Nearly 25 million people in the United States have asthma, including 4.7 million children and adolescents. Almost 10 percent of these individuals had one or more asthma attacks within the past 12 months. Asthma can cause coughing, wheezing, chest tightness, and shortness of breath. In severe cases, breathing becomes extremely difficult. Worsening asthma can lead to missed time at school and work, emergency room visits, and even death.

Today on World Asthma Day, NIAID reaffirms its commitment to reducing illness from this chronic lung syndrome and improving quality of life for people with asthma through research that informs the development of new asthma prevention and treatment strategies. NIAID-funded studies in children and adolescents recently uncovered new risk factors for asthma and a previously unreported cause of frequent, severe asthma attacks. In addition, two new NIAID-supported studies aim to further asthma therapeutics development by shedding light on the behavior of airway-cell genes and proteins involved in regulating asthma severity and by defining poorly understood causes of airway inflammation in underserved youth with the disorder. Learn more about these recent research highlights below.

Asthma Risk Factors 

Nearly a third of infants who are hospitalized with a severe form of a common childhood lung infection called bronchiolitis develop asthma later in childhood. Predicting which infants with severe bronchiolitis are at highest risk for asthma, understanding why, and developing effective interventions remain challenges. Investigators from the NIAID-supported 35th Multicenter Airway Research Collaboration (MARC-35) recently identified genetic factors that may underlie the bronchiolitis–asthma link.

• Environmental exposures such as tobacco smoke are known to modify the function of certain genes in people, potentially resulting in long-term health effects. In one study, MARC-35 researchers examined such modifications by analyzing DNA in nasal swabs from 625 infants hospitalized with bronchiolitis. The scientists found that the genomes of some infants with severe bronchiolitis had modifications potentially caused by environmental exposures in the uterus or after birth, and these changes were associated with increased risk for asthma later in childhood. Now investigators want to identify which exposures had this detrimental effect.
• In a second study, MARC-35 researchers focused on small molecules called microRNAs, which derive from DNA and help control the genetic information that directs the building of proteins. The scientists analyzed microRNAs in nasal-swab DNA from 575 children who were hospitalized with bronchiolitis in infancy and followed until 6 years of age. The investigators identified 23 microRNAs that were turned on or off to different extents in the children who developed asthma by age 6 compared to those who did not. Now scientists want to identify what is triggering these differences and how to block them to reduce asthma risk.

Other investigators from the NIAID-funded Urban Environment and Childhood Asthma (URECA) study linked the composition of all the microbes found in the nose—the nasal microbiota—at age 3 years to respiratory health profiles ranging from high to low risk for developing asthma by age 7 years. The scientists also found that both exposure to certain microbes in house dust during infancy and a genetic predisposition to developing allergic diseases later in childhood influence how the airway microbiota develops. 

Therapeutic Insights

Scientists in NIAID’s Laboratory of Allergic Diseases recently demonstrated that a protein called RSG4 in smooth muscle cells of airway walls affects asthma severity in part by regulating airway inflammation independent of so-called G proteins. This finding builds on the lab’s 2020 discovery that blocking RSG4 in a mouse model of asthma reduced a key feature of the disease called airway hyper-responsiveness. This is a heightened sensitivity to molecules that activate smooth muscle cells in airway walls, leading to excessive airway constriction. Together the findings suggest that RSG4 in these cells could be a therapeutic target for asthma.

NIAID-supported researchers discovered recently that structural changes to nerve-cell networks in upper-airway tissues underlie asthma attacks in children who are hospitalized due to these attacks more than once a year. This contrasts with asthma attacks in children who are hospitalized less frequently, as those attacks are characterized by immune-system activity like allergic inflammation and responses to infections. The new findings, reported by the Ohio site in the NIAID-funded Childhood Asthma in Urban Settings (CAUSE) network, suggest that preventing and treating frequent severe asthma attacks in children may require an untraditional approach that targets the nervous system.

The CAUSE network also launched a new study in April 2024 to improve understanding of how airway inflammation influences asthma severity at a cellular and molecular level in children and adolescents who live in low-income urban communities. Airway inflammation in asthma may be categorized as related to a “type 2” immune response, which also plays a role in allergic diseases, or a non-type 2 immune response. The new study aims to define the cellular and molecular mechanisms associated with each type of airway inflammation in severe asthma to identify potential targets for new therapies.

NIAID thanks the hundreds of study participants and their caregivers who made these research advances possible and who help scientists continue to illuminate the complex and varied nature of asthma to reduce the burden of this disease.

Why do some people hospitalized with COVID-19 succumb, while others—with apparently similar disease severity at the time of hospitalization—survive? Among older individuals, are there particular immune responses to SARS-CoV-2 virus infection that set the stage for the increased risk of severe COVID-19?  These are among the questions addressed in the NIAID-funded Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study. Two recent publications by IMPACC network investigators provide a detailed picture of the immunologic dynamics of COVID-19 disease in a large cohort of patients who were hospitalized prior to the wide-spread availability of COVID vaccines.

A report by Leying Guan, Ph.D., of Yale School of Public Health and colleagues in the Journal of Clinical Investigation describes data from this longitudinal study of 1,152 adult COVID-19 patients who were hospitalized between May 2020 and March 2021. Participants were assigned to one of five disease trajectory groups (TG) based on factors including length of hospital stay until discharge or death. Individuals in both TG4 and TG5 were considered critically ill, with those in TG5 dying within 28 days of hospitalization. Blood and nasal swab samples, collected up to six times for each patient, underwent an integrated series of “omics” analyses. This allowed the investigators to track coordinated changes in relevant phenomena including gene expression, the appearance of various immune response proteins and metabolites, and frequency of certain effector immune cells (T cells) as well as antibody-producing B cells over the course of illness. The multi-omics analysis identified a “severity factor” that predicted seriousness of illness among all participants and another distinct immune signature, termed a “mortality factor,” that distinguished those in the critically ill groups who survived (TG4) from those who died (TG5). 

The “severity factor” comprised a spectrum of immune changes that began early in the course of illness and included dysregulation in the metabolism of three essential amino acids (tryptophan, phenylalanine, and histidine). These amino acids, note the investigators, act as important protein building blocks, critical sources of energy, and modulators of immunity, and so disturbances in their metabolism could signal an increased likelihood of severe illness or death. The metabolic dysregulation revealed by the analysis demonstrated the greatest power at distinguishing TG4 from TG5 and appears to act as an early hallmark of eventual mortality among critically ill patients. These observations regarding dysregulation of amino acid metabolism suggest that methods to assess metabolites in the clinical setting early in the course of disease might prompt trials of interventions such as amino acid supplementation in those cases where a signal of dysregulation is detected. 

The “mortality factor” was driven by immune system disturbances and included elevated levels of inflammation-promoting molecules called cytokines, reduced levels of infection-fighting immunoglobulins and antibody-producing B cells, and a dysregulation in the body’s responsiveness to interferon.  These observations support the early administration of antiviral and antibody therapies as critical interventions to reduce COVID-19 mortality.

Charles R. Langelier, M.D., Ph.D., of University of California, San Francisco, and colleagues recently published another analysis of data from the IMPACC cohort in Science Translational Medicine. This analysis sought to better characterize the association between increased age and greater odds of severe or fatal COVID-19 disease. Blood and nasal swab samples from 1,031 IMPACC participants were collected up to six times from each patient over a span of 28 days, yielding 2,523 samples for analysis. 

In general, the investigators note, an effective response to a viral infection involves a well- controlled series of immune reactions, beginning with proinflammatory and other responses from innate immune components, followed by a regulated response from antibodies and other components of the adaptive immune system leading to viral clearance, and then a diminishment of inflammatory signals so that unnecessary tissue damage is avoided. Compared to people under 63 years of age, those who were older had higher respiratory viral loads at hospital admission, produced lower amounts of anti-SARS-CoV-2 antibodies over time, and cleared the virus more slowly. Older age was strongly associated with increased expression of genes involved in several innate immune-related pathways, including ones leading to increased abundance of proinflammatory interferons, and these remained high over time, suggesting an age-dependent impairment in inflammation resolution.

In summary, these analyses demonstrate the value of collecting and analyzing comprehensive longitudinal immunologic assays combined with careful clinical phenotyping to identify mechanisms of disease heterogeneity in both novel and infectious diseases, an approach that may allow the identification of potential novel therapeutic targets.

References: JP Gygi et al. Integrated longitudinal multi-omics study identifies immune programs associated with acute COVID-19 severity and mortality. Journal of Clinical Investigation. DOI: 10.1172/JCI176640 (2024).

H Van Phan et al. Host-microbe multi-omic profiling reveals age-dependent immune dysregulation associated with COVID-19 immunopathology. Science Translational Medicine. DOI: 10.1126/scitranslmed.adj5154. (2024).

by Jeanne Marrazzo, M.D., M.P.H., NIAID Director

The HIV research community is led by scientists with deep personal commitments to improving the lives of people with and affected by HIV. Some researchers, like me, have pursued this cause since the start of the HIV pandemic, growing our careers studying HIV from basic to implementation science. Our collective decades of work have generated HIV testing, prevention and treatment options beyond what we could have imagined in the 1980s. Those advances enable NIAID to explore new frontiers: expanding HIV prevention and treatment modalities, increasing understanding of the interplay between HIV and other infectious and non-communicable diseases, optimizing choice and convenience, and building on the ever-growing knowledge base that we need to develop a preventive vaccine and cure. The next generation of leaders will bring these concepts to fruition, and we need to welcome and support them into the complex and competitive field of HIV science.

Click below for a video in which NIAID grantees and I discuss the value and experience of early-stage HIV investigators (the audio described version is here):

NIAID wants to fund more new HIV scientists and we have special programs and funding approaches to meet that goal. This week, the NIH Office of AIDS Research will host a virtual workshop on early-career HIV investigators tomorrow, April 24, and NIAID will host its next grant writing Webinars in May, June, and July.

For more information about programs and support for new and early-stage investigators as well as people starting to implement their first independent grant, visit these NIAID and NIH resources: 

Information for New Investigators (NIAID)

HIV/AIDS Information for Researchers (NIAID)

OAR Early Career Investigator Resources (NIH)

Resources of Interest to Early-Stage Investigators (NIH)

Early Career Reviewer Program (NIH)

NIAID has awarded 11 new cooperative agreements to support the Consortium for Food Allergy Research, or CoFAR, in the latest renewal of the program since its establishment 19 years ago. The institute expects to fund the awards with more than $11 million annually for seven years, contingent upon the availability of funds. 

CoFAR’s goal is to conduct groundbreaking clinical research on food allergy prevention and therapy and on the biological mechanisms underlying food allergy. Conducting clinical research with a consortium of multiple study sites enables investigators to pursue questions that can only be answered through the participation of high numbers of study volunteers. Consortia also can potentially recruit a more diverse set of study participants than any single site could. 

Most recently, CoFAR’s OUtMATCH clinical trial found that treatment with omalizumab (Xolair) substantially increased the amount of peanut, tree nuts, egg, milk and wheat that multi-food allergic children as young as 1 year could consume without experiencing an allergic reaction. The Food and Drug Administration approved Xolair for people with food allergy based on the study findings. 

The new awards will support consortium-wide clinical research projects, which may include treatment or prevention clinical trials. The selection process for these consortium-wide projects began in March 2024. The awards also will support local food allergy-related clinical studies conducted by individual CoFAR sites and the completion of the remaining stages of the OUtMATCH trial. 

The awards have been issued to the following institutions as one leadership center and ten clinical research centers:

Leadership Center

Johns Hopkins University (JHU) 

Principal Investigators: Robert A. Wood (JHU); Supinda Bunyavanich and Scott H. Sicherer (Icahn School of Medicine at Mount Sinai) 
Grant number UM1-AI182034-01

Clinical Research Centers

Arkansas Children's Hospital Research Institute 

Principal Investigator: Stacie M. Jones 
Grant number U01-AI181962-01

Boston Children's Hospital 

Principal Investigator: Rima Rachid 
Grant number U01-AI181964-01

Cincinnati Children's Hospital Medical Center 

Principal Investigators: Amal Halim Assa’ad, Marc E. Rothenberg 
Grant number U01-AI181966-01

Icahn School Of Medicine at Mount Sinai 

Principal Investigator: Scott H. Sicherer 
Grant number U01-AI181883-01

Johns Hopkins University  

Principal Investigator: Robert A. Wood 
Grant number U01-AI182032-01

Northwestern University at Chicago 

Principal Investigators: Ruchi S. Gupta, Maria Cecilia Berin 
Grant number U01-AI181897-01

Stanford University 

Principal Investigators: Sayantani B. Sindher, R. Sharon Chinthrajah  
Grant number U01-AI182039-01

University of Michigan at Ann Arbor 

Principal Investigators: James R. Baker, Johann Eli Gudjonsson, Charles F. Schuler 
Grant number U01-AI181882-01

University of North Carolina Chapel Hill 

Principal Investigators: Edwin Kim, Corinne Keet 
Grant number U01-AI182033-01

Vanderbilt University Medical Center 

Principal Investigators: Leonard B. Bacharier, Rachel Glick Robison 
Grant number U01-AI181927-01

NIH Trial Gives People with Lupus Data to Inform Treatment Decisions 

In people with a form of lupus called systemic lupus erythematosus (SLE), the risk for a severe flare-up of disease was low for both individuals who tapered off long-term immunosuppressive therapy and those who remained on it, a clinical trial has found. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, sponsored and funded the trial. The findings were reported today in the journal The Lancet Rheumatology.

SLE is a chronic autoimmune disease in which the immune system attacks healthy tissues and organs.  An estimated 450,000 people in the United States have the disease. Medications that doctors prescribe for people with SLE help suppress or tamp down their overactive immune systems. One of the most prescribed immunosuppressants for SLE, mycophenolate mofetil or MMF, effectively treats moderate and severe forms of the disease but also increases the risk of infections, cancers, severe birth defects, miscarriage, and impaired responses to vaccines when the drug is used long-term. Tapering off MMF once SLE symptoms subside reduces these side effects but could risk exposing the individual to a disease flare with the potential to cause a range of symptoms, including fatigue, rash, arthritis and internal organ damage. 

Until today's report, little evidence existed to help people with SLE and their physicians understand the likelihood of a flare after tapering off MMF. The new findings will help people with SLE make informed decisions about withdrawing treatment based on their personal circumstances and risk tolerance. 

The NIAID-funded Autoimmunity Centers of Excellence network conducted the trial under the leadership of Judith A. James, M.D., Ph.D., and Eliza F. Chakravarty, M.D. Dr. James is professor and chair of the Arthritis & Clinical Immunology Research Program at the Oklahoma Medical Research Foundation. Dr. Chakravarty was an associate professor in the same program during the study. The National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of NIH, supports the database for the biological samples processed during the trial.

The trial involved 102 people with SLE ages 18 to 70 whose symptoms had subsided after treatment with MMF. Participants had been taking the drug for an average of 6.6 years. Eighty-four percent of participants were female, reflecting the disproportionate prevalence of lupus in women. Seventy-six percent of participants had a history of lupus nephritis—kidney inflammation that can harm kidney function. Forty-one percent of participants were Black, 40% were White, 21% were Hispanic/Latino, 10% were Asian, and 2% were American Indian/Alaska Native.

The study team assigned participants at random to either taper off MMF over a 12-week period or to remain on their baseline MMF dose. Investigators followed the participants for 60 weeks to monitor if and when they experienced a flare severe or persistent enough to require either new immunosuppressive therapy or higher doses of it. 

By week 60, 9 of 51 participants in the MMF withdrawal group and 5 of 49 in the MMF maintenance group had severe or persistent flares requiring new or increased immunosuppressive therapy. The estimated risk of such flares by week 60—a metric that reflected both occurrence and timing—was up to 18% in the withdrawal group and 11% in the maintenance group. The investigators also looked at five different measures of lupus flares and found that treatment withdrawal consistently led to a 6% to 8% increase in the risk for flares. For participants with a history of kidney disease, the increase in risk was higher, at 14%. One benefit of MMF withdrawal, however, was a reduction in infections. Forty-six percent of the withdrawal group had at least one infection compared with 64% of the maintenance group. 

This study is the first clinical trial of therapy withdrawal in people with SLE who no longer experience symptoms on long-term MMF, according to the researchers. Their findings suggest that MMF may be safely withdrawn in many people with stable SLE, they write, but larger studies and longer follow-up are still needed.

Reference: EF Chakravarty, et al. Mycophenolate mofetil withdrawal in systemic lupus erythematosus patients. The Lancet Rheumatology DOI: 10.1016/S2665-9913(23)00320-X (2024).