Antinucleosome antibodies as early predictors of lupus nephritis

Background: The role of the nucleosome in the induction of antibody response in lupus mediated tissue damage especially glomerulonephritis, may provide a new insight in the early diagnosis and alternative therapeutic developments in systemic lupus erythematosus (SLE). Objectives: To evaluate the frequency and specificity of antinucleosome antibody expression in SLE patients in relation to disease activity. Also, to assess their predictive value in subclinical lupus nephritis. Methods: This study included 26 patients with SLE and 52 control subjects (26 were healthy and 26 had juvenile rheumatoid arthritis "JRA"). Among lupus patients, 15 had clinical evidence of renal involvement. After clinical evaluation to calculate the SLE disease activity index (SLEDAI), measurements of urinary microalbumin and serum antinucleosome antibodies (antinucleosome specific, antihistone and anti ds-DNA antibodies by ELISA) were performed. Patients without clinical evidence of renal involvement were followed up for one year and measurement of urinary microalbumin was repeated at the end of the study period. Those who later developed microalbuminurea were categorized as patients with subclinical lupus nephritis. Results: The expression of the 3 studied antinucleosome antibodies was significantly higher among lupus patients as compared to JRA patients and healthy controls. Seropositivity for one or more antinucleosome antibodies was elicited in 84.5% of lupus patients. Serum levels of the 3 antinucleosome antibodies were significantly higher among lupus patients with clinical nephritis than those without nephritis. ANSAb had higher sensitivity, specificity and positive and negative predictive values for subclinical lupus nephritis (100%) than antihistone and anti ds-DNA antibodies (43%, 100%, 100% and 50% respectively for either antibodies). All patients with lupus nephritis were seropositive for at least one of the antinucleosome antibodies, while those without clinical or subclinical nephritis were seronegative for the 3 antinucleosome antibodies. In 27.3% of patients with lupus nephritis, ANSAB was positive while both antihistone and ds-DNA antibodies were negative. Antinucleosome antibodies correlated positively with SLEDAI and cumulative steroid dose and negatively with corrected creatinine clearance. Conclusions: The observed sensitivity and specificity of antinucleosome specific antibodies as early indicators of subclinical lupus nephritis appear encouraging and deserve further analysis on a large scale in order to confirm their validity, especially in the anti ds-DNA seronegative lupus patients.Keywords: antinucleosome antibodies, antinucleosome specific antibodies, anti ds-DNA antibodies, antihistone antibodies, SLE, lupus nephritisEgypt J Pediatr Allergy Immunol 2005; 3(2):54-6

Brain-derived neurotrophic factor in asthmatic children

Background: Brain-derived neurotrophic factor (BDNF) regulates the cross-talk between the immune and nervous systems which may play an important role in asthma pathophysiology. Objective: This study was aimed to investigate the relation between BDNF and asthma exacerbation and severity, and to study its possible correlation to eosinophilic counts in blood and sputum. Methods: Twenty-seven asthmatic children were studied during both exacerbation and remission. According to acute exacerbation severity as assessed clinically and by peak expiratory flow rate (PEFR), they were equally subdivided into 3 groups (mild, moderate and severe). Serum and sputum BDNF levels as well as blood and sputum eosinophilic counts were estimated in all patients in comparison to 30 healthy children with no personal or family history of atopy. Results: BDNF levels (in serum and sputum) and eosinophilic counts (in blood and sputum) were significantly elevated in asthmatic patients, whether studied as one group or subgrouped into mild, moderate and severe as compared to controls. Patients with mild, moderate and severe acute asthma exacerbation had significantly higher values of BDNF (in serum and sputum) and eosinophilic count (in blood and sputum) than the corresponding values measured during remission. The latter values were still higher than those of the control group. BDNF in serum and sputum indirectly correlated with asthma severity as evidenced by their negative correlation with PEFR. However, sputum BDNF correlated better with the severity of asthma exacerbation as evidenced directly by its significant increase with clinical severity. Both serum and sputum BDNF levels revealed significant positive correlations with eosinophilic count in blood and sputum among all studied groups. Conclusion: BDNF probably plays a role in the evolution of asthma exacerbation and it reflects the degree of asthma severity during exacerbation. It might also represent an objective indicator of remission and treatment efficacy. Studies with specific BDNF receptor antagonists or synthesis inhibitors are required as BDNF may prove to be a reasonable target for a new therapy in future.Keywords: BDNF, neurotrophins, bronchial asthma, asthma severity, neurogenic inflammationEgypt J Pediatr Allergy Immunol 2003; 1(2): 102-

High plasma levels of adrenomedullin in collagen diseases

Background: Adrenomedullin (ADM), a potent vasorelaxant/hypotensive peptide, was shown recently to be over-expressed in inflammatory rheumatic diseases. Objectives: The aim of this study was to investigate the value of ADM as a laboratory marker of disease activity in juvenile rheumatoid arthritis (JRA) and pediatric onset- systemic lupus erythematosus (SLE) and its relation to other markers of disease activity such as clinical scores, the ESR and tumor necrosis factor-α (TNF-α). Methods: The study included 24 patients with JRA, 17 with childhood onset- SLE, as well as, 19 with rheumatic arthritis and twenty clinically healthy age- and sex- matched subjects. Clinical evaluation for disease activity was performed using the clinical activity score index in JRA, and SLE-DAI in SLE. Subjects were investigated to verify the diagnosis and disease activity. Plasma ADM and serum of TNF-α levels were then assayed. Results: Serum TNF-α and plasma ADM levels were significantly higher in JRA and SLE patients than in rheumatic arthritis patients and healthy controls. Though serum TNF-α and plasma ADM levels were both higher in JRA (73.88 ± 11.6 pg/ml and 156.5 ± 22.4 pg/ml, respectively) compared to SLE (48.82 ± 7.5 pg/ml and 85.12 ± 15.7 pg/ml, respectively), the difference was of statistical significance only in ADM. Both serum TNF-α and plasma ADM levels were significantly higher in systemic onset-JRA (139.75 ± 18.5 and 260.25 &#177 28.6 pg/ml, respectively) compared to the pauciarticular-onset type (33.8 ± 3.04 and 93.4 ± 9.35 pg/ml, respectively), but comparable to the polyarticular onset cases (69.97 ± 8.45 and 149.87 ± 21.15 pg/ml, respectively). Positive correlations were noticed between plasma ADM and activity score index (r=0.72), ESR (r=0.59) and serum TNF-α (r=0.64) in JRA. The serum TNF- α was not influenced by the site of lupus activity unlike plasma ADM that was higher in subjects suffering from lupus arthritis or cardiovascular manifestations. The afore-mentioned markers correlated positively to the ESR in SLE but not to the SLE-DAI. With a cut-off value of TNF-α = 31 pg/ml and that for ADM = 80 pg/ml calculated from the results of the included rheumatic arthritis patients, ADM appeared to be a more sensitive marker of activity in JRA and SLE compared to TNF-α. Conclusion: Plasma ADM was over-expressed in JRA and SLE. It correlated with the clinical and biochemical activity markers in JRA suggesting that it can be used as an indicator of disease activity. In SLE, ADM levels correlated with ESR and TNF- α levels and it could be of value in identifying patients with arthritis and cardiac involvement.<br.Keywords: Adrenomedullin, JRA, SLE, TNF-α, arthritisEgypt J Pediatr Allergy Immunol 2004; 2(1): 28-3

Monocyte chemotactic protein-4 (MCP-4/CCL-13) and CC chemokine receptor 3 (CCR3) in the sputum of asthmatic children

Background: Monocyte chemotactic protein-4 (MCP-4/CCL-13) is a potent chemoattractant to eosinophils, monocytes and lymphocytes. Objective: We aimed to investigate MCP-4 and its CC chemokine receptor 3 (CCR3) expression on cells of induced sputum during acute asthma exacerbation. Methods: Immunohistochemistry was used to assess MCP-4 and CCR3 expression on induced sputum cells of 30 children during asthma exacerbation and 20 healthy matched controls. Patients were divided into three groups according to exacerbation severity; mild, moderate and severe (n = 10 for each). Patients were followed until quiescence, when sputum was re-examined. Results: MCP-4 and CCR3 were expressed on eosinophils and monocytes. Lymphocytes expressed only MCP-4. The percentages of sputum total cells, eosinophils and lymphocytes expressing MCP-4 and/or CCR3 were significantly higher during asthma exacerbation than in controls and negatively correlated with peak expiratory flow rate, whereas that of monocytes was not. The percentages of sputum total cells, eosinophils, monocytes and lymphocytes expressing MCP-4; and total cells and eosinophils expressing CCR3 were significantly higher in patients with severe than those with mild and moderate exacerbations. When patients were followed till remission, the percentages of sputum cells expressing MCP-4 and CCR3 decreased. Sputum eosinophil percentage correlated positively with the percentage of eosinophils expressing MCP-4 and CCR3 (r = 0.69, p < 0.0001; r = 0.62, p < 0.001, respectively). The percentage of sputum eosinophils expressing MCP-4 correlated positively with that of cells expressing CCR3 (r = 0.95, p < 0.0001). Conclusion: The expression of MCP-4 and CCR3 on sputum cells increases during acute asthma exacerbation and this increase correlates with exacerbation severity, and it decreases during remission. Modification of their expression could be a potential target for asthma therapy.Keywords: asthma, CCL-13; CCR3; chemokines; eosinophils; MCP-4; sputumEgypt J Pediatr Allergy Immunol 2008; 6(1): 13-2

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Nasal lavage fluid nuclear factor kappa B and cytology in asthmatic children and their correlation with severity and control

Background: Asthma is the most common chronic inflammatory disease in childhood. The relevance of NFκB which is known to be an inflammatory marker in upper airway epithelium and its relation to lower airway inflammation has not been fully studied in childhood asthma. Aim of study: The study aimed at evaluating the diagnostic value of nasal lavage nuclear factor kappa B and cells as a less-invasive bench-side maneuver and inflammatory biomarkers in asthmatic children and correlating with asthma severity. Methods: This case-control study recruited 60 asthmatic children from Pediatric Chest Clinic, Children’s Hospital; Ain Shams University. Thirty healthy non-asthmatic children-age and sex-matched were included as a control group. Nasal lavage cytology, nasal lavage NFκB and forced expiratory volume in 1 s (FEV1) % of predicted for age and sex were estimated. Results: Nasal lavage NFκB levels were significantly higher in asthmatics than in controls with a mean of 0.129 ± 0.113 μg/μg nuclear proteins and 0.0176 ± 0.013 μg/μg nuclear proteins, respectively. Nasal lavage NFκB and eosinophil levels were significantly higher with increasing asthma severity and with worsening levels of asthma control. Nasal lavage NFκB showed a sensitivity of 87% and a specificity of 87% in predicting asthma severity. Conclusions: Despite that spirometry and clinical classification are the gold standards for grading of asthma, Nasal lavage NFκB and cells can be considered as a new less-invasive non-subjective inflammatory marker for assessment of different grades of asthma severity and control