FDA Grants Fast Track Designation For Idiopathic Pulmonary Fibrosis Drug

By Dr Deepu

Healio (9/11) reports that the Food and Drug Administration gave fast track designation to tipelukast, MediciNova’s experimental drug “for the treatment of patients with idiopathic pulmonary fibrosis.” The drug “demonstrated anti-inflammatory and anti-fibrotic activity in preclinical models through leukotriene receptor antagonism, as well as inhibition of phosphodiesterases and 5-lipoxygenase.” According to a company press release, “5-lipoxygenase/leukotriene pathway is believed to be a pathogenic factor in development of fibrosis, so the inhibitory effects demonstrated by tipelukast may be a novel treatment approach.”

Study: Long-Lived Smokers May Be Biologically Distinct

By Dr Deepu

The Washington Post (9/11, Cha) reports that “in an intriguing study published this week by University of California at Los Angeles researchers delved into the genetic makeup of long-lived smokers...and found that their survival may be due to an innate resilience they were born with.” While “on average, smokers’ life expectancy is 10 years less than non-smokers...the long-lived smokers are the exception and the researchers said that their findings suggest that they may be a ‘biologically distinct group’ that is endowed with genetic variants that allow them to respond differently to exposure.”

Study: E-Cigarette Use Reduces Carbon Monoxide, Acrolein Exposure Even For Occasional Smokers

By Dr Deepu

Reuters Health (9/10, Rapaport) reports on a study that found that smokers who switched to exclusive use of e-cigarettes were 80% less exposed to carbon monoxide and acrolein after four weeks while those who vaped and smoked reduced their exposures by 52% and 60% respectively. The authors noted that the most significant finding was that those who used both cigarettes and e-cigarettes showed significantly lower acrolein levels despite the presence of vegetable glycerin in the e-liquid, which could have increased exposure.

Study: Lung Cancer Rates Double Among Never-Smokers In US, UK

By Dr Deepu

MedPage Today (9/10) reports on research presented at the World Conference On Lung Cancer in Denver, Colorado, which examined a doubling of lung cancer rates among individuals who had never smoked between 2008 and 2014 at three U.S. medical centers. Noting that the cases are of undetermined etiology, Eric Lim, MD of the Royal Brompton Hospital in London said, “research into early detection – ideally, by noninvasive or molecular screening – is urgently required to identify early lung cancer in nonsmokers.” A similar increase in cases was also found at the Royal Brompton Hospital.

“Extremely Premature” Infants See Improving Outcomes

By Dr Deepu

The AP (9/9, Tanner) reports that a 20-year study published in the Journal of the American Medical Association found that “odds have improved that many extremely premature U.S. infants will survive without major problems.” However, “prospects remain poor for the smallest and youngest, born nearly four months too soon.” For the study, the researchers analyzed hospital records of nearly 35,000 extremely premature babies born between 1993 to 2012 at “26 academic centers participating in a National Institutes of Health research network.” The study included infants “born at 22 weeks to 28 weeks of pregnancy.”

        The Washington Post (9/9, Bernstein) reports that “babies born between 22 and 28 weeks of gestation and who weighed 400 to 1,500 grams (14.1 to 52.9 ounces) have benefited from new practices instituted between 1993 and 2012...said Rosemary Higgins, program scientist for the neonatal research network at the National Institute of Child Health and Human Development” and senior author of the study.

        The Huffington Post (9/9) reports that investigators found that between “2009 and 2012, survival rates for preemies born at 23 weeks increased from 27 percent to 33 percent.” Meanwhile, “for babies born at 24 weeks, survival rates jumped from 63 percent to 65 percent, and there were smaller increases for babies born at 25 and 27 weeks respectively.” The article adds that “survival without any major health complications improved by roughly 2 percent per year for babies born between 25 and 28 weeks gestation.”

        According to NPR (9/9) “these improvements are most likely to due to two major interventions: steroid treatment before birth to help preemies’ lungs develop faster, and the willingness of doctors to perform cesareans to deliver extreme preemies.” Challenges remain for smaller preemies born before 25 weeks.

Sleep-Disordered Breathing In Kids May Be Linked To Academic Problems

By Dr Deepu

HealthDay (9/9) reports that research suggests that “when children have sleep troubles due to breathing problems – such as sleep apnea – they may struggle in school.” Investigators “reviewed the results of 16 studies dealing with sleep apnea or related disorders in children and academic achievement.” The data indicated that kids “with sleep-disordered breathing did worse in language arts, math and science tests compared to those without such conditions.” The findings were published online in Pediatrics.

The researchers reviewed the results of 16 studies dealing with sleep apnea or related disorders in children and academic achievement. The investigators found that children with sleep-disordered breathing did worse in language arts, math and science tests compared to those without such conditions.

Varenicline May Not Increase Risk Of Heart Attack Or Depression, Study Suggests

By Dr Deepu

Reuters (9/8, Kelland) reports that a 150,000-participant study published in The Lancet Respiratory Medicine found that the smoking cessation medication Chantix (varenicline) does not raise the risk of heart attack or depression, despite prior reports to the contrary.

Chantix reduces both the craving for and pleasurable effects of cigarettes and is used by heavy smokers who find it difficult to quit. It is one of the biggest-selling stop-smoking drugs in the United States and Britain, and generated $647 million in revenue in 2014.

The latest research, published in The Lancet Respiratory Medicine journal, studied patients who had been prescribed either varenicline or Zyban, an anti-smoking drug from GlaxoSmithKline known generically as bupropion, to help them quit, or had used nicotine therapies such as patches, gum or lozenges.

Siblings Most Common Source Of Pertussis Infection In Newborns, Study Suggests

By Dr Deepu

The New York Times (9/7) “Well” blog reported that a study published online in Pediatrics suggests that “siblings, not mothers, are now the most common source of pertussis infection in newborns.” Researchers determined the source of pertussis infection in 569 infants between 2006 and 2013, finding that fathers “were the source of 10 percent of the infections, mothers of 20.6 percent, and siblings of 35.5 percent.”

        The AP (9/7, Tanner) pointed out that in order to protect babies, “experts have recommended two strategies – vaccinating close contacts after birth, including parents and siblings, and vaccinating pregnant women, who can transfer some disease protection before birth.” The results of this study, however, indicate that “the first option may not be as effective as hoped, so boosting low vaccination rates among pregnant women should be a top priority, the study authors said.” Reuters (9/8, Seaman) and HealthDay (9/8, Norton) also cover the study.

Immune Therapy overtakes Chemo in NSCLC- Nivolumab increases survival in Squamous cell cancer

By Dr Deepu

Patients with previously treated advanced or metastatic squamous non-small cell lung cancer (NSCLC) had improved survival with an immunotherapeutic drug than with chemotherapy, according to updated results from a randomized trial.

Twice as many patients treated with nivolumab (Opdivo) remained alive at 18 months as compared with those treated with docetaxel, and six times as many patients were alive without progression at 18 months with nivolumab as compared with the chemotherapy standard for NSCLC.

Median overall survival was 9.2 months with nivolumab and 6.0 months with docetaxel,  reported here at the World Conference on Lung Cancer.

A second trial involving patients with treatment-refractory squamous NSCLC similar improvement in outcomes with nivolumab versus docetaxel.

Accounting for about 20% of NSCLC cases, patients with squamous-cell NSCLC represent a poor-prognosis minority who have few options after progression or failure of first-line platinum-based chemotherapy. Second-line docetaxel is associated with modest clinical activity (median overall survival of 5 to 8 months, objective response rate of 3% to 9%) and significant toxicity.

Nivolumab, a fully human PD-1 immune checkpoint inhibitor antibody, has demonstrated activity in both squamous and nonsquamous NSCLC and received FDA approval earlier this year for patients with squamous NSCLC that had progressed during or after platinum-based chemotherapy.

At the American Society of Clinical Oncology meeting in June, investigators reported preliminary results from a randomized comparison of nivolumab and docetaxel in patients with previously treated advanced/metastatic squamous NSCLC. At that point the data showed a 1-year survival of 42% with nivolumab versus 24% with docetaxel, and a median PFS of 9.2 vs 6.0 months, also in favor of nivolumab.

The anti-PD-1 antibody maintained superiority across all prespecified subgroups, including age, geographic location, performance status, and prior therapy. Moreover, the survival benefit persisted across all categories of PD-L1 expression: positive, negative, and not quantifiable.

Patients treated with nivolumab had substantially fewer treatment-related adverse events, including any adverse events (59% vs 87%), grade 3-5 adverse events (8% vs 58%) and adverse events leading to discontinuation (5% vs 10%). No treatment-related deaths occurred in the nivolumab arm as compared with a 2% rate in the docetaxel group.

Similar superiority for nivolumab emerged from the phase II, single-arm CheckMate 063trial, which involved 117 patients with advanced/metastatic squamous NSCLC that had progressed during or after platinum-based chemotherapy plus at least one other systemic regimen.

The trial had a primary endpoint of independently reviewed and confirmed objective response. The data showed an overall response rate of 15% (17 of 117), three fourths of which are ongoing said Horn. The median time to response was 3.3 months, and the median duration of response has yet to be reached (range of 1.9 to 11.5 months). The cohort had a median PFS of 1.9 months and a 1-year PFS of 20%.

Responses were observed across all predefined subgroups, including age, number of prior therapies, performance status, and level of PD-L1 expression.

After a median follow-up of 8 months, the cohort had a median overall survival of 8.1 months, a 1-year overall survival of 39%, and 18-month survival of 27%. The updated data remained consistent with the primary analysis in July 2014, which showed a median overall survival of 8.2 months and 1-year overall survival of 41%.

Overall, 17% of the patients had grade 3/4 adverse events, the most common being gastrointestinal and pulmonary in nature (3% each). Horn noted that no new grade 3/4 adverse events occurred from the initial assessment through the updated analysis in June 2015.

Pregnant Women Being Urged To Get Whooping Cough Vaccine

By Dr Deepu

The Daily Mail (UK) (9/4) reports that “pregnant women are being urged to have the whooping cough vaccine after figures showed an increase in the number of cases.” According to the Daily Mail, “New data from Public Health England (PHE) showed a 24 per cent rise in cases of whooping cough in the first six months of the year compared to the same period last year.”

Early Treatment With Flu Antivirals May Reduce Length Of Seniors’ Hospital Stay

By Dr Deepu
HealthDay (9/4, Preidt) reports a new government study finds that “early antiviral treatment for seniors with severe cases of the flu may shorten their hospital stay and reduce the need for extended care after discharge.” In a news release, Dr. Dan Jernigan, director of the US Centers for Disease Control and Prevention’s influenza division, said, “This important study shows that people 65 and older should seek medical care early when they develop flu symptoms.”

Egg Shortage Will Not Affect Flu Vaccine Supply

By Dr Deepu
The Philadelphia Inquirer (9/4, Avril) reports that the recent avian flu outbreak in the Midwest has driven up egg prices at supermarkets but “health officials say...the supply of certain eggs...used to grow and incubate the flu vaccine for humans” should not be affected. Lynnette Brammer, an epidemiologist with the CDC, said that vaccine manufacturers use “a totally separate supply” of eggs from chickens raised in a controlled environment.

NIAID To Launch RSV Study

By Dr Deepu
Healio (8/28) reports that the National Institutes of Health “has announced plans for its National Institute of Allergy and Infectious Diseases to conduct a pilot study to evaluate how respiratory syncytial virus infection develops in adults, and how it affects immune system responses, according to a press release.” NIAID Director Dr. Anthony Fauci said the study will enable “scientists to monitor, in a controlled setting, the natural history of a disease in exquisite detail.” He added, “By studying [respiratory syncytial virus] infection in healthy adults, we hope to improve understanding of how this infection develops and determine the suitability of this particular strain of the virus for use in future [respiratory syncytial virus] vaccine and treatment trials.”

Researchers Working To Bring Lung Cancer Vaccine Developed In Cuba To US

By Dr Deepu

The Philadelphia Inquirer (8/28) “Check Up” blog reports that “Cuba has developed a novel lung cancer vaccine that American researchers are working to bring to the” US. According to the blog, “Now that diplomatic relations between the U.S. and Cuba have thawed,” Roswell Park Cancer Center in Buffalo “has reached an agreement with Cuba’s Center for Molecular Immunology to bring” the “vaccine, called CimaVax, to the U.S. for clinical testing – with an eye toward U.S. Food and Drug Administration approval.”

Researchers Seek To Make Flu Vaccine Work Better

By Dr Deepu

The Baltimore Sun (8/29, Cohn) reported on efforts to make the flu vaccine “work better.” Currently, influenza vaccines are “less effective than vaccines for other diseases.” For scientists at the NIH, “that means developing a universal vaccine.” Each year, the flu “vaccine must currently be matched months ahead of the flu season to circulating strains, which is something of a ‘guessing game,’ said Dr. Anthony S. Fauci, director of NIH’s National Institute of Allergy and Infectious Diseases. “ Dr. Fauci said, “Most of the time we guess correctly,” adding, “But not always.”

GSK’s malaria candidate vaccine, Mosquirix™ (RTS,S), receives positive opinion from European regulators for the prevention of malaria in young children in sub-Saharan Africa

By Dr Deepu

24 July 2015

Issued: London, UK

• WHO will now assess how the world’s first malaria candidate vaccine might be used alongside other tools to prevent malaria

GSK announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive scientific opinion for its malaria candidate vaccine Mosquirix^TM, also known as RTS,S, in children aged 6 weeks to 17 months. Following this decision, the World Health Organization (WHO) will now formulate a policy recommendation on use of the vaccine in national immunisation programmes once approved by national regulatory authorities.

RTS,S, which was developed in partnership with the PATH Malaria Vaccine Initiative (MVI), is the first candidate vaccine for the prevention of malaria to reach this milestone. While other vaccines tackle viruses or bacteria, RTS,S has been designed to prevent malaria caused by the Plasmodium falciparum parasite, which is most prevalent in sub-Saharan Africa (SSA). In 2013, there were an estimated 584,000 deaths from malaria with around 90% of these occurring in SSA, and 83% in children under the age of five in SSA.¹

The CHMP scientific opinion is a key step in the regulatory process toward making RTS,S available alongside existing tools currently recommended for malaria prevention. The positive opinion for young children was based on the review of data assessing the candidate vaccine’s safety, efficacy and quality. Clinical data submitted for CHMP assessment were mainly from a phase III clinical trial programme involving more than 16,000 young children that was conducted by 13 African research centres in eight African countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, Nigeria, and Tanzania).

Data from this trial programme demonstrate that over the first 18 months following three doses of RTS,S, malaria cases were reduced by almost half in children aged 5-17 months at the time of first vaccination and by 27% in infants aged 6-12 weeks. At study end, four doses of RTS,S reduced malaria cases by 39% over four years of follow-up in children, and by 27% over three years of follow-up in infants.²  In areas of the highest malaria burden, more than 6,000 clinical malaria cases were prevented over the study period for every 1,000 children vaccinated.² The efficacy of RTS,S was evaluated in addition to existing malaria control measures, such as insecticide treated bed nets, which were used by approximately 80% of the children and infants in the trial.

Sir Andrew Witty, CEO of GSK said: “Today’s scientific opinion represents a further important step towards making available for young children the world's first malaria vaccine. While RTS,S on its own is not the complete answer to malaria, its use alongside those interventions currently available such as bed nets and insecticides, would provide a very meaningful contribution to controlling the impact of malaria on children in those African communities that need it the most. The work doesn’t stop here and GSK remains committed to investing in R&D for malaria vaccines and treatments to find more ways to tackle this devastating disease.”

Dr David C. Kaslow, Vice President of Product Development at PATH said: “Today marks a significant scientific milestone for the long-standing partnership to develop a vaccine, yet several more steps remain before a malaria vaccine might reach the young children in Africa who most need protection against this deadly human parasite. PATH will continue to work with GSK and other partners to ensure that the evidence is available, as soon as possible, to support informed decision-making on those remaining steps.”

GSK has committed to a not-for-profit price for RTS,S so that, if approved, the price of RTS,S would cover the cost of manufacturing the vaccine together with a small return of around five per cent that will be reinvested in research and development for second-generation malaria vaccines, or vaccines against other neglected tropical diseases.

Next steps

Following the CHMP positive scientific opinion, two of the WHO’s independent advisory groups, the Strategic Advisory Group of Experts (SAGE) on Immunization and the Malaria Policy Advisory Committee (MPAC) will now jointly review the evidence base for RTS,S and make a joint policy recommendation for how it might be used alongside other tools to prevent malaria in the event the vaccine candidate is approved by national regulatory authorities in SSA. The WHO has indicated that such a policy recommendation may be possible by end of this year.

Following the WHO policy recommendation, GSK will also submit an application to the WHO for pre-qualification of RTS,S. WHO pre-qualification involves a scientific assessment of the quality, safety and efficacy of any new vaccine proposed for introduction in WHO Expanded Programme on Immunization. A pre-qualification decision is used by the United Nations agencies and other large scale public procurement agencies to help inform vaccine purchasing decisions.

Once a WHO pre-qualification is granted, GSK would then apply for marketing authorisation in countries in sub-Saharan Africa on a country-by-country basis. These regulatory and policy decisions would, if positive, enable countries to begin implementation of RTS,S through their universal immunisation programmes.

Both a WHO policy recommendation and WHO pre-qualification are requirements for Gavi, the Vaccine Alliance, to support eligible African countries introducing RTS,S into local immunisation programmes supported by UNICEF.

Notes to Editors

• Mosquirix is the brand name given to this malaria candidate vaccine. Its scientific name, RTS,S, reflects the composition. RTS,S also contains the AS01 adjuvant system.[i]
• RTS,S aims to trigger the body’s immune system to defend against the Plasmodium falciparum malaria parasite when it first enters the human host’s bloodstream and/or when the parasite infects liver cells. It is designed to prevent the parasite from infecting, maturing and multiplying in the liver, after which time the parasite would re-enter the bloodstream and infect red blood cells, leading to disease symptoms.
• The safety and efficacy of RTS,S has been evaluated in a large-scale phase III trial, in which it was administered in three doses, one month apart, with an additional fourth dose given 18 months later. Results from this trial have consistently demonstrated that RTS,S can help to protect children against malaria in endemic countries, when used in addition to other malaria control measures such as bed nets.
• RTS,S is the most advanced malaria vaccine candidate in development globally. It was created in 1987 by scientists working at GSK laboratories. Early clinical development was done in collaboration with the Walter Reed Army Institute for Research. In January 2001, GSK and PATH, with grant monies from the Bill & Melinda Gates Foundation to PATH, entered into a public-private partnership to develop an RTS,S-based vaccine for infants and young children living in malaria-endemic regions in sub-Saharan Africa.
• GSK has invested more than $365 million to date and expects to invest a further $200 to $250 million until development is completed. Between 2001 and the end of 2014, the MVI, supported by grants from Bill & Melinda Gates Foundation, invested more than $200 million to advance the RTS,S project.
• The EMA’s CHMP opinion is a final stage in the Article 58 procedure initiated in July 2014, by which the CHMP gives a scientific opinion, in co-operation with the World Health Organization (WHO), on a medicinal product for human use that is intended exclusively for markets outside of the European Union (EU). This assessment requires medicinal products to meet the same standards as those intended for use in the EU.

References

1.      http://www.who.int/malaria/media/world_malaria_report_2014/en/

2.      RTS,S Clinical Trials Partnership, The Lancet. 2015; 386 (9988): 31–45.

Lung CD200 Receptor Activation Abrogates Airway Hyperresponsiveness in Experimental Asthma

By Dr Deepu

The August issue of AJRCMB,study by Lauzon-Joset and colleagues demonstrate, in an experimental model of asthma, that local administration of CD200 inhibits airway hyperresponsiveness and lung accumulation of T helper type 2 cells, in addition to modulating the cytokine milieu within the lung. The authors note that "Given that airway hyperresponsiveness and inflammation are the root causes of asthma, these results pave the way to further investigations conducive to improved treatment."

Chloride Channel 3 Channels in the Activation and Migration of Human Blood Eosinophils in Allergic Asthma

By Dr Deepu

In the August issue of AJRCMB, Gaurav and colleagues report, for the first timein their study, a critical role for chloride channel 3 (CLC3) channels in the migration and activation of human blood eosinophils. The researchers also report, in addition to the known presence of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 2, the existence of subtypes of NOX, including NOX1, NOX3, NOX5, dual oxidase (DUOX) 1, and DUOX2, albeit at low levels, in human blood eosinophils. Very high levels of NOX2 messenger RNA transcripts were found in the eosinophils of subjects with moderate to severe asthma compared with subjects with mild to moderate asthma and healthy subjects, suggesting a positive correlation between the expression of NOX2 messenger RNA transcripts and disease severity. The authors conclude that their findings provide a novel target in regulating eosinophil infiltration and activation in allergic airway inflammation in asthma.

Benefit Confirmed for Combo Therapy in PAH-'Concrete, A-plus evidence' for better outcomes with tadalafil-ambrisentan

By Dr Deepu

Combination therapy with ambrisentan (Letairis) and tadalafil (Adcirca, Cialis) can significantly reduce the risk of clinical-failure events for pulmonary arterial hypertension (PAH) patients compared with either drug alone, according to complete results from a clinical trial now published in a major peer-reviewed journal.

Risk of first clinical failure -- defined as either death, hospitalization for worsening PAH, disease progression or unsatisfactory long-term clinical response to medication -- was reduced by half in the combination therapy group versus the two single therapy groups combined (hazard ratio 0.50; 95% CI 0.35-0.72; P<0.0001), Nazzareno Galiè, MD, of the University of Bologna, Italy, and colleagues reported in the New England Journal of Medicine.
Major findings from the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) study were also presented earlier this year at the American Thoracic Society's annual meeting. The NEJM publication confirms and extends that report.

AMBITION was a randomized, double-blind, 14-center study that included 500 treatment-naïve patients with World Health Organization class II or III symptoms of PAH.

During the trial, patients were randomly assigned in a 2:1:1 ratio to receive either 10 mg of ambrisentan plus 40 mg of tadalafil, 10 mg of ambrisentan plus placebo, or 40 mg of tadalafil plus placebo once a day. A clinical failure event occurred in 46 of 253 patients (18%) in the combination therapy group, 43 of 126 patients (34%) in the ambrisentan monotherapy group and 34 of 121 patients (28%) in the tadalafil monotherapy group, for a total of 77 of 247 patients (31%) in the two monotherapy groups combined.

At 24 weeks, the combination therapy group had greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than the pooled monotherapy group (-67.2% vs. -50.4%; P<0.001). Those receiving combination therapy also had a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio 1.56, 95% CI 1.05-2.32; P=0.03), and a greater improvement in 6-minute walk distance (median change from baseline 48.98 m vs. 23.80 m; P<0.001).

"Most previous clinical studies that have investigated combination therapy for PAH have evaluated sequential add-on therapies," the authors wrote. "The AMBITION trial supports the rationale for targeting multiple pathways in pulmonary arterial hypertension and showed that early combination therapy can be beneficial."

Mean duration of use of a study medication was 517 days (550 in the combination therapy group and 484 in the pooled monotherapy group, P=0.03). Mean duration of study participation was 609 days (629 for combination therapy and 593 for pooled monotherapy, P=0.27). Sixty-four participants (13%) withdrew from the study before having a clinical failure event.

Peripheral edema, headache, nasal congestion and anemia were among the adverse events (AEs) that occurred more frequently in the combination therapy group than in either monotherapy group. Dizziness was more common with combination therapy than with tadalafil alone, and syncope was more common with tadalafil monotherapy than with the other groups. The most common AEs resulting in discontinuation of a study drug were peripheral edema and dyspnea; the most common serious AEs were worsening of PAH and pneumonia.

There were several limitations to the study, the authors noted, including finding no significant difference in WHO functional class among the study groups at week 24. In addition, they said, it isn't known whether the study findings can be extrapolated to other drugs in the same classes or whether initial combination therapy with drugs for other classes of approved therapies for PAH would produce similar results.

Timing and Duration of Traffic-related Air Pollution Exposure and the Risk for Childhood Wheeze and Asthma

By Dr Deepu

In a study in the August 15 issue of AJRCCM, Brunst and colleagues examine the relationship between exposure to traffic-related air pollution (TRAP) and longitudinal wheezing phenotypes and asthma at age seven. The authors found that early-life exposure to TRAP is associated with increased risk for persistent wheezing, but only long-term exposure to high levels of TRAP throughout childhood was associated with asthma development. The authors state that "These findings provide new evidence that early-life exposure to high levels of TRAP sets a trajectory toward persistent wheeze and that chronic early-life exposure to high levels of TRAP may be necessary for sufficient pathophysiological changes to occur in the lungs of children leading to asthma development. A strategy of prevention or intervention during this critical time period may be able to interrupt this chain of events."