https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(07)61690-0.pdf

Maternal and child undernutrition: global and regional exposures and health consequences

admission. This proportion could already be greater in some parts of the country and may increase if referrals of cases of self-poisoning increase faster than the facilities for their assessment and management. The provision of social work and psychiatric expertise in casualty departments may be one means of preventing unnecessary medical admissions without risk to the patients. Dr Blake's and Dr Bramble's figures do not demonstrate, however, that any advantage would attach to medical teams taking over assessment from psychiatrists except that, by implication, assessments would be completed sooner by staff working on the ward full time. What the figures actually suggest is that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units (by 19°U), outpatients (by 5O°'), and referrals to social services (by 140o). So for house doctors to assess overdoses would provide no economy for the psychiatric or social services. The study does not tell us what the consequences would have been for the six patients who the psychiatrists would have admitted but to whom the house doctors would have offered outpatient appointments. E J SALTER

Vitamin D deficiency.

Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

/pdf/international-ers-ats-guidelines-on-definition-evaluation-sedelwbk4v.pdf

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(10)61388-8.pdf

Worldwide burden of disease from exposure to second-hand smoke: a retrospective analysis of data from 192 countries.

Multisystem inflammatory syndrome in a neonate, temporally associated with prenatal exposure to SARS-CoV-2: a case report.

To the Editors:

The recently proposed term “problematic severe asthma” (PSA) [1] describes children with persistent symptoms and/or severe exacerbations despite high dose treatment [2]. They suffer significant morbidity and consume a disproportionate amount of healthcare resources. Children with PSA are heterogeneous with respect to lung function [3] and asthma phenotype [4] and warrant careful evaluation. PSA [5] encompasses 1) wrong diagnosis; 2) significant comorbidities; 3) difficult asthma with potentially reversible factors such as poor inhaler technique, ongoing allergen exposure or poor adherence to treatment [6]; and 4) severe therapy-resistant asthma (STRA) that is refractory to maximal treatment despite optimised standard management [7].

PSA children were enrolled in a staged assessment protocol to differentiate difficult asthma from STRA [6]. The different stages were as follows. Stage 1: a detailed re-evaluation of the child including a nurse-led outpatient assessment with evaluation of inhaler device and technique, psychosocial questionnaire, a home and school visit, an assessment of adherence including prescription uptake check and a final multidisciplinary team discussion to decide whether the child had difficult asthma or STRA [6]. Stages 2 and 3: children identified as STRA progressed to invasive investigations including bronchoscopy and assessment of steroid response [7]. Differentiating difficult asthma from STRA is important to avoid unnecessary invasive procedures and side effects from additional treatments such as methotrexate. Furthermore, the healthcare costs of these approaches cannot be justified if simply improving basic management may improve asthma control. There have been no longitudinal studies that have assessed the long-term efficacy of a staged assessment of paediatric PSA. We hypothesised that the stage 1 assessment distinguishes difficult asthma from STRA and results in …

https://erj.ersjournals.com/content/erj/40/1/264.full.pdf

Long-term effectiveness of a staged assessment for paediatric problematic severe asthma

Background
Episodic viral wheeze (EVW) associated with viral respiratory tract infections is a common reason for pre-school children to utilise health care resources and for carers to take time away from employment. About a third of children experience a wheezing episode before the age of five years. EVW therefore represents a significant public health problem. Many pre-school children only wheeze in association with viral infections and in such cases EVW appears to be a separate entity from atopic asthma. Some trials have explored the effectiveness of leukotriene receptor antagonists (LTRAs) as regular (maintenance) or episodic (intermittent) treatment in this context.

Objectives
To evaluate the evidence for the efficacy and safety of maintenance and intermittent LTRAs in the management of EVW in children aged one to six years.

Search methods
We searched the Cochrane Airways Group register of trials with pre-specified terms. We performed additional searches by consulting the authors of identified trials, online trial registries of manufacturers' web sites, and reference lists of identified primary papers and reviews. Search results are current to June 2015.

Selection criteria
We included randomised controlled trials with a parallel-group or cross-over (for intermittent LTRA only) design. Maintenance was considered as treatment for more than two months and intermittent as less than 14 days. EVW was defined as a history of at least one previous episode of wheezing in association with a viral respiratory tract infection in the absence of symptoms between episodes. As far as possible, relevant specific data were obtained from authors of studies that included children of a wider age group or phenotype.  

Data collection and analysis
Two authors independently assessed studies for inclusion in the review and assessed risk of bias. The primary outcome was number of children with one or more viral-induced episodes requiring one or more treatments with rescue oral corticosteroids. We analysed combined continuous data outcomes with the mean difference and dichotomous data outcomes with an odds ratio (OR).

Main results
We identified five studies eligible for inclusion in the review (one investigated maintenance treatment, three intermittent therapy and one had both maintenance and intermittent treatment arms) these included 3741 participants. Each study involved oral montelukast and was of good methodological quality, but differed in choice of outcome measures thus limiting our ability to aggregate data across studies. Only primary outcome and adverse event data are reported in this abstract.

For maintenance treatment, specific data obtained from a single study, pertaining to children with only an EVW phenotype, showed no statistically significant group reduction in the number of episodes requiring rescue oral corticosteroids associated with daily montelukast versus placebo (OR 1.20, 95% CI 0.70 to 2.06, moderate quality evidence).

For intermittent LTRA, pooled data showed no statistically significant reduction in the number of episodes requiring rescue oral steroids in children treated with LTRA versus placebo (OR 0.77, 95% CI 0.48 to 1.25, moderate quality evidence). Specific data for children with an EVW phenotype obtained from a single study of intermittent montelukast treatment showed a small, but statistically significant reduction in unscheduled medical attendances due to wheeze (RR 0.83, 95% CI 0.71 to 0.98).

For maintenance compared to intermittent LTRA treatment no data relating to the primary outcome of the review were identified.

There were no other significant group differences identified in other secondary efficacy outcomes for maintenance or intermittent LTRA treatment versus placebo, or maintenance versus intermittent LTRA treatment. We collected descriptive data on adverse events as reported by four of the five included studies, and rates were similar between treatment and placebo groups.

Potential heterogeneity in the phenotype of participants within and across trials is a limitation of the evidence.

Authors' conclusions
In pre-school children with EVW, there is no evidence of benefit associated with maintenance or intermittent LTRA treatment, compared to placebo, for reducing the number of children with one or more viral-induced episodes requiring rescue oral corticosteroids, and little evidence of significant clinical benefit for other secondary outcomes. Therefore until further data are available, LTRA should be used with caution in individual children. When used, we suggest a therapeutic trial is undertaken, during which efficacy should be carefully monitored. It is likely that children with an apparent EVW phenotype are not a homogeneous group and that subgroups may respond to LTRA treatment depending on the exact patho-physiological mechanisms involved.

/pdf/leukotriene-receptor-antagonists-as-maintenance-and-3iskwwwjri.pdf

Leukotriene receptor antagonists as maintenance and intermittent therapy for episodic viral wheeze in children

To the Editor:

Vitamin D insufficiency is an environmental factor that has been strongly associated with asthma and its severity.1 The genes IL33 and IL1RL1 have been repeatedly identified as predisposing to asthma risk in genome-wide association studies.2 IL-33 is an alarmin cytokine that acts on multiple pulmonary cell types, including TH2 lymphocytes, mast cells, and innate lymphoid cells, to promote TH2-type cytokine secretion and airway inflammatory responses of the kind observed in asthmatic patients.3,4 The receptor for IL-33 is encoded by IL1RL1; differential splicing of the gene can produce a functional membrane-bound receptor (ST2L) or a soluble decoy receptor (sST2).5 Therefore we investigated whether IL1RL1 is regulated by vitamin D in cells relevant to asthma. We did this first by measuring gene expression by means of quantitative real-time PCR with 2 different TaqMan probe sets: Hs01073300, which detects mRNA splice variants encoding both the membrane-bound and soluble receptors (the total mRNA for IL1RL1), and Hs00249389, which detects mRNA only for the splice variant encoding the membrane-bound receptor ST2L (Fig 1, A). Methods are provided in this article's Online Repository at www.jacionline.org.



Fig 1

Vitamin D induces expression of sST2. A, Schematic for IL1RL1 mRNA: the 2 splice variants are differentially detected in PCR by using the probe sets Hs01073300 and Hs00249389. B-D,IL1RL1 transcripts detected by each probe set in cultures of HBECs at 24 ...



Both probe sets display similar efficiency of amplification (data not shown). Human primary bronchial epithelial cells (HBECs), CD4 lymphocytes, CD8 lymphocytes, eosinophils, and LUVA mast cells were cultured in the presence or absence of 1α,25-dihydroxyvitamin D3 (1,25[OH]D3), the active form of vitamin D (Fig 1, B-D, and see Fig E1, A and B, in this article's Online Repository at www.jacionline.org). Addition of 1,25(OH)D3 significantly increased the total number of IL1RL1 mRNA transcripts expressed by HBECs and CD4 and CD8 lymphocytes, as measured by using the Hs01073300 probe set. However, 1,25(OH)D3 did not significantly increase expression of IL1RL1 mRNA transcripts by primary eosinophils and LUVA mast cells, despite it significantly increasing expression of the gene cathelicidin antimicrobial peptide (CAMP), which is known to be induced by vitamin D (see Fig E1, A and B).

Higher IL1RL1 expression levels were detected with the Hs01073300 probe set than with the Hs00249389 probe set in HBEC and lymphocyte cultures. Although 1,25(OH)D3 increased the total copies of IL1RL1 mRNA measured by using the Hs01073300 probe set in these cell types, it did not increase the number of transcripts encoding ST2L detected with Hs00249389, indicating that vitamin D selectively upregulates the expression of mRNA for the soluble decoy receptor sST2. sST2 concentrations in culture supernatants were measured by means of ELISA to confirm the findings of gene expression studies at the protein level. sST2 concentrations were significantly increased by 1,25(OH)D3 in both HBEC and CD4 lymphocyte cultures (Fig 1, E and F). In contrast, CD8 lymphocytes produced less than 200 pg/mL sST2 in all conditions, and there was no evidence of upregulation by 1,25(OH)D3 (data not shown).

Vitamin D circulates primarily as the inactive precursor 25-hydroxyvitamin D3 (25[OH]D3); however, epithelial cells constitutively express CYP27B1, the enzyme that converts 25(OH)D3 to 1,25(OH)D3.6 HBECs cultured with 100 nmol/L 25(OH)D3, a physiologic concentration, increased expression of IL1RL1 (see Fig E1, C) and produced significantly greater amounts of sST2 (Fig 1, G). Primary human nasal epithelial cells (HNECs) cultured with a similar concentration range of 25(OH)D3 also showed a clear concentration-dependent increase in sST2 production (Fig 1, H). CD4 lymphocytes did not respond to 25(OH)D3, which is consistent with their lower expression of CYP27B1 (see Fig E1, D).

An IL-33 sensitive bioassay was developed using the LUVA mast cell line to test the biological activity of sST2. Twenty-four hours of exposure of LUVA cell cultures to IL-33 resulted in marked homotypic aggregation, which was associated with increased expression of CD54 (intercellular adhesion molecule 1; see Fig E2, A and B, in this article's Online Repository at www.jacionline.org). IL-33 increased CD54 expression on LUVA cells in a concentration-dependent manner (Fig 2, A). Other stimuli can also induce mast cell CD54 expression, and a similar concentration-dependent induction of CD54 expression was achieved with a combination of IFN-γ and IL-4 (Fig 2, A). Treatment of LUVA cells with a recombinant sST2-Fc chimera significantly inhibited IL-33–induced CD54 expression (P = .0076; Fig 2, B, and see Fig E2, C) but not IFN-γ plus IL-4–induced CD54 expression (see Fig E2, D). Addition of 1,25(OH)D3 itself to LUVA cell cultures did not significantly alter constitutive or induced CD54 expression (P > .05; see Fig E2, E), as previously reported for another mast cell line.7



Fig 2

Conditioned medium from vitamin D–treated epithelial cultures inhibits IL-33–induced expression of CD54 by LUVA cells. A, Induction of CD54 on LUVA cells above that of unstimulated cells by different stimuli in the presence of conditioned ...



To examine the effect of vitamin D–enhanced epithelial sST2 production on the IL-33 bioassay, HNECs were cultured in the presence or absence of 25(OH)D3 for 48 hours, and then the supernatants were added to cultures of LUVA cells stimulated with concentrations of IL-33 or IFN-γ plus IL-4 that induced comparable CD54 expression. Conditioned medium from vitamin D–treated epithelial cells significantly reduced IL-33–induced CD54 expression on LUVA cells compared with conditioned medium from matched epithelial cell cultures not treated with vitamin D (P = .015; Fig 2, C and E). In contrast, there was no significant difference in IFN-γ plus IL-4–induced CD54 expression between LUVA cells cultured with the different epithelial cell–conditioned media (P > .05; Fig 2, D and E). Although mediators in the epithelial cell–conditioned medium other than sST2 might conceivably have affected LUVA cell CD54 expression, the selective effect of vitamin D treatment on IL-33–induced CD54 expression suggests that the sST2 in the vitamin D–treated epithelial cell supernatants is biologically active.

The capacity of IL-33 to induce production of TH2-type proinflammatory cytokines by multiple cell types likely underpins the reported genetic associations of IL33 and IL1RL1 with asthma. Here we report the novel finding that 100 nmol/L vitamin D is able to augment expression by epithelial cells and lymphocytes of the soluble decoy receptor sST2, which in turn inhibits the actions of IL-33. Importantly, this effect occurs at physiologic concentrations (vitamin D sufficiency is defined as a serum 25[OH]D level of 75 to 150 nmol/L), and similar concentrations of 1,25(OH)D3 have been shown to be able to be generated from 25(OH)D3 in culture.1 We hypothesize that the capacity of vitamin D to augment the synthesis of an inhibitor of IL-33 in situ in the airways mucosa is of potential benefit in the limitation of asthmatic mucosal inflammation. Furthermore, this might in part account for the paradox that epidemiologic studies have repeatedly revealed associations between vitamin D insufficiency and both the risk of more severe asthma1 and increased serum IgE concentrations,8 whereas other studies have reported that in culture vitamin D can act directly on TH2 lymphocytes to promote TH2 cytokine secretion (eg, Boonstra et al9). The apparent beneficial association of vitamin D in asthma in vivo, which in many patients is a TH2-type cytokine pathology, suggests that the direct action of vitamin D in promoting TH2 lymphocyte responses is less important in vivo than other vitamin D–mediated mechanisms (eg, vitamin D upregulated production of sST2 and the induction of regulatory mechanisms) in inhibiting TH2-type cytokine responses. Because the enhancement by vitamin D of sST2 production is concentration dependent, this supports therapeutic strategies to boost pulmonary vitamin D levels to reduce asthmatic inflammation.

Atul Gupta

Papers

Multisystem inflammatory syndrome in a neonate, temporally associated with prenatal exposure to SARS-CoV-2: a case report.

Long-term effectiveness of a staged assessment for paediatric problematic severe asthma

Leukotriene receptor antagonists as maintenance and intermittent therapy for episodic viral wheeze in children

Vitamin D enhances production of soluble ST2, inhibiting the action of IL-33

Ethnicity and COVID-19 in children with comorbidities.