Severe COVID-19 in pediatric age: an update on the role of the anti-rheumatic agents

Abstract Background SARS-CoV-2 can induce an immune impairment and dysregulation, finally resulting in the massive release of inflammatory mediators (cytokine storm), strongly contributing to the pulmonary and systemic manifestations in severe coronavirus disease 2019 (COVID-19). As a consequence, different drugs active on the immune system have been proposed for the treatment of the disease in adults. Role of the anti-rheumatic agents in children Children are more likely to develop a mild disease course, as the severe form of COVID-19 is identified in less than 5% of the pediatric patients. Moreover, in children a peculiar disease phenotype, defined as multisystem inflammatory syndrome in children (MIS-C) is observed, representing the most severe expression of the inflammatory dysregulation caused by SARS-CoV-2. The limited experience with the severe pediatric COVID-19 and MIS-C does not allow conclusions about the role of the immune pharmacological approach, and therefore the treatment of these conditions represents a considerable clinical challenge. The use of chloroquine, hydroxychloroquine, and colchicine in the early disease stages is not sufficiently supported by evidence, and there is an increasing interest in the role of biologic agents, including anti-IL-1 and anti-IL-6 agents, in the prevention and treatment of the severe manifestations of COVID-19. Conclusion The therapeutic approach to pediatric COVID-19 is multidisciplinary, and anti-rheumatic agents have a prominent role in severe disease. This paper reviews the rationale for the use of anti-rheumatic agents in pediatric COVID-19 and MIS-C and the clinical experience with the single drugs. Finally, the areas of potential improvement in the use of anti-rheumatic agents, including the optimization of the drug choice and the timing of administration, are discussed.

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Role of high-dose exposure in transmission hot zones as a driver of SARS-CoV2 dynamics

10.1101/2020.10.07.20208231 ◽

2020 ◽

Author(s):

Dominik Wodarz ◽

Natalia L. Komarova ◽

Luis M. Schang

Keyword(s):

Severe Disease ◽

Epidemiological Data ◽

High Dose ◽

Infection Prevalence ◽

Targeted Interventions ◽

Mild Disease ◽

Successful Infection ◽

Hot Zone ◽

Infection Spread

AbstractEpidemiological data on the spread of SARS-CoV-2 in the absence and presence of various non-pharmaceutical interventions indicate that the virus is not transmitted uniformly in the population. Transmission tends to be more effective in select settings that involve exposure to relatively high viral dose, such as in crowded indoor settings, assisted living facilities, prisons, or food processing plants. To explore the effect on infection dynamics, we describe a new mathematical model where transmission can occur (i) in the community at large, characterized by low dose exposure and mostly mild disease, and (ii) in so called transmission hot zones, characterized by high dose exposure that can be associated with more severe disease. Interestingly, we find that successful infection spread can hinge upon high-dose hot zone transmission, yet the majority of infections are predicted to occur in the community at large with mild disease. This gives rise to the prediction that targeted interventions that specifically reduce virus transmission in the hot zones (but not in the community at large) have the potential to suppress overall infection spread, including in the community at large. The model can further reconcile seemingly contradicting epidemiological observations. While in some locations like California, strict stay-home orders failed to significantly reduce infection prevalence, in other locations, such as New York and several European countries, stay-home orders lead to a pronounced fall in infection levels, which remained suppressed for some months after re-opening of society. Differences in hot zone transmission levels during and after social distancing interventions can account for these diverging infection patterns. These modeling results warrant further epidemiological investigations into the role of high dose hot zone transmission for the maintenance of SARS-CoV-2 spread.

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The role of maternal antibodies in the emergence of severe disease as a result of fragmentation

Journal of The Royal Society Interface ◽

10.1098/rsif.2006.0189 ◽

2006 ◽

Vol 4 (14) ◽

pp. 479-489 ◽

Cited By ~ 9

Author(s):

David Fouchet ◽

Stéphane Marchandeau ◽

Nargès Bahi-Jaber ◽

Dominique Pontier

Keyword(s):

Severe Disease ◽

Mammalian Species ◽

Severe Form ◽

Local Scale ◽

Host Population ◽

Maternal Antibodies ◽

Population Fragmentation ◽

Disease Emergence ◽

Severity Of The Disease

Population fragmentation is a major problem for the conservation of mammalian species. Since the spread of an infectious disease is related to the intensity of contacts between individuals, fragmentation destabilizes the way the parasites circulate in their host population. Recently, Zinkernagel has proposed that a reduction in the frequency of infections by a parasite could lead to the emergence of severe forms of the disease, previously avoided because the disease was contracted early in life and attenuated by maternal antibodies. However, it is still unclear whether this change in disease expression increases the global mortality it induces because the disease becomes more severe and also less frequent. Here, we use a mathematical model to link population fragmentation with the hypothesis of Zinkernagel. Firstly, we show that there is a change in the severity of the disease during the fragmentation process, especially at a local scale, suggesting that host population fragmentation could be a widespread mechanism of disease emergence. Secondly, we show that the emergence of the severe form of the disease can lead to a significant increase in its induced mortality. Finally, we determine the types of interactions for which the fragmentation of the host population could be the most dangerous.

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Detection of antibodies to the SARS-CoV-2 spike glycoprotein in both serum and saliva enhances detection of infection

10.1101/2020.06.16.20133025 ◽

2020 ◽

Cited By ~ 7

Author(s):

Sian E. Faustini ◽

Sian E. Jossi ◽

Marisol Perez-Toledo ◽

Adrian M. Shields ◽

Joel D. Allen ◽

...

Keyword(s):

Severe Disease ◽

Hospitalized Patients ◽

Antibody Responses ◽

Spike Glycoprotein ◽

Mild Disease ◽

Antibody Assays ◽

Gates Foundation ◽

Asymptomatic Individuals ◽

The University

AbstractBackgroundDetecting antibody responses during and after SARS-CoV-2 infection is essential in determining the seroepidemiology of the virus and the potential role of antibody in disease. Scalable, sensitive and specific serological assays are essential to this process. The detection of antibody in hospitalized patients with severe disease has proven straightforward; detecting responses in subjects with mild disease and asymptomatic infections has proven less reliable. We hypothesized that the suboptimal sensitivity of antibody assays and the compartmentalization of the antibody response may contribute to this effect.MethodsWe systemically developed an ELISA assay, optimising different antigens and amplification steps, in serum and saliva from symptomatic and asymptomatic SARS-CoV-2-infected subjects.ResultsUsing trimeric spike glycoprotein, rather than nucleocapsid enabled detection of responses in individuals with low antibody responses. IgG1 and IgG3 predominate to both antigens, but more anti-spike IgG1 than IgG3 was detectable. All antigens were effective for detecting responses in hospitalized patients. Anti-spike, but not nucleocapsid, IgG, IgA and IgM antibody responses were readily detectable in saliva from non-hospitalized symptomatic and asymptomatic individuals. Antibody responses in saliva and serum were largely independent of each other and symptom reporting.ConclusionsDetecting antibody responses in both saliva and serum is optimal for determining virus exposure and understanding immune responses after SARS-CoV-2 infection.FundingThis work was funded by the University of Birmingham, the National Institute for Health Research (UK), the NIH National Institute for Allergy and Infectious Diseases, the Bill and Melinda Gates Foundation and the University of Southampton.

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Low Sensitivity of Admission Lung US Compared to Chest CT for Diagnosis of Lung Involvement in a Cohort of 82 Patients with COVID-19 Pneumonia

Medicina ◽

10.3390/medicina57030236 ◽

2021 ◽

Vol 57 (3) ◽

pp. 236

Author(s):

Carla Maria Irene Quarato ◽

Antonio Mirijello ◽

Donato Lacedonia ◽

Raffaele Russo ◽

Michele Maria Maggi ◽

...

Keyword(s):

Severe Disease ◽

Chest Ct ◽

Nasopharyngeal Swab ◽

Lung Involvement ◽

Reference Standard ◽

Mild Disease ◽

Imaging Tool ◽

Moderate Disease ◽

Low Sensitivity

Background and Objectives: The potential role of lung ultrasound (LUS) in characterizing lung involvement in Coronavirus disease 2019 (COVID-19) is still debated. The aim of the study was to estimate sensitivity of admission LUS for the detection of SARS-CoV-2 lung involvement using Chest-CT (Computed Tomography) as reference standard in order to assess LUS usefulness in ruling out COVID-19 pneumonia in the Emergency Department (ED). Methods: Eighty-two patients with confirmed COVID-19 and signs of lung involvement on Chest-CT were consecutively admitted to our hospital and recruited in the study. Chest-CT and LUS examination were concurrently performed within the first 6–12h from admission. Sensitivity of LUS was calculated using CT findings as a reference standard. Results: Global LUS sensitivity in detecting COVID-19 pulmonary lesions was 52%. LUS sensitivity ranged from 8% in case of focal and sporadic ground-glass opacities (mild disease), to 52% for a crazy-paving pattern (moderate disease) and up to 100% in case of extensive subpleural consolidations (severe disease), although LUS was not always able to detect all the consolidations assessed at Chest-CT. LUS sensitivity was higher in detecting a typical Chest-CT pattern (60%) and abnormalities showing a middle-lower zone predominance (79%). Conclusions: As admission LUS may result falsely negative in most cases, it should not be considered as a reliable imaging tool in ruling out COVID-19 pneumonia in patients presenting in ED. It may at least represent an expanded clinical evaluation that needs integration with other diagnostic tests (e.g., nasopharyngeal swab, Chest-CT).

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Revised Self-Monitoring Scale

Neurology ◽

10.1212/wnl.0000000000009451 ◽

2020 ◽

Vol 94 (22) ◽

pp. e2384-e2395 ◽

Cited By ~ 2

Author(s):

Gianina Toller ◽

Kamalini Ranasinghe ◽

Yann Cobigo ◽

Adam Staffaroni ◽

Brian Appleby ◽

...

Keyword(s):

Caregiver Burden ◽

Gray Matter ◽

Severe Disease ◽

Behavioral Symptoms ◽

Self Monitoring ◽

Informant Ratings ◽

Mild Disease ◽

Gray Matter Atrophy ◽

Disease Stages ◽

Over Time

ObjectiveTo investigate whether the Revised Self-Monitoring Scale (RSMS), an informant measure of socioemotional sensitivity, is a potential clinical endpoint for treatment trials for patients with behavioral variant frontotemporal dementia (bvFTD).MethodsWe investigated whether RSMS informant ratings reflected disease severity in 475 participants (71 bvFTD mutation+, 154 bvFTD mutation−, 12 behavioral mild cognitive impairment [MCI] mutation+, 98 asymptomatic mutation+, 140 asymptomatic mutation−). In a subset of 62 patients (20 bvFTD mutation+, 35 bvFTD mutation−, 7 MCI mutation+) who had at least 2 time points of T1-weighted images available on the same 3T scanner, we examined longitudinal changes in RSMS score over time and its correspondence to progressive gray matter atrophy.ResultsRSMS score showed a similar pattern in mutation carriers and noncarriers, with significant drops at each stage of progression from asymptomatic to very mild, mild, moderate, and severe disease (F4,48 = 140.10, p < 0.001) and a significant slope of decline over time in patients with bvFTD (p = 0.004, 95% confidence interval [CI] −1.90 to −0.23). More rapid declines on the RSMS corresponded to faster gray matter atrophy predominantly in the salience network (SN), and RSMS score progression best predicted thalamic volume in very mild and mild disease stages of bvFTD. Higher RSMS score predicted more caregiver burden (p < 0.001, 95% CI −0.30 to −0.11).ConclusionsThe RSMS is sensitive to progression of both socioemotional symptoms and SN atrophy in patients with bvFTD and corresponds directly to caregiver burden. The RSMS may be useful in both neurologic practice and clinical trials aiming to treat behavioral symptoms of patients with bvFTD.

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Adenosine and Immune Imbalance in Visceral Leishmaniasis: The Possible Role of Ectonucleotidases

Journal of Tropical Medicine ◽

10.1155/2012/650874 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 14

Author(s):

Rafael Paletta-Silva ◽

José Roberto Meyer-Fernandes

Keyword(s):

Public Health ◽

Immune Response ◽

Visceral Leishmaniasis ◽

Immune Evasion ◽

Extracellular Enzymes ◽

Public Health Problem ◽

Severe Form ◽

Immune Impairment ◽

Immune Imbalance

Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is responsible for mostLeishmania-associated deaths. VL represents a serious public health problem that affects many countries. The immune response in leishmaniasis is very complex and is poorly understood. The Th1 versus Th2 paradigm does not appear to be so clear in visceral leishmaniasis, suggesting that other immunosuppressive or immune-evasion mechanisms contribute to the pathogenesis of VL. It has been demonstrated that generation of adenosine, a potent endogenous immunosuppressant, by extracellular enzymes capable to hydrolyze adenosine tri-nucleotide (ATP) at the site of infection, can lead to immune impairment and contribute to leishmaniasis progression. In this regard, this paper discusses the unique features in VL immunopathogenesis, including a possible role for ectonucleotidases in leishmaniasis.

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SARS-COV2 virus and Coronavirus disease (COVID-19)

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v11ispl1.3401 ◽

2020 ◽

Vol 11 (SPL1) ◽

pp. 977-982

Author(s):

Mohamed J. Saadh ◽

Bashar Haj Rashid M ◽

Roa’a Matar ◽

Sajeda Riyad Aldibs ◽

Hala Sbaih ◽

...

Keyword(s):

Close Contact ◽

Antiviral Agents ◽

Health Concern ◽

The Novel ◽

Global Public Health ◽

Fatal Disease ◽

Mild Disease ◽

Life Threatening ◽

Novel Coronavirus

SARS-COV2 virus causes Coronavirus disease (COVID-19) and represents the causative agent of a potentially fatal disease that is of great global public health concern. The novel coronavirus (2019) was discovered in 2019 in Wuhan, the market of the wet animal, China with viral pneumonia cases and is life-threatening. Today, WHO announces COVID-19 outbreak as a pandemic. COVID-19 is likely to be zoonotic. It is transmitted from bats as intermediary animals to human. Also, the virus is transmitted from human to human who is in close contact with others. The computerized tomographic chest scan is usually abnormal even in those with no symptoms or mild disease. Treatment is nearly supportive; the role of antiviral agents is yet to be established. The SARS-COV2 virus spreads faster than its two ancestors, the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), but has lower fatality. In this article, we aimed to summarize the transmission, symptoms, pathogenesis, diagnosis, treatment, and vaccine to control the spread of this fatal disease.

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COVID-19 and Comorbidities: is Inflammation the Underlying Condition in Children? A narrative Review

Current Pediatric Reviews ◽

10.2174/1573396316666201112093920 ◽

2020 ◽

Vol 16 ◽

Author(s):

Giulia Pinna ◽

Lavinia Sanfilippo ◽

Pier Paolo Bassareo ◽

Vassilios Fanos ◽

Maria Antonietta Marcialis

Keyword(s):

Risk Factor ◽

Severe Form ◽

Narrative Review ◽

Underlying Condition ◽

Pathogenic Mechanisms ◽

Associated Diseases ◽

Potential Link

: This paper examines the potential link between COVID-19 and the presence of comorbidities and assesses the role of inflammation in this correlation. In COVID-19 patients, the most frequently associated diseases share a pathogenic inflammatory basis and apparently act as a risk factor in the onset of a more severe form of the disease, particularly in adulthood. However, in children, the understanding of the underlying pathogenic mechanisms is often complicated by the milder symptoms presented. A series of theories have therefore been put forward with a view of providing a better understanding of the role played by inflammation in this dramatic setting. All evidence available to date on this topic is discussed in this review.

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Acute interstitial nephritis and drug-induced systemic lupus erythematosus due to chlorthalidone and amiodarone: A case report

SAGE Open Medical Case Reports ◽

10.1177/2050313x20910029 ◽

2020 ◽

Vol 8 ◽

pp. 2050313X2091002 ◽

Cited By ~ 1

Author(s):

Umut Selamet ◽

Ramy M Hanna ◽

Anthony Sisk ◽

Lama Abdelnour ◽

Lena Ghobry ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Interstitial Nephritis ◽

Lupus Erythematosus ◽

Kidney Biopsy ◽

Kidney Injury ◽

Acute Interstitial Nephritis ◽

Systemic Lupus ◽

Drug Induced ◽

Systemic Manifestations

Drug-induced lupus erythematosus has features distinct from primary systemic lupus erythematosus. It can occur with a wide variety of agents that result in the generation of anti-histone or other types of antibodies. Systemic manifestations of drug-induced systemic lupus erythematosus may include renal dysfunction due to circulating immune complexes or due to other immune reactions to the culprit medication(s). Acute interstitial nephritis occurs due to DNA–drug or protein–drug complexes that trigger an allergic immune response. We report a patient who developed acute kidney injury, rash, and drug-induced systemic lupus diagnosed by serologies after starting chlorthalidone and amiodarone. A renal biopsy showed acute interstitial nephritis and not lupus-induced glomerulonephritis. It is important to note that systemic lupus erythematosus and acute interstitial nephritis can occur together, and this report highlights the role of the kidney biopsy in ascertaining the pathological diagnosis and outlining therapy in drug-induced lupus erythematosus.

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H-Ras gene takes part to the host immune response to COVID-19

Cell Death Discovery ◽

10.1038/s41420-021-00541-w ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Salvatore Sciacchitano ◽

Andrea Sacconi ◽

Claudia De Vitis ◽

Giovanni Blandino ◽

Giulia Piaggio ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Severe Disease ◽

Host Immune Response ◽

Severe Form ◽

Ras Gene ◽

Peripheral Blood Mononuclear ◽

Ras Genes

AbstractRas gene family members play a relevant role in cancer, especially when they are mutated. However, they may play additional roles in other conditions beside cancer. We performed gene expression analysis using the NanoString PanCancer IO 360 panel in the peripheral blood mononuclear cell (PBMC) of six COVID-19 patients and we found that H-Ras gene was significantly upregulated, while both K-Ras and N-Ras genes were downregulated. In particular, H-Ras gene upregulation was more evident in COVID-19 patients with a more severe disease. We compared our results with those obtained by analyzing two different and independent datasets, including a total of 53 COVID-19 patients, in which the gene expression analysis was performed using the Immunology_V2 panel. Comparative analysis of the H-Ras gene expression in these patients confirmed our preliminary results. In both of them, in fact, we were able to confirm the upregulation of the expression of the H-Ras gene. The exact role of this specific upregulation of the H-Ras gene in response to SARS-CoV-2 infection and its possible role in cancer still remains to be elucidated. In conclusion, H-Ras gene participates to the host immune response to SARS-CoV-2 virus infection, especially in patients affected by the most severe form of the COVID-19.

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