Findings From NIH-Funded Study Could Facilitate Early Treatment of Neonatal Sepsis

Scientists have identified a four-gene signature detectable in newborns’ blood at birth that predicts before symptom onset whether a baby will develop sepsis during the first week of life, according to a study co-funded by the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIAID). Sepsis is a potentially life-threatening condition that arises when the body's response to infection injures its own tissues and organs. Using the newly discovered genetic signature to identify newborns who will develop sepsis could facilitate early treatment and obviate the need to give antibiotics to all newborns with suspected sepsis but lacking a definitive diagnosis. The findings were published today in the journal eBioMedicine. 

Two to 3% of newborns globally develop sepsis, and 17.6% of those babies die. The signs of sepsis in newborns—such as irritability, poor feeding and respiratory distress—are common to many illnesses. Consequently, clinicians sometimes misdiagnose newborn sepsis or suspect it too late, leading to death. If a clinician does suspect that a newborn has sepsis, they give the baby antibiotics pending confirmatory laboratory diagnosis of infection. The most common diagnostic technique takes several days, however, and is often inconclusive. As a result, clinicians often must decide between stopping antibiotics early and risking under-treatment, or giving antibiotics based only on a clinical diagnosis and risking serious side effects and development of antimicrobial resistance.

The NIAID-supported study aimed to find a way to accurately predict sepsis in newborns so it can be diagnosed and treated early while avoiding unnecessary antibiotic use. The researchers conducted their study in a subset of 720 initially healthy, full-term newborns who were enrolled in a larger clinical trial at two community health centers in The Gambia, West Africa. Blood was collected from all babies at birth.

Thirty-three infants were hospitalized within the first month of life for clinical signs suggestive of sepsis. Of those, 21 babies were diagnosed with sepsis, including 15 within the first week of life, which is considered early-onset sepsis. Twelve babies were diagnosed with non-septic localized infections. The researchers matched these 33 babies with 33 healthy controls and analyzed their blood to identify genes that were comparatively more active or less active at birth in each of the four groups. Using machine learning methods, the researchers detected four genes that were comparatively more active at birth only in those newborns who developed early-onset sepsis. The four-gene signature was 92.5% accurate at predicting at birth which of the 66 infants would develop early-onset sepsis. 

The researchers tested the predictive accuracy of this gene signature in a different group of 12 infants whose blood had been collected soon after birth. Half had developed early-onset sepsis, while the other half had remained healthy. The four-gene signature predicted sepsis with 83% accuracy in this group. Further research is needed to determine how well the gene signature predicts early-onset sepsis in much larger groups of newborns.

The study was led by Robert E. W. Hancock, Ph.D.; Tobias R. Kollmann, M.D., Ph.D.; Beate Kampmann, M.D., Ph.D.; and Amy H. Lee, Ph.D. NIAID co-funded the study through its Human Immunology Project Consortium (HIPC) and Immune Development in Early Life program. 

The larger study that enrolled the 720 newborns was called Systems Biology to Identify Biomarkers of Neonatal Vaccine Immunogenicity, sponsored by Boston Children's Hospital and funded by NIAID through the HIPC. More information is available in ClinicalTrials.gov at study identifier NCT03246230.

Reference: An et al. Predictive gene expression signature diagnoses neonatal sepsis before clinical presentation. eBioMedicine DOI: 10.1016/j.ebiom.2024.105411 (2024).

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

The power of word choice is obvious every day in my life as a researcher, clinician, colleague, patient, spouse, and friend. Language can inform, delight and inspire, but it can mislead and wound if words are not chosen carefully. At worst, language can invoke stigma, shame, and even violence, all of which undermine NIAID’s mission as part of a health agency. Our institute is responsible not only for advancing scientific knowledge, but for doing so in a way that honors the dignity, individuality, and autonomy of the people affected by the health issues we address. For this reason, I am very proud to share the updated NIAID HIV Language Guide, a thoroughly vetted resource to inform our written and verbal communications.

NIAID has long been engaged in rich and multifaceted collaborations with HIV advocates and community stakeholders—partnerships that I prize and am honored to carry forward. Among their many contributions to HIV science, our community partners ensure that our language evolves as fluidly as our knowledge of the virus itself. Through their insights, the words we choose to describe the pathogen, its effects on the body, and the people who are affected by and living with HIV, have become increasingly person-centered. This progress reflects and upholds a commitment to avoid defining people by the disease with which they live. 

Despite this progress, the scientific community often lags in adopting evolving language, and many of the terms and phrases we use today are still insensitive and disrespectful to the people we aim to serve. Harmful language undermines people’s trust in biomedical research, and language-driven stigma prevents people from seeking health services which provide benefit. Non-inclusive language perpetuates knowledge gaps, limiting our ability to fully understand the people participating in research. As scientists and public health practitioners, we cannot be cavalier about language. Our words matter.

This guide originated as a resource for the HIV field, but respectful, inclusive, and person-first language is essential in all scientific communication. To that end, I am committed to following the NIAID HIV Language Guide in my communications, and strongly encourage all NIAID staff, funded research networks, sites, centers, investigators, and partners to do the same. We will not always get it right, but we will continue to try. We must support each other in learning, hold each other accountable, and continue to adapt as terms and norms change. 

For more information about the language guide and supporting resources, please visit https://www.niaid.nih.gov/research/hiv-language-guide. Spanish and Portuguese translations are coming soon.

An HIV drug that suppresses the activity of the CCR5 receptor—a collection of proteins on the surface of certain immune cells—was associated with better renal function in kidney transplant recipients with HIV compared to people who took a placebo in a randomized trial. Study participants taking the drug, called maraviroc, also experienced lower rates of transplant rejection than those taking placebo, but the difference was not statistically significant due to lower-than-expected rejection rates across the entire study population. The findings of the NIAID-sponsored trial were presented today at the 2024 American Transplant Congress in Philadelphia. 

The CCR5 receptor helps HIV enter CD4+ T cells. Some people have a genetic mutation that prevents the CCR5 receptor from working, and either cannot acquire HIV or experience slower HIV-related disease progression if living with the virus. It has separately been observed that people with the same CCR5 genetic mutation have better outcomes following kidney and liver transplantation. The CCR5 antagonist class of antiretroviral drugs was developed to mimic the naturally occurring CCR5 mutation and is a well tolerated component of HIV treatment, but the drugs have not been evaluated as an intervention to improve transplantation outcomes in people. Furthermore, transplant recipients with HIV more frequently experience transplant rejection and elevated CCR5 activity than transplant recipients without HIV.

A research team led by the University of California San Francisco conducted a U.S.-based Phase 2 trial to assess the safety and tolerability of the CCR5 antagonist maraviroc given daily from the time of transplant onward among kidney transplant recipients, and to compare renal function of people taking daily maraviroc to those taking a placebo one year (52 weeks) post-transplant. All study participants were living with HIV and were virally suppressed on antiretroviral therapy (ART) regimens. The study randomized 97 participants to receive maraviroc or a placebo in addition to their continued ART regimens post-transplant. Of them, only 27 participants were able to complete all necessary study examinations through 52 weeks due to logistical complications from the SARS-CoV-2 pandemic. At one-year post-transplant, the mean estimated glomerular filtration rate—a measure of how well kidneys were working—was significantly higher in participants receiving maraviroc in addition to their ART regimen compared with participants receiving ART and placebo (59.2 versus 49.3 mL/min/1.73m²). The drug was safe and well tolerated. 

Four of the 49 participants taking maraviroc and 6 of the 48 participants taking placebo experienced transplant rejection, but this difference was not statistically significant given the relatively small sample size. Transplant rejection rates were lower than expected across both study groups, which the study team suggests may be a favorable outcome of the ART regimens most participants were taking. 

The addition of maraviroc significantly improved renal function in kidney transplant recipients with HIV compared to placebo. According to the authors, these findings warrant further exploration of the benefit of CCR5 antagonists in all kidney transplant recipients regardless of HIV status.

For more information about this study, please visit ClinicalTrials.gov and use the identifier NCT02741323.

Reference:

Brown et al. Beneficial Impact of CCR5 Blockade in Kidney Transplant Recipients with HIV. American Transplant Congress in Philadelphia, Pennsylvania. Tuesday, June 4, 2024.

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)