Pediatric COVID-19 is described by many different syndromes. No matter, a Thorn Is Still A Thorn By Any Other Name. A thorn by any other name remains a thorn. Scientifically literate Humans are able to see through a disguised or witless thorn and overcome or circumvent the thorny pricks.
Viral pathogenesis and host-virus crosstalk begin this presentation.
“The host- and virus-encoded microRNAs (miRNAs) and their targets together thus form a new, unbeknownst regulatory layer of genetic interactions between the host and the virus. Recent reports have thrown light on this new regulatory layer, Host-Virus Crosstalk.
A clear understanding of the Host-Virus Crosstalk between the Host and Virus would enable scientists to understand the molecular basis of viral pathogenesis, and enable scientists to develop better therapeutic strategies. [Scaria V, Hariharan M, Pillai B, Maiti S, Brahmachari SK. Host-virus genome interactions: macro roles for microRNAs. Cell Microbiol. 2007;9(12):2784‐2794. doi:10.1111/j.1462-5822.2007.01050.x]
“Virus dissemination is a major cause of epidemic diseases. Understanding al of the interactions between the virus and the host is very important for prevention and treatment of viral infection.
“The virus injection method, the virus load measurement, and an antiviral pathway are important to viral survival rate analysis. This infection in this research method can be applied to screen for virus-host interaction factors and to analyze the ‘Host-Virus Crosstalk’ between innate immune signaling and other biological pathways in response to viral infection. [Yang S, Zhao Y, Yu J, et al. Establishment of Viral Infection and Analysis of Host-Virus Interaction in Drosophila Melanogaster. J Vis Exp. 2019;(145):10.3791/58845. Published 2019 Mar 14. doi:10.3791/58845]
“Technological breakthroughs have opened a new era in the field of viral pathogenesis and previously challenging questions are being undertaken. These include genome-wide analysis of Host-Virus Crosstalk and identification of all host factors critical for viral pathogenesis, [Kim J, Koo BK, Yoon KJ. Modeling Host-Virus Interactions in Viral Infectious Diseases Using Stem-Cell-Derived Systems and CRISPR/Cas9 Technology. Viruses. 2019;11(2):124. Published 2019 Jan 30. doi:10.3390/v11020124]]
“Important insights into virus interactions with host intracellular membrane trafficking pathways have been provided over the last decade via the establishment of novel transformative omics technologies (sophisticated analysis to quantify gene expression (transcriptomics), proteins (proteomics), lipids (lipidomics) and metabolites (metabolomics) and advanced imaging tools.
Virus–host interactions have several unanswered questions.
- · the host factors that mediate the membrane alterations required for the formation of viral replication factories of RNA viruses
- · and how they coordinate with viral proteins to facilitate this process.
- · Cryo-Electron Tomography described for the study of RNA replication compartments of the non-human flock house nodavirus [256], might facilitate answers.
- · Mechanisms for RNA virus particles directions to specific cell membrane sites for cell-to-cell vs. cell-free spread remain unresolved.
- · Certain host factors appear to maintain at least some of their distinct sorting properties in non-polarized cell culture models
- · Biologically relevant polarized cell models that support authentic apical and basolateral differentiation events are necessary.
- · Three-dimensional polarized cellular systems [257], might elucidate unknowns.
- · Improved bioinformatics, large-scale data analysis tools and comparative omics are required to facilitate a more effective delivery of broadly required host targets with high confidence.
- · Further mechanistic studies are required to better understand the precise roles of the discovered, broadly required host factors in viral infections and their mode of interactions with viruses.
- · These efforts will continue to provide insight into the workings and regulation of cellular transport machinery in cell biology and viral infections and will advance the discovery of druggable host targets and the development of host-targeted antiviral approaches. [Robinson M, Schor S, Barouch-Bentov R, Einav S. Viral journeys on the intracellular highways. Cell Mol Life Sci. 2018;75(20):3693‐3714. doi:10.1007/s00018-018-2882-0]
Pediatric Multi-System Inflammatory Syndrome associated with COVID-19, Kawasaki Disease, Pediatric COVID-19 Disease and other similar Pediatric syndromes, all manifest generally the same COVID-19 pathogenesis, but sometimes with different Hosts, intermediaries, syndrome expressions but with different names, having been discovered in different locations by different scientists.
Students are taught that Common things occur commonly. [Dr Jack Shafer, UK Internal Medicine 1967] [Theodore E. Woodward 1914-2005]
When you hear hoof-beats think of horses. not zebras like Kawasaki Disease. [Dr. Ben Eiseman UK Surgery 1964] [Theodore E. Woodward 1914-2005]
Please note that Bats migrate to-Japan-from-China and to-China-from-Japan. For example “Japanese Encephalitis Virus (JEV) has been isolated from various species of bats since 1963 in multiple Yunnan Province, LiYujie, China locations (5,6).” COVID-19 in every nation by any other name is COVID-19. Kawasaki Disease and COVID-19 need similar isolations from various species of bats to confirm this hypothesis, a "thorn by any other name remains a thorn."
Evidence that Pediatric COVID-19 Disease broadly and variably encompasses Pediatric Multi-System Inflammatory Syndrome, associated with COVID-19, Kawasaki Disease, and other similar syndromes and do not require a myriad for different name variations of the same disease. Diagnoses, treatments and research for 1 disease are conducted efficaciously.
“ The outbreak of Severe Acute Respiratory Syndrome (SARS) during 2002 to 2003 epidemic and emergence of Middle East Respiratory Syndrome (MERS) 10 years later have drawn attention to the investigations for the natural Hosts of Coronaviruses, especially bats.
“Bat Hosts can migrate very long distances and roost within Human communities. It is very important to assess the risk of Coronaviral Host transition and the outbreaks of emerging Coronavirus by investigating the prevalence of Bat Coronaviruses (BtCoV).
“Bat Coronaviruses have been detected around the world, including the countries of Taiwan, Japan, China, Hong Kong, Philippines, and Thailand.
“These research findings suggest that BtCoVs exit in the Bat population endemically in at least 4 Bat species in Taiwan. Further CoV genomics and surveillance studies in Bats throughout the world are necessary to understand the role of BtCoVs to public health. [Detection of bat coronaviruses in the bat population in Taiwan by Y.N. Chen, H.C. Chen and H.C. Cheng, Type Presentation: POSTER PRESENTATION| VOLUME 21, SUPPLEMENT 1, 226, APRIL 01, 2014,PDF [62 KB]
Kawasaki Disease and Pediatric COVID-19 Kawasaki Disease are actually Pediatric COVID-19.
“Kawasaki Disease (KD) is an acute febrile Respiratory usually and (/or) Gastroenteric illness + that primarily affected children in Japan and described in Japan by Dr. Tomisaku Kawasaki in 1967. {{Although Bat Hosts migrate to and from China and Japan.}}
Causative viruses enter through respiratory (usually) and (/or) gastrointestinal tract, where an immune response is activated.
KD Gastroenteritis (Abdominal) manifestations identify a group at major risk for Intravenous immunoglobulin (IVIG)-resistance and coronary lesions.
KD Gastroenteritis symptoms, regardless of symptom magnitude have a higher risk group for IVIG-resistance and coronary disease lesions. {{ because of the formation of E. coli bacteriologic i.e. E.coli becomes host of COVID-19 virus in gastrointestinal mucous and resultant sepsis, organ damage and possible gram negative endotoxin shock with excess blood lactate, mbmsrmd postulates }}
Please see the picture above. research Surgeons at the College of Medicine University of Kentucky were the first to describe the excess blood lactate associated with gram negative endotoxin shock ~56 years ago. Recently, scientists are reinventing this research concept i.e. excess lactate associated with gram negative endotoxin sepsis and shock.
KD Autopsies reveal systemic vasculitis and inflammatory lesions in various organs and tissues, including the heart and digestive system (salivary duct-adenitis, catarrhal gastroenteritis (“copious discharge of mucus associated with inflammation”), hepatitis, cholangitis, hydrops of gallbladder, pancreatitis, pancreas adenitis) and research sscientists propose that vasculitis of a certain system can cause the corresponding clinical manifestations [17].
Increased intestinal permeability with capillary leak and hypoalbuminemia can result from different mechanisms mediated by hormones, such as thyroid hormones and glucocorticoids, nerves, and cytokines, such as interleukin-1, 2, 6 and interferon alpha[18]. {{ others propose intermediary Hosts, E. coli and the gastric mucosa interactions are responsible }}
Of note, a selective expansion of circulating Vβ2T cells has been found in the small intestinal mucosa and in the blood, presumably caused by exotoxins produced by bacteria (E. coli bacteriophage) colonizing jejunal mucosa in these patients [19].
intestinal microbiota [20, 21] plays a crucial role in the development of KD arteritis [Fabi M, Corinaldesi E, Pierantoni L, et al. Gastrointestinal presentation of Kawasaki disease: A red flag for severe disease?. PLoS One. 2018;13(9):e0202658. Published 2018 Sep 4. doi:10.1371/journal.pone.0202658]
==
“Japanese encephalitis virus (JEV) is the etiologic agent of severe encephalitic diseases in humans.
Japanese Encephalitis Virus (JEV) has been isolated from Bats of various species since 1963 in multiple Yunnan Province, LiYujie, China locations (5,6).
Like COVID-19, “JEV has been isolated from various hosts, e.g., mosquitoes, birds, pigs, and horses (3,4).
2 JEV strains most closely related to the Bat viruses were all isolated from Yunnan Province, LiYujie, China from a human in 1979 and BN19 from mosquitoes in 1982.
The annual case rate of Japanese encephalitis in Yunnan, China is >twice (2x) the average case rate of the whole country (7).
Wang et al reported the molecular and virulence characterization of 2 Bat Host JEV isolates from Yunnan: B58, obtained from a Leschenault’s rousette (Rousettus leschenaultia), a fruit bat, in 1989; and GB30, obtained from a little tube-nosed bat (Murina aurata), an insectivore, in 1997.”
[Japanese Encephalitis Viruses (JEV) from Bats in Yunnan Province, South China Epidemiology: JEV isolated from various bats since 1963 many locations(5,6) [Wang JL, Pan XL, Zhang HL, et al. Japanese encephalitis viruses from bats in Yunnan, China. Emerg Infect Dis. 2009;15(6):939‐942. doi:10.3201/eid1506.081525] [COVID-19 Diagnostic and Management Protocol for Pediatric Patients. Carlotti APCP, Carvalho WB, Johnston C, Rodriguez IS, Delgado AF. Clinics (Sao Paulo). 2020;75:e1894. Published 2020 Apr 17. doi:10.6061/clinics/2020/e1894]
Acute febrile Respiratory illness and Gastrointestinal illness characterize both Kawasaki Disease and Pediatric COVID-19
Both enter the respiratory and/or gastrointestinal tract where they activate an immune response
{{mbmsrmd postulates that Kawasaki Disease is actually Pediatric COVID-19 respiratory or gastrointestinal tract disease where they activate an immune response, complex.}}
Kawasaki Disease Gastrointestinal symptoms were reported in 98 (50%), vomiting in 88 (44%), decreased food/fluid intake in 73 (37%), cough in 55 (28%), diarrhea in 52 (26%), rhinorrhea in 37 (19%), weakness in 37 (19%), abdominal pain in 35 (18%), and joint pain (arthralgia or arthritis) in 29 (15%). One or more gastrointestinal symptom (vomiting, diarrhea, or abdominal pain) was present in 120 patients (61%) and 69 patients (35%) had >or= 1 respiratory symptom (rhinorrhea or cough). [Associated symptoms in the ten days before diagnosis of Kawasaki disease. AU Baker AL, Lu M, Minich LL, Atz AM, Klein GL, Korsin R, Lambert L, Li JS, Mason W, Radojewski E, Vetter VL, Newburger JW, Pediatric Heart Network Investigators SO, J Pediatr. 2009;154(4):592. Epub 2008 Nov 28.]
Kawasaki Disease and Pediatric COVID-19 Kawasaki Disease are actually Pediatric COVID-19
==
“COVID-19 Diagnostic and Management Protocol for Pediatric Patients
Coronavirus disease 2019 (COVID-19) is a viral respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded RNA virus that most likely originated in bats. The virus is thought to spread mainly from person-to-person via close contact (the virus can be transferred from the hands to the eyes, nose, or mouth) and respiratory droplets (produced when an infected person coughs or sneezes).
There is no evidence of vertical transmission or transmission via breastfeeding. Transmission from asymptomatic or mildly symptomatic carriers or during the incubation period, estimated to be between 1 and 14 days (mean, 5 days), can also occur; 95% of patients develop symptoms up to 12.5 days after exposure. This gave rise to the established quarantine period of 14 days after exposure 1,2.
Clinical presentation: The clinical spectrum of COVID-19 ranges from being asymptomatic to being in severe acute respiratory distress (Figure 1) 3.
According to a case series of 2143 pediatric patients 3 registered in the China Center for Disease Control and Prevention (CDC) database, 731 cases were confirmed using laboratory testing, 94 (4.4%) patients were asymptomatic, 1091 (50.9%) patients presented with mild symptoms, and 831 (38.8%) patients presented with moderate symptoms. Only 125 (5.8%) patients developed severe or critical disease. Younger children were more susceptible to severe or critical symptoms (10.6% <1 year old vs. 3% ≥16 years old); there were 13 critical cases, and in seven (53.8%) of them the patient was less than 1 year old. Only one death was reported, that is, of a 14-year-old boy.
According to another series of 171 pediatric cases 4 (1 day to 15 years old; median, 6.7 years) admitted to a hospital in Wuhan, China, all patients tested positive for COVID-19, 27 (15.8%) were asymptomatic, 33 (19.3%) had upper airway symptoms, and 111 (64.9%) had pneumonia. Seventy-one pediatric patients presented with fever (41.5%) which lasted 1 to 16 days (median, 3 days). Three patients were admitted to the intensive care unit; all of them had comorbidities such as hydronephrosis, leukemia (during chemotherapy), and intussusception. The patient presenting with intussusception was 10 months old; the patient's condition deteriorated, leading to multiple organ dysfunction and death.
Various cutaneous rashes have been recently observed in some pediatric cases with variable clinical presentations 5,6.
See the diagram in reference [COVID-19 Diagnostic and Management Protocol for Pediatric Patients.Carlotti APCP, Carvalho WB, Johnston C, Rodriguez IS, Delgado AF. Clinics (Sao Paulo). 2020;75:e1894. Published 2020 Apr 17. doi:10.6061/clinics/2020/e1894]
Q - So are there poor hygiene or other reasons for pediatric contaminations initiating Pediatric COVID-19 Epidemics ?
[DK, Lee SY, Leung LC, Wong SF, Ho JC. Bacteriological screening of expressed breast milk revealed a high rate of bacterial contamination in Chinese women. J Hosp Infect. 2004;58(2):146‐150. doi:10.1016/j.jhin.2004.05.018]
Answers: Abstract: “A screening program for expressed breast milk (EBM) revealed the alarming fact that our study group had the highest rate of contamination ever reported. The program started in July 2002 and involved a group of Chinese women whose premature babies were in the neonatal intensive care unit.
Expressed breast milk (EBM) was considered to be contaminated if there was any growth of pathogens, including Gram-negative bacteria, enterococci or Staphylococcus aureus, or if the total bacterial count was >10(5) cfu/mL.
Of 59 samples from 23 mothers, 63% were contaminated. This high contamination rate could be due to the Chinese tradition of avoiding bathing for one month after childbirth. Previous studies have shown that feeding EBM rather than premature infant formula milk has advantages in terms of decreased incidence of necrotizing enterocolitis and neonatal sepsis.
However, in this population, with such a high incidence of contaminated EBM, this may not be the case. Further studies to compare EBM with premature infant formula in this population are required.
- · Contamination of breast milk obtained by manual expression and breast pumps in mothers of very low birthweight infants.
- · Boo NY, Nordiah AJ, Alfizah H, Nor-Rohaini AH, Lim VK.J Hosp Infect. 2001 Dec;49(4):274-81. doi: 10.1053/jhin.2001.1117.PMID: 11740876 Clinical Trial.
- · Follow-up study on contamination rate of expressed breast milk samples and necrotizing enterocolitis in Chinese mothers.
- · Lee RS, Ng DK, Wong S, Tong T, Chan C.J Hosp Infect. 2005 Dec;61(4):359-60. doi: 10.1016/j.jhin.2005.05.011. Epub 2005 Oct 24.PMID: 16246461 No abstract available.
- · Growth, efficacy, and safety of feeding an iron-fortified human milk fortifier.
- · Berseth CL, Van Aerde JE, Gross S, Stolz SI, Harris CL, Hansen JW.Pediatrics. 2004 Dec;114(6):e699-706. doi: 10.1542/peds.2004-0911. Epub 2004 Nov 15.PMID: 15545616 Clinical Trial.
- · The use of expressed breast milk for the premature newborn.
- · Hodge D, Puntis JW.Clin Nutr. 2000 Apr;19(2):75-7. doi: 10.1054/clnu.2000.0112.PMID: 10867723 Review. No abstract available.
- · Question 1. Is there an increased risk of necrotising enterocolitis in preterm infants whose mothers' expressed breast milk is fortified with multicomponent fortifier?
- · Martin I, Jackson L.Arch Dis Child. 2011 Dec;96(12):1199-201. doi: 10.1136/archdischild-2011-300999.PMID: 22080461 Review. No abstract available.
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- · Most commensally bacterial strains in human milk of healthy mothers display multiple antibiotic resistance.
- · Huang MS, Cheng CC, Tseng SY, Lin YL, Lo HM, Chen PW.Microbiologyopen. 2019 Jan;8(1):e00618. doi: 10.1002/mbo3.618. Epub 2018 Mar 25.PMID: 29577668 Free PMC article.
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- · Castro JM, Tornadijo ME, Fresno JM, Sandoval H.Biomed Res Int. 2015;2015:723056. doi: 10.1155/2015/723056. Epub 2015 Feb 23.PMID: 25802862 Free PMC article. Review.
- · Microbial contamination of human milk purchased via the Internet.
- · Keim SA, Hogan JS, McNamara KA, Gudimetla V, Dillon CE, Kwiek JJ, Geraghty SR.Pediatrics. 2013 Nov;132(5):e1227-35. doi: 10.1542/peds.2013-1687. Epub 2013 Oct 21.PMID: 24144714 Free PMC article.
- · Impact of pasteurization on the antibacterial properties of human milk.
- · Van Gysel M, Cossey V, Fieuws S, Schuermans A.Eur J Pediatr. 2012 Aug;171(8):1231-7. doi: 10.1007/s00431-012-1750-4. Epub 2012 May 12.PMID: 22581208
