Not Diagnosed Sooner Because He Wasn’t White

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This story is from the Anamnesis episode called Mysteries at 21:45 in the podcast. It’s from pediatric and adult pulmonologist Jennifer Taylor-Cousar, MD, of National Jewish Health in Denver, Colorado.

Taylor-Cousar: When I walked in to meet this 34-year-old South Asian man, he was very, very anxious. I remember just the expression on his face that he was nervous about being there. He wasn’t exactly sure why he was there. We started to talk and I explained to him why he had been referred to me. He told me that as a child, as far as he knew, he was born and had a normal birth, and wasn’t really sick, except for maybe one episode of bronchitis where he had coughing and chest pain, and then they treated him and it was fine. He and his family didn’t really think anything else of it. He was really athletic during his childhood and early teen years.

But then he had another episode where he was having wheezing, and feeling short of breath, and coughing, which was unusual because he had been so athletic. It had gotten so bad that they decided they needed to do a bronchoscopy, where they look into his lungs and try to figure out what was wrong. What they saw was something called bronchial cast, where he had huge plugs in his airways that they had to try to remove with the bronchoscope.

It turned out that he was growing a fungus called aspergillus. In fact, when they did a blood test, it showed that he was having an allergic reaction to that fungus called allergic bronchopulmonary aspergillosis, or ABPA. They treated him with antifungal treatment and they treated him with steroids. He got better, but he kept having episodes where he would get sick and they had to treat him with steroids and antibiotics, and then he would be better for a little while.

Moving to America

Then he decided in his 30s that he was going to move to the United States, really mostly for work, not for medical care, but he also needed to establish medical care because he frequently needed antibiotics and steroids. When he was seen, he first lived in the Midwest. They just diagnosed him again with the allergic bronchopulmonary aspergillosis and treated him like the same way they had treated him when he was still at home in South Asia.

At that point, his lung function had already taken a huge hit. In other words, his lung function was only 40% to 50% of what you would expect for a man his age and height. But no one really looked further to see if there was anything else going on. He just kept getting more and more antibiotics, including some intravenous antibiotics.

Then he got a job that led to him moving to Colorado. He had to find another doctor to try to help give him antibiotics when he needed it. But at that time he also had started to grow not just Pseudomonas, which is sort of a classic bacteria for people who have chronic airway diseases, specifically for cystic fibrosis, but he had also grown non-tuberculous mycobacteria. He was referred for evaluation by our infectious disease doctors. It was at that point that they said, “Well, you have Pseudomonas and you have non-tuberculous mycobacteria.”

Then he also mentioned that he had just undergone evaluation for infertility because he and his wife had been married for several years and weren’t able to conceive. He was diagnosed with congenital bilateral absence of the vas deferens, or CBAVD, which again is classic for cystic fibrosis.

‘It Was Obvious to Me’

When I met him, he had all of these things. But at some point someone had done one really simple test that only looks for about 32 mutations, and said, “Oh, you have F508del, which is the most common mutation in people with CF [cystic fibrosis]. But you only have one copy, so you don’t have CF.” There is still just the asthma, the bronchiectasis, and the ABPA, and they weren’t tying all of his signs and symptoms together. When I saw him, it was obvious to me that he clearly had cystic fibrosis because of all these signs and symptoms.

When CF was first described, literally people were told to take your child home and just love them because they are not going to live very long. Gradually, they figured out that it’s a genetic disorder. It’s called autosomal recessive, meaning you have to have one abnormal copy from your mom and one abnormal copy from your dad of the CFTR [cystic fibrosis transmembrane conductance regulator] gene. Currently, in the United States, every single state does newborn screening. There is a test that looks at how well basically a baby is absorbing their calories in their pancreas or how well their pancreas functions. If that test is abnormal, then people move on to get a sweat test, which is the gold standard for diagnosis.

The CFTR gene tells the cell to make a protein called the CFTR protein. That protein we know is a chloride channel that sits at the top of cells in places like in the lung lining and the gut lining. When that channel doesn’t work, the secretions get very, very dried out and thick. Over time, what happens in people with CF, and the reason they die much younger than people in the general population, is because that thick, sticky mucus starts to clog the airways, and then infection sets in, and your body’s natural response to infection is to fight it off with inflammation. But that inflammation ultimately damages the airways, so you get into a vicious cycle of infection, inflammation, and airway damage. Ultimately, the majority of people with CF die from their lung disease.

Cracking the Case

We had a sweat test, which is the classic gold-standard test that you get for people with CF. His sweat test was in fact abnormal. A normal sweat test is less than 30 mmol/L of chloride in the sweat. Then intermediate is considered basically 30 to 60. But his sweat test was markedly positive at 74 and 75. He clearly had cystic fibrosis.

The first thing we do when we diagnose someone, especially at his age — because at that point, very sadly, his lung function had dropped from the 40% to 50% of normal to the 30% of normal — is we admitted him to the hospital and started giving him all of the standard therapies. You can imagine how hard it would be for somebody who is working and has a 3-month-old baby at home, and a wife who is a stay-at-home mom, how hard it was for him to say, “Okay. I will stop working for 2 weeks and go into the hospital so that you all can treat me.”

But he was scared because his lung function was so low. In fact, a lung function of 30% is something that we usually consider referring somebody to transplant for. He really wanted to figure out how he could get better. It was really high stakes for him, not just because of his health in general, but also, as I said, he was the only breadwinner in his family and he was here on a work visa. If he couldn’t work, he couldn’t stay in the United States.

I had to keep it together while I was in the room with him. But as soon as I walked out, I just remember taking a deep breath and like thinking, “Oh, how? How did we do this? We, as the medical system, to this poor, relatively young man with a young wife and a baby. How did we put him in a situation where he is so sick and at risk of not being able to stay in the country and get treatment?”

Frankly, he wasn’t diagnosed earlier in his life because he wasn’t white. If he had been white with all of these symptoms, people would have immediately figured out that he had cystic fibrosis. The other issue was that when somebody sort of thought, “Oh, well, I guess we should test him for this,” and had done the 32-mutation panel, again, that 32-mutation panel was developed with the common variants in people who are of European ancestry. It did not consider all of the much more rare variants that occur in people of color.

The first issue was that they looked at him and said, “Oh, well, you can’t have cystic fibrosis because you’re not of European ancestry.” Then when they ordered a test, sort of nonchalantly, they didn’t order the correct test and also they didn’t order a sweat test. We had to identify his second mutation by doing full CFTR gene sequencing, which is the common way you have to diagnose CF in people of color. Essentially, it was just based on his race and ethnicity that prevented him from being diagnosed earlier, unfortunately. I say “unfortunately” because, as I mentioned, when he and I met his lung function was already in the very severe disease range and it could have been prevented. Like he did not have to be so sick when I met him if someone had diagnosed him and started him on the standard-of-care therapies earlier.

When Dorothy Andersen described the disease, she literally said it occurs in a wide geographic range. She described a patient who was Black, and she described a patient who was Puerto Rican, in addition to describing the children who were white who had died from the disease. But really the message was just never continued. When it’s taught in medical schools and in physician assistant school, and in nursing school, and respiratory therapy school, everyone is taught that it is a disease of white people. That’s just something that is the bias that’s been created by the way we do our medical training and so we are working really, really hard to increase awareness and undo that misconception.

We admitted him to the hospital and started him on all of the standard-of-care therapies and he did get better, although his lung function didn’t improve all that much. He went back to work and continued to work, but unfortunately over the course of the next year, even though we were able to make him feel much, much better, he had frequent exacerbations.

Over the course of about a year and a half, he had eight courses of oral steroids and antibiotics. He had two inpatient hospital admissions, where we gave him very aggressive IV antibiotics and we did airway clearance to help him try to shake up the mucus and get it out. We also, because of his work status, were giving him courses of home intravenous antibiotics. He had to go to work every day in his job and work 8 to 12 hours with an IV in his arm getting IV antibiotics. It was very frustrating for him and it was very frustrating for us. We were very worried that he was not going to be able to continue to work, then he was going to have to go home and not be able to access the therapies that we have here in the United States.

At that time, everything we were doing for CF was treating the signs and symptoms of the disease, the cough and the sinus disease, and in some people the lack of function of their pancreas. They couldn’t absorb enough calories. Fortunately for him, his pancreas was working, but we were giving him all these standard-of-care therapies.

But in 2012 was the very first time there was approval of a drug for CF that actually affected the basic defect. It helped that chloride channel worked better for people who had the chloride channel at the surface of their cells, but it just wasn’t opening.

His mutations, which we eventually identified as the second variant… but it was a very, very rare variant. There are over 2,000 mutations in the CF gene that have been described. Most of them are quite uncommon and his had only been described in two other people in the world at that time. There was no way that he was going to be included in a clinical trial because people didn’t even know what his mutation caused, like what the problem was with his chloride channel exactly.

But at that time because ivacaftor, or Kalydeco, had been approved for a certain class of mutations and then later it was decided that it probably worked on other mutations where you had chloride channels at the cell surface, but they just weren’t working. Based on his clinical presentation, he had classic signs and symptoms of CF, but he did have a working pancreas. That suggested that he had what we call residual function or some function of his chloride channel. People we knew at that point who had some chloride channel function would most likely respond to this life-changing drug called ivacaftor.

FDA’s Compassionate Use

Essentially, what I did was reach out to the company that makes the drug and I reached out to the FDA, the Federal Drug Administration, and submitted an application requesting that they provide him this drug under a compassionate use investigational new drug application, or compassionate IND, because essentially he had all of the symptoms. He had a mutation that probably would respond and really his life depended on it at this point because he was no longer going to be able to work if he had to continue to get admitted to the hospital over and over again. Again, if he couldn’t work, he was going to have to go back to South Asia. We fortunately did get approval from the company and from the FDA and started him on ivacaftor.

In the clinical trials, for the original group of people that were studied, ivacaftor had improved lung function about 10%. It had decreased the rate at which people were having exacerbations and helped them maintain their weight. His lung function within a couple of days hadn’t really increased, but he felt completely different. He basically said it was a miracle. He was not coughing any more. He felt like he could breathe much better. Many people with CF describe breathing as like feeling like you’re breathing through a straw. He no longer felt like he was breathing through a straw and his energy level got better. Fortunately, we were able to continue to get approval for this drug for him, so he stopped getting admitted to the hospital. He stopped getting oral antibiotics and he had a whole new lease on life.

Now, he has been treated since 2013 with this drug. Then in 2019, a triple combination of these drugs called CFTR modulators that improve the function of the protein, was approved. He qualified for that and now is on that drug. His son is doing really, really well. He is still working full-time and just living the full life that he had always wanted to live.

I think the first time I saw him after he had been on ivacaftor and just seeing how like his color was better, and even in talking to him and hearing his voice, you could tell that he was less sick than he was. That was a really gratifying moment because his life really had been almost miraculously changed.

Check out the other stories from the Mysteries episode, including “Prepare for the Worst, Hope for the Best” and “You Have to Treat the Entire Patient.”

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