In contrast to other respiratory viruses, children have less severe symptoms when infected with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, we discuss ...proposed hypotheses for the age-related difference in severity of coronavirus disease 2019 (COVID-19).Factors proposed to explain the difference in severity of COVID-19 in children and adults include those that put adults at higher risk and those that protect children. The former include: (1) age-related increase in endothelial damage and changes in clotting function; (2) higher density, increased affinity and different distribution of angiotensin converting enzyme 2 receptors and transmembrane serine protease 2; (3) pre-existing coronavirus antibodies (including antibody-dependent enhancement) and T cells; (4) immunosenescence and inflammaging, including the effects of chronic cytomegalovirus infection; (5) a higher prevalence of comorbidities associated with severe COVID-19 and (6) lower levels of vitamin D. Factors that might protect children include: (1) differences in innate and adaptive immunity; (2) more frequent recurrent and concurrent infections; (3) pre-existing immunity to coronaviruses; (4) differences in microbiota; (5) higher levels of melatonin; (6) protective off-target effects of live vaccines and (7) lower intensity of exposure to SARS-CoV-2.
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has spread rapidly across the globe. In contrast to initial reports, recent studies suggest that children are just as ...likely as adults to become infected with the virus but have fewer symptoms and less severe disease. In this review, we summarize the epidemiologic and clinical features of children infected with SARS-CoV-2 reported in pediatric case series to date. We also summarize the perinatal outcomes of neonates born to women infected with SARS-CoV-2 in pregnancy. We found 11 case series including a total of 333 infants and children. Overall, 83% of the children had a positive contact history, mostly with family members. The incubation period varied between 2 and 25 days with a mean of 7 days. The virus could be isolated from nasopharyngeal secretions for up to 22 days and from stool for more than 30 days. Co-infections were reported in up to 79% of children (mainly mycoplasma and influenza). Up to 35% of children were asymptomatic. The most common symptoms were cough (48%; range 19%–100%), fever (42%; 11%–100%) and pharyngitis (30%; 11%–100%). Further symptoms were nasal congestion, rhinorrhea, tachypnoea, wheezing, diarrhea, vomiting, headache and fatigue. Laboratory test parameters were only minimally altered. Radiologic findings were unspecific and included unilateral or bilateral infiltrates with, in some cases, ground-glass opacities or consolidation with a surrounding halo sign. Children rarely needed admission to intensive care units (3%), and to date, only a small number of deaths have been reported in children globally. Nine case series and 2 case reports described outcomes of maternal SARS-CoV-2 infection during pregnancy in 65 women and 67 neonates. Two mothers (3%) were admitted to intensive care unit. Fetal distress was reported in 30% of pregnancies. Thirty-seven percent of women delivered preterm. Neonatal complications included respiratory distress or pneumonia (18%), disseminated intravascular coagulation (3%), asphyxia (2%) and 2 perinatal deaths. Four neonates (3 with pneumonia) have been reported to be SARS-CoV-2 positive despite strict infection control and prevention procedures during delivery and separation of mother and neonates, meaning vertical transmission could not be excluded.
•Antibiotics cause profound changes in the intestinal microbiota. These changes including a decrease in bacterial diversity, changes in the abundances of certain bacteria and an increase in ...antibiotic resistance.•The longest duration of changes was observed after treatment with ciprofloxacin (one year), clindamycin (two years) and clarithromycin plus metronidazole (four years). However, these findings are limited by follow-up times.•Understanding the effects of antibiotics on the intestinal microbiota will help tailor antibiotic treatment to minimise this ‘collateral damage’.
Antibiotics change the composition of the intestinal microbiota. The magnitude of the effect of antibiotics on the microbiota and whether the effects are short-term or persist long-term remain uncertain. In this review, we summarise studies that have investigated the effect of antibiotics on the composition of the human intestinal microbiota.
A systematic search was done to identify original studies that have investigated the effect of systemic antibiotics on the intestinal microbiota in humans.
We identified 129 studies investigating 2076 participants and 301 controls. Many studies reported a decrease in bacterial diversity with antibiotic treatment. Penicillin only had minor effects on the intestinal microbiota. Amoxicillin, amoxcillin/clavulanate, cephalosporins, lipopolyglycopeptides, macrolides, ketolides, clindamycin, tigecycline, quinolones and fosfomycin all increased abundance of Enterobacteriaea other than E. coli (mainly Citrobacter spp., Enterobacter spp. and Klebsiella spp.). Amoxcillin, cephalosporins, macrolides, clindamycin, quinolones and sulphonamides decreased abundance of E. coli, while amoxcillin/clavulante, in contrast to other penicillins, increased abundance of E. coli. Amoxicllin, piperacillin and ticarcillin, cephalosporins (except fifth generation cephalosporins), carbapenems and lipoglycopeptides were associated with increased abundance of Enterococcus spp., while macrolides and doxycycline decreased its abundance. Piperacillin and ticarcillin, carbapenems, macrolides, clindamycin and quinolones strongly decreased the abundance of anaerobic bacteria. In the studies that investigated persistence, the longest duration of changes was reported after treatment with ciprofloxacin (one year), clindamycin (two years) and clarithromycin plus metronidazole (four years). Many antibiotics were associated with a decrease in butyrate or butryrate-producing bacteria.
Antibiotics have profound and sometimes persisting effects on the intestinal microbiota, characterised by diminished abundance of beneficial commensals and increased abundance of potentially detrimental microorganisms. Understanding these effects will help tailor antibiotic treatment and the use of probiotics to minimise this ‘collateral damage’.
There is substantial variation between individuals in the immune response to vaccinations. The intestinal microbiome plays a crucial rule in the development and regulation of the immune system and ...therefore its composition might affect how individuals respond to vaccinations. In this review, we summarise studies that investigated the influence of the intestinal microbiome on humoral and cellular vaccine responses.
To date, only four studies (three in infants and one in adults) have investigated the influence of the intestinal microbiome on vaccine responses. All found an association between the intestinal microbiome and vaccine responses. Despite the heterogeneity in study designs (including different vaccines, schedules, timing of collection of stool and blood samples, analysis methods and reporting of results on different taxonomic levels), findings across studies were consistent: a higher relative abundance of the phylum Actinobacteria (oral and parenteral vaccines) and Firmicutes (oral vaccines) was associated with both higher humoral and higher cellular vaccine responses, while a higher relative abundance of the phylum Proteobacteria (oral and parenteral vaccines) and Bacteroidetes (oral vaccines) was associated with lower responses.
Further, well-designed, adequately powered studies using whole-genome sequencing (to include the influence of viruses, fungi and parasites) are needed to investigate in more detail the influence of the intestinal microbiome on vaccine responses. This will help identify strategies to improve vaccine efficacy and duration of protection, particularly in infancy when the intestinal microbiome is more amenable to external influences and plays an important role in the development of the immune system.
In children, the risk of coronavirus disease (COVID) being severe is low. However, the risk of persistent symptoms following infection with severe acute respiratory syndrome coronavirus 2 ...(SARS-CoV-2) is uncertain in this age group, and the features of "long COVID" are poorly characterized. We reviewed the 14 studies to date that have reported persistent symptoms following COVID in children and adolescents. Almost all the studies have major limitations, including the lack of a clear case definition, variable follow-up times, inclusion of children without confirmation of SARS-CoV-2 infection, reliance on self- or parent-reported symptoms without clinical assessment, nonresponse and other biases, and the absence of a control group. Of the 5 studies which included children and adolescents without SARS-CoV-2 infection as controls, 2 did not find persistent symptoms to be more prevalent in children and adolescents with evidence of SARS-CoV-2 infection. This highlights that long-term SARS-CoV-2 infection-associated symptoms are difficult to distinguish from pandemic-associated symptoms.
In addition to its specific effect against tuberculosis, the BCG vaccine has beneficial nonspecific (off-target) effects on the immune system that protect against a wide range of other infections and ...are used routinely to treat bladder cancer.1,2 This has led to the suggestion that vaccination with BCG might have a role in protecting health-care workers and other vulnerable individuals against severe coronavirus disease 2019 (COVID-19). In Guinea-Bissau, a high-mortality setting, BCG-Danish reduced all-cause neonatal mortality by 38% (95% CI 17–54), mainly because there were fewer deaths from pneumonia and sepsis.3 In South Africa, BCG-Danish reduced respiratory tract infections by 73% (95% CI 39–88) in adolescents.4 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded positive-sense RNA virus, and the BCG vaccine has been shown to reduce the severity of infections by other viruses with that structure in controlled trials. ...whether BCG will be effective remains unknown: findings from the ecological studies suggesting less COVID-19 in countries with routine BCG immunisation are weak evidence because they are based on population rather than individual data and are prone to confounding.11 Also, it is unlikely that a BCG vaccine given decades ago in childhood will ameliorate COVID-19 now.
The incidence of nontuberculous mycobacterial (NTM) infections is increasing worldwide, particularly NTM lymphadenitis and skin infections (Buruli ulcer). This review summarizes the evidence for the ...protective effectiveness of BCG vaccination against NTM disease.
A systematic search using PRISMA guidelines was done for controlled studies investigating the protective effectiveness of BCG vaccination against NTM disease in immunocompetent individuals. This revealed 10 studies, including almost 12 million participants.
Three cohort studies in industrialized countries suggest that the incidence of NTM lymphadenitis is greatly reduced among BCG-vaccinated children compared with BCG-unvaccinated children, with a risk ratio (RR) of 0.04 (95% confidence interval CI, .01-.21). In two randomized trials in low-income countries, BCG protected against Buruli ulcer for the first 12 months following vaccination (RR, 0.50 95% CI, .37-.69). Four case-control studies had conflicting results. One cohort study found that individuals with Buruli ulcer are less likely to develop osteomyelitis if they have a BCG scar (RR, 0.36 95% CI, .22-.58). No studies have compared different BCG vaccine strains or the effect of revaccination in this setting.
The protective effect of BCG vaccination against NTM should be taken into consideration when deciding on recommendations for discontinuation of universal BCG vaccination programs and in assessing new vaccines designed to replace BCG.
SARS-CoV-2 infection is mild in the majority of individuals but progresses into severe pneumonia in a small proportion of patients. The increased susceptibility to severe disease in the elderly and ...individuals with co-morbidities argues for an initial defect in anti-viral host defense mechanisms. Long-term boosting of innate immune responses, also termed “trained immunity,” by certain live vaccines (BCG, oral polio vaccine, measles) induces heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells. We propose that induction of trained immunity by whole-microorganism vaccines may represent an important tool for reducing susceptibility to and severity of SARS-CoV-2.
Netea and colleagues argue that we may be able to prevent or decrease the severity of SARS-CoV-2 infection through certain clinically approved live vaccines that “train” the innate immune system to be broadly vigilant against viral infection.
The mechanisms underlying the non-antimicrobial immunomodulatory properties of macrolides are not well understood.
To systematically review the evidence for the immunomodulatory properties of ...macrolides in humans and to describe the underlying mechanism and extent of their influence on the innate and adaptive immune system.
A systematic literature search was done in MEDLINE using the OVID interface from 1946 to December 2016 according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA). Original articles investigating the influence of four macrolides (azithromycin, clarithromycin, erythromycin, and roxithromycin) on immunological markers in humans were included.
We identified 22 randomized, controlled trials, 16 prospective cohort studies, and 8 case-control studies investigating 47 different immunological markers (186 measurements) in 1,834 participants. The most frequently reported outcomes were a decrease in the number of neutrophils, and the concentrations of neutrophil elastase, interleukin (IL)-8, IL-6, IL-1beta, tumor necrosis factor (TNF)-alpha, eosinophilic cationic protein, and matrix metalloproteinase 9. Inhibition of neutrophil function was reported more frequently than eosinophil function. A decrease in T helper (Th) 2 cells cytokines (IL-4, IL-5, IL-6) was reported more frequently than a decrease in Th1 cytokines (IL-2, INF-gamma).
Macrolides influence a broad range of immunological mechanisms resulting in immunomodulatory effects. To optimize the treatment of chronic inflammatory diseases by macrolides, further studies are necessary, particularly comparing different macrolides and dose effect relationships.
Chronic nonbacterial osteomyelitis (CNO) and SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome are auto-inflammatory disorders manifesting as chronic inflammation of bones and ...joints, which in SAPHO is often accompanying by skin changes. The aetiology of these diseases is unknown, but includes genetic, infectious and immunological components. It has been proposed that
Cutibacterium
(formerly
Propionibacterium) acnes
plays a role in the pathogenesis. In this review, we summarise reported cases of CNO or SAPHO syndrome in which
C. acnes
has been isolated from bones. To identify cases, a search was done in May 2018 using the MEDLINE Ovid interface (1946 to present). We found 14 publications reporting 98 patients with auto-inflammatory bone disorders, of whom 48 (49%) had positive bone biopsies for
C. acnes.
This bacterium was more frequently isolated from open biopsies than percutaneous ones (43/69 (62%) vs 1/7 (14%);
p
= 0.04) and biopsies were more frequently positive in patients who presented with simultaneous skin manifestations (19/36 (53%) vs 4/12 (33%);
p
= 0.03).
Conclusion
: In patients with CNO or SAPHO,
C. acnes
can be isolated from open biopsies suggesting that in these patients,
C. acnes
might be a pathogen rather than a contaminant. The fact that biopsies are more frequently positive in patients who present with simultaneous skin manifestations suggests that these individuals might have a genetic predisposition for impaired clearance of
C. acnes
.
What is known
•
Chronic nonbacterial osteomyelitis (CNO) and SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome are auto-inflammatory disorders manifesting as inflammation of bones. Both diseases are an important differential diagnosis in children who present with symptoms of (multifocal) osteomyelitis.
•
The pathogenesis of CNO and SAPHO is multifactorial emcompassing genetic, infectious and immunological components, including interleukin (IL)-1 dysregulation. There is a controversy as to whether Cutibacterium (formerly Propionibacterium) acnes plays a role in the aetiology of CNO and SAPHO. It has been postulated that the presence of C. acnes might trigger auto-inflammatory chronic inflammation in genetically predisposed individuals.
What is new
•
In patients with CNO or SAPHO, C. acnes can be isolated more frequently from open biopsies, than from percutaneous ones, suggesting that C. acnes might be a pathogen rather than a contaminant.
•
Biopsies are more frequently positive in patients who present with simultaneous skin manifestations suggesting that these individuals might have a genetic predisposition for impaired clearance of C. acnes. Impaired C. acnes clearance likely leads to increased IL-1 beta (β) production by skin cells, bone cells and phagocytes, which is one of the main cytokines underlying chronic inflammatory bone disorders.
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