Study on roots of asthma hints at potential of ‘birth cohort’ project

Early-life infections are linked to high asthma rates for Puerto Ricans, researchers showed

A recent study led by researchers from UC San Francisco and the City University of New York (CUNY) showed that early-life respiratory viruses may play an outsized role in Puerto Rico’s sky-high rates of childhood asthma. But the paper is just a warmup for an upcoming birth cohort study in which researchers follow the health of Puerto Rican newborns through infancy, childhood, and beyond, according to one of its authors.

“I tell people this was just the appetizer,” says Sam Oh, PhD, MPH, one of the authors of the new paper. “I’ve always wanted to work on a birth cohort. We have the potential to learn about so many health issues beyond asthma.”

The recent paper showed that Puerto Ricans were more likely to have early-life respiratory infections, like respiratory syncytial virus (RSV) or bronchiolitis, when compared to Mexican-Americans and African-Americans. Puerto Rican children who had these infections were also more likely to develop asthma.

The study, published May 5, 2020, in PLOS ONE, was led by senior author Esteban Burchard, MD, MPH. Burchard is a faculty member in the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine, and he is the director of the UCSF Asthma Collaboratory, which has been probing the genetic roots of asthma for 20 years.

For this paper, researchers took a retrospective look at two parallel studies of asthma led by the Burchard lab, known as the GALA II and SAGE studies, which were conducted from 2006 to 2014 in Latino (Mexican American and Puerto Rican) and African American children aged 8 to 21, respectively. SAGE participants were recruited from the San Francisco Bay Area and GALA II participants were recruited from across the continental United States (Chicago, Houston, New York City, and the San Francisco Bay Area) and Puerto Rico.

Data from the GALA II and SAGE studies allowed Oh, Burchard, and their colleagues to show just how important early-stage respiratory infections are in the development of childhood asthma, but they are hopeful that an upcoming birth cohort study will be even more groundbreaking. That study will track babies from birth, documenting the health impacts of a wide variety of environmental factors in real time.

Oh, a member of the UCSF Asthma Collaboratory, spoke to the School of Pharmacy’s editorial director, Grant Burningham, about the research and the upcoming birth cohort study.

Burningham: What do we know about Puerto Ricans and asthma generally?

Oh: Puerto Ricans have the highest asthma prevalence in the U.S. and the highest asthma mortality.

What we found in this paper is that certain respiratory infections tend to be more common in Puerto Ricans. But also, if you compare children who have had respiratory infections, Puerto Ricans are much more likely to develop asthma later in life, much more likely than Mexican Americans and African Americans [who also had respiratory infections].

Burningham: Do you think genetics are at play in the odds in developing asthma? How come?

Oh: Asthma is a complex disease. It’s not just genetics or behavior. It’s genetics and genetic ancestry, but it also matters where we live, our zip code, and then there are our behaviors. All those things interact with each other.

What we’ve seen from our own studies is that African Americans have a higher risk for asthma than the Mexican American people they live next to, even accounting for things like socioeconomic conditions and smoking.

That suggests that in addition to socioeconomic status, there might be a genetic component.

Burningham: So this study showed that Puerto Ricans who get these infections are more likely than other groups to develop asthma later, but do we know why?

Oh: That's what we're trying to figure out in our current work. In our next study we’re asking a follow-up question. There are decades of research that have established a link between early-life viral illnesses and later childhood asthma, but what we don't know is if these kids are just unlucky.

Does getting a viral illness set them up for asthma later in life? Does it damage your body or change your immune system? Or is an early life viral infection just an early symptom of asthma?

We just don't know that yet.

Burningham: So where do you go from here?

Oh: We’ve been studying asthma for decades and this current work is the culmination of all those decades. We know a lot of the risk factors for asthma. We understand pretty well what happens in early life to increase risk for asthma starting at school age, but we don't know about the earliest years of life, starting when children are born.

So initially we wanted to study one-year-olds with respiratory disease, and then compare them to their daycare classmates who didn't have those diseases, to find out what happens when you have early respiratory disease. But when we proposed the one-year-old study, the peer review comments said you should start a birth cohort instead.

Burningham: What is a birth cohort?

Oh: There are many types of cohort studies, where you study the health of a group and try to find correlations. One is a retrospective cohort, this might be like following what happened to baby boomers, looking back at their health history and the life events that happened to them. One problem with those types of studies is that it can be very hard to get high-quality data on important measures, like when someone got sick, how sick they got, if it was accompanied by fever, and so on. Sometimes it’s also difficult to pin down when important events occurred. This can make it near impossible to tease out causation: Did a health effect happen because of something or was it the other way around?

PRIMERO, which stands for Puerto Rican Infant Metagenomic and Epidemiologic study of Respiratory Outcomes, is a prospective cohort, so we’re going to follow patients in real time.

Birth cohorts are basically the dream in my field. They’re also rare. They’re very expensive, and they require a lot of organization and infrastructure. One of the critical factors to establishing our birth cohort was the presence that Esteban has had in this space. The infrastructure and recruitment backbone for this study have been born out of relationships he’s nurtured with clinical recruitment sites over decades. You can’t just create a birth cohort, like you can’t expect to flip a light switch without appreciating all the labor and work that went into laying down the electrical wires.

We’ll get to follow children before any health outcomes have happened. We’ll be able to see the impact of living poor, or of having a mother who is under a lot of stress during pregnancy, or the effect of certain policies. There’s just so much more than looking at the effect on viruses on asthma risk. We can’t do it all by ourselves, and we want to make our cohort a UCSF resource.

One exciting thing is that we’ll be tracking where these babies live. Because Puerto Rico has microclimates, we’ll get to look at things like exposure to dust or certain fungal spores. We’ll get a good mix of environmental information.

Burningham: So how do you find these babies?

Oh: We’ve had a recruitment and clinical presence in Puerto Rico for a long time. In particular, Esteban has worked with a clinician in Puerto Rico by the name of Jose Rodriguez Santana, MD, since 1998. Jose’s recruitment infrastructure was so productive that he provided half of the participants in our 4,000-participant GALA II study. He’s invested time not only running his practice but also in working with UCSF as a collaborator. He’s built up this recruitment infrastructure over decades and has invested quite a bit of political capital by liaising between UCSF and the clinical practices and administrators in Puerto Rico.

We’ll approach mothers who are pregnant. Dr. Rodriguez Santana’s clinic is in a hospital, and he has worked with obstetricians, gynecologists, and hospital leadership to get lists of pregnant mothers for his team to approach and tell them about the study. Those who are interested sign an informed consent form.

After they’ve agreed to join our study, when they go into labor, we immediately start the follow-up process. Our goal is to enroll 3,000 mother-infant pairs over the recruitment period. The first child was born in March, and then lockdown happened from COVID-19, so we’ve had to slow things down quite a bit. But we’re up to 24 infants.

Burningham: Does this study give you any hints of where to go next?

Oh: Well if we go back to the study we just published, with our new birth cohort we can look at how early-life respiratory illnesses change gene expression patterns in real time. The body has 20,000 genes, and those genes are in every cell in our body. But every cell can’t express all those genes, or our heart cells would grow hair and bones, for instance. So gene expression, which is where cells produce certain proteins and not others, is a tightly regulated process.

If we take that to the respiratory system, we can actually look at the patterns of how many of these genes are turned on or off, or more likely, like a dimmer switch, get set to low, medium, or high. We can see what conditions make genes become active or inactive.

When these children are born, before they leave the hospital, we take a nasal swab and we’ll look at the gene expression pattern of those respiratory cells in the first day of life. Every year at healthy doctor’s visits we take another nasal swab so we can track how these patterns change over time.

In the first two years of life we also take nasal swabs when these babies have respiratory illnesses. We can compare those samples with healthy samples, and see how those gene expression patterns change over time. We’ll be able to tease out which molecular signatures lead to healthy development and which might be altered permanently because of an illness. We can track patterns that might lead to asthma. The amount we have to learn here is astounding.

Burningham: And you will follow these babies forever?

Oh: Well, right now, it’s just for the first five years of life, because the NIH (National Institutes of Health) only funds grants in five-year increments. But because of the amount of resources that have gone into creating this cohort, it would be a shame and almost unethical not to follow them for longer.

My dream is to have this cohort outlive me. We want to build the infrastructure to follow these children for many decades.

Burningham: I look forward to seeing the research that comes out of this cohort. Thank you for talking to me.

Oh: Any time.


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