COVID 19 and immune phenomenon in children

Anu Maheshwari; Kaveri Pandit; Virendra Kumar; Deonath Mahto

doi:10.4103/INJMS.INJMS_59_20

REVIEW ARTICLE

Year : 2020 | Volume : 11 | Issue : 2 | Page : 65-69

COVID 19 and immune phenomenon in children

Anu Maheshwari, Kaveri Pandit, Virendra Kumar, Deonath Mahto
Department of paediatrics, Kalawati Saran Children's Hospital and Lady Hardinge Medical College, New Delhi, India

Date of Submission	10-Jun-2020
Date of Acceptance	11-Jun-2020
Date of Web Publication	09-Jul-2020

Correspondence Address:
Dr. Anu Maheshwari
Department of Paediatrics, Kalawati Saran Children's Hospital and Lady Hardinge Medical College, Bangla Sahib Marg, New Delhi - 110 001
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/INJMS.INJMS_59_20

Abstract

The novel coronavirus, named as severe acute respiratory syndrome (SARS)-CoV-2 has emerged as a global emergency. In December 2019, from a local outbreak in Wuhan, China, it has rapidly progressed to a global pandemic causing high morbidity and mortality exhausting all health-care facilities. COVID-19 is like any other respiratory virus but has more propensity to infect the lower parts of the respiratory system, namely bronchioles and alveoli. The innate and adaptive immune response helps the body to fight the virus. Atypical presentations such as Kawasaki disease, chilblain like lesions and other cutaneous manifestations, systemic inflammatory response syndrome-like illness (Toxic shock syndrome), Guillain–Barre syndrome, and other immune-related disorders have also been reported in various countries. Rapidly increasing cases worldwide have aroused global concerns regarding the need to understand the immunopathogenesis of the virus and possible explanations for various atypical manifestations occurring in children. This review is aimed at providing a complete understanding of the probable immune response in children and might predict future therapeutic target points.

Keywords: COVID-19, Kawasaki disease, myocarditis, pediatric multi-system inflammatory syndrome

How to cite this article:
Maheshwari A, Pandit K, Kumar V, Mahto D. COVID 19 and immune phenomenon in children. Indian J Med Spec 2020;11:65-9

How to cite this URL:
Maheshwari A, Pandit K, Kumar V, Mahto D. COVID 19 and immune phenomenon in children. Indian J Med Spec [serial online] 2020 [cited 2023 Mar 29];11:65-9. Available from: http://www.ijms.in/text.asp?2020/11/2/65/289343

Introduction

The novel coronavirus, named as severe acute respiratory syndrome (SARS)-CoV-2 has emerged as a global emergency. In December 2019, from a local outbreak in Wuhan, China,^[1] it has rapidly progressed to a global pandemic causing high morbidity and mortality exhausting all healthcare facilities. COVID-19 belongs to the coronaviruses family of positive single-strand RNA viruses which include hundreds of members that infect humans and other viruses that infect animals such as bats, snakes, birds, and others.^[2] Up to 85% of total cases were reported to be mild-to-moderate illness, 10% had severe infections requiring hospitalization and oxygen support and around 5% were as critically ill requiring intensive care with 50% mortality. The symptoms included flu-like illness-fever, cough, sore throat, dyspnea, rhinorrhea, myalgia, headache, and gastrointestinal symptoms.^[3] In severe cases, complications such as acute respiratory distress syndrome (ARDS), septic shock, multi-organ dysfunction syndrome including acute kidney injury, and cardiac injury can be seen.^[4],[5]

Phylogenetic analysis and full-genome sequencing have indicated that the coronavirus that causes COVID-19 is a betacoronavirus in the same subgenus as the SARS virus (as well as several bat coronaviruses). The structure of the receptor-binding gene region is very similar to that of the SARS coronavirus, and the virus has been shown to use the same receptor, the angiotensin-converting enzyme 2 (ACE2), for cell entry. The Middle East respiratory syndrome (MERS) virus, another betacoronavirus, is closely related to COVID-19. The closest RNA sequence similarity is to two bat coronaviruses, and it appears likely that bats are the primary source; whether COVID-19 virus is transmitted directly from bats or through some other mechanism including an unknown intermediate host is not known.

COVID 19 is like any other respiratory virus but has more propensity to infect the lower parts of the respiratory system, namely bronchioles and alveoli.^[6],[7] The innate and adaptive immune response helps the body to fight the virus. Healthy individuals with intact immunity can limit the infection. In those individuals with immunocompromised state, the elderly with co-morbidity and weak immune response, the virus reaches alveoli where alveolar lymphocytes and macrophages in response to viral antigen release huge amounts of cytokines, chemokines, and other factors causing devastating severe alveolar pneumonitis and interstitial inflammation leading to severe pneumonia to ARDS like illness.^[8] Antibodies to the virus are induced in those who have become infected as in any other infection. Although some of the antibodies maybe protective this needs to be researched further. It is also unknown whether all infected patients mount a protective immune response and how long this protective immunity lasts. Data on protective immunity following COVID-19 are emerging. The use of convalescent plasma for the treatment of COVID-19 may indicate that neutralizing antibodies may be present in the plasma which are transferred to the recipient.

COVID-19 affects people of all age groups but was reported initially in adults and the elderly with comorbidities. It was initially postulated that children will also be among the high-risk group owing to the immaturity of their immune system. However, recent literature in children has shown milder illness and mainly asymptomatic mild and moderate disease in up to 90%, 5.2% with severe disease and 0.6% with critical illness.^[9] The pediatric population seems to be relatively immune to the effects of this deadly virus as compared to adults. The possible explanation for this may be the inability to mount an exaggerated immune response by cell-mediated immunity due to the lack of sufficient memory to antigenic repertoire of coronaviruses.^[8] Co-morbidities^[10] such as diabetes, hypertension, metabolic syndrome, immunocompromised state, chronic diseases (renal, cardiac, pulmonary, and rheumatological), primary immunodeficiency disease, those receiving steroid therapy are possible high-risk factors in children.

Atypical presentations such as Kawasaki disease (KD),^[11] chilblain like lesions (CLL)^[12],[13] and other cutaneous manifestations, systemic inflammatory response syndrome (SIRS) like illness^[14] (Toxic shock syndrome), Guillain–Barre syndrome (GBS),^[15] and other immune-related disorders have also been reported in various countries. Rapidly increasing cases worldwide have aroused global concerns regarding the need to understand the immuno-pathogenesis of the virus and possible explanations for various atypical manifestations occurring in children. This review is aimed at providing a complete understanding of the probable immune response in children and might predict future therapeutic target points.

Covid 19 and Immune-Dysregulation

The immune system is classified into innate and adaptive immunity. Innate immunity is the first responder that mounts a rapid immediate response with broad antigenic specificity, no memory, and recognition of self. Its cellular components include phagocytes, antigen-presenting cells (APCs) such as neutrophils, monocytes, macrophages and dendritic cells, innate lymphocytes, cytokines, and chemokines. The adaptive immunity has a delayed highly specific antigenic response, immunologic memory, and occasional nonrecognition of self, resulting in autoimmune diseases. It has three phases; recognition of antigen, activation of T- and B- lymphocytes, and the effector phase. Activation of T-cells (Tc) results in cytokine production, clonal expansion, and production of effector cells. The cellular components include nonlymphoid APCs, B-lymphocytes, T-lymphocytes, and effector cells (activated Tc and phagocytes). Functionally different T-lymphocyte subsets are recognized by certain surface molecules known as “Classification determinant” (CD) and their cytokines. Cytotoxic Tc express CD8+ and mediate cellular immune responses. Modulatory Tc express CD4 and include T-helper cells (Th1, Th2) which stimulate immunity; T-regulatory cells (Tregs) which express CD25, suppress immunity and are important in countering allergic and autoimmune disease; and Th17 cells that are pro-inflammatory and may be involved in allergic rhinitis and conjunctivitis, food protein-induced enterocolitis, atopic dermatitis, and contact dermatitis. Recent data in adults show that anti-Ro and antinuclear antibody is positive in as high as 25% and 50% of critically ill COVID-19 adults.^[16] These observations may provide the rationale for the strategy of the prevention of dysfunction of the immune system and optimal immunosuppressive therapy in the future in addition to the conventional management of the illness.

Lymphocyte Subset Alteration and Serum Cytokine Levels in Covid 19

The innate and adaptive immune response plays an important role in controlling viral infection. Lymphocytes and subsets of CD4 Tc, CD8 Tc, B-cells, and NK cells are the most important mediators of the response. There is no evidence of lymphopenia in children as per available data.^[17] The function and alteration of lymphocyte subsets and serum cytokine levels in COVID 19 infection remain unclear. CD 8 Tc plays a very critical role in viral clearance as seen in animal studies.^[18] Certain adult studies suggest that CD8+ Tc may be a reliable indicator of disease severity and recovery.^[19] Furthermore, clinical characteristics of COVID 19 are associated with altered peripheral lymphocytic subset. A pediatric study^[20] compared the spectrum of lymphocyte subsets in 40 COVID patients with 16 respiratory syncytial virus (RSV) patients. It was observed that patients with COVID pneumonia have a higher percentage of CD3+ CD8+ lymphocytes, whereas there was no significant difference between CD4+/CD 8+ Tc counts. It was also noticed that CD8+ Tc were lower in patients with severe disease and no improvement in the levels after therapy is a poor prognostic indicator.^[19] Various serum cytokines such as interleukin (IL)-2, IL-4, IL-6, tumor necrosis factors-alpha (TNF-α), and interferon gamma were detected. IL-10, an anti-inflammatory cytokine helps the host to limit the inflammation, avoid tissue injury, and was found to be elevated in those with RSV pneumonia.^[20] It was also noticed that IL-6, a pro-inflammatory cytokine, increased rapidly with bacterial infection along with other inflammatory markers like C-reactive protein (CRP) and procalcitonin (PCT) and gradually returned to normal with therapy. This study provided some insight into the alterations of subsets and cytokine levels.^[20] However, there is an urgent need to study these alterations on a larger group of population to get more information about the type of pharmacologic therapy.

Other Immunological Phenomena in Covid 19

Kawasaki disease and COVID 19

KD is an acute, self-limiting multi-systemic vasculitis involving medium-sized arteries with a predilection to involve coronary arteries. It is an immune-mediated injury by multiple triggers including infections. It is the most common pediatric vasculitis and the leading cause of acquired heart disease in children in the developed world.^[21] An association between respiratory viral infections and KD has been previously described in the literature. 9%–42% of patients with KD, test positive for a respiratory viral infection in the past 30 days before clinical presentation.^{[22],[23],[24]} Interestingly, Turnier et al. in 2015 described that 28% of positive results were attributable to rhinovirus/enterovirus, 8.7% due to parainfluenza, and the remaining pathogens such as RSV, influenza, adenovirus, and human coronavirus were each positive in <5% of the time.^[22] COVID 19 infection is currently suspected as a trigger as we have found surge of multiple case reports of KD in this pandemic. Jones et al.^[11] reported a case of classical KD in a 6-month-old previously healthy fully immunized child who tested positive for COVID 19. The child was treated with IVIG and showed tremendous response within 48 h of therapy. Many such cases might be missed and a strong suspicion of typical and atypical manifestation of KD should be kept in mind. The etio-pathogenesis is probably the massive release of the inflammatory cytokines leading to systemic involvement and viral triggered super-antigen response similar to toxic shock syndrome. A report from New York^[25] has described 15 children admitted to emergency with a multi-systemic inflammatory syndrome-like illness suggesting atypical KD like disease, KD shock syndrome. Half of these patients required inotropes for hemodynamic support, 5 patients received mechanical ventilation but no mortality was observed. Four of 15 patients tested positive on reverse transcription-polymerase chain reaction (PCR) for COVID 19. Out of 11 who tested negative, 6 were positive for COVID by serology. It is essential for the health-care providers to identify such syndromes and treat them as per protocol as there is rapid recovery minimizing life-threatening long-term cardiac complications. Further studies are required to establish the exact mechanism by which COVID 19 causes vasculitis like illness to modulate therapy accordingly. The role of adding steroids initially or infliximab as part of initial protocol to treat KD too needs to be further studied.

Cutaneous Manifestations Associated With Covid 19

Since the pandemic has shifted the focus of the clinicians to urgent critically ill patients thereby many of the cutaneous manifestations might have not been reported to the doctors. The first report of skin manifestations was by Recalcati et al. done by a google performa-based survey that showed 20.4% of the adults developed cutaneous manifestations.^[12] These lesions were erythematous rash in 78%, widespread urticaria in 16.6% and chicken-pox like vesicles in 0.1%. Another report from Italy by Piccolo et al. involving 63 patients showed CLL.^[27] These lesions involved feet (87%) followed by both hands and feet (7%), followed by hands (6%) alone. The lesions were asymptomatic in 25.4% of cases, pain, itch, or both were seen in 27%, 27%, and 20.6%, respectively. In most of the cases, the systemic signs and symptoms such as gastrointestinal (11.1%) followed by respiratory (7.9%) preceded the cutaneous manifestations. There was no history of exposure to cold. There was a history of autoimmunity in six patients with one patient demonstrating anti-nuclear antigen positivity.^[26] The possible etiology of these chilblains-like lesions was in all likelihood secondary to autoimmune and haematological phenomenon due to viral infections.^[27] Because of young age, absence of comorbidities, latency between mild symptoms, and CLL and morphology of cutaneous findings, it was hypothesized that these lesions were a result of the delayed immune-mediated reaction to the virus in genetically predisposed patients.^[26] Due to concerns regarding the spread of disease and containment of the patients, histopathological evaluation was difficult. Another pediatric series described dusky erythematous CLL who tested negative for COVID.^[13] Histopathology of one of these patients showed dense lymphocytic perivascular cuffing and peri-adnexal infiltrates suggestive of small to medium vessel vasculitis with endothelial swelling.^[13] This shows that a delayed inflammatory process is ongoing, causing a multitude of cutaneous manifestations.

[TAG:2]Sirs, Toxic Shock Syndrome (Tss), Hyper-Inflammatory Shock in Children With Covid 19[/TAG:2]

The multi-systemic inflammatory process releasing massive cytokines causing cytokine storm-like illness creates endothelial damage and inflammation-causing multi-organ failure syndromes secondary to COVID-19 are increasingly being reported, referred to as Multisystem inflammatory syndrome in children (MIS-C). It is also referred to as pediatric MIS, pediatric hyperinflammatory syndrome, and pediatric hyperinflammatory shock. According to reports,^[14] eight previously healthy children presented with features of atypical KD, KD shock syndrome, and TSS. All presented with fluid refractory warm shock requiring nor-adrenaline and milrinone for hemodynamic support and seven required mechanical ventilation for cardiovascular stabilization. Other notable features include pleural, pericardial effusion, and ascites. All inflammatory markers were markedly raised. There was a significant myocardial injury in the form of poor left ventricular function, arrhythmias, and features of myocarditis.^[28]

Although 50% of the patients had family exposure to COVID-19, all of these patients tested negative for COVID-19 on RT-PCR in BAL and nasopharyngeal specimens. In the background of pandemic causing danger to lives and livelihood, we must have the knowledge and anticipate such atypical presentations and inflammatory syndrome to formulate guidelines for therapy and avoid preventable mortality. Clinical features include persistent fever, hypotension, gastrointestinal symptoms, rash, myocarditis, and laboratory findings associated with increased inflammation with or without typical respiratory complaints classically associated with COVID-19 infection. The case definition requires all four of the following:

Age <21 years
Clinical presentation consistent with MIS-C, including all of the following:
Documented fever ≥38°C (100.4°F) for ≥24 h or report of subjective fever lasting ≥24 h
Laboratory evidence of inflammation (including, but not limited to: elevated CRP, erythrocyte sedimentation rate, fibrinogen, PCT, D-dimer, ferritin, lactate dehydrogenase, or IL-6; elevated neutrophils; reduced lymphocytes; low albumin)
Severe illness requiring hospitalization with involvement of ≥2 organ systems (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, neurologic).
No alternative plausible diagnoses (although some patients may meet full or partial criteria for KD)
Evidence of current or recent SARS-CoV-2 infection (positive reverse transcriptase PCR, serology, or antigen test) or COVID-19 exposure within the 4 weeks before symptom onset.

The treatment protocol in addition to the antimicrobials may need IVIG, biological agents like toclizumab or infliximab may be beneficial to control the effects of cytokine storm. Insight into the pathogenesis and immune dysregulation in these patients may help us to rationalize the use of immune agents for therapy to have maximum benefit and minimize complications.

Guillain Barre Syndrome Associated With Covid 19

GBS is a common cause of acute flaccid paralysis in children. It is an immune-mediated disease of the peripheral nerves and nerve roots (polyradiculoneuropathy) usually of postinfectious etiology. There are the reports of members of the coronavirus family being one of the causes of GBS in adults as they have neurotrophic and neuroinvasive characteristics.^[29] COVID-19 and GBS have been reported in various countries in adults^[15],[30] but there is no reported case in children to the best of our knowledge to date. A total of 7 adult cases have been reported with a classical illness out of which 6 were found to be positive for COVID-19 infection either 2 weeks before illness or till day 10 of hospitalization for current illness.^[15],[30] As per Toscano et al.,^[30] the interval between the onset of symptoms of COVID 19 and the first symptom of GBS is 5–10 days. Three out of 5 reported patient's CSF analysis showed albumino-cytological dissociation and antiganglioside antibody could be done in only 3 negative patients. Nerve conduction velocity study for these patients suggested the presence of axonal variants in three patients and rest had a demyelinating type of polyneuropathy.^[30] This virus enters the cell by attaching itself to ACE 2 receptors (same as other members of the family-SARS and MERS) which are present on various cells of human organs including lung, kidney, liver, nervous system, and skeletal muscle.^[31] Hence, a possible etio-pathogenesis appears to be an inflammatory process involving the release of cytokines and molecular mimicry. Whether COVID-19 infections produce antiganglioside antibodies or not is a topic of future research. The exact pathogenesis of the infection in producing GBS like illness is not known and more studies are required for the validation of the same.

Conclusions

Atypical presentations such as KD,^[11] CLL^[12],[13] and other cutaneous manifestations, SIRS like illness^[14] (Toxic shock syndrome), GBS^[15] and other immune-related disorders are being increasingly reported in the context of COVID-19 infection. Rapidly increasing cases worldwide have aroused global concerns regarding the need to understand the immuno-pathogenesis of the virus and possible explanations for various atypical manifestations occurring in children. Timely recognition of these phenomenon is important for early treatment and to minimize long-term complications and morbidities.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

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