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Tag: Asthma

  • Food insecurity fuels fatty liver disease in Latinx kids

    Food insecurity fuels fatty liver disease in Latinx kids

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    For Latinx kids, unreliable access to food at age 4 raises the odds of having fatty liver disease later in childhood by nearly four times, a new UC San Francisco-led study found. 

    About 5% to 10% of children in the United States have nonalcoholic fatty liver disease, putting its prevalence on par with asthma. Pediatric cases have spiked in the last decade, with millions now affected by a disease marked by pain, fatigue and jaundice that can lead to cirrhosis, cancer and organ transplantation. Latinx children and adults have a higher prevalence of fatty liver disease than white or Black people, and the condition is the number one indicator for a liver transplant as an adult.

    In 2022, 13.2% of children in Hispanic households had unreliable access to food (food insecurity), up from 9.7% in 2021. Nearly 16% of children in Black households had unreliable access to food in 2022, up from 12% in 2021, compared to 5.5% of children in white households in 2022, up from 3.4% in 2021.

    “We’ve seen studies in adults associating food insecurity with fatty liver disease and liver fibrosis, but very few studies have looked at children,” said Sarah Maxwell, MD, a pediatrician currently completing her pediatric transplant hepatology fellowship at UCSF Benioff Children’s Hospitals and the study’s lead author. “This is especially important for Latinx children, who have both high rates of household food insecurity and fatty liver disease.”

    The study was published in Pediatric Obesity.

    Kids should be screened earlier

    The researchers recruited two groups of Latinx mothers in San Francisco during pregnancy and followed them and their children to mid-childhood, one group from 2006-07 and the other from 2011-13. They measured food insecurity at age 4 using the U.S. Household Food Security Food Module and assessed fatty liver disease – officially called metabolic dysfunction-associated steatotic liver disease (MASLD) – between ages 5 and 12. The 136 children were followed with annual visits from birth until 2021.

    Twenty-nine percent of the children had household food insecurity at age 4 and 27% had fatty liver disease in early to middle childhood. Children with fatty liver disease were more than twice as likely to live in food-insecure households (49%) at age 4 as children without fatty liver disease (21%). Food insecurity at age 4 raised the odds of having fatty liver disease by age 12 by nearly four times. 

    Children with overweight or obesity at age 2 also had higher risk of developing fatty liver disease in later childhood. 

    It’s not yet known how food insecurity leads to fatty liver disease. Past research suggests food-insecure children may have diets of poorer nutritional quality, with less produce and more sugar-sweetened beverages that directly increase fat in the liver. Household food insecurity can also cause irregular eating patterns that disrupt metabolism, leading to higher stress and greater inflammation, as well as a deterioration in the relationship between gut microbiota and the liver. 

    Given our findings and how young patients are presenting with the condition to our liver clinics, we believe screening for MASLD should begin earlier than current guidelines recommend, which is age 9-11 years for children with obesity and age 2-9 years for those with severe obesity. Food insecurity screening is also important early on, especially for Latinx children who are at higher risk and could be connected to healthier food resources in their communities.”


    Sarah Maxwell, Pediatrician, Benioff Children’s Hospitals

    Ensuring that public meal programs widely available to children, such as school lunches, offer nutritious, balanced meals is also key, she added. 

    Source:

    University of California – San Francisco

    Journal reference:

    Maxwell, S. L., et al. (2024) Food insecurity is a risk factor for metabolic dysfunction-associated steatotic liver disease in Latinx children. Pediatric Obesity. doi.org/10.1111/ijpo.13109.

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  • Association of volatile aromatic compounds in blood with hearing impairment

    Association of volatile aromatic compounds in blood with hearing impairment

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    In a recent study published in BMC Public Health, researchers evaluated the impact of benzene, ethylbenzene, and xylene (BEX) exposure on auditory health among United States (US) adults.

    Study: Association between blood volatile organic aromatic compound concentrations and hearing loss in US adults. Image Credit: Ground Picture/Shutterstock.comStudy: Association between blood volatile organic aromatic compound concentrations and hearing loss in US adults. Image Credit: Ground Picture/Shutterstock.com

    Background

    Hearing loss (HL) is associated with financial hardships, an increased risk of diseases such as Alzheimer’s disease and dementia, and communication difficulties.

    There are few effective hearing loss (HL) treatments, highlighting the need for developing prevention strategies. Ototoxic processes and trace heavy metals are HL risk factors. The link between environmental contaminants in human blood and HL is unclear.

    The concentration of polycyclic aromatic hydrocarbons (PAHs) in urine correlates with HL frequency across ages. However, using organic solvents in urine as HL biomarkers has limitations due to their short biological half-lives and varied metabolism.

    BEX chemicals, a significant component of volatile-type organic aromatic compounds (VOACs), are recognized as carcinogens by the International Agency for Research on Cancer, causing reproductive dysfunction, asthma, leukemia, benzene poisoning, immune suppression, splenic damage, and premature birth.

    About the study

    The present study researchers comprehensively explored the link between BEX concentration in blood and hearing impairment among US adults.

    The researchers analyzed the National Health and Nutrition Examination Survey (NHANES) data for 2003-2004, 2011-2012, and 2015-2016, including demographics, VOAC exposure, and audiometry measurements.

    They performed weighted multivariable logistic regression modeling to determine the odds ratios (ORs) for the relationship between BEX concentration in blood with high-frequency HL (HFHL) and speech-frequency HL (SFHL).

    Study covariates included age, sex, race, ethnicity, body mass index (BMI), marital status, education level, smoking habits, drinking status, diabetes, hypertension, and household income.

    The team used the Linden and Jerger classification to define peak middle ear pressures as type C (<99 daPa), type B (0.2 compliance value), and other pressures as type A.

    They analyzed participant blood samples at mobile examination centers (MECs) using mass spectrometry (MS), capillary gas chromatography (GC), selected ion monitoring (SIM), and isotope dilution methods.

    Trained examiners conducted audiometry examinations, defining hearing loss as pure-tone averages exceeding 25 dB in both ears.

    They conducted SFHL assessments at frequencies of 500, 1,000, 2,000, and 4,000 Hz and HFHL evaluations at 3,000, 4,000, 6,000, and 8,000 Hz.

    The team conducted sensitivity analyses to examine the relationship between BEX and hearing loss, reclassifying individuals into three levels based on average hearing threshold, excluding those aged >40 years, and extracting serum cotinine data from NHANES to quantify tobacco smoke exposure.

    The team excluded individuals below 20 or above 60 years with tympanometric type B or C in one or both ears.

    They also excluded individuals with missing data for VOACs such as benzene, ethylbenzene, o-xylene, m/p-xylene, family income-poverty ratio (PIR), and marital status.

    Further, they excluded individuals prescribed hydrocodone, acetaminophen, phenytoin, ciprofloxacin, rifampin, levofloxacin, aspirin, minocycline, bumetanide, nitroglycerin, or metronidazole from the study.

    Study participants did not suffer from cerumen or collapsing external ear canals, did not use hearing aids, or suffered from Parkinson’s disease.

    Results

    The study included 2,174 participants with a mean age of 39 years and weighted prevalences of HL, HFHL, and SFHL, being 47% (n=995), 46% (n=973), and 25% (n=513), respectively.

    Individuals with advanced age, male gender, married status, higher BMI, educational attainment, occupational noise exposure, smoking history, alcohol use, diabetes, and hypertension had higher hearing impairment prevalence than those with no impairment.

    However, the dose-response assessments indicated increased risk among older females with weight in the normal range.

    Benzene, ethylbenzene, ortho-xylene, and para/meta-xylene exposures and cumulative BEX concentrations elevated hearing impairment risk with ORs of 1.4, 1.2, 1.2, 1.4, and 1.3, respectively). 

    Concerning the SFHL endpoint, benzene, ethylbenzene, ortho-xylene, para/meta-xylene, and cumulative BEX concentrations elevated the risk with ORs of 1.2, 1.3, 1.3, 1.2, and 1.3, respectively.

    For HFHL, benzene, ethylbenzene, ortho-xylene, para/meta-xylene, and cumulative BEX exposures increased hearing impairment risk with ORs of 1.2, 1.4, 1.4, 1.2, and 1.3, respectively.

    Surprisingly, the correlation between HL severity and BEX concentration was positive for HL and HFHL, not SFHL. Sensitivity analyses yielded similar findings, indicating the robustness of the primary results.

    Low doses of benzene can activate cellular oxidative stress, contributing to hearing loss. Obesity may lower the risk of hearing impairment induced by BEX by altering insulin-like growth factor (IGF-1) levels.

    Prolonged progesterone and estrogen stimulation in females can elevate hearing thresholds and negatively impact hearing. The team hypothesizes that BEX may disrupt the female endocrine system, with compensatory increases in estrogen outweighing the protective benefits.

    Conclusions

    The study findings showed a positive association between BEX exposure and hearing impairment (HL, HFHL, and SFHL) risk among American adults.

    Future studies could elucidate the mechanisms underlying BEX-related hearing impairment and validate findings from longitudinal environmental research.

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  • Poorly controlled asthma linked to excessive greenhouse gas emissions, study finds

    Poorly controlled asthma linked to excessive greenhouse gas emissions, study finds

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    Patients whose asthma is poorly controlled have eight times excess greenhouse gas emissions compared with those whose condition is well controlled—equivalent to that produced by 124,000 homes each year in the UK—indicates the first study of its kind, published online in the journal Thorax.

    Improving the care of asthma patients could achieve substantial carbon emissions savings, and help the NHS meet its net zero target, say the researchers.

    Healthcare is a major contributor to greenhouse gas emissions and in 2020 the NHS set an ambitious target of reducing its carbon footprint by 80% over the next 15 years, with the aim of reaching net zero by 2045, note the researchers.

    Asthma is poorly controlled in around half of those with the condition in the UK and Europe, increasing the risk of hospital admission and severe illness as well as healthcare costs. 

    To gauge the environmental footprint of asthma care in the UK, the researchers retrospectively analysed the anonymised health records of 236,506 people with asthma whose data had been submitted to the Clinical Practice Research Datalink between 2008 and 2019.

    Greenhouse gas (GHG) emissions, measured as carbon dioxide equivalent (CO2e), were estimated for asthma-related medication use, healthcare resource utilisation and severe exacerbations during follow-up of patients with asthma.

    Well controlled asthma was categorised as no episodes of severe worsening symptoms and fewer than 3 prescriptions of short-acting beta-agonists (SABAs) reliever inhalers in a year.

    Poorly controlled asthma was categorised as 3 or more SABA canister prescriptions or 1 or more episodes of severe worsening symptoms in a year.

    A severe exacerbation of asthma was defined as worsening symptoms requiring a short course of oral corticosteroids, an emergency department visit, or hospitalisation.

    Excess GHG emissions due to suboptimal asthma control included at least 3 or more SABA canisters per year, severe exacerbations and any GP visits within 10 days of hospitalisation or an emergency department visit.

    The researchers calculated that the overall carbon footprint attributed to asthma care when scaled to the entire UK asthma population added up to 750,540 tonnes CO22/year.

    Asthma was poorly controlled in just under half (47%; 111,844) of the patients. And poorly controlled asthma contributed to excess greenhouse gas emissions of 303,874 tonnes CO2e/year—equivalent to emissions from more than 124,000 homes in the UK, they estimate. The excess GHG emissions were 8-fold higher on average for a person with poorly controlled asthma than in the well controlled asthma patients.

    The excess GHG emissions were 90% comprised of inappropriate SABA use with the remainder mostly due to healthcare resource utilisation such as GP and hospital visits, required to treat severe worsening symptoms.

    Poorly controlled asthma generated 3-fold higher greenhouse gas emissions on average for a person with poorly controlled asthma compared with well controlled asthma when taking into account GHG emissions related to all aspects of asthma care including routine prescribing and management.

    The researchers acknowledge various limitations to their findings, including that the study results were largely descriptive in nature. And factors other than the level of asthma symptom control, such as prescribing patterns, may also have contributed to high SABA use.

    But they nevertheless write: “Our study indicates that poorly controlled asthma contributes to a large proportion of asthma-care related greenhouse gas emissions with inappropriate SABA use emerging as the single largest contributor.”

    The Global Initiative for Asthma no longer recommends SABA used alone as the preferred reliever for acute asthma symptoms, they add.

    The authors conclude that efforts to improve asthma treatment practices including curtailing inappropriate SABA use and implementing evidence-based treatment recommendations, could result in substantial carbon savings.

    Source:

    Journal reference:

    Wilkinson, A. J. K., et al. (2024). Greenhouse gas emissions associated with suboptimal asthma care in the UK: the SABINA healthCARe-Based envirONmental cost of treatment (CARBON) study. Thorax. doi.org/10.1136/thorax-2023-220259.

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  • Omalizumab shows promise in preventing food allergy reactions in children, study finds

    Omalizumab shows promise in preventing food allergy reactions in children, study finds

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    A drug can make life safer for children with food allergies by preventing dangerous allergic responses to small quantities of allergy-triggering foods, according to a new study led by scientists at the Stanford School of Medicine.

    The research will be published Feb. 25 in the New England Journal of Medicine. The findings suggest that regular use of the drug, omalizumab, could protect people from severe allergic responses, such as difficulty breathing, if they accidentally eat a small amount of a food they are allergic to.

    I’m excited that we have a promising new treatment for multifood allergic patients. This new approach showed really great responses for many of the foods that trigger their allergies.”


    Sharon Chinthrajah, MD, study’s senior author, associate professor of medicine and of pediatrics, and the acting director of the Sean N. Parker Center for Allergy and Asthma Research at Stanford Medicine

    “Patients impacted by food allergies face a daily threat of life-threatening reactions due to accidental exposures,” said the study’s lead author, Robert Wood, MD, professor of pediatrics at Johns Hopkins University School of Medicine. “The study showed that omalizumab can be a layer of protection against small, accidental exposures.”

    Omalizumab, which the Food and Drug Administration originally approved to treat diseases such as allergic asthma and chronic hives, binds to and inactivates the antibodies that cause many kinds of allergic disease. Based on the data collected in the new study, the FDA approved omalizumab for reducing risk of allergic reactions to foods on Feb. 16.

    All study participants were severely allergic to peanuts and at least two other foods. After four months of monthly or bimonthly omalizumab injections, two-thirds of the 118 participants receiving the drug safely ate small amounts of their allergy-triggering foods. Notably, 38.4% of the study participants were younger than 6 years, an age group at high risk from accidental ingestions of allergy-triggering foods.

    Allergies are common

    Food allergies affect about 8% of children and 10% of adults in the United States. People with severe allergies are advised to fully avoid foods containing their allergy triggers, but common allergens such as peanuts, milk, eggs and wheat can be hidden in so many places that everyday activities such as attending parties and eating in restaurants can be challenging.

    “Food allergies have significant social and psychological impacts, including the threat of allergic reactions upon accidental exposures, some of which can be life-threatening,” Chinthrajah said. Families also face economic impacts from purchasing more expensive foods to avoid allergens, she added.

    In the best available treatment for food allergies, called oral immunotherapy, patients ingest tiny, gradually increasing doses of allergy-triggering foods under a doctor’s supervision to build tolerance. But oral immunotherapy itself can trigger allergic responses, desensitization to allergens can take months or years, and the process is especially lengthy for people with several food allergies, as they are usually treated for one allergy at a time. Once they are desensitized to an allergen, patients also must continue to eat the food regularly to maintain their tolerance to it -; but people often dislike foods they were long required to avoid.

    “There is a real need for treatment that goes beyond vigilance and offers choices for our food allergic patients,” Chinthrajah said.

    Omalizumab is an injected antibody that binds and deactivates all types of immunoglobin E, or IgE, the allergy-causing molecule in the blood and on the body’s immune cells. So far, omalizumab appears able to provide relief from multiple food allergens at once.

    “We think it should have the same impact regardless of what food it is,” Chinthrajah said.

    The study included 177 children with at least three food allergies each, of whom 38% were 1 to 5 years old, 37% were 6 to 11 years old, and 24% were 12 or older. Participants’ severe food allergies were verified by skin-prick testing and food challenges; they reacted to less than 100 milligrams of peanut protein and less than 300 milligrams of each other food.

    Two-thirds of the participants were randomly assigned to receive omalizumab injections, and one-third received an injected placebo; the injections took place over 16 weeks. Medication doses were set based on each participant’s body weight and IgE levels, with injections given once every two or four weeks, depending on the dose needed. The participants were re-tested between weeks 16 and 20 to see how much of each allergy-triggering food they could safely tolerate.

    Upon re-testing, 79 patients (66.9%) who had taken omalizumab could tolerate at least 600 mg of peanut protein, the amount in two or three peanuts, compared with only four patients (6.8%) who had the placebo. Similar proportions of patients showed improvement in their reactions to the other foods in the study.

    About 80% of patients taking omalizumab were able to consume small amounts of at least one allergy-triggering food without inducing an allergenic reaction, 69% of patients could consume small amounts of two allergenic foods and 47% could eat small amounts of all three allergenic foods.

    Omalizumab was safe and did not cause side effects, other than some instances of minor reactions at the site of injection. This study marks the first time its safety has been assessed in children as young as 1.

    More questions

    More research is needed to further understand how omalizumab could help people with food allergies, the researchers said.

    “We have a lot of unanswered questions: How long do patients need to take this drug? Have we permanently changed the immune system? What factors predict which people will have the strongest response?” Chinthrajah said. “We don’t know yet.”

    The team is planning studies to answer these questions and others, such as finding what type of monitoring would be needed to determine when a patient gains meaningful tolerance to an allergy-triggering food.

    Many patients who have food allergies also experience other allergic conditions treated by omalizumab, Chinthrajah noted, such as asthma, allergic rhinitis (hay fever and allergies to environmental triggers such as mold, dogs or cats, or dust mites) or eczema. “One drug that could improve all of their allergic conditions is exactly what we’re hoping for,” she said.

    The drug could be especially helpful for young children with severe food allergies, she added, because they tend to put things in their mouths and may not understand the dangers their allergies pose, she added.

    The drug could also make it safer for community physicians to treat food allergy patients, since it cannot trigger dangerous allergic reactions, as oral immunotherapy sometimes does. “This is something that our food allergy community has been waiting a long time for,” Chinthrajah said. “It’s an easy drug regimen to implement in a medical practice, and many allergists are already using this for other allergic conditions.”

    The research team included scientists from the Johns Hopkins University School of Medicine, the National Institutes of Allergy and Infectious Diseases, the Icahn School of Medicine at Mount Sinai, Massachusetts General Hospital, the University of North Carolina School of Medicine, the University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Emory University School of Medicine and Children’s Healthcare of Atlanta, University of Texas Southwestern Medical Center, Perelman School of Medicine at the University of Pennsylvania, Genentech/Roche, Novartis Pharmaceuticals Corporation, and Rho, Inc.

    The research was funded by the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, both part of the National Institutes of Health (grant numbers UM2AI130836, UM1AI130838, UL1TR003098, UM1TR004408, UM1AI130570, UM1AI130839, UM1AI130936, UM1TR004406, UL1TR002535, UM1TR004399, UL1TR001878, UM1AI130781, UL1TR002378 and UL1TR003107), and the Claudia and Steve Stange Family Fund. Genentech/Novartis provided the investigational product and monetary support to Johns Hopkins University and collaborated on the study design.

    Source:

    Journal reference:

    Wood, R. A., et al. (2024) Omalizumab for the Treatment of Multiple Food Allergies. New England Journal of Medicine. doi.org/10.1056/NEJMoa2312382.

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  • Researchers identify new therapeutic for patients with a rare autoimmune disease EGPA

    Researchers identify new therapeutic for patients with a rare autoimmune disease EGPA

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    An international team, including researchers from McMaster University and St. Joseph’s Healthcare Hamilton, has identified a new therapeutic for patients with a rare autoimmune disease called eosinophilic granulomatosis with polyangiitis (EGPA). A biologic drug called benralizumab has been shown to be non-inferior to mepolizumab in the treatment of EGPA.

    In a clinical trial involving 140 patients with the rare disease, researchers directly compared two biologic drugs, mepolizumab and benralizumab. Patients received monthly subcutaneous injections of either 300 mg of mepolizumab or 30 mg of benralizumab for one year. The findings of the trial were published on Feb. 23, 2024, in the New England Journal of Medicine.

    Our findings show that benralizumab was just as effective as mepolizumab at reducing exacerbations and providing disease remission during the 52 weeks of the study.”


    Parameswaran Nair, professor with McMaster’s Department of Medicine and respirologist at St. Joe’s Firestone Institute for Respiratory Health

    Nair was one of the study’s principal investigators who led the Canadian team. He worked closely with Nader Khalidi, a professor with McMaster’s Department of Medicine and a rheumatologist with St. Joe’s, to design the study and recruit patients.

    “The single 30 mg subcutaneous dosing of benralizumab offers an advantage to patients over the three 100 mg subcutaneous dosing of mepolizumab,” says Nair.

    EGPA, also known as Churg-Strauss Syndrome, is a rare autoimmune disease caused by inflammation of small and medium sized blood vessels and is associated with very high blood and tissue eosinophil counts. This can lead to damage of the lungs, skin, heart, gastrointestinal tract, and nerves. Most patients with EGPA experience breathing and lung issues.

    The researchers noted that approximately 16 per cent more patients in the benralizumab group were able to abstain from using oral corticosteroids compared to the mepolizumab group. Typically, patients with EGPA use oral corticosteroids like prednisone for symptom control despite the adverse effects.

    “Without biologics, we’re relying predominantly on oral corticosteroids to control EGPA symptoms. Prolonged treatment with prednisone reduces the risk of a relapse of EGPA symptoms, but it comes with progressive toxic effects,” says Khalidi. “In our study, treatment with benralizumab allowed more patients to discontinue prednisone over a 52-week period compared to mepolizumab.”

    Mepolizumab and benralizumab are biologic drugs. Biologics are a class of drugs that come from living organisms or from their cells, often made using biotechnology.

    The two biologics used in this study work by targeting either the signals or the receptors of eosinophils, a type of immune cell that is found in high concentrations in the blood and tissue of EGPA patients. By blocking the signals or receptors that draw eosinophils into various tissues, such as the lungs, mepolizumab and benralizumab effectively decrease eosinophils, reducing symptoms.

    “Benralizumab was associated with greater blood eosinophil depletion than mepolizumab from week one onwards,” says Nair. “Both drugs were well tolerated without any new adverse events.”

    The study builds on a long history of research on eosinophilic conditions from the Firestone Institute for Respiratory Health at St. Joe’s. Pioneering work into the study of severe eosinophilic asthma by Freddy Hargreave led to a method for enumerating eosinophils in sputum samples for accurate asthma diagnoses.

    For patients with severe prednisone-dependent asthma, Hargreave, Nair, and their colleagues were the first to demonstrate the efficacy of mepolizumab in 2009. By 2017, Nair had further demonstrated the efficacy of benralizumab for the same condition. Both landmark studies were published in the New England Journal of Medicine.

    “It is very gratifying that our research program at the Firestone Institute at St. Joe’s has led to the development of these new treatment options for patients with severe eosinophilic diseases,” Nair says.

    Funding for this study was provided by AstraZeneca.

    Source:

    Journal reference:

    Wechsler, M. E., et al. (2024). Benralizumab versus Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis. The New England Journal of Medicine. doi.org/10.1056/nejmoa2311155.

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  • Exome sequencing unravels complex genetic diagnoses in growth disorders

    Exome sequencing unravels complex genetic diagnoses in growth disorders

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    In an article published in the Journal of Pediatrics, researchers based in Brazil describe the case of a nine-year-old boy admitted to hospital with multiple symptoms and overlapping conditions that made diagnosis difficult, such as short stature, thin tooth enamel (dental enamel hypoplasia), moderate mental deficiency, speech delay, asthma, mildly altered blood sugar, and a history of recurring infections in infancy. 

    The team used exome sequencing, in which only the protein-coding portion of the genome is analyzed, to look for genetic mutations, and found them in GCK and BCL11B. As a result, the diagnosis was monogenic diabetes and T-cell abnormality syndrome, both of which are rare diseases. Identification of the exact cause of the problem and the discovery of a blood sugar alteration significantly influenced their choice of treatment. 

    This is one of six cases involving syndromic growth disorders with multiple genetic diagnoses (two or more distinct genetic conditions in the same patient) described in the article, which concerns a study conducted by researchers at the University of São Paulo’s Medical School (FM-USP) with FAPESP’s support. 

    Exome sequencing is a very useful technology to reduce what we call the diagnostic odyssey – the long journey patients with rare or complex conditions have to undergo until they receive a proper diagnosis. Ten years ago, private labs charged BRL 10,000. The price has now fallen to BRL 4,000 [about USD 800]. That’s still a lot of money for a test, but it has proved essential to accurate diagnosis and treatment in cases of this kind.”


    Alexander Augusto de Lima Jorge, last author of the article

    The team sequenced the exomes of 115 patients with syndromic growth disorders that had hitherto unknown causes, diagnosing 63 on the basis of the genetic analysis; 9.5% of these had a multiple diagnosis, far more than in previous studies. 

    “The cases involved two or more rare monogenic conditions in the same patient. Such cases are very hard to diagnose, especially by clinical assessment alone. The study highlights the need to use broad genetic tests such as whole exome or whole genome sequencing for these patients as the only way to identify the rare diseases that explain such clusters of conditions,” Lima Jorge said. 

    There are numerous rare diseases, including growth disorders, so it is naturally difficult to identify many of them, he added. Between 5% and 10% of the world population is believed to have a rare disease. 

    Short stature or tall stature is not a diagnosis but a clinical finding. “Short stature may have an external cause, such as an infection or malnutrition. Even so, genetic factors will always be important to growth. In healthy children with short or tall stature as the only manifestation, there will probably be a polygenic basis [where stature is influenced by several genetic variants], but in syndromic growth disorders, in which short or tall stature is accompanied by other findings such as mental deficiency, deafness, autism spectrum disorder or malformation, an alteration in one or more genes is more likely as a justification for the complex phenotype involved,” Lima Jorge said. 

    In light of the results, the researchers advocate recognition of multiple genetic diagnoses as a possibility in complex cases of growth disorder, opening up novel prospects for treatment and genetic counseling for such patients, in place of the typical paradigm that calls for a single diagnosis to explain all findings. 

    In the article, the researchers state that the development of next-generation sequencing techniques such as whole exome or whole genome sequencing has made selecting a single gene as the candidate to explain a case unnecessary. This particular benefit has proved useful in the research environment to foster the discovery of novel disease-associated genes, to further the study of conditions with a high degree of genetic heterogeneity, and to help care for patients with complex syndromic conditions, where diagnoses cannot be obtained by traditional clinical and genetic methods. 

    Several challenges noted by Lima Jorge include the high cost of genetic tests and the fact that exome sequencing has a success rate of about 50% in the diagnosis of complex cases. In other words, about half the patients submitted to this kind of analysis will have to go on looking for a conclusive diagnosis.

    Source:

    São Paulo Research Foundation (FAPESP)

    Journal reference:

    Rezende, R. C., et al. (2024). Exome Sequencing Identifies Multiple Genetic Diagnoses in Children with Syndromic Growth Disorders. The Journal of Pediatrics. doi.org/10.1016/j.jpeds.2023.113841.

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  • FDA approves omalizumab for food allergy reactions based on NIH research

    FDA approves omalizumab for food allergy reactions based on NIH research

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    Today’s Food and Drug Administration approval of a supplemental biologics license for the monoclonal antibody omalizumab (Xolair) highlights the vital role of the National Institutes of Health-supported research that underpins the FDA decision.

    FDA has approved omalizumab for the reduction of allergic reactions, including anaphylaxis, that may occur with an accidental exposure to one or more foods in adults and children aged 1 year and older with food allergy. People taking omalizumab still need to avoid exposure to foods to which they are allergic. Omalizumab previously received FDA approval for three other indications, including the treatment of moderate-to-severe persistent allergic asthma in certain patients.

    The new FDA approval is based on data from a planned interim analysis of a Phase 3 clinical trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH. The trial is called Omalizumab as Monotherapy and as Adjunct Therapy to Multi-Allergen OIT in Food Allergic Children and Adults, or OUtMATCH. Investigators in the NIAID-funded Consortium for Food Allergy Research conducted the trial.

    Detailed final results from the first stage of the trial will be presented at the American Academy of Allergy, Asthma & Immunology Annual Meeting in Washington, D.C. during a late-breaking symposium titled, “Omalizumab for the Treatment of Food Allergy: The OUtMATCH Study” on Sunday, Feb. 25, 2024, at 1:45 pm ET. An online supplement of the Journal of Allergy and Clinical Immunology published an abstract outlining the final results on Feb. 5, 2024. 

    NIAID funds the trial with additional support from and collaboration with Genentech, a member of the Roche Group, and Novartis Pharmaceuticals Corporation. The two companies collaborate to develop and promote omalizumab and are supplying it for the trial. 

    Additional information about the ongoing OUtMATCH trial is available at ClinicalTrials.gov under study identifier NCT03881696.

    Source:

    NIH/National Institute of Allergy and Infectious Diseases

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  • Research uncovers link between reproductive factors and COPD risk in women

    Research uncovers link between reproductive factors and COPD risk in women

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    A range of reproductive factors, including age when periods first start and an early menopause, are all linked to a heightened risk of COPD—the umbrella term for progressive lung conditions that cause breathing difficulties—finds research published online in the journal Thorax.

    Miscarriage, stillbirth, infertility, and having 3 or more children are also associated with a heightened risk of COPD, which includes emphysema and chronic bronchitis, the findings show.

    Recent evidence indicates substantial gender  differences in susceptibility to, and severity of, COPD, note the researchers. Women seem to develop severe COPD at younger ages than men. And while smoking is a major risk factor, non-smokers with COPD are more likely to be women, they add.

    Previously published studies looking at the potential influence of female hormones on COPD risk have been hampered by methodological flaws, note the researchers. To try and get round these issues, they drew on the International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE) consortium.

    This is a collection of 27 observational studies, pooling individual level data from more than 850,000 women in 12 countries.

    For the purposes of the current study, the researchers included three groups of women (283,070; average age 54) with data on reproductive factors and COPD: the Australian Longitudinal Study on Women’s Health 1946-51 (ALSWH-mid); the UK Biobank; and the Swedish Women’s Lifestyle and Health Study (WLH).

    In the ALSWH-mid and UK Biobank groups, women were tracked until the end of December 2019. Women in WLH were tracked up to the end of 2010.

    Information on reproductive factors was collected at study entry or at subsequent data collection points, along with potentially influential factors: birth year (before or after 1950), ethnicity, educational level, duration of smoking, asthma (never and ever), and weight (BMI).

    COPD was retrospectively and prospectively identified through self-report and medical records, which included prescriptions, hospital admissions, emergency care visits, and death registry data.

    The women’s health was monitored for an average of 11 years. During this time, 10,737 (4%) women developed COPD at an average age of 63. 

    Women with COPD were more likely to be older when recruited to their studies, to have fewer than 10 years of formal education, to be obese, to have smoked for at least 10 years, and to have asthma-all risk factors for the condition. Some 53, 205 (16%) women were excluded because of missing data.

    Several reproductive factors were associated with the risk of COPD, including age when periods first started; number of children; a history of infertility, miscarriage or stillbirth, especially multiple miscarriages or stillbirths; and age at menopause.

    A U-shaped pattern emerged for the age at which periods first started. Those who began menstruating before or at the age of 11 were 17% more likely to develop COPD than those who did so at the age of 13; after the age of 16, the risk was 24% higher.

    Women with children were at higher risk of COPD than childless women. Compared with having 2 children, more than 3 was associated with a 34% higher risk, while women with one child were at 18% higher risk.

    Women who experienced infertility also had a 13% higher risk of COPD than women who were fertile. 

    And among those who had ever been pregnant, a history of miscarriage was associated with a 15% higher risk of COPD, with the risk rising in tandem with the number of miscarriages: 28% higher for 2; and 36% higher for 3 or more.

    Similarly, stillbirth was associated with a 42% overall higher risk of COPD, with the risk rising in tandem with the number of stillbirths.

    Menopause before the age of 40 was associated with a 69% higher risk, compared with those experiencing it naturally at the age of 50-51, while the risk was 21% lower for those who went through it at or after the age of 54.

    This is an observational study, so can’t establish cause, and the researchers acknowledge various limitations to their findings, including potentially influential factors. 

    For example, they had no detailed information on hormonal contraception and HRT use, and data on parental history of COPD, childhood respiratory infections, secondhand smoking or occupational exposures, weren’t available for all 3 of the groups. 

    But by way of an explanation for their findings, they suggest that the female hormone estrogen is likely to have a key role in COPD risk in women, because of its various effects on the lung. 

    “The overall effect of estrogen might differ depending on the timing,” they suggest. “In the early or middle reproductive stage, long or higher accumulated exposure to estrogen would be detrimental to the lung, leading to a higher risk of COPD among women with early menarche or multiple live births. 

    “In the later stage, estrogen may be protective, since earlier age at menopause or [ovary removal] (indicates shorter exposure to estrogen) were associated with a higher risk of COPD.” 

    Other factors, including autoimmune disease, such as type 1 diabetes, and social and environmental factors, such as air pollution, underweight, and socioeconomic deprivation, might also be influential, they add.

    Source:

    Journal reference:

    Liang, C., et al. (2024). Female reproductive histories and the risk of chronic obstructive pulmonary disease. Thorax. doi.org/10.1136/thorax-2023-220388.

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  • Early onset of menstruation and menopause associated with increased risk of COPD

    Early onset of menstruation and menopause associated with increased risk of COPD

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    In a recent study published in Thorax, a group of researchers evaluated the association between female reproductive factors such as age at menarche, stillbirth, number of children, infertility, miscarriage, and age at natural menopause—and the risk of developing chronic obstructive pulmonary disease (COPD).

    Study: Female reproductive histories and the risk of chronic obstructive pulmonary disease. Image Credit: Image Point Fr/Shutterstock.com

    Background 

    COPD is a significant global health issue, with a prevalence of approximately 3.9% in 2017, showing slight gender differences in rates between men and women. Notably, women are more susceptible to developing severe COPD at younger ages than men, and the majority of non-smokers with COPD are women.

    This suggests that female sex hormones, such as estrogen and progesterone, play crucial roles in lung development and the pathogenesis of COPD. These hormones influence bronchodilation, inflammation, and cellular proliferation, key factors in COPD development.

    The variability in the female hormonal environment throughout different reproductive stages- menarche, pregnancy, menopause, and conditions like infertility or pregnancy loss- highlights the complex relationship between female reproductive health and COPD risk.

    However, research specifically exploring this connection remains limited, indicating a need for further research into how reproductive history impacts COPD risk.

    About the study 

    The present study conducted by the Inter­national Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE) consortium utilized data from over 850,000 women across 12 countries.

    It focused on three cohorts with information on reproductive factors and COPD: the Australian Longitudinal Study on Women’s Health, the United Kingdom (UK) Biobank, and the Swedish Women’s Lifestyle and Health Study. 

    To ensure accuracy, the study excluded women who had developed COPD by age 40 from analyses involving infertility, miscarriage, stillbirths, and parity due to the absence of specific ages for these events.

    Only women who had experienced natural menopause were considered for analysis regarding menopause age, and those with COPD before natural menopause were omitted.

    The researchers carefully handled missing data, ensuring participants had complete records on critical factors such as race, education, smoking history, body mass index, and asthma.

    To address potential biases, including the impacts of coronavirus disease 2019 (COVID-19), follow-up adjustments were made across cohorts, and reproductive histories were detailed, including menarche to menopause.

    COPD was identified through diverse data, ensuring accuracy. Statistical analysis, including Cox regression and sensitivity tests, explored reproductive factors’ influence on COPD risk, highlighting their importance in women’s health research.

    Study results 

    In the present comprehensive study encompassing 283,070 women with a median age of 54 years, researchers embarked on an 11-year journey to unravel the intricate relationship between women’s reproductive history and the development of COPD.

    Throughout this period, 3.8% of the participants, equivalent to 10,737 women, were diagnosed with COPD at a median age of 63 years.

    The identification of COPD cases varied, with 7,983 cases recognized through a singular data source—ranging from survey data to hospital records—and 2,754 through multiple sources.

    The initial characteristics of these women highlighted certain risk factors, including advanced age at cohort entry, lower educational attainment, higher body mass indices, significant smoking histories, and pre-existing asthma conditions.

    The researchers excluded 53,205 women due to incomplete data, particularly regarding smoking habits and body mass index, ensuring the robustness of their findings.

    A nuanced pattern emerged, linking the age of menarche with COPD risk; notably, women who experienced menarche at age 11 or younger, as well as those who began menstruating after 13, saw an increased risk, with a particularly sharp rise observed in those who started menstruating at age 14 or beyond.

    Furthermore, the study revealed that motherhood also influenced COPD risk, with women having one or more children facing higher risks compared to childless counterparts. This risk escalated with the number of children borne.

    Additionally, experiences of infertility and miscarriages further intensified COPD risks, painting a complex picture of how reproductive history shapes respiratory health.

    Women who had undergone natural menopause presented an inverse risk relationship with COPD, dependent on the age at menopause. Those entering menopause before age 40 faced the highest risk, whereas the risk diminished for women experiencing menopause at or beyond age 54.

    The study also used rigorous sensitivity analyses, including random effects modeling and competing risk analysis, to validate these findings.

    Notably, the association between infertility and COPD risk diminished in some analyses, yet the overarching trends remained consistent across various subgroups, including smokers and non-smokers, as well as women with and without a history of asthma.

    The analysis extended to explore the impact of bilateral oophorectomy age on COPD risk, finding a heightened risk among women who underwent the procedure at younger ages.

    Further, the study delved into the specific effects of reproductive history facets such as age at menarche, miscarriages, stillbirths, and menopause timing on COPD risk, with findings echoing across individual cohort studies and meta-analyses.

    Despite some variability, especially concerning the age at menarche, most evidence pointed towards a consistent relationship between reproductive factors and the development of COPD.

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  • A closer look reveals lasting impacts

    A closer look reveals lasting impacts

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    In a recent study published in the journal Pediatrics, a large team of scientists from the United States (U.S.) reviewed existing studies on post-acute sequelae of coronavirus disease 2019 (COVID-19) (PASC) to understand the long-term impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the pediatric population, including factors such as prevalence, clinical characteristics, risk factors, and underlying mechanisms.

    ​STATE-OF-THE-ART REVIEW – Postacute Sequelae of SARS-CoV-2 in Children. Image Credit: Donkeyworx / Shutterstock

    Background

    The global impact of the COVID-19 pandemic has touched multiple spheres of life, with economic and social consequences apart from the massive effect on the medical and healthcare fields. Studies have shown that the pandemic has disproportionately affected specific racial and socioeconomic groups. Furthermore, a significant portion of the population continues to struggle with persistent and debilitating aftereffects and symptoms of COVID-19, which has now been called PASC or long coronavirus disease (long COVID).

    Estimates indicate that the U.S. had approximately 20% pediatric cases of COVID-19, of which 10%–20% were thought to develop into PASC, which translates to roughly 5.8 million children in the country. The present study summarizes the current understanding of the epidemiology, prevalence, underlying mechanisms, clinical characteristics, and outcomes of PASC in the pediatric population.

    PASC epidemiology

    The review found no consensus on the prevalence of PASC among children, with a 4% to 62% prevalence being reported across studies. The researchers believe that differences in factors such as study design, follow-up durations, diagnostic criteria, and study population are responsible for the wide range of prevalence estimates. Furthermore, the broad symptoms, affecting multiple organ systems, and overlaps with existing comorbidities also make it challenging to diagnose PASC.

    There is also a paucity of studies examining the trajectory of PASC in the pediatric population, with very few studies having examined the progression of the disease beyond a year. Studies found that only 15% of asymptomatic SARS-CoV-2 infections in children progress to PASC, while 45% of the symptomatic infections were found to result in long-lasting sequelae.

    Furthermore, infections with variants before the emergence of Omicron were found to increase the risk of PASC. Increasing age, severity of the infection, higher body weight, chronic underlying medical conditions, and the organ systems affected during the acute SARS-CoV-2 infection were all found to be risk factors for developing PASC.

    While the contribution of environmental and psycho-social factors in the development and manifestation of PASC has not been well investigated, the scientists believe that the escalating food and housing insecurity, disruption of educational and health care resources, and lower family income could have increased the mental and physical health problems in children, lowering immunity, and exacerbating existing illnesses.

    PASC in children

    Based on existing information, the team formulated a conceptual model for PASC in the pediatric population. They defined PASC in children as a heterogeneous group of symptoms occurring after a SARS-CoV-2 infection, consisting of persistent COVID-19 symptoms such as cough, dyspnea, fatigue, headaches, anosmia, ageusia, and chronic pain. Furthermore, exacerbation of existing conditions such as increased cough in children with asthma, deterioration of neurodevelopmental and mental health conditions, and diabetic ketoacidosis in pediatric diabetes cases are also thought to be a part of PASC.

    The review emphasizes the need to give special consideration to understanding the development of PASC in children at a higher risk of SARS-CoV-2 infections due to existing comorbidities and medical conditions. The researchers also discussed the potential development of de-novo post-acute conditions and the onset of autoimmune disorders. Studies have already reported multisystem inflammatory syndrome in children (MIS-C) as being one of the prevalent complications of COVID-19 in children.

    The review also provided a comprehensive summary of the wide range of manifestations and symptoms of PASC, including constitutional symptoms such as persistent fatigue, post-exertional malaise, brain fog or difficulty concentrating, depressive symptoms, and somnolence. The researchers also discussed the respiratory, cardiac, neurological, olfactory, gastrointestinal, mental health, musculoskeletal, dermatological, and inflammatory or hematological manifestations of PASC in detail.

    Furthermore, the study also examined the role of PASC in exacerbating underlying conditions in children, such as asthma, fibromyalgia, and connective tissue disorders, as well as post-infectious conditions such as MIS-C and de-novo conditions such as diabetes, autoimmune disorders, and neurological problems that could potentially develop during PASC.

    Conclusions

    To summarize, the review examined studies investigating the long-term consequences of SARS-CoV-2 infections in children and presented a comprehensive picture of the current understanding of PASC in children. The findings indicate that while the severity and prevalence of COVID-19 in the pediatric population were not as high as in adults, PASC does entail severe and long-lasting consequences, including the development of new autoimmune conditions and diabetes. These results highlight the need to form initiatives to further understand the susceptibility of children with underlying medical conditions to SARS-CoV-2 infections.

    Journal reference:

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