
The reported incidence of IVIG-related adverse reactions varies widely. Adverse reactions are typically categorized as immediate or delayed based on their time of occurrence. Immediate adverse reactions mainly include influenza-like syndrome, dermatological side effects, cardiac arrhythmia, hypotension and transfusion-related acute lung injury (TRALI). Delayed adverse reactions, although they affect less than 1% of patients, can be serious and even fatal. These events include thrombotic events, neurological disorders, renal impairment, hematologic disorders, electrolyte imbalances, and transfusion-related infections. Research by Yi Guo et al. shows that the most common side effects of IVIg are influenza-like syndrome (about 87.5%) and headache (about 50%) [78]. All reported events were mostly mild to moderate in severity and self-limiting; they included headache, flushing, chills, myalgia, wheezing, tachycardia, low back pain, nausea, and hypotension [79]. Neurologic disorders associated with IVIg therapy include headache, aseptic meningitis, posterior reversible encephalopathy syndrome (PRES), seizures, and abducens nerve palsy [80, 81]. Post-IVIG headache is a common adverse reaction, with more than half of patients experiencing headache after immunoglobulin administration. However, no specific drug has been found to treat IVIG-related headache [82].
To avoid the above adverse effects, we recommend risk assessment and comprehensive monitoring for every patient considered for immune globulin therapy. At the same time, slowing down the infusion rate and using antihistamines, corticosteroids, or nonsteroidal anti-inflammatory drugs before the administration can significantly reduce the severity and incidence of IVIG-induced adverse reactions [83]. M. Lasica et al. have shown that prehydration with normal saline has a positive effect on preventing and reducing adverse reactions induced by IVIg [84]. Regarding contraindications, the presence of minor ingredients in IVIg preparations may constitute a warning, but overall it is not clear [85].
4.4 IVIG in the treatment of L-C19 treatment
As COVID-19 continues to spread, the prevention and treatment of L-C19 has gradually become an unavoidable topic. By virtue of its mechanism in neutralizing deleterious autoimmune antibodies, IVIG has become one of the promising candidate therapies for the treatment of severe L-C19.
Thompson et al. treated six L-C19 patients with IVIG, all of whom exhibited severe neurological symptoms, including fatigue and brain fog. The treatment regimen involved administering 0.5 g kg−1 of IVIG every two weeks (except for one young woman, who received 0.4 g kg−1 every two weeks), with evaluations conducted every three months. All patients showed significant improvement with long-term IVIG therapy, and as of this report, are still receiving treatment [86].
Suniya Naeem et al. treated and reported a L-C19 patient who suffered from significant cognitive and behavioural disorders. The patient was administered 0.5 g kg−1 of IVIG every two weeks, resulting in gradual improvement of his mental state over the course of three months. This treatment regimen lasted for two years, after which, in October 2023, it was adjusted to IVIG administration every four weeks and this schedule continues to the present day [87].
Hogeweg et al. conducted a case-control study on long-term COVID-19, comparing the effects of IVIG treatment, glucocorticoid treatment, and supportive care. All patients in the IVIG group reported symptom relief, with significant improvements in fatigue and cognitive dysfunction, whereas only 40% and 60% of patients in the glucocorticoid and supportive care groups, respectively, reported symptom relief [88].
Although the above three reports on L-C19 in adults are limited in scale, they provide valuable insights for the treatment and future research of COVID-19 in pediatric populations. Future studies should include large-scale clinical trials to confirm the efficacy of IVIG in treating L-C19 in children and to determine the optimal duration of treatment. Notably, the U.S. National Institutes of Health (NIH) has initiated two randomized clinical trials evaluating different treatments for L-C19, including IVIG treatment, although the results have not been published so far [89].
5 Conclusion
The latest COVID-19 treatment guidelines in the United States do not exclude the use of IVIG for treating potential symptoms or complications of COVID-19, but the guidelines do not indicate the specific dosage of IVIG. Only for children with MIS-C, it is recommended that IVIG should be taken at an ideal weight dosage of 2 g kg−1; the maximum total dose is 100 g [90]. IVIG is the standard medication for the treatment of Kawasaki disease cases. According to the guidelines of the AAP (American Academy of Pediatrics) and AHA (American Heart Association), a single dose of IVIG 2 g kg−1 should be administered over 12 h within 10 days of the onset of symptoms of Kawasaki disease, as this timing yields the most optimal therapeutic effect. Intravenous immunoglobulin (IVIG) is mainly indicated in the acute phase, for severe cases, or for patients with rapidly progressing conditions, such as respiratory failure, coma, or seizures [90–92]. Based on the cases concerning the application of IVIg in children, we hypothesize that the appropriate dose of IVIG for treating neurological symptoms of COVID-19 in children is approximately 2 g kg−1 for 3–5 days. If symptoms persist, an additional dose of IVIG may be administered after an appropriate interval. Due to its potential side effects and high cost, IVIG should be administered with caution, especially in cases of abnormal immune activation or excessive inflammatory response, and only after thorough consideration. This immunoglobulin dose takes into account factors such as children's physiological characteristics, safety, efficacy, and individual differences. Despite the promising results, more research and clinical trials are needed to determine the best method of use.
In summary, as the research on COVID-19 continues to deepen, the understanding of the neurological symptoms of COVID-19 and L-C19 in children is also constantly improving. Although the prospects of IVIG in treating neurological symptoms of COVID-19 in children are promising, due to insufficient data, more clinical studies are still required to confirm its safety and effectiveness. Further studies are necessary to refine the treatment plan and determine the appropriate dosage to better serve clinical practice.
Ethical, review board approval
Not applicable.
Author contributions
This review was conceived by Fangyuan Long, data collected and written by Dingfei Li and Fangyuan Long, and pictures drawn by Shungeng Zhang. It was revised due to the evaluation of Teacher Baohua Yu, and was reviewed, commented and approved by all authors.
Financial support and conflict of interest disclosure
Publication funds sponsored by Clinical Research Fund Project LCYJ-020 of Jining Medical College Affiliated Hospital.
Declaration of interest statement
No potential conflict of interest.
Acknowledgments
We thank the the Affiliated Hospital of Jining Medical College for their extensive assistance in data collection and analysis research.
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