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Review Article
Published: 17 July 2020

A literature review of 2019 novel coronavirus (SARS-CoV2) infection in neonates and children

Matteo Di Nardo 1 ,
Grace van Leeuwen 2 ,
Alessandra Loreti 3 ,
Maria Antonietta Barbieri 4 ,
Yit Guner 5 ,
Franco Locatelli 6 &
Vito Marco Ranieri 7

Pediatric Research volume 89 , pages 1101–1108 ( 2021 ) Cite this article

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At the time of writing, there are already millions of documented infections worldwide by the novel coronavirus 2019 (2019-nCoV or severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)), with hundreds of thousands of deaths. The great majority of fatal events have been recorded in adults older than 70 years; of them, a large proportion had comorbidities. Since data regarding the epidemiologic and clinical characteristics in neonates and children developing coronavirus disease 2019 (COVID-19) are scarce and originate mainly from one country (China), we reviewed all the current literature from 1 December 2019 to 7 May 2020 to provide useful information about SARS-CoV2 viral biology, epidemiology, diagnosis, clinical features, treatment, prevention, and hospital organization for clinicians dealing with this selected population.

Children usually develop a mild form of COVID-19, rarely requiring high-intensity medical treatment in pediatric intensive care unit.

Vertical transmission is unlikely, but not completely excluded.

Children with confirmed or suspected COVID-19 must be isolated and healthcare workers should wear appropriate protective equipment.

Some clinical features (higher incidence of fever, vomiting and diarrhea, and a longer incubation period) are more common in children than in adults, as well as some radiologic aspects (more patchy shadow opacities on CT scan images than ground-glass opacities).

Supportive and symptomatic treatments (oxygen therapy and antibiotics for preventing/treating bacterial coinfections) are recommended in these patients.

Synthesis and systematic review of reported neonatal SARS-CoV-2 infections

Roberto Raschetti, Alexandre J. Vivanti, … Daniele De Luca

Demographics, clinical characteristics, and outcomes in hospitalized patients during six waves of COVID‑19 in Northern Iran: a large cohort study

Hoda Shirafkan, Farzin Sadeghi, … Yousef Yahyapour

A COVID-19 pandemic guideline in evidence-based medicine

Erfan Shamsoddin

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. 1 Since its first outbreak in Wuhan, in the Hubei province of China in early December 2019, 2 SARS-CoV2 has spread all over the world infecting millions of people and causing hundreds of thousands o deaths [case fatality rate (CFR): 6.25%, John Hopkins Coronavirus Resource Center, accessed 7 May 2020]. 3

Respiratory viral infections, in general, are more frequent and severe in children than in adults. SARS-CoV2, instead, showed a different scenario. Infection rates appear to be similar between children and adults; however, children develop a milder illness with a low CFR (<0.1%). 3 , 4 , 5 , 6 , 7 The reasons for this milder severity in childhood are not yet understood, and the actual epidemiologic and clinical data of infected neonates and children are not sufficient to solve these gaps. Thus, due to the scarcity of data on SARS-CoV2 in children, we aimed at evaluating the current literature available to provide useful information for clinicians dealing with this particular population.

Search strategy

References for this review were identified through searches on PubMED, Ovid MEDLINE, and EMBASE from 1 December 2019 to 7 May 2020, by two highly experienced librarians at Children’s Hospital Bambino Gesù by using relevant terms related to 2019-nCoV, COVID-19, and SARS-CoV2 in neonates and children (Supplementary Material 1 ). Reference lists of the articles identified by this search strategy were also searched. Earlier reports were not excluded, especially if they were highly cited articles. Only articles published in English were included in this review. Three hundred and seventy-four papers were published in PubMed, 117 in Ovid MEDLINE, and 119 in EMBASE. Among them, 73 were deemed relevant to the purposes of this review (PRISMA flowchart Supplementary Material 2 ).

Biological mechanisms of viral infection and lung injury

Coronaviruses are single-strand, positive-sense RNA viruses with spike-like projections on their surface. 8 These viruses can infect both animals and humans. Among human-infecting coronaviruses, four types (HKU1, NL63, 229E, and OC43) are responsible for mild forms of respiratory disease. 9 , 10 SARS-CoV2, SARS-CoV, and the Middle East respiratory syndrome coronavirus (MERS-CoV) are zoonotic viruses and can infect humans, causing severe respiratory infections, only crossing from animals (Fig. 1 ).

Summary of coronavirus diseases (adapted from Zimmermann and Curtis 8 ).

SARS-CoV2 infects the host cells through an envelope spike (S) protein that mediates the binding and membrane fusion through the angiotensin-converting enzyme 2 (ACE-2) receptor (Fig. 2a, b ). The spike protein is functionally divided into an S1 domain, responsible for receptor binding, and an S2 domain, responsible for cell membrane fusion. 11 SARS-CoV2 employs the transmembrane serine protease 2 of the host cell to prime the S protein and bind the ACE-2 receptor. Other transmembrane pore-forming viral proteins (viroporins) can trigger the NLRP3 (NOD-like receptor 3 inflammasome)-inducing pyroptosis in the host cell. 12

a Renin–angiotensin system (RAS): normal physiology. Renin converts angiotensinogen in angiotensin 1 (ANG 1). Angiotensin-converting enzyme (ACE) converts ANG1 in angiotensin 2 (ANG2). Angiotensin-converting enzyme 2 (ACE-2), a homolog of ACE, is a monocarboxypeptidase that converts ANG2 into angiotensin 1–7 (ANG1–7), which, by virtue of its actions on the MasR (mitocondrial assembly receptor), opposes the molecular and cellular effects of ANG2. ANG2 promotes vasoconstriction, inflammation, and oxidative stress via the activation of AT1R (angiotensin 2 receptor 1). b SARS-CoV2 host cell entry mechanism: Spike protein (S1) binds the ACE-2 receptor once primed by the transmembrane protease serine 2 inhibitor (TMPRSS2). This binding leads to viral entry and replication and induces mechanisms of lung injury. c Potential therapeutic strategies against SARS-COV2. Spike protein-based vaccine; TMPRSS2 inhibitors to block the priming of the spike protein; surface ACE-2 receptor blocker; soluble form of ACE-2 receptor compete with the binding of SARS-CoV2 to the surface ACE-2 receptor.

ACE-2 receptors are expressed in many tissues; however, the majority are present on the alveolar epithelial type II cells. 13 In addition, gene ontology enrichment analysis showed that the ACE-2-expressing epithelial cells have high levels of multiple viral process-related genes, including regulatory genes for viral processes, life cycle, assembly, and genome replication. 13 All these features strongly support the hypothesis that the ACE-2 receptor mediates SARS-CoV2 replication in the lung. SARS-CoV2, through the binding to the ACE-2 receptor, downregulates the ACE-2 intracellular signaling (mitochondrial assembly receptor), causing inflammation, vasoconstriction, and fibrosis in the lung. 13

Epidemiology and pathogenesis in neonates and children

Published data and anecdotal reports support the notion that the number of children found to be infected by SARS-CoV2 is small and their clinical manifestations of COVID-19 are milder compared to adults. 4 , 5 , 6 , 14 , 15 , 16 , 17 , 18

The incidence of SARS-CoV2 confirmed that pediatric cases are low and variable among countries (China: 2–12.3%, 4 , 5 Italy: 1.2%, 19 Korea: 4.8%, 20 USA: 5% 21 ). Several reasons justify this variable incidence: testing availability, testing policy 22 , 23 (at the beginning of pandemics some countries tested only children with established contact with a person with COVID-19, then only hospitalized children with symptoms), and the fact that the infection in children is mild or without symptoms. 24 , 25 Available data also suggest that all ages (0–18) can be infected, but infants seem to be most vulnerable. 5 , 26

Human-to-human transmission (mainly family clustered) is the major transmission mode. 4 , 5 , 27 Children can be infected by inhalation of large droplets generated during coughing or sneezing or by contact with contaminated surface (fomite). 9 , 10 , 28 , 29 , 30 As the virus can be also released in the stool, the fecal–oral transmission cannot be ruled out. 31 , 32 , 33 , 34 Similar to SARS-CoV and MERS-CoV, nosocomial transmission of SARS-CoV2 is high, 9 , 10 , 35 , 36 although no cases of nosocomial infections have been described in children during hospital recovery.

Despite the absence of clinical features of infection or positive microbiological findings in neonates born from SARS-CoV2-positive mothers, 14 , 18 , 37 , 38 , 39 , 40 , 41 , 42 vertical maternal–fetal transmission cannot be ruled out completely. 43 , 44 Conversely, SARS-CoV2 has not been isolated from cord blood, amniotic fluid, and breast milk to date. However, it is crucial to screen pregnant women, implement strict infection control measures on those who tested positive, and monitor the neonates at risk. 44 , 45

Since the incubation period (median 5–7 days) in children and young adolescent varies from 2 to 14 days, but is generally longer than in adults, 10 , 46 , 47 , 48 dynamic observation is mandatory for suspected children. 49 , 50 The median period from symptom onset to hospital admission for patients who were hospitalized is 2 days (1.00–3.50). Recovery generally happens in 1–2 weeks after onset. 40 , 48 Both symptomatic patients and asymptomatic carriers can transmit SARS-CoV2. 49 , 51 , 52

The basic case reproduction (R0) of SARS-CoV2 is variable (2–3.5 in the early stage of the disease); 9 however, the R0 of SARS-CoV2 is higher than SARS-CoV and H1N1. 10 The CFR is ~6.25% (data from 7 May, John Hopkins Coronavirus Resource Center) 3 and varies among countries, 53 patients’ age, and is influenced by testing availability. 54 CFR of patients below 18 years is below <0.1% (adapted from John Hopkins Coronavirus Resource center at 7 May 2020). 3 , 7

This age specificity is still not completely understood. 24 , 55 It is speculated that children, as compared with adults, may have a higher expression of ACE-2 receptors in the type II lung pneumocytes, protecting them from the severe clinical manifestation of COVID-19 (low cytokine release, low pulmonary vascular permeability, etc.). 55 Other immunologic mechanisms (trained immunity, an early and high polyclonal B cell response to SARS-CoV2 with the production of substantial numbers of plasmablasts, and an high level natural killer cells) could also contribute to explain this age-specific characteristic. 55 , 56 A less intense mechanism of antibody-dependent enhancement, instead, could explain why COVID-19 clinical features are milder in children than in adults. 12

Since the World Health Organization (WHO) recently declared COVID-19 a pandemic on 11 March 2020, every patient presenting with evidence of fever, respiratory symptoms, gastrointestinal symptoms, or fatigue should be considered potentially infected (suspected case) with SARS-CoV-2.

Diagnosis of COVID-19 is made by using real-time polymerase chain reaction (RT-PCR) on samples from nasopharyngeal, oropharyngeal swabs, and lower respiratory tract samples whenever possible. 4 , 5 Negative nasopharyngeal swab is generally re-tested after 24 h due to the low negative predictive value of this testing. 57 SARS-CoV2 can be also detected on stools. 33 , 58 , 59 A “positive” RT-PCR result reflects only the detection of viral RNA and does not necessarily indicate the presence of a viable virus. 52

Confirmed cases are defined by positive molecular tests, while asymptomatic cases are defined by positive molecular tests without symptoms.

In children, more than in adults, COVID-19 poses important diagnostic challenges due to the longer incubation period that includes a prolonged interval (~5–6 days) of viral shedding prior to the onset of symptoms. 51 , 60 Moreover, the duration of asymptomatic shedding is not only variable, but also differs according to the anatomic level (upper versus lower airways) of the infection. 49 , 50

At present, among adult patients in affected areas, the most common cause of viral pneumonia with unclear etiology is SARS-CoV2; 2 conversely, in children several other pathogens (influenza, para-influenza, adenovirus, respiratory syncytial virus, metapneumovirus, or other human coronaviruses) can produce very similar clinical and radiologic findings and should be considered in the differential diagnosis. 6 , 8 , 26 , 61 Atypical microorganisms, such as chlamydia pneumoniae and mycoplasma, must be also excluded. 10

No laboratory investigations and radiological findings are diagnostic of SARS-CoV2. 4 , 5 , 6 , 10 , 47 , 62

Clinical features

Clinical manifestations of COVID-19 in neonates and children reported are generally mild and similar among countries. 4 , 5 , 6 , 14 , 16 , 22 , 23 , 37 , 38 , 46 , 63 , 64 , 65 Most commonly, at hospital admission, children presented with fever and respiratory symptoms with cough, sore throat, pharyngeal erythema, nasal congestion, tachypnea/dyspnea, and tachycardia. 22 , 23 , 65 Often, gastrointestinal symptoms, including abdominal pain, nausea, vomiting, and diarrhea, were the first manifestations. 4 , 5 , 15 , 46 , 64 , 66 Neurological manifestations such as seizures, dystonia, and altered mental status were rare. 66 Neonates, instead, showed tachypnea, cough, grunting, nasal flaring, vomiting, poor feeding, diarrhea, and lethargy. 45 , 61 , 67 , 68 , 69 Hospital admission was higher in Italy and Spain than in China and USA; 4 , 21 , 22 , 65 however, this was mainly due to local policies (testing availability and policy, need of patient isolation) rather than clinical condition. 22 , 65

In the largest retrospective cohort of COVID-19 pediatric patients reported so far [2134 patients including 731 (34.1%) laboratory-confirmed and 1412 (65.9%) suspected cases], Dong et al. 5 defined the severity of COVID-19 in asymptomatic infection, mild, moderate, severe, and critical cases, based on the clinical features, laboratory testing, and X-ray imaging (Table 1 ). In this cohort, 4.4% of infected children were asymptomatic, while the remaining children presented a mild (50.9%) or moderate disease (38.8%), respectively. Only 5.2% had severe disease, while 0.6% had critical disease. The proportion of severe and critical cases was 10.6%, 7.3%, 4.2%, 4.1%, and 3.0% for the age group of <1, 1–5, 6–10, 11–15, and >16 years, respectively.

Lu et al. 4 showed 15.8% of COVID-19 children included in their retrospective cohort (171 SARS-CoV2 confirmed cases) were completely asymptomatic and did not show any radiological findings of pneumonia.

Respiratory coinfections were present in almost half of the cases. 4 , 5 , 26 Comorbidities, as in adult patients, 70 may affect outcome 23 and the likelihood of Pediatric Intensive Care Unit (PICU) admission. 4 , 23

In adults, the incidence of ICU admission was high and variable among countries (5% in China and 9% in Italy); 70 , 71 in children, the incidence was lower (0.21–5.2% among Chinese PICUs, 4 , 5 , 15 0.04% in USA 23 ). Of note, several biases (retrospective nature of these studies, 5 , 61 the proportion of the detected cases, the use of different PICU admission criteria among centers, 5 the use of the same data source with overlapping data—Chinese Centers for Disease Control and Prevention database—and the high number of suspected cases 47 ) could have affected the interpretation of these results.

Most of the laboratory abnormalities in children with COVID-19 are nonspecific. Henry et al. 62 reviewed the data of 66 children from 12 different studies and found that 69.2% of children had normal leukocyte counts and that neutrophilia or neutropenia were rare (<5%). Platelet count was variable among studies (generally higher than the normal range), while C-reactive protein and procalcitonin were increased in 13.6% and 10.6% of the cases, respectively. 62

Children admitted to the PICU 15 showed normal or increased whole blood counts (7/8) and increased C-reactive protein, procalcitonin, and lactate dehydrogenase (6/8). High levels of pro-inflammatory and anti-inflammatory cytokines were also present similarly to the adult patients. 72 , 73

Although lymphocytopenia is very common in adults with severe COVID-19 and associated with worse outcomes, 47 it is less common in children (2–3.5%), likely due to the constitutional high percentage of lymphocytes typical of this age. 62 , 74 In adult patients, high ferritin, high d -dimers, and coagulopathy were associated with poor prognosis, 70 but these laboratory findings were rare in children; high d -dimers levels were found in one of the two patients who died from COVID-19. 4 , 15 However, during April 2020, a surge of anecdotal cases showing a hyper-inflammatory state (pediatric multisystem inflammatory syndrome temporally associated with COVID-19) and features similar to atypical Kawasaki disease or Kawasaki disease shock syndrome were reported in Europe (United Kingdom, Spain, Italy). 75 , 76 Many of these patients had positive SARS-CoV2 antibodies and presented an inflammatory state (elevated concentration of C-reactive protein, procalcitonin, ferritin triglycerides, and d -dimers) with cutaneous rash, peripheral edema, conjunctivitis, myocardial dysfunction (elevated cardiac enzymes), and coronary vessels inflammation.

Radiologic findings of SARS-CoV2 viral pneumonia were also variable among children (Fig. 3 ). 4 At hospital admission, many children presented a chest X-ray showing an interstitial pneumonia, 26 while chest computed tomography (CT) scan showed patchy shadows (unilateral and bilateral) with opacities of high density. The typical adult feature of ground-glass opacity was less frequent at hospital admission (32.7%); 4 instead, it was more common in patients admitted to the PICU for respiratory failure. 4 , 5 , 6 , 26 , 77 , 78 , 79 Bedside lung ultrasonography was also used as a diagnostic tool in the emergency departments in a minority of patients; 80 90% of these received a diagnosis of interstitial lung syndrome without further radiographic imaging. 65

a Chest X ray and b chest computed tomography. Vital signs: respiratory rate 22 breaths/min, SpO 2 : 97% in room air. The patient was supported with high-flow nasal cannula 25 L/min, FiO 2 : 30% in the pediatric ward.

Treatment of COVID-19 in neonates and children mainly relies on supportive care. 4 , 10

Home isolation is the first step to manage children with mild symptoms and no underlying chronic conditions. Hospitalization may be considered if rapid deterioration is anticipated or if the patient is not able to urgently return to hospital when signs and symptoms of complicated disease arise. Moderate cases should be managed in hospital, monitoring vital signs and oxygen saturation. Supportive care for these children includes temperature control with antipyretics, bed rest, hydration, and good nutrition. Routine antibiotics and antifungal drugs must be avoided and used only when coinfections are proven or strongly suspected. 10 , 15

In hypoxic patients, oxygen therapy should be immediately initiated. 81 Several devices [low flow nasal cannula, high-flow nasal cannula (HFNC), and noninvasive ventilation (NIV)] can be used according to the centers’ experience. Caution must be taken, since all noninvasive techniques bear the risk of aerosol contamination; strict personal protection equipment (PPE) must be used when caring for these patients.

Invasive mechanical ventilation is indicated if: SpO 2 /FiO 2 < 221 or if there is no improvement in oxygenation (target SpO 2 92–97% with FiO 2 < 0.4) within 30–60 min of HFNC or if there is no improvement in oxygenation (target SpO 2 92–97% and FiO 2 < 0.6) within 60–90 min of CPAP/NIV. 81 Escalating therapies are recommended in case of refractory hypoxia (surfactant therapy in neonates, inhaled nitric oxide, high frequency oscillatory ventilation, and extracorporeal membrane oxygenation). 81 , 82 , 83

A small portion of children with COVID-19 developed septic shock; 5 , 15 , 84 thus, this condition must be always suspected and managed according to the current pediatric guidelines since specific issues for COVID-19 have not been reported so far. 85 Corticosteroids should not be used in pediatric patients, 86 except when required for other indications, such as asthma exacerbations, refractory shock, or evidence of cytokine storm. 16

Several treatment options (intravenous immunoglobulin, interleukin-1 (IL-1) blockade, IL-6 receptor blockade, azythromycin-chloroquine, plasma exchange, infusion of plasma from convalescent subjects, cytokine adsorption filters) have been used in critically ill adult patients; however, data on their efficacy and safety have not been reported yet, thus caution should be used also in children. 87

Antiviral drugs should be used with caution after weighing advantages and disadvantages. For those with mild symptoms, low dosage of interferon-α nebulization has been used 16 in combination with oral ribavirin. Lopinavir/litonavir 15 and remdesivir 88 , 89 have been used in more severe cases; however, their efficacy and safety in children remain to be determined. 90 Remdesivir should be preferred in children because of its positive effects in a recent adult trial; 88 , 89 however, when not available, or when patients are not good candidate to remdesivir, hydroxychloroquine could be considered. 88 The combination of three or more antiviral drugs is generally not recommended. 90

Potential therapeutic strategies for SARS-COV2 are the spike protein-based vaccine, the inhibitors of transmembrane protease serine 2 activity, and the delivery of excessive soluble form of ACE-2 or antibody against the surface of ACE-2 receptors (Fig. 2c ). 13

Prevention and healthcare organization

COVID-19 has no approved treatment in neonates and children and a large-scale vaccine is still under development; thus, prevention is crucial. 10 , 91

SARS-CoV-2 has unique characteristics that makes its prevention complex. SARS-CoV-2 can cause an asymptomatic infection, can be transmitted during the incubation period and after clinical recovery, 13 has a very high affinity to ACE-2 receptors, which are expressed on many mucosal surfaces, resulting in high transmissibility, and can be spread also by fomite. 10

The high transmissibility and low CFR, combined with the discouraging projections of the spread of the virus among adults, 70 fostered many governments, at the beginning of March 2020, to adopt stringent containment and self-isolation measures to reduce the spread of the virus. An intense public health response was started by many countries after the pandemic declaration and involved many strategies: lockdown of the cities and mass quarantine, social distancing mandates, schools closure, cancellation of public gatherings, reduction of domestic and international flights, development of environmental measures and personal protection procedures, and strict contacts tracings by the medical and public health professionals. These measures aim to delay major surges of patients and to lower the demand for hospital extra beds, while protecting the most vulnerable subjects from infection, especially the elderly and those with comorbidities. 92

Data showed that pediatric cases requiring high-intensity medical assistance are uncommon; 5 , 15 however, isolation of all suspected and confirmed patients remains mandatory to avoid the spread of SARS-CoV2 among caregivers and healthcare workers. Therefore, many pediatric hospitals have developed local guidelines and logistic plans (simulations and training courses, reduction of elective surgeries and visits to outpatient clinics, etc.) to identify in advance potential surge capacity in the form of dedicated environment with extra beds for isolation, quarantine, and dedicated staff. As stocks of PPE might run low during a period of pandemic, strict hospital policies should also be adopted according to the WHO guidelines. 93 Furthermore, considering the high number of adult ICU admissions and the difficulties associated to create extra beds in a short period of time, 70 pediatric intensivists and nurses should be ready and prepared to offer help by managing adult patients in PICU 94 or to help in adult ICUs.

Differently from adults, home isolation is not easily performed in children, because they often require the presence of the parents, limiting the use of protective distances (>1.5 m). In those cases, all people sharing a common environment with a SARS-CoV2-positive child should consider the use of gloves and face masks, if available. Hand hygiene practices are extremely important to prevent the spread of the COVID-19 virus at home and in public environments. The WHO recommends washing hands, especially after coughing or sneezing (including sneeze/cough into elbow or tissue), before eating and after using the toilet or sharing common spaces. 95 Hand washing also interrupts transmission of other viruses and bacteria causing common colds, flu, and pneumonia, thus reducing the general burden of disease. Relatives at risk (e.g., people over the age of 65 years, pregnant women, people who are immunocompromised or who have chronic heart, lung, or kidney conditions) 96 should be isolated in protected environment, avoiding exposures to infected children. Because infants cannot wear masks, parents must wear masks, wash hands before close contacts, and sterilize the toys and tablet regularly. 97

All suspected children requiring hospital assistance must be isolated in single rooms (whenever possible, or in dedicated environments, maintaining adequate distances between beds) until the results of the test are available; confirmed patients must be placed in dedicated area for quarantine. A dedicated algorithm must be adopted for the use of the operating theaters in suspected or confirmed COVID-19 cases, according to the urgency of the operation, anticipated viral burden at the surgical site, and the risk that a procedure could spread the virus by aereosol. 98 , 99 Negative pressure rooms are of help, but not mandatory to manage these patients. 10 All rooms and transition environments must be decontaminated after the patient discharge (Fig. 3 ).

Since a high number of health care workers has been infected by SARS-CoV2, all suspected patients, until proven negative, must be assisted by health care providers using PPE 93 and all aerosol generating procedures (intubation, bronchoscopy, tube/tracheostomy suctioning, etc.) must be also performed using airborne transmission precautions. 93

Enhanced traffic control bundling strategies must be adopted by all emergency departments, 100 including a triage zone, transition zones conduction to a quarantine ward or to an isolation ward (Fig. 4 ). A dedicated pathway for children non-SARS-CoV2 suspected (e.g., trauma, poisoning, etc.) must also be created in parallel to avoid contact. Telemedicine should be implemented to help reduce hospital and clinic visits, 101 , 102 by triaging low-acuity patients while delivering high-quality care. 103

Enhanced traffic control system used in Children’s Hospital Bambino Gesù, Rome, Italy.

The scarcity of pediatric cases and the current literature on the topic, as well as the absence of high-quality evidence-based guidelines, has led pediatricians to share experiences and personal communication via online meetings and open access medical education channels. The use of webinars and communication about newly released papers on social media channels such as Twitter, Telegram and WhatsApp, greatly improved the dissemination of knowledge among health care providers.

At the time of this review (7 May 2020), SARS-CoV2 has infected millions of people in the world and caused hundreds of thousands confirmed deaths, but data regarding the epidemiologic and clinical characteristics in neonates and children are still scarce. The purpose of this review was to evaluate the current literature that includes neonates and children to date, providing useful information for clinicians dealing with this selected population. The earliest epidemiologic data show that SARS-CoV2 has a dominant family-cluster transmission and that children present a mild form of COVID-19 (CFR: <0.1%), rarely requiring high-intensity medical treatment in PICU. Vertical transmission is unlikely, but not completely excluded. Diagnosis is performed primarily via molecular nucleic acid amplification testing. Patients with confirmed or suspected COVID-19 should be isolated and healthcare workers should wear appropriate protective equipment. Some clinical features (higher incidence of fever, vomiting and diarrhea, and a longer incubation period) are more common in children than in adults, as well as some radiologic aspects, including the presence of patchy shadow opacities on CT scan images. Treatment options are extrapolated from adult data. Thus, supportive and symptomatic treatments (oxygen therapy and antibiotics for bacterial coinfections) are recommended in these patients. More studies on neonates and children are needed to address these gaps and to provide more robust recommendations to manage COVID-19.

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Matteo Di Nardo

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Each author made a substantial contribution to this review and met the Pediatric Research authorship requirements. M.D.N., G.V.L., and A.L. contributed to the review design, data acquisition, and screening. M.D.N., M.A.B., and Y.G. contributed to the interpretation of the data and article drafting. M.D.N., F.L., and V.M.R. contributed to the article drafting and revisions. All authors have approved the final manuscript.

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Di Nardo, M., van Leeuwen, G., Loreti, A. et al. A literature review of 2019 novel coronavirus (SARS-CoV2) infection in neonates and children. Pediatr Res 89 , 1101–1108 (2021). https://doi.org/10.1038/s41390-020-1065-5

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Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration

Vaccines are a public health success story, as they have prevented or lessened the effects of many infectious diseases. To address concerns around potential vaccine injuries, the Health Resources and Services Administration (HRSA) administers the Vaccine Injury Compensation Program (VICP) and the Countermeasures Injury Compensation Program (CICP), which provide compensation to those who assert that they were injured by routine vaccines or medical countermeasures, respectively. The National Academies of Sciences, Engineering, and Medicine have contributed to the scientific basis for VICP compensation decisions for decades.

HRSA asked the National Academies to convene an expert committee to review the epidemiological, clinical, and biological evidence about the relationship between COVID-19 vaccines and specific adverse events, as well as intramuscular administration of vaccines and shoulder injuries. This report outlines the committee findings and conclusions.

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Digital Resource: Evidence Review of the Adverse Effects of COVID-19 Vaccination
Digital Resource: Evidence Review of Shoulder Injuries from Intramuscular Administration of Vaccines
Health and Medicine — Health Sciences
Health and Medicine — Public Health and Prevention
Health and Medicine — Policy, Reviews and Evaluations

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National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration . Washington, DC: The National Academies Press. https://doi.org/10.17226/27746. Import this citation to: Bibtex EndNote Reference Manager

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Cijara Leonice Freitas 1 ,
Ayane Cristine Alves Sarmento 1 , 2 ,
Nicoli Serquiz 1 ,
http://orcid.org/0000-0003-0969-4806 Maria Luisa Nobre 3 ,
Ana Paula Ferreira Costa 1 , 4 ,
http://orcid.org/0000-0002-4105-7535 Kleyton Santos Medeiros 4 ,
http://orcid.org/0000-0002-8351-5119 Ana Katherine Gonçalves 1 , 5
1 Postgraduate Program student in Health Science , Federal University of Rio Grande do Norte , Natal , Brazil
2 Department of Clinical Analysis and Toxicology , Universidade Federal do Rio Grande do Norte , Natal , Brazil
3 Surgery Department , Federal University of Rio Grande do Norte , Natal , Brazil
4 Institute of Teaching, Research and Innovation, League Against Cancer , Natal , Brazil
5 Department of Obstetrics and Gynecology , Federal University of Rio Grande do Norte , Natal , Brazil
Correspondence to Dr Ana Katherine Gonçalves; anakatherineufrnet{at}gmail.com

Introduction The paediatric population represents a quarter of the world’s population, and like adult patients, they have also suffered immeasurably from the SARS-CoV-2 pandemic. Immunisation is an effective strategy for reducing the number of COVID-19 cases. With the advancements in vaccination for younger age groups, parents or guardians have raised doubts and questions about adverse effects and the number of doses required. Therefore, systematic reviews focusing on this population are needed to consolidate evidence that can help in decision-making and clinical practice. This protocol aims to assess the safety of COVID-19 vaccines in paediatric patients and evaluate the correlation between the number of vaccine doses and side effects.

Methods and analysis We will search the PubMed, ClinicalTrials.gov, Web of Science, Embase, CINAHL, Latin American and Caribbean Health Sciences Literature, Scopus and Cochrane databases for randomised and quasi-randomised clinical trials that list the adverse effects of the COVID-19 vaccine and assess its correlation with the number of doses, without any language restrictions. Two reviewers will select the studies according to the inclusion and exclusion criteria, extract data and asses for risk of bias using the Cochrane risk-of-bias tool. The Review Software Manager (RevMan V.5.4.1) will be used to synthesise the data. We will use the Working Group’s Grading of Recommendations Assessment, Development and Evaluations to grade the strength of the evidence of the results.

Ethics and dissemination Formal ethical approval is not required as no primary data are collected. This systematic review will be disseminated through a peer-reviewed publication.

PROSPERO registration number CRD42023390077.

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This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/bmjopen-2023-076064

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STRENGTHS AND LIMITATIONS OF THIS STUDY

A comprehensive search strategy was developed by a librarian.

The possible heterogeneity among the included studies and comparisons between different types of vaccines can be challenging.

The risk of bias will be evaluated using a validated tool.

The protocol employed by pairs of independent researchers for the selection of studies increases the reliability of the results.

No language restrictions will be adopted.

Introduction

With more than 6 million deaths reported worldwide due to the COVID-19 pandemic, there is an urgency to expand immunisation. 1 According to the Centers for Disease Control and Prevention, unlike the adult population, paediatric patients, who represent a quarter of the world’s population, have a higher number of critical or severe cases (>5 years). 2 WHO defines paediatric patients as persons aged >2 to <19 years at the time of their diagnosis or treatment. 3

Vaccines against COVID-19 have been developed and used in a relatively short period compared with other vaccines. Therefore, their efficacy, safety and side effects require continuous and extensive surveillance and research. Since then, randomised controlled trials have been conducted to confirm the efficacy of the existing vaccines against new variants. 4 5

The primary hurdle in accepting the COVID-19 vaccine has been the lack of confidence in the safety of newly discovered vaccines. The most common reactions observed in adult patients are local pain, erythema, swelling and lymphadenopathy at the injection site. The most common systemic side effects associated with the COVID-19 vaccines are headache, fatigue, myalgia and nausea. 6 7

Currently, with the efforts of regulatory agencies, the scientific community and government, the vaccinations for younger age groups have advanced, in addition to the administration of existing vaccines and emergence of others with different mechanisms of action. 8–10

The benefits and security of vaccines in the paediatric population are yet to be widely publicised. Furthermore, this population has particular characteristics, and the behaviours adopted by parents or guardians directly affect childhood vaccination. 11 12

This systematic review protocol aims to evaluate the safety of COVID-19 vaccines in paediatric patients and identify the correlation between the number of doses and side effects.

Materials and methods

This systematic review protocol was developed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIDMA) Protocol. 13 This review was registered in PROSPERO (No: CRD42023390077).

Inclusion criteria

Randomised and quasi-randomised clinical trials that evaluated COVID-19 vaccine side effects in paediatric patients and were published from January 2020 in any language will be included in the study.

Exclusion criteria

Articles that are not peer-reviewed and that are observational studies, review articles, reports and case series will be excluded. Additionally, studies that did not have paediatric patients as a population will be excluded.

Patients, intervention, comparison, outcome strategy and types of studies

Patients: children and adolescents (0–17 years) who were healthy and previously SARS-CoV-2 infection-free.

Intervention: COVID-19 vaccine or a combination of vaccines against COVID-19.

Comparator/control: placebo or no vaccination.

Outcome: Side effects, safety and tolerability of the COVID-19 vaccine or the combination of vaccines against COVID-19.

Types of studies: Clinical trials.

Primary outcome

Side effects, safety and tolerability of the COVID-19 vaccine or the combination of COVID-19 vaccines.

Secondary outcomes

Correlation between the number of vaccine doses and side effects, and death caused by adverse events of vaccination.

Patient and public involvement

Search strategy.

The following databases will be searched: PubMed, ClinicalTrials.gov, Web of Science, Embase, CINAHL, Latin American and Caribbean Health Sciences Literature, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL). In addition, the reference lists of the retrieved articles will be manually searched to identify eligible studies. No language restrictions will be imposed.

Our search keywords will be based on Medical Subject Headings (MeSH) in the following combinations: “Pediatrics”, “Infant”, “Child”, “Adolescents” “vaccines”, “vaccination”, “vaccine COVID-19”, “SARS-CoV-2 vaccine”, “toxicity”, “side effects”, “adverse events”, “clinical trial”, “controlled clinical trial”. The search strategy to be used in PubMed is presented in table 1 . The search strategy for all databases is available in online supplemental file .

Supplemental material

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Search strategy for PubMed

Data collection and analysis

Study selection.

Three researchers (CLF, ACAS and KSM) will independently select the studies of interest. Initially, the Rayyan (Mourad Ouzzani, University of Oxford, UK) will be used to identify duplicates. Subsequently, the titles and abstracts of the selected articles will be analysed to identify relevant papers. The same authors will analyse the whole texts according to the inclusion criteria. Discrepancies will be resolved by a fourth author (AKG). The study selection process is summarised in the PRISMA flow chart ( figure 1 ).

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PRISMA flow diagram for systematic review and meta-analysis. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.*Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers).**If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.

Data extraction

The authors developed and tested a data collection form. Data from each included study will be extracted independently by two authors (CLF and ACAS), and any subsequent discrepancies will be resolved through discussion with a third author (AKG). The extracted data will include authors, year of publication, study site, study type, main objectives, mean age of the population, vaccination schedule, follow-up of participants and side effects.

Missing data

For studies with incomplete or missing data, the authors will contact the article authors by telephone or email. In case of no response, the data will be excluded from the analysis and discussed in the discussion section.

Data synthesis

Data will be entered and analysed using Review Manager (RevMan, V.5.4, The Cochrane Collaboration, 2020). We will evaluate the heterogeneity between studies using the I 2 statistic (<25%, low heterogeneity; 25%–50%, moderate heterogeneity and >50%, high heterogeneity). Fixed-effects models will be used, except when significant heterogeneity exists in the included studies (I 2 >50%). ORs with 95% CI will be estimated to determine the corresponding risk. Dichotomous data from each eligible study will be combined for meta-analysis using the Mantel/Haenszel model.

A sensitivity analysis will be performed to verify the possible sources of heterogeneity, removing one study at a time and verifying whether there is a considerable change in the 95% CI. Studies with high risks of bias will be excluded.

Quality assessment

KSM, ACAS and CLF will independently assess the risk of bias in eligible studies using the Cochrane risk-of-bias tool. 14 Bias will be assessed as high, low or unclear for individual elements from five domains (selection, performance, attrition, reporting and others). Publication bias will be assessed by inspecting the funnel plot and asymmetry of the funnel plot will be tested using Egger’s test.

Assessing certainty in the findings

The quality of the evidence will be assessed based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE). The GRADE tool classifies studies as low, moderate or high quality. 15

Ethics and dissemination

The result of this systematic review will be disseminated through publication in an open-access peer-reviewed journal, scientific publications and reports. Ethical review is not required because we will only search and evaluate against publicly available literature.

The decision to vaccinate paediatric patients raises several questions even though the rigour of vaccine production and release is constantly being disclosed. 16 According to the WHO emergency list, 13 vaccines have been approved, and more than 90 are still under development and exploration. 17 Even with the approval and clearance by regulatory health agencies, legal guardians or parents of children still have doubts about the safety and possible adverse reactions. 18 19

In a systematic review of the safety and efficacy of vaccinations against COVID-19 in children and adolescents, local reactions had a low occurrence, with some reports of myocarditis and pericarditis. 20 However, this review only evaluated English-language publications and did not include children younger than 1 year.

Currently, vaccinations continue to develop for younger age groups (from the age of 6 months), as new cases and virus variants continue to emerge every day. 21

It is not possible to measure all the effects of the SARS-CoV-2 pandemic on the paediatric population. The suspension of face-to-face classes and social distancing has damaged cognitive and social development. In addition, the WHO warns of a reduction in childhood vaccination coverage; in 2021, about of 25 million children were not vaccinated. 22 Non-adherence to the schedule of other vaccines may affect susceptibility to other diseases. During the pandemic outbreak, some children developed multisystem inflammatory syndrome after contact with the SARS-CoV-2 virus, which had symptoms similar to incomplete Kawasaki disease; it was reported in several countries 23–25 with a mortality rate of approximately 1%–2%. 16

Postmarketing pharmacovigilance, especially in the paediatric population, will help parents or guardians in decision-making. This protocol is designed to include large numbers of vaccinated paediatric patients across all age groups and different vaccines, to provide reliable results on childhood COVID-19 vaccination.

Ethics statements

Patient consent for publication.

Not applicable.

↵ Coronavirus COVID-19 global cases by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU) . 2022 . Available : https://coronavirus.jhu.edu/map.html
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Contributors Conceptualisation: CLF, ACAS, KSM and AKG. Data curation: CLF, NS and MLN. Formal analysis: CLF, KSM, APFC and ACAS. Methodology: CLF, KSM, APFC and ACAS. Supervision: CLF, KSM and AKG. Validation: CLF, KSM, ACAS and AKG. Writing–original draft: CLF, NS, MLN and KSM. Writing–review and editing CLF, ACAS, KSM and AKG.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Read the full text or download the PDF:

Literature Review of COVID-19, Pulmonary and Extrapulmonary Disease

Affiliations.

1 University of Maryland Medical System, Capital Region Health, Internal Medicine Department, Cheverly, MD.
2 University of Maryland Medical System, Capital Region Health, Internal Medicine Department, Cheverly, MD. Electronic address: [email protected].
3 Federal University of Santa Catarina, Dentistry Department, Florianopolis, Brazil. Electronic address: [email protected].
PMID: 33785204
PMCID: PMC7859706
DOI: 10.1016/j.amjms.2021.01.023

In December 2019 novel coronavirus-Severe Acute Respiratory Syndrome-Corona Virus2 (SARS-CoV2)-originated from Wuhan, China, and spread rapidly around the world. This literature review highlights the dynamic nature of COVID-19 transmission and presentation. Analyzing 59 relevant articles up to May 1st, 2020 reflects that the main reported clinical manifestation of COVID-19 pandemic is fever and respiratory involvement. Also, current literature demonstrates a wide spectrum of different and atypical presentation(s) of COVID-19. The definite route of SARS-CoV2 transmission is respiratory droplets, however, virus nucleic acid has been detected in the stool and urine specimens as well. The severity of symptoms and outcomes of COVID-19 vary based on the patient's medical background, age, sex, and concurrent medical conditions (e.g. pregnancy). This is the first review that classifies all essential points regarding COVID-19 manifestations at a glance to improve the outcome of the patients by a better insight into diagnosis and management.

Keywords: COVID-19; Manifestations; Novel corona virus (2019-ncov); Presentations; Severe acute respiratory syndrome-corona virus2 (sars-cov2); Transmission.

Publication types

COVID-19* / epidemiology
COVID-19* / metabolism
COVID-19* / physiopathology
COVID-19* / transmission
Lung* / metabolism
Lung* / physiopathology
Lung* / virology
SARS-CoV-2 / metabolism*

Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration

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Digital Resource: Evidence Review of the Adverse Effects of COVID-19 Vaccination
Digital Resource: Evidence Review of Shoulder Injuries from Intramuscular Administration of Vaccines
Press Release

CASE REPORT article

Antiphospholipid antibody-related hepatic vasculitis in a juvenile after non-severe covid-19: a case report and literature review.

1 Tsinghua Medicine, School of Medicine, Tsinghua University, Beijing, China
2 Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
3 State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
4 Department of Infectious Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China

Antiphospholipid antibodies (aPL) are both laboratory evidence and causative factors for a broad spectrum of clinical manifestations of antiphospholipid syndrome (APS), with thrombotic and obstetric events being the most prevalent. Despite the aPL-triggered vasculopathy nature of APS, vasculitic-like manifestations rarely exist in APS and mainly appear associated with other concurrent connective tissue diseases like systemic lupus erythematous. Several studies have characterized pulmonary capillaritis related to pathogenic aPL, suggesting vasculitis as a potential associated non-thrombotic manifestation. Here, we describe a 15-year-old girl who develops hepatic infarction in the presence of highly positive aPL, temporally related to prior non-severe COVID-19 infection. aPL-related hepatic vasculitis, which has not been reported before, contributes to liver ischemic necrosis. Immunosuppression therapy brings about favorable outcomes. Our case together with retrieved literature provides supportive evidence for aPL-related vasculitis, extending the spectrum of vascular changes raised by pathogenic aPL. Differentiation between thrombotic and vasculitic forms of vascular lesions is essential for appropriate therapeutic decision to include additional immunosuppression therapy. We also perform a systematic review to characterize the prevalence and clinical features of new-onset APS and APS relapses after COVID-19 for the first time, indicating the pathogenicity of aPL in a subset of COVID-19 patients.

1 Introduction

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characteristic of arterial, venous, or microvascular thrombosis, obstetric morbidity, and well-defined non-thrombotic manifestations in the setting of persistent antiphospholipid antibodies (aPL) ( 1 , 2 ). aPL, composed of a diverse family of acquired autoantibodies, are recognized as causative factors for clinical manifestations of APS ( 3 ). Both genetic and environmental elements could exert as precipitating factors for aPL production, with infection being the most prevalent trigger ( 4 – 6 ). In the recent COVID-19 pandemic, the observed high prevalence of aPL has been reported, yet the potential pathogenicity of these antibodies remains uncertain and controversial ( 7 ). The molecular mimicry between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins and native tissues and the neoepitope caused by SARS-CoV-2-induced oxidative stress probably contribute to aPL generation ( 8 ). In addition to widely reported aPL-related thrombosis, associated non-thrombotic manifestations are emerging with considerable evidence ( 9 ). Compared with adult patients, aPL-related non-thrombotic complications, both criteria and non-criteria, are more frequently presented in pediatric patients ( 10 ). aPL-related vasculitis is characterized as the inflammation of vessel walls and is only well-confirmed in pulmonary capillaries as diffuse alveolar hemorrhage (DAH) ( 11 ). This rare manifestation can result in occlusion of vessel lumen in the absence of thrombus, which might make it clinically indistinguishable to thrombotic events. Differentiation between thrombotic and vasculitic causes of aPL-related vascular damage is essential for proper therapeutic decision to adequately include immunosuppression therapy ( 12 ). Here, we describe an uncommon case of a young girl with aPL-related vasculitis-induced liver infarction after non-severe COVID-19 infection, providing valuable information for development of pathogenic aPL in infectious diseases and aPL-related vasculitic manifestations.

2 Case report

A 15-year-old girl presented to the emergency department with hyperpyrexia and abdominal pain persisting for over a month. Initial laboratory results revealed elevated inflammation markers, liver dysfunction, and prolonged activated partial thromboplastin time (aPTT) (62.2 s; normal: 25–37 s) and prothrombin time (PT) (17.8 s; normal: 11–14 s). There were no bleeding signs clinically. Abdominal CT demonstrated liver “abscess-like” lesions ( Figures 1A, B ) as well as possible cholecystitis ( Figures 1C, D ), and the histopathological examination of liver biopsy specimens confirmed the acute hepatic necrosis. An empiric anti-infective therapy was initiated with intravenous ertapenem and changed to meropenem and metronidazole later. Vitamin K and plasma transfusion were applied for correction of coagulation disorders but turned out to be ineffective. Possible pathogens were under intense exploration, but all proved negative after following tests: traditional microbiologic culture and metagenomic next-generation sequencing of peripheral blood samples and liver biopsy specimens; serology screenings for fungi, SASR-CoV-2, hepatitis viruses, TORCH pathogens, Leishmania, and mycobacteria tuberculosis; Epstein–Barr virus DNA analysis; and microscopic examination of parasites in stool samples. In addition, tumor marker analysis, bone marrow examination, specific staining of liver biopsy specimens, and ceruloplasmin test showed no abnormalities. The efficacy of anti-infective therapy was undetermined with fluctuating inflammation markers and unrelieved abdominal pain. Elevated D-dimer (14.87 mg/L; normal: 0–0.55 mg/L), fibrin and fibrinogen degradation products (FDP) (27.6 μg/mL; normal: 0–5 μg/mL), and fibrinogen (7.52 g/mL; normal: 1.8–3.5 g/mL) were also indicated. Repeated CT demonstrated enlargement or reduction of some liver lesions, as well as the emergence of new lesions. The antibiotics were improved to intravenous ertapenem and vancomycin after the re-elevation of C-reactive protein. Unexpectedly, her symptoms worsened with a re-elevated fever peak and persistent coagulation disorders ( Figure 2 ).

Figure 1 (A, B) CT scan without and with contrast demonstrates liver "abscess-like" lesions. (C, D) CT scan without and with contrast demonstrates possible cholecystitis (red arrowhead). (E, F) Histopathological examination reveals vasculitis of hepatic arteries and resultant liver infarction (black arrowhead) (bar is 50 μm).

Figure 2 Positive correlation between clinical course and the administration of dexamethasone but not antibiotics. Laboratory reference range for indicators: CRP<3.0 mg/L; ALT: 9–50 U/L. CRP, C-reactive protein; ALT, alanine aminotransferase; DXM, dextromethorphan; ETP, ertapenem; MEM, meropenem; MTR, metronidazole; VAN, vancomycin; CMZ, cefmetazole; PDN, prednisone; MMF, mycophenolate mofetil; HCQ, hydroxychloroquine.

The young girl had a medical history of mild SARS-CoV-2 Omicron variant infection, presented with only nasal congestion and fatigue. The onset of abdominal pain occurred 7 days after testing negative for SARS-CoV-2 antigen and complete remission of COVID-19 symptoms. As the efficacy of low-dose dexamethasone given during plasma transfusion could not be excluded for transient improvement of the patient ( Figure 2 ), an immune dysregulation secondary to infection was considered. Serologic testing of antinuclear antibodies and autoimmune hepatitis antibodies only revealed the presence of low titers of antinuclear antibody (1:80) and smooth muscle antibody (1:80). Autoimmune liver diseases were ruled out. Antibodies associated with other systemic autoimmune diseases were comprehensively evaluated, and the presence of IgG anticardiolipin (aCL) and IgG anti-β2-glycoprotein I (anti-β2GPI) antibodies, as well as lupus anticoagulant (LA), was demonstrated ( Table 1 ). Other autoantibodies were undetected. The aPTT and PT correction tests showed negative results. Consecutive examinations demonstrated disease progression following changes of aPL titers, and hepatic lesions were considered to be related to aPL. Considering the hypercoagulable state of pathogenic aPL, the patient underwent CT scan, MRI, MRA, and vascular ultrasound and multiple small acute to subacute cerebral infarcts were indicated. No thrombus and other abnormalities were detected. The liver biopsy specimen was histologically re-evaluated. Immune infiltration with a large number of neutrophils and fibrinoid necrosis were evident in some small- and medium-sized arteries, and adjacent hepatic tissues underwent ischemic infarction consequently ( Figures 1D–F ). The patient traversed the most severe phase because of administered low-dose dexamethasone. Further therapy included 40 mg prednisone once a day, 500 mg mycophenolate mofetil (MMF) twice a day, and 200 mg hydroxychloroquine twice a day for immunosuppression, along with 100 mg aspirin once a day to prevent future thrombosis. The patient were discharged from the hospital with reduced inflammation markers, diminished abdominal pain, and healed liver lesions as shown in CT examination. The administration of MMF, hydroxychloroquine and aspirin remained unchanged after discharge, whereas prednisone was gradually tapered. The dose reduction proceeded at 5 mg per week until reaching a daily dose of 20 mg, followed by a weekly reduction of 2.5 mg until reaching a daily dose of 15 mg. Scheduled follow-up appointments were conducted. Six months after discharge, the patient discontinued medication autonomously and subsequently experienced a relapsed right-upper quadrant pain with re-elevated aPL titers and significantly prolonged aPTT ( Table 1 ). D-dimer, FDP, and fibrinogen were within normal ranges. Resumption of treatment yielded amelioration. Considering the persistence of medium-to-highly positive aCL and LA for over 12 weeks, as well as aPL-related hepatic vasculitis and cerebral infarction, the diagnosis was made as highly probable APS with vasculitis as a non-criteria manifestation.

Table 1 Disease parameters and titers of autoantibodies.

3 Discussion

Compared with the updated Sapporo criteria with only vascular thrombosis and pregnancy morbidity as diagnostic manifestations of APS ( 1 ), the new 2023 ACR/EULAR criteria has introduced several well-defined non-thrombotic manifestations into the clinical criteria for APS classification, including microvascular diseases, cardiac valve diseases, and thrombocytopenia ( 2 ). A progression and advancement of the comprehension of aPL-related clinical manifestations is indicated. However, limitations still exist as patients with criteria aPL and comparatively uncommon non-thrombotic manifestations and patients with fulfillment of clinical criteria but seronegative conventional aPL might be inadequately excluded. These conditions are therefore suggested to be referred as “probable APS” or “non-criteria APS” ( 15 ). Our case met the laboratory criteria based on persistence of medium-to-highly positive aCL and LA. The complete and sustained remission of hepatic vasculitis was achieved only when aPL were managed at lower titers with pathogenic effects effectively suppressed. The development of cerebral infarction happened in the setting of highly positive aPL and in the absence of other vascular risk factors. Hepatic vasculitis and cerebral infarction were therefore considered to be associated manifestations. The pathophysiology of cerebral infarcts was undetermined, yet the remarkably elevated D-dimer and FDP suggested a possibility of thrombotic events. Accordingly, our case was assessed as highly probable APS with aPL-related hepatic vasculitis as a non-criteria manifestation, and the development of pathogenic aPL was associated with prior COVID-19 infection.

Infections have been implicated in induction of autoimmunity including aPL production ( 16 ), with the recent COVID-19 pandemic being no exception ( 7 ). A large number of studies have reported high prevalence of aPL (5%–71%), both criteria and non-criteria types, in COVID-19 patients ( 7 , 17 ). Several potential mechanisms have been proposed but require further validation ( 8 ). Molecular mimicry supposes that the S1 and S2 subunits of the SARS-CoV-2 viral S protein might form a phospholipid-like epitope shared with native tissues, triggering aPL production and provoking an immunogenic response ( 18 – 20 ). The neoepitope model posits that oxidative stress induced by SARS-CoV-2 can alter the conformation of β2GPI ( 21 , 22 ) and create a neoepitope for antibody generation ( 23 ).

Despite the observed high prevalence, the pathogenicity of COVID-19-associated aPL remains uncertain and controversial. To explore the potential roles of aPL, numerous studies have analyzed the correlations of aPL and clinical manifestations in COVID-19 patients, yet a consensus could not be reached. COVID-19-associated aPL were demonstrated to be natural or nonpathogenic in most studies ( 24 – 50 ), which was also shown in the largest meta-analysis published in 2021 ( 51 ). Additionally, anti-β2GPI in COVID-19 was reported to rarely (5%) recognize domain I of β2GPI, the molecular region most commonly associated with pathogenicity ( 24 ). On the contrary, associations of aPL with disease severity and thrombosis in COVID-19 patients were also reported ( 52 – 67 ). Notably, the largest cohort study demonstrated a correlation between the presence of aCL or IgA anti-β2GPI and thrombotic events ( 65 ). IgG antibodies purified from COVID-19 patients with high aPL titers were found to trigger neutrophil extracellular trap release and potentiate thrombosis in mice, similarly to IgG isolated from individuals with definite APS ( 59 ). Additionally, infections have been reported as the most common causative factor of catastrophic APS (CAPS), suggesting that infection-induced aPL could exhibit biological activity in a subset of patients ( 6 ). Several theories have been proposed to explain the heterogeneity. The “two hits” theory holds that aPL (first hit) induce a thrombophilic state, but clotting requires additional thrombophilic condition (second hit), often involving an innate immunity activator like inflammation, infection, or surgery ( 3 ). Furthermore, infections are proposed to more likely trigger APS in individuals with genetic propensity, immune defects, or hormonal abnormalities ( 16 ). Therefore, the pathogenicity of aPL exhibits heterogeneity across COVID-19 patients and susceptible individuals with predisposing factors might present aPL-related manifestations in the presence of COVID-19-associated aPL.

Albeit the intense exploration of aPL in COVID-19 patients by multiple studies, most of them neither specify the duration of aPL positivity nor subgroup patients according to antibody levels. All COVID-19 patients with positive aPL were incorporated, and individuals with or without pathogenic aPL were merged together for characterization and analysis, contributing to the debatable pathogenicity of aPL. Systematic analyses based on these studies could not reveal the prevalence and features of patients developing pathogenic aPL after COVID-19. Conversely, new-onset APS in COVID-19 patients have also been reported, wherein persistently high-titer aPL, associated thrombotic and non-thrombotic manifestations, and recovery following treatments based on APS management guidelines substantially indicate the pathogenicity of aPL. Therefore, new-onset APS cases could be a narrow representative of COVID-19 patients with pathogenic aPL. We systematically reviewed the literature of relevant cases up to February 2024 using PubMed and EMBASE to analyze the APS onset after COVID-19 for the first time. The cases reported as APS after COVID-19 infection with sufficient information to meet the updated Sapporo criteria or the new 2023 ACR/EULAR criteria ( 1 , 2 ) or with limited information but compelling evidence to support the diagnosis of APS were included. The former and the latter were annotated as definite APS and highly probable APS respectively. Nine cases ( 68 – 76 ) were identified and evaluated together with our case ( Table 2 ). The patients ranged from 15 to 89 (mean = 41.10) years of age and most of the patients were female, consistent with the epidemiology of APS that is more common in middle-aged women ( 82 ). According to WHO-issued guidelines ( 83 ), COVID-19 severity of these cases encompassed a spectrum from non-severe to critical, indicating that aPL-related manifestations did not merely develop on the basis of cytokine storms in critical patients. The time interval from COVID-19 to the onset of APS varied from 7 to 41 days (mean = 18 days) and a probably more frequent occurrence during the convalescent period was suggested. Definite or probable CAPS was reported in three cases (30%), significantly higher than the approximate 1% incidence of CAPS in all APS patients ( 84 ). Thrombosis and corresponding organ infarctions (80%) were the most common manifestation, followed by thrombocytopenia (30%). There were 12 patients mentioned in four cohort studies who also fulfilled the inclusion criteria but were not included due to the lack of individualized information ( 50 , 64 , 67 , 77 – 81 , 85 ). In addition to newly diagnosed APS, five cases have reported relapses of completely remitted APS following COVID-19 infections ( Table 2 ), reiterating SARS-CoV-2 as a potential trigger for pathogenic effects of aPL and exacerbation of APS in some patients. Here, we report the first case of developing pathogenic aPL in a juvenile after non-severe COVID-19, diagnosed as highly probable APS. Notably, the absence of any medical history in the patient alerts the possibility of developing severe aPL-related symptoms following non-severe COVID-19 infection in previously healthy individuals, which was also indicated in a healthy woman developing obstetric APS (OAPS) after non-severe COVID-19 infection ( 73 ).

Table 2 Demographic and clinical characteristics of APS after COVID-19.

Differences in distribution, clinical presentations, and outcomes exist between pediatric and adult APS ( 86 ). Compared with adult patients, juvenile patients more frequently exhibit non-thrombotic aPL-related manifestations ( 10 ). A study including 121 juveniles fulfilling the updated Sapporo criteria demonstrated a high prevalence of associated non-thrombotic manifestations with neurologic, hematologic, and skin disorders being the most common ( 87 ). Non-thrombotic manifestations sometimes precede later thrombotic events ( 88 ), leaving pediatric patients with isolated non-thrombotic manifestations being inadequately excluded from APS patient population. Accordingly, diagnostic criteria for definite APS are inapplicable in juveniles. Recommendations for management of pediatric APS published by SHARE initiative advocated for the incorporation of non-criteria manifestations into classification criteria for pediatric APS ( 86 ). Therefore, recent studies in pediatric APS have concentrated mainly on pathogenic aPL and associated manifestations rather than definite APS. A study of pediatric APS including definite and probable cases revealed high percentage of hematologic and skin disorders ( 89 ). Moreover, another analysis of children with medium or highly positive aPL suggested that more than half exhibited non-thrombotic aPL-related manifestations alone ( 90 ).

In our case, the histopathology of liver biopsy specimens revealed immune infiltration and fibrinoid necrosis of arteries without granulomatosis, indicating the existence of hepatic vasculitis that has not been reported in association with pathogenic aPL before. The resultant occlusion of arteries gave rise to liver ischemic necrosis in the absence of any notable thrombus or microthrombus. The patient was successfully treated with immunosuppression, further supporting a vasculitic other than thrombotic etiology.

Although debatable, vascular lesions raised by aPL could be inflammatory. DAH, characterized by bleeding into the alveolar space resulting from disruption and injury of pulmonary microcirculation, represents a genuine inflammatory complication of APS and has been included into clinical criteria for APS in the 2023 ACR/EULAR criteria ( 2 , 91 ). Several studies have investigated the primary APS-associated DAH in recent years ( 11 , 92 – 94 ). Surgical or transbronchial biopsies were performed in 20 cases and capillaritis without thrombus or microthrombus was histologically documented in 11 of them (55%), indicating an isolated inflammatory vasculopathy in DAH development. The recommended and efficient treatment of DAH in APS with glucocorticoids and immunomodulatory agents re-emphasizes an inflammatory instead of thrombotic etiopathology of DAH ( 91 ). Additionally, mesenteric vasculitis is considered to be one of aPL-related microvascular manifestations as well ( 95 ). Sporadic cases with authentic associated vasculitic manifestations have also been reported in cerebral ( 96 ), renal ( 97 ), aortic ( 98 ), and cutaneous ( 99 ) vasculature, and no local thrombus or microthrombus was noted in these inflammatory lesions.

Therapy for APS is diverse and individualized based on a broad spectrum of manifestations. Long-term oral anticoagulants like warfarin are recommended for thrombotic APS ( 100 ), and alternative therapies such as extended therapeutic dose of low-molecular-weight heparin can be utilized for patients with recurrent thrombotic events despite warfarin ( 101 ). For aPL carriers with high-risk profiles or OAPS patients, low-dose aspirin is proposed for primary thrombosis prevention, particularly in individuals with additional vascular risk factors ( 100 , 102 ). Glucocorticoids; immunomodulatory agents including MMF, cyclophosphamide, and azathioprine; and B-cell-modulating agents like rituximab and belimumab, are recommended in cases with non-thrombotic manifestations ( 103 , 104 ). Notably, these recommendations, based on adult-derived studies, might be improper for pediatric populations due to differences in physiological conditions, metabolic capacities and duration of medication. Additionally, the low prevalence and heterogeneity of APS in juveniles impede the formation and limit the strength of evidence-based guidelines ( 86 , 105 ), contributing to substantial variations in treatment regimens that are mostly based on physicians’ experience or observational studies.

In our case, aspirin was administered without anticoagulants. The decision was made based on vasculitis-induced hepatic infarction as the major clinical presentation, repair of cerebral lesions with indefinite pathology before systemic treatment, impaired liver synthetic function for coagulation factors, and the absence of other thrombosis risk factors. As concurrent thrombosis risk factors like arterial hypertension, hyperlipidemia, atherosclerosis and smoking are rarely observed in younger subjects, long-term anticoagulation therapy is not indicated in pediatric thrombotic APS patients harboring discontinuous aPL ( 106 – 108 ). Likewise, immunosuppressive therapy in our case reduced aPL titers close to baseline levels and suppressed their pathogenicity, reminiscent of patients with discontinuous aPL. Combined together, anticoagulants were not administered temporarily. However, the patient underwent intensive and regular follow-up to monitor for emergence of any additional thrombosis risk factors, in which scenario, anticoagulants would be introduced as a replacement of aspirin.

aPL-related thrombosis and vasculitis can cause similar clinical presentations including organ infarctions, whereas the treatment decision is different due to the underlying pathologies. The histopathologic results helped us to confirm the inflammatory vasculopathy and guided the treatment to adequately include immunosuppression comprising glucocorticoids and immunomodulatory agents. Therefore, when no thrombus is detected by non-invasive examinations, biopsy for confirmation of the underlying vasculopathy is suggested in APS, if possible and especially when liver is involved.

Our treatments were individualized based on an atypical case. Although the outcome was favorable, the efficacy and safety of aspirin without anticoagulants require further validation during extended follow-up. We merely recommend the addition of immunosuppressants to conventional therapy for managing aPL-related vasculitis.

4 Conclusion

Given the perplexing and contentious nature of aPL produced during infections, the COVID-19 pandemic provides a distinctive opportunity to comprehensively assess this issue. The literature review and analysis evaluate the onset and relapse of APS after COVID-19 infection, suggesting that SARS-CoV-2-triggered aPL may exert pathogenic effects in a subset of COVID-19 patients.

Altogether, we endorse the hypothesis that pathogenic aPL can raise vascular damage manifested as vasculitis other than thrombosis, conveying distinct therapeutic considerations to include immunosuppression therapy. In addition to vasculitis, other forms of vascular lesions including proliferative vascular diseases have also been described in APS ( 109 ), extending the spectrum of vascular changes associated with pathogenic aPL. Such cumulative evidence supports the statement that the nature of APS should be extended to both thrombophilia and vasculopathy.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Ethics statement

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author contributions

QL: Conceptualization, Formal analysis, Investigation, Writing – original draft. JL: Conceptualization, Formal analysis, Investigation, Writing – original draft. MZ: Writing – review & editing. YG: Writing – review & editing. ZL: Funding acquisition, Writing – review & editing. TL: Funding acquisition, Writing – review & editing. LZ: Resources, Supervision, Writing – review & editing.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the National High Level Hospital Clinical Research Funding (2022-PUMCH-B-043) and the National Natural Science Foundation of China (82202541).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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104. Xourgia E, Tektonidou MG. Management of non-criteria manifestations in antiphospholipid syndrome. Curr Rheumatol Rep . (2020) 22:51. doi: 10.1007/s11926-020-00935-2

105. Tarango C, Palumbo JS. Antiphospholipid syndrome in pediatric patients. Curr Opin Hematol . (2019) 26:366–71. doi: 10.1097/MOH.0000000000000523

106. Coloma Bazán E, Donate López C, Moreno Lozano P, Cervera R, Espinosa G. Discontinuation of anticoagulation or antiaggregation treatment may be safe in patients with primary antiphospholipid syndrome when antiphospholipid antibodies became persistently negative. Immunol Res . (2013) 56:358–61. doi: 10.1007/s12026-013-8407-x

107. Criado-García J, Fernández-Puebla RA, Jiménez LL, Velasco F, Santamaría M, Blanco-Molina A. [Anticoagulation treatment withdrawal in primary antiphospholipid syndrome when anticardiolipin antibodies become negative]. Rev Clin Esp . (2008) 208:135–7. doi: 10.1157/13115821

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109. Knight JS, Kanthi Y. Mechanisms of immunothrombosis and vasculopathy in antiphospholipid syndrome. Semin Immunopathol . (2022) 44:347–62. doi: 10.1007/s00281-022-00916-w

Keywords: antiphospholipid antibodies, COVID-19, pediatrics, vasculitis, non-thrombotic manifestation, vasculopathy

Citation: Li Q, Li J, Zhou M, Ge Y, Liu Z, Li T and Zhang L (2024) Antiphospholipid antibody-related hepatic vasculitis in a juvenile after non-severe COVID-19: a case report and literature review. Front. Immunol. 15:1354349. doi: 10.3389/fimmu.2024.1354349

Received: 12 December 2023; Accepted: 29 March 2024; Published: 19 April 2024.

Reviewed by:

Copyright © 2024 Li, Li, Zhou, Ge, Liu, Li and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Li Zhang, [email protected]

† These authors have contributed equally to this work and share first authorship

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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A Review of Coronavirus Disease-2019 (COVID-19)

Tanu singhal.

Department of Pediatrics and Infectious Disease, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, India

There is a new public health crises threatening the world with the emergence and spread of 2019 novel coronavirus (2019-nCoV) or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus originated in bats and was transmitted to humans through yet unknown intermediary animals in Wuhan, Hubei province, China in December 2019. There have been around 96,000 reported cases of coronavirus disease 2019 (COVID-2019) and 3300 reported deaths to date (05/03/2020). The disease is transmitted by inhalation or contact with infected droplets and the incubation period ranges from 2 to 14 d. The symptoms are usually fever, cough, sore throat, breathlessness, fatigue, malaise among others. The disease is mild in most people; in some (usually the elderly and those with comorbidities), it may progress to pneumonia, acute respiratory distress syndrome (ARDS) and multi organ dysfunction. Many people are asymptomatic. The case fatality rate is estimated to range from 2 to 3%. Diagnosis is by demonstration of the virus in respiratory secretions by special molecular tests. Common laboratory findings include normal/ low white cell counts with elevated C-reactive protein (CRP). The computerized tomographic chest scan is usually abnormal even in those with no symptoms or mild disease. Treatment is essentially supportive; role of antiviral agents is yet to be established. Prevention entails home isolation of suspected cases and those with mild illnesses and strict infection control measures at hospitals that include contact and droplet precautions. The virus spreads faster than its two ancestors the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), but has lower fatality. The global impact of this new epidemic is yet uncertain.

Introduction

The 2019 novel coronavirus (2019-nCoV) or the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) as it is now called, is rapidly spreading from its origin in Wuhan City of Hubei Province of China to the rest of the world [ 1 ]. Till 05/03/2020 around 96,000 cases of coronavirus disease 2019 (COVID-19) and 3300 deaths have been reported [ 2 ]. India has reported 29 cases till date. Fortunately so far, children have been infrequently affected with no deaths. But the future course of this virus is unknown. This article gives a bird’s eye view about this new virus. Since knowledge about this virus is rapidly evolving, readers are urged to update themselves regularly.

Coronaviruses are enveloped positive sense RNA viruses ranging from 60 nm to 140 nm in diameter with spike like projections on its surface giving it a crown like appearance under the electron microscope; hence the name coronavirus [ 3 ]. Four corona viruses namely HKU1, NL63, 229E and OC43 have been in circulation in humans, and generally cause mild respiratory disease.

There have been two events in the past two decades wherein crossover of animal betacorona viruses to humans has resulted in severe disease. The first such instance was in 2002–2003 when a new coronavirus of the β genera and with origin in bats crossed over to humans via the intermediary host of palm civet cats in the Guangdong province of China. This virus, designated as severe acute respiratory syndrome coronavirus affected 8422 people mostly in China and Hong Kong and caused 916 deaths (mortality rate 11%) before being contained [ 4 ]. Almost a decade later in 2012, the Middle East respiratory syndrome coronavirus (MERS-CoV), also of bat origin, emerged in Saudi Arabia with dromedary camels as the intermediate host and affected 2494 people and caused 858 deaths (fatality rate 34%) [ 5 ].

Origin and Spread of COVID-19 [ 1 , 2 , 6 ]

In December 2019, adults in Wuhan, capital city of Hubei province and a major transportation hub of China started presenting to local hospitals with severe pneumonia of unknown cause. Many of the initial cases had a common exposure to the Huanan wholesale seafood market that also traded live animals. The surveillance system (put into place after the SARS outbreak) was activated and respiratory samples of patients were sent to reference labs for etiologic investigations. On December 31st 2019, China notified the outbreak to the World Health Organization and on 1st January the Huanan sea food market was closed. On 7th January the virus was identified as a coronavirus that had >95% homology with the bat coronavirus and > 70% similarity with the SARS- CoV. Environmental samples from the Huanan sea food market also tested positive, signifying that the virus originated from there [ 7 ]. The number of cases started increasing exponentially, some of which did not have exposure to the live animal market, suggestive of the fact that human-to-human transmission was occurring [ 8 ]. The first fatal case was reported on 11th Jan 2020. The massive migration of Chinese during the Chinese New Year fuelled the epidemic. Cases in other provinces of China, other countries (Thailand, Japan and South Korea in quick succession) were reported in people who were returning from Wuhan. Transmission to healthcare workers caring for patients was described on 20th Jan, 2020. By 23rd January, the 11 million population of Wuhan was placed under lock down with restrictions of entry and exit from the region. Soon this lock down was extended to other cities of Hubei province. Cases of COVID-19 in countries outside China were reported in those with no history of travel to China suggesting that local human-to-human transmission was occurring in these countries [ 9 ]. Airports in different countries including India put in screening mechanisms to detect symptomatic people returning from China and placed them in isolation and testing them for COVID-19. Soon it was apparent that the infection could be transmitted from asymptomatic people and also before onset of symptoms. Therefore, countries including India who evacuated their citizens from Wuhan through special flights or had travellers returning from China, placed all people symptomatic or otherwise in isolation for 14 d and tested them for the virus.

Cases continued to increase exponentially and modelling studies reported an epidemic doubling time of 1.8 d [ 10 ]. In fact on the 12th of February, China changed its definition of confirmed cases to include patients with negative/ pending molecular tests but with clinical, radiologic and epidemiologic features of COVID-19 leading to an increase in cases by 15,000 in a single day [ 6 ]. As of 05/03/2020 96,000 cases worldwide (80,000 in China) and 87 other countries and 1 international conveyance (696, in the cruise ship Diamond Princess parked off the coast of Japan) have been reported [ 2 ]. It is important to note that while the number of new cases has reduced in China lately, they have increased exponentially in other countries including South Korea, Italy and Iran. Of those infected, 20% are in critical condition, 25% have recovered, and 3310 (3013 in China and 297 in other countries) have died [ 2 ]. India, which had reported only 3 cases till 2/3/2020, has also seen a sudden spurt in cases. By 5/3/2020, 29 cases had been reported; mostly in Delhi, Jaipur and Agra in Italian tourists and their contacts. One case was reported in an Indian who traveled back from Vienna and exposed a large number of school children in a birthday party at a city hotel. Many of the contacts of these cases have been quarantined.

These numbers are possibly an underestimate of the infected and dead due to limitations of surveillance and testing. Though the SARS-CoV-2 originated from bats, the intermediary animal through which it crossed over to humans is uncertain. Pangolins and snakes are the current suspects.

Epidemiology and Pathogenesis [ 10 , 11 ]

All ages are susceptible. Infection is transmitted through large droplets generated during coughing and sneezing by symptomatic patients but can also occur from asymptomatic people and before onset of symptoms [ 9 ]. Studies have shown higher viral loads in the nasal cavity as compared to the throat with no difference in viral burden between symptomatic and asymptomatic people [ 12 ]. Patients can be infectious for as long as the symptoms last and even on clinical recovery. Some people may act as super spreaders; a UK citizen who attended a conference in Singapore infected 11 other people while staying in a resort in the French Alps and upon return to the UK [ 6 ]. These infected droplets can spread 1–2 m and deposit on surfaces. The virus can remain viable on surfaces for days in favourable atmospheric conditions but are destroyed in less than a minute by common disinfectants like sodium hypochlorite, hydrogen peroxide etc. [ 13 ]. Infection is acquired either by inhalation of these droplets or touching surfaces contaminated by them and then touching the nose, mouth and eyes. The virus is also present in the stool and contamination of the water supply and subsequent transmission via aerosolization/feco oral route is also hypothesized [ 6 ]. As per current information, transplacental transmission from pregnant women to their fetus has not been described [ 14 ]. However, neonatal disease due to post natal transmission is described [ 14 ]. The incubation period varies from 2 to 14 d [median 5 d]. Studies have identified angiotensin receptor 2 (ACE 2 ) as the receptor through which the virus enters the respiratory mucosa [ 11 ].

The basic case reproduction rate (BCR) is estimated to range from 2 to 6.47 in various modelling studies [ 11 ]. In comparison, the BCR of SARS was 2 and 1.3 for pandemic flu H1N1 2009 [ 2 ].

Clinical Features [ 8 , 15 – 18 ]

The clinical features of COVID-19 are varied, ranging from asymptomatic state to acute respiratory distress syndrome and multi organ dysfunction. The common clinical features include fever (not in all), cough, sore throat, headache, fatigue, headache, myalgia and breathlessness. Conjunctivitis has also been described. Thus, they are indistinguishable from other respiratory infections. In a subset of patients, by the end of the first week the disease can progress to pneumonia, respiratory failure and death. This progression is associated with extreme rise in inflammatory cytokines including IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1A, and TNFα [ 15 ]. The median time from onset of symptoms to dyspnea was 5 d, hospitalization 7 d and acute respiratory distress syndrome (ARDS) 8 d. The need for intensive care admission was in 25–30% of affected patients in published series. Complications witnessed included acute lung injury, ARDS, shock and acute kidney injury. Recovery started in the 2nd or 3rd wk. The median duration of hospital stay in those who recovered was 10 d. Adverse outcomes and death are more common in the elderly and those with underlying co-morbidities (50–75% of fatal cases). Fatality rate in hospitalized adult patients ranged from 4 to 11%. The overall case fatality rate is estimated to range between 2 and 3% [ 2 ].

Interestingly, disease in patients outside Hubei province has been reported to be milder than those from Wuhan [ 17 ]. Similarly, the severity and case fatality rate in patients outside China has been reported to be milder [ 6 ]. This may either be due to selection bias wherein the cases reporting from Wuhan included only the severe cases or due to predisposition of the Asian population to the virus due to higher expression of ACE 2 receptors on the respiratory mucosa [ 11 ].

Disease in neonates, infants and children has been also reported to be significantly milder than their adult counterparts. In a series of 34 children admitted to a hospital in Shenzhen, China between January 19th and February 7th, there were 14 males and 20 females. The median age was 8 y 11 mo and in 28 children the infection was linked to a family member and 26 children had history of travel/residence to Hubei province in China. All the patients were either asymptomatic (9%) or had mild disease. No severe or critical cases were seen. The most common symptoms were fever (50%) and cough (38%). All patients recovered with symptomatic therapy and there were no deaths. One case of severe pneumonia and multiorgan dysfunction in a child has also been reported [ 19 ]. Similarly the neonatal cases that have been reported have been mild [ 20 ].

Diagnosis [ 21 ]

A suspect case is defined as one with fever, sore throat and cough who has history of travel to China or other areas of persistent local transmission or contact with patients with similar travel history or those with confirmed COVID-19 infection. However cases may be asymptomatic or even without fever. A confirmed case is a suspect case with a positive molecular test.

Specific diagnosis is by specific molecular tests on respiratory samples (throat swab/ nasopharyngeal swab/ sputum/ endotracheal aspirates and bronchoalveolar lavage). Virus may also be detected in the stool and in severe cases, the blood. It must be remembered that the multiplex PCR panels currently available do not include the COVID-19. Commercial tests are also not available at present. In a suspect case in India, the appropriate sample has to be sent to designated reference labs in India or the National Institute of Virology in Pune. As the epidemic progresses, commercial tests will become available.

Other laboratory investigations are usually non specific. The white cell count is usually normal or low. There may be lymphopenia; a lymphocyte count <1000 has been associated with severe disease. The platelet count is usually normal or mildly low. The CRP and ESR are generally elevated but procalcitonin levels are usually normal. A high procalcitonin level may indicate a bacterial co-infection. The ALT/AST, prothrombin time, creatinine, D-dimer, CPK and LDH may be elevated and high levels are associated with severe disease.

The chest X-ray (CXR) usually shows bilateral infiltrates but may be normal in early disease. The CT is more sensitive and specific. CT imaging generally shows infiltrates, ground glass opacities and sub segmental consolidation. It is also abnormal in asymptomatic patients/ patients with no clinical evidence of lower respiratory tract involvement. In fact, abnormal CT scans have been used to diagnose COVID-19 in suspect cases with negative molecular diagnosis; many of these patients had positive molecular tests on repeat testing [ 22 ].

Differential Diagnosis [ 21 ]

The differential diagnosis includes all types of respiratory viral infections [influenza, parainfluenza, respiratory syncytial virus (RSV), adenovirus, human metapneumovirus, non COVID-19 coronavirus], atypical organisms (mycoplasma, chlamydia) and bacterial infections. It is not possible to differentiate COVID-19 from these infections clinically or through routine lab tests. Therefore travel history becomes important. However, as the epidemic spreads, the travel history will become irrelevant.

Treatment [ 21 , 23 ]

Treatment is essentially supportive and symptomatic.

The first step is to ensure adequate isolation (discussed later) to prevent transmission to other contacts, patients and healthcare workers. Mild illness should be managed at home with counseling about danger signs. The usual principles are maintaining hydration and nutrition and controlling fever and cough. Routine use of antibiotics and antivirals such as oseltamivir should be avoided in confirmed cases. In hypoxic patients, provision of oxygen through nasal prongs, face mask, high flow nasal cannula (HFNC) or non-invasive ventilation is indicated. Mechanical ventilation and even extra corporeal membrane oxygen support may be needed. Renal replacement therapy may be needed in some. Antibiotics and antifungals are required if co-infections are suspected or proven. The role of corticosteroids is unproven; while current international consensus and WHO advocate against their use, Chinese guidelines do recommend short term therapy with low-to-moderate dose corticosteroids in COVID-19 ARDS [ 24 , 25 ]. Detailed guidelines for critical care management for COVID-19 have been published by the WHO [ 26 ]. There is, as of now, no approved treatment for COVID-19. Antiviral drugs such as ribavirin, lopinavir-ritonavir have been used based on the experience with SARS and MERS. In a historical control study in patients with SARS, patients treated with lopinavir-ritonavir with ribavirin had better outcomes as compared to those given ribavirin alone [ 15 ].

In the case series of 99 hospitalized patients with COVID-19 infection from Wuhan, oxygen was given to 76%, non-invasive ventilation in 13%, mechanical ventilation in 4%, extracorporeal membrane oxygenation (ECMO) in 3%, continuous renal replacement therapy (CRRT) in 9%, antibiotics in 71%, antifungals in 15%, glucocorticoids in 19% and intravenous immunoglobulin therapy in 27% [ 15 ]. Antiviral therapy consisting of oseltamivir, ganciclovir and lopinavir-ritonavir was given to 75% of the patients. The duration of non-invasive ventilation was 4–22 d [median 9 d] and mechanical ventilation for 3–20 d [median 17 d]. In the case series of children discussed earlier, all children recovered with basic treatment and did not need intensive care [ 17 ].

There is anecdotal experience with use of remdeswir, a broad spectrum anti RNA drug developed for Ebola in management of COVID-19 [ 27 ]. More evidence is needed before these drugs are recommended. Other drugs proposed for therapy are arbidol (an antiviral drug available in Russia and China), intravenous immunoglobulin, interferons, chloroquine and plasma of patients recovered from COVID-19 [ 21 , 28 , 29 ]. Additionally, recommendations about using traditional Chinese herbs find place in the Chinese guidelines [ 21 ].

Prevention [ 21 , 30 ]

Since at this time there are no approved treatments for this infection, prevention is crucial. Several properties of this virus make prevention difficult namely, non-specific features of the disease, the infectivity even before onset of symptoms in the incubation period, transmission from asymptomatic people, long incubation period, tropism for mucosal surfaces such as the conjunctiva, prolonged duration of the illness and transmission even after clinical recovery.

Isolation of confirmed or suspected cases with mild illness at home is recommended. The ventilation at home should be good with sunlight to allow for destruction of virus. Patients should be asked to wear a simple surgical mask and practice cough hygiene. Caregivers should be asked to wear a surgical mask when in the same room as patient and use hand hygiene every 15–20 min.

The greatest risk in COVID-19 is transmission to healthcare workers. In the SARS outbreak of 2002, 21% of those affected were healthcare workers [ 31 ]. Till date, almost 1500 healthcare workers in China have been infected with 6 deaths. The doctor who first warned about the virus has died too. It is important to protect healthcare workers to ensure continuity of care and to prevent transmission of infection to other patients. While COVID-19 transmits as a droplet pathogen and is placed in Category B of infectious agents (highly pathogenic H5N1 and SARS), by the China National Health Commission, infection control measures recommended are those for category A agents (cholera, plague). Patients should be placed in separate rooms or cohorted together. Negative pressure rooms are not generally needed. The rooms and surfaces and equipment should undergo regular decontamination preferably with sodium hypochlorite. Healthcare workers should be provided with fit tested N95 respirators and protective suits and goggles. Airborne transmission precautions should be taken during aerosol generating procedures such as intubation, suction and tracheostomies. All contacts including healthcare workers should be monitored for development of symptoms of COVID-19. Patients can be discharged from isolation once they are afebrile for atleast 3 d and have two consecutive negative molecular tests at 1 d sampling interval. This recommendation is different from pandemic flu where patients were asked to resume work/school once afebrile for 24 h or by day 7 of illness. Negative molecular tests were not a prerequisite for discharge.

At the community level, people should be asked to avoid crowded areas and postpone non-essential travel to places with ongoing transmission. They should be asked to practice cough hygiene by coughing in sleeve/ tissue rather than hands and practice hand hygiene frequently every 15–20 min. Patients with respiratory symptoms should be asked to use surgical masks. The use of mask by healthy people in public places has not shown to protect against respiratory viral infections and is currently not recommended by WHO. However, in China, the public has been asked to wear masks in public and especially in crowded places and large scale gatherings are prohibited (entertainment parks etc). China is also considering introducing legislation to prohibit selling and trading of wild animals [ 32 ].

The international response has been dramatic. Initially, there were massive travel restrictions to China and people returning from China/ evacuated from China are being evaluated for clinical symptoms, isolated and tested for COVID-19 for 2 wks even if asymptomatic. However, now with rapid world wide spread of the virus these travel restrictions have extended to other countries. Whether these efforts will lead to slowing of viral spread is not known.

A candidate vaccine is under development.

Practice Points from an Indian Perspective

At the time of writing this article, the risk of coronavirus in India is extremely low. But that may change in the next few weeks. Hence the following is recommended:

Healthcare providers should take travel history of all patients with respiratory symptoms, and any international travel in the past 2 wks as well as contact with sick people who have travelled internationally.
They should set up a system of triage of patients with respiratory illness in the outpatient department and give them a simple surgical mask to wear. They should use surgical masks themselves while examining such patients and practice hand hygiene frequently.
Suspected cases should be referred to government designated centres for isolation and testing (in Mumbai, at this time, it is Kasturba hospital). Commercial kits for testing are not yet available in India.
Patients admitted with severe pneumonia and acute respiratory distress syndrome should be evaluated for travel history and placed under contact and droplet isolation. Regular decontamination of surfaces should be done. They should be tested for etiology using multiplex PCR panels if logistics permit and if no pathogen is identified, refer the samples for testing for SARS-CoV-2.
All clinicians should keep themselves updated about recent developments including global spread of the disease.
Non-essential international travel should be avoided at this time.
People should stop spreading myths and false information about the disease and try to allay panic and anxiety of the public.

Conclusions

This new virus outbreak has challenged the economic, medical and public health infrastructure of China and to some extent, of other countries especially, its neighbours. Time alone will tell how the virus will impact our lives here in India. More so, future outbreaks of viruses and pathogens of zoonotic origin are likely to continue. Therefore, apart from curbing this outbreak, efforts should be made to devise comprehensive measures to prevent future outbreaks of zoonotic origin.

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Download PDF ReadCube EPUB XML (NLM) Share on. Export citation EndNote ... Y, Liu Z, Li T and Zhang L (2024) Antiphospholipid antibody-related hepatic vasculitis in a juvenile after non-severe COVID-19: a case report and literature review. Front. Immunol. 15:1354349. doi: 10.3389/fimmu.2024.1354349. Received: 12 December 2023 ...
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Another systematic review of 30 studies involving 3834 COVID-19 patients revealed that overall co-infection rate in hospitalized patients was 7%. In a mixed setting of hospital ward and intensive care unit (ICU), the most common germs were Mycoplasma pneumoniae, Pseudomonas aeruginosa, and Haemophilus influenzae.
Literature Review about the Relationship between Foreign Aid and
The literature review featured here is a key step in that assessment. The 140-page literature review covers 30 studies, with an emphasis on attempts to estimate the economic impact of foreign aid on recipient communities. Other topics covered include the impact of foreign aid on corruption and conflict.
A Review of Coronavirus Disease-2019 (COVID-19)
There have been around 96,000 reported cases of coronavirus disease 2019 (COVID-2019) and 3300 reported deaths to date (05/03/2020). The disease is transmitted by inhalation or contact with infected droplets and the incubation period ranges from 2 to 14 d. The symptoms are usually fever, cough, sore throat, breathlessness, fatigue, malaise ...

A literature review of 2019 novel coronavirus (SARS-CoV2) infection in neonates and children

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Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration

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STRENGTHS AND LIMITATIONS OF THIS STUDY

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Patients, intervention, comparison, outcome strategy and types of studies

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Literature Review of COVID-19, Pulmonary and Extrapulmonary Disease

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Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration

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A Review of Coronavirus Disease-2019 (COVID-19)

Introduction

Origin and Spread of COVID-19 [ 1 , 2 , 6 ]

Epidemiology and Pathogenesis [ 10 , 11 ]

Clinical Features [ 8 , 15 – 18 ]

Diagnosis [ 21 ]

Differential Diagnosis [ 21 ]

Treatment [ 21 , 23 ]