key: cord-0770337-uc6xmdjo
authors: Seth, Shrey; Rashid, Femida; Khera, Kanav
title: An overview of the COVID‐19 complications in paediatric population: A pandemic dilemma
date: 2021-06-22
journal: Int J Clin Pract
DOI: 10.1111/ijcp.14494
sha: 2e2bd69be7fdfed1cefe88765b235d4965654df8
doc_id: 770337
cord_uid: uc6xmdjo

AIM: The primary objective of this article is to understand the various complications caused by the coronavirus in the paediatric population. METHOD: An electronic search was conducted using PubMed and incorporated forward and backward research methods on clinical trials, case reports, case series, guidelines and reports from the centre for disease control and prevention (CDC), and the keywords included COVID‐19, paediatrics, multisystem inflammatory syndrome in children (MIS‐C), complications, acute kidney injury and heart failure. Secondary resources included one study from preprint servers (www.preprints.org), last search 8 May 2021, with notion of nonpeer review status. Data were collected and analysed to stay current with the most recent alerts and guidelines for the best care for children during the COVID‐19 pandemic. RESULTS: Evaluation and analysis of literature revealed MIS‐C to be the most prevalent followed by neurological complications. Whereas the least prevalent were septic shock and ophthalmic complications. CONCLUSION: Even though COVID‐19 is known to be a less severe in the paediatric population, the complications of the virus have caused a great deal of stress to the paediatric patients’ parents and paediatricians worldwide, and hence, emphasis should be given to the management of coronavirus complications in paediatrics.

in breathing. [12] [13] [14] [15] [16] [17] [18] Aching throat, myalgia, nose blockage and headache were also reported. Although gastrointestinal (GI) symptoms were noted less frequently, the occurred symptoms included pain in the abdomen, nausea or vomiting and loose motions. 15, 19, 20 Loss of smell and loss of taste in the adult population have been often noted in coronavirus patients, seldom as the primary and only clinical presentation. [21] [22] [23] [24] Due to the challenges of obtaining such symptoms in children, these presentations have had negative reports.

In chronically ill children 25 and adults 26, 27 with COVID19, hypoalbuminemia is thought to be an indicator of worse outcomes.

Hypoalbuminemia has been shown to be an indicator of vascular disease and mortality in previous studies. 26, 27 Children with a moderate type of COVID-19 have been confirmed to have hypoalbuminemia.

We did not find hypoalbuminemia in children with moderate to mild COVID19, contrary to an earlier report, 28 but we did find hypoalbuminemia in children with potentially life-threatening disorders, such as those with multisystem inflammatory syndrome. 29 This variation in behaviour may be due to the severity of the inflammatory response, which is likely to be higher in patients with multisystem inflammatory syndrome. Like those with extreme COVID-19 who need intensive care, these infants have hypoalbuminemia, which is defined by a high inflammatory status and albumin levels of less than 3.0 g/dL. 30 A literature search was conducted and incorporated forward and backward research methods from December 2020 to April 2021.

The complications caused by the recent coronavirus infection in paediatric patients were then reviewed, and the data was compiled, summarised and discussed.

Long COVID has been found to be a significant complication in paediatrics, according to a cross-sectional study conducted in Italy.

Amongst the 129 patients amongst in the study, 52.7% reported of at least one recurring symptoms even after 120 days from diagnosis of the infection, and 42.6% experienced impairments in routine activities due to these symptoms, which include headache, joint and muscle pain, respiratory problems, palpitations and fatigue. 31, 32 Assessment of the patients was conducted on average 162.5 ± 113.7 days post-COVID-19 microbiological diagnosis. The most common symptom was found to be insomnia (18.6%) followed by respiratory symptoms (like chest tightness and pain) (14.7%), nasal congestion (12.4%), fatigue (10.8%), muscle pain (10.1%) and joint pain (6.9%) being the least common amongst the most often reported symptoms. Conclusively, 41.8% of patients had a complete recovery, whereas 35.7% presented with 1 or 2 symptoms and 22 .5% presented with three or more symptoms. 33 Between January 2020 and January 2021, 510 children (56.3% females) were infected. Twenty-two (4.3%) of the children were admitted after they were first infected with COVID-19. COVID-19 was shown to be persistent in children for an average of 8.2 months. 

According to The Centers for Disease Control and Prevention (CDC) case definition, 35 a case with multisystem inflammatory syndrome in children (MIS-C) was defined as follows:

• An individual aged <21 years presenting with fever, laboratory evidence of inflammation including an elevated level of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase (LDH) or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes, and low albumin and evidence of clinically severe illness requiring hospitalisation, with more than two multisystem organ How was the information gathered? According to news from New York, 102 cases of MIS-C were diagnosed, amongst which three children between 5 and 18 years of age passed away. The focal point of this surge was found to be New York City, reporting 50 cases. 36 Kawasaki shock syndrome and MIS-C have some common features between them in physiology; however, heart dysfunction was observed in all patients with low systolic BP. 30 Evidence from an Iranian study conducted in three paediatric hospitals reported details of 45 children that met the inclusion criteria for MIS-C. The children were on average 7 years old (ranging from 10 months to 17 years), and 53% of them were male. The most common presenting symptoms are fever 91%, stomach pain 58%, nausea/vomiting 51%, mucocutaneous rash 53%, conjunctivitis 51% and hands and feet inflammation 40% with a median time of symptoms of 5 days prior to presentation.

The majority of MIS-C patients (69%) had Kawasaki-like disease, whereas 20% had sepsis-like diseases, and 11% had toxic shock-like cases. Abdominal pain was more common in Kawasaki-like conditions and sepsis like conditions than in toxic shock-like conditions. Many cases had significantly increased inflammatory parameters such as ESR and CRP, which is used as an alternate marker for Interleukin-6 (IL-6), at the time of admission (97%). Hypoalbuminemia was observed in 20 of the 31 patients (64.5%), and hyponatremia was found in 64% of the reports. 37 Evidence from another study conducted in the United States reported 186 patients suffering from MIS-C, with the peak incidence being observed when the action of the COVID-19 virus was declining. 29 The majority of the patients had involvement of a minimum of four organ systems. The most frequently involved systems included respiratory (70%), mucocutaneous (74%), haematological (76%), cardiovascular (80%) and GI system(92%). 29 Additionally, MIS-C has been proved to play a key role in the development of other complications proven by a study recruiting one 49 patients showing cardiovascular involvement, amongst which 48% required supportive treatment with vasoactive agents. An elevation of BNP and troponin levels were the major findings. A minimum of one echocardiogram was taken for almost all patients (91%).

Incidence of coronary artery aneurysms was found to be 8% of the total study population. A total of 59% of the patients showed respiratory deficits, whereas 85% had no evidence of underlying conditions relating to the respiratory system. Conclusively, 17% of the patients required non-invasive mechanical ventilation, and 20% required invasive mechanical ventilation. A total of 92% of the patients showed alteration in inflammatory marker suggesting inflammation inclusive of high levels of CRP or ESR, ferritin, fibrinogen, alanine aminotransferase level and D-dimer levels, and others included anaemia, neutrophilia, thrombocytopenia, hypoalbuminemia and prolongation of international normalised ratio. 29 

Data from a Chinese case study, of an infant (55 days old) with coronavirus infection, presented with heart damage, pneumonia, and injury to the liver, which was confirmed via occasional arrhythmias as well as a myocardial zymogram. A small case series including a 13-month-old infant reported the development of heart failure along with multi-organ failure. 38 A French case series reported acute myocarditis as well as systemic inflammation succeeding viral infection in 20 children who were critically ill. Significantly elevated levels of immunoglobulin (IgG and IgA) were observed, suggesting a postviral immunological reaction that causes myocardial damage. A notable decrease was observed in the levels of inflammatory biomarkers as well as an enhancement in the functioning of the cardiac system post-treatment with IVIG. 39 

A few critical heart failure cases were reported linked to MIS-C. The cases had shown abdominal and GI as the presentations instead of chest pain. High fever with intense asthenia was observed in all children. When a larger population was considered, blood flow dynamics during admission to the ICU for paediatrics were low systemic blood pressure (BP) with shock and respiratory distress, causing immediate initiation on the ventilator. 38 Pro-inflammatory and regulatory T cells, which induce a cytokine storm, have been suggested to generate myocardial and lung injury caused by COVID-19. 40 In a retrospective study, only six children out of a total of 35 cried of chest discomfort in which the ECG conducted was not distinct, and only one patient had ST-segment elevation. The average lag amongst the initial clinical symptoms and heart failure symptoms was 6 days. Many patients were admitted immediately to the ICU; six patients, who were initially admitted to the general paediatric, had to be moved immediately after their condition worsened on the first day itself. On admittance to the ICU, two-thirds required invasive mechanical ventilation due to the development of respiratory distress, whereas 80% of them of patients required intravenous inotropic drugs due to being in cardiogenic shock and mechanical circulatory assistance with oxygen through the veno-arterial extracorporeal membrane, which was favourably taken out in all. 38 A single-centre retrospective study organised at the Birmingham Children's Hospital also reported the involvement of the cardiac system in COVID-19 infection. 38 On echocardiogram, ECG abnormalities were found in nine patients (60%). Six of them had their ECGs normalised before discharge, which took an average of 5 days. 40 

Seven had prominent coronary arteries on echocardiography, but 14 patients had coronary artery defects on regular measurements, amongst which six patients had ectatic dilated coronaries. One patient had a moderate right coronary artery (RCA) fusiform aneurysm and a mild left anterior descending artery fusiform aneurysm (LAD). 

According to a hospital in the United Kingdom, including 52 paediatric patients, 46% of the patients had an increase in serum creatinine levels than the upper limit of reference interval (ULRI). At the same time, 29% of the patients met the specific requirement for BAPN criteria, used for diagnosis of acute kidney injury (AKI). The majority of these cases were observed in ICU patients and patients suffering from Paediatric Inflammatory Multisystem Syndrome (PIMS-TS), which were 93% and 73%, respectively. Prerenal involvement was indicated as most of the patients presented with vomiting and diarrhoea. Additionally, 33% of the patients with AKI also had enlarged kidneys (>95% for age in bipolar length), observed using renal ultrasound. 41 The proposed mechanism for AKI is through the binding of angiotensin-converting enzyme 2 (ACE2) with the spike (S) of viral protein, which causes activation of the angiotensin II. Priming and cleavage of the S protein take place by transmembrane protease 

Evidence from a study conducted in Geneva, Switzerland, reported the characteristics of septic shock in three paediatric patients.

A 12-year-old Hispanic male suffering from asthma and obesity was the first patient. He had odynophagia, cough, fever, dyspnoea and headache for 1 day. Inflammatory markers were not elevated in laboratory studies, but lymphocytopenia was discovered. When the patient was receiving treatment in the emergency room, an increase in tachycardia up to 170 beats per minute was seen, and he also presented with symptoms of compensated shock, including cold extremities, a 6-s capillary refill period and a 41 mmol/L lactate concentration.

A previously healthy 10-year-old with mixed race (white and Asian) suffering with obesity was the second patient. He had a fever of 40℃ for 5 days and cough, vomiting, abdominal pain and odynophagia.

Physical examination revealed a sick but not toxic patient who was conversant but slightly nervous, well-hydrated, tachycardic to 120 beats per minute, with low BP (85/50 mm Hg), tachypnea (respiratory rate 36 breaths per minute) and oxygen saturation of 89%-95% at normal room environment. COVID-19 hypotensive septic shock accompanied by multiorgan dysfunction syndrome (MODS) was the final diagnosis. 

Acute chilblains have been reported as a complication of coronavirus in paediatrics and teenagers. 51 It is understood that it is a localised inflammatory condition due to a maladaptive vascular response to nonfreezing low temperature. 52 It is most common in women and middle-aged adults and seems to be uncommon in children. [52] [53] [54] [55] In a retrospective study involving 22 children and teenagers, lesions were noted that were clinically like chilblains. These patients, who had no predisposing factors or previous history of chilblains, presented the symptoms in a short duration of time during the warm weather. Cases were reported during the peak of the coronavirus in places such as Madrid and other profoundly affected places. In 59% of the reports, being in close contact with an asymptomatically affected adult was seen and the cases having mild or moderate disease. In 55% of the reports, chilblains were the only symptoms seen, and 45% had mild presentations that may be due to coronavirus. 51 In such cases, chilblains were detected after an average of 16 days from the initial symptoms. Only one patient out of the 19 tested patients was PCR positive for the coronavirus disease. However, the sensitivity of the test may be low in mild cases and paediatrics, which could be due to a lesser viral load-considering that the positivity of the PCR is about 11.2% in paediatrics requiring to be admitted into the hospital for coronavirus. 56 On the other hand, chilblains could have been detected much later in the disease duration, and thus, the PCR test may have turned negative when conducted. 51

In one Italian study, video capillaroscopy was used to examine 19 teenagers. 57 Even though the skin lesions were confined to the feet, capillary abnormalities of the fingers and toes were defined.

Microhemorrhages accompanied by peripheral edema were the most common presentation, whereas dilation of capillaries was seen in both the toes and fingers. COVID 19 chilblains may be a result of systemic interference rather than being caused because of local causes. Furthermore, these characteristics tend to be more extreme than those seen in idiopathic chilblains, with absence of microhemorrhages. 58 

In a case report, a 17-year-old patient presented with isolated acral papules and targetoid lesions. 59 In another study, four patients with chilblain-like lesions also had associated EM, with both true target and targetoid lesions; one of the children tested positive for the COVID-19 infection through results of PCR, and skin biopsies taken in two of the cases revealed endothelial positive immunohistochemistry stain to SARS-CoV-2 spike protein. 60 A positive COVID-19 PCR result was found in a 6-year-old boy with acral target lesions of erythema multiforme (EM), conjunctivitis and serious, painful cheilitis. 61 Full clinical analysis showed skin lesions associated with EM affecting the palms, feet, forearms, elbows, arms, calves, thighs, hips and ears in four Spanish children with chilblains on the feet, two of whom also had involvement of the hands. 62 An Italian patient also developed skin target lesions of EM after chilblains. 63 

A case series conducted in Italy provided information about an 8-year-old patient that presented with varicella-like exanthem as a COVID-19 specific skin manifestation. 64 

Several reports have shown rounded, well-circumscribed erythematous or violaceous plaques or nodules, chilblain-like lesions and diffuse digital erythema on the dorsal surfaces of the toes in patients with COVID-19, 65,66 ranging from asymptomatic or mild to rapidly progressing disease. 67 In the absence of COVID-19 pneumonia, however, skin lesions are a common finding in children and younger adults. These patients' COVID-19 skin lesions display vasculitic changes, such as perivascular cuffing and inflammatory lymphocytic infiltration, which could lead to luminal thrombosis. 68, 69 In one study, a child with chilblains showed asymptomatic fundoscopic changes typical of retinal vasculitis, which is synonymous with a predominant vasculitic condition. 70 In addition, a sole case of peripheral vasculitis was reported in a case study conducted in Italy. 47 

We suspected that complement activation is a significant factor in COVID-19 in the paediatric population and wanted to know whether these patients had thrombotic microangiopathy (TMA). We admitted 

The recent outbreak of COVID-19 has had a major impact on both the adult and paediatric population. However, the paediatric population, as seen above, has affected children in many ways. Paediatricians all over the world are concerned that this may have longer-lasting effects on the paediatric population, especially in the coming days due to the unpredictable mutations of the virus. A compilation of our results (Table 1) indicated MIS-C to be the most prevalent of the complications and the root cause of many other complications, as it affects multiple organs due to the aggravated inflammatory response of the body. The least prevalent were found to be septic shock and ophthalmic complications. Childhood is a fragile and crucial time in one's life when behavioural, social and educational development takes place. The evidence that COVID-19 may have a long-term effect on children, particularly those with asymptomatic COVID-19, emphasises the importance of paediatricians, mental health specialists and authorities responsible for policymaking to enforce measures to minimise the pandemic's impact on the health of children.

We would also like to show our gratitude to Dr Ajit Singh, PhD 

The authors declare no conflict of interest.

The data that support the findings of this study are openly available in PubMed at https://doi.org/10.25504/ FAIRs haring.a5sv8.

Kanav Khera https://orcid.org/0000-0003-0901-5842

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