Undiagnosed PI Disease Can Lead to COPD with Irreversible Results

World PI Week

By Mel Berger, MD, PhD

World PI Week is held each year to raise awareness and improve diagnosis and treatment of primary immunodeficiency diseases (PI). It also provides an opportunity to draw attention to a related therapeutic area, which is the third leading cause of death worldwide – chronic obstructive pulmonary disease (COPD).

COPD results in approximately 700,000 hospitalizations a year in the U.S. alone according to the Agency for Healthcare Research and Quality. Although COPD is historically associated with smoking, 20–30% of COPD patients never smoked. Since the 1980s, research has increasingly pointed to an interrelationship between COPD and PI that may hold the key to ameliorating COPD.

Research has increasingly pointed to an interrelationship between COPD and PI that may hold the key to ameliorating COPD.

In my immunology practice, as well as in studies that have been conducted over the years, we’ve found that a significant number of PI patients (30-40%) also had chronic, recurrent sinopulmonary respiratory disease.

Airway hyperactivity and remodelling may not be reversible

Chronic recurrent sinopulmonary respiratory disease is often recognized as reversible airway obstruction or asthma. However, for patients with PI, if not treated correctly, it can fuel a chronic inflammatory response causing airway hyperactivity and lung damage. The resulting remodeling that occurs may not be reversible, and can lead to the need for a lung transplant and even result in death.

In one study investigators looked at 34-year-old PI patients. Of that group, 23% were diagnosed with asthma before they were diagnosed with PI. The average delay in diagnosis of PI was 10-12 years. Moreover, the gap is getting longer. More people in their 30s and 40s who had an asthma diagnosis 10 years earlier are turning up with PI. Unfortunately, damage to their lungs has often started by then and it is sometimes irreversible.

A survey in Olmstead County, Minnesota by the Mayo Clinic yielded additional evidence that there is a significant number of people being diagnosed with asthma who have underlying PI. In the study mentioned above, another 7% of these PI patients were later diagnosed with asthma. And in a retrospective analysis of 913 patients with COPD and recurrent infections referred to Papworth Hospital in Cambridge, England, 17 had established diagnoses of common variable immune deficiency (CVID), another 18 had suspected diagnoses of CVID confirmed during their work-up, and 5 new cases of CVID were discovered, giving an overall prevalence of CVID of 4.4%.

There is a significant number of people being diagnosed with asthma who have underlying PI.

During the same time period when we were recognizing the presence of chronic recurrent respiratory disease in some PI patients, intravenous [infusion of] immunoglobulin (IVIg) came into use for the treatment of PI. It subsequently became apparent that IVIg was not only effective in decreasing death from acute infections due to PI, but that it could also improve lung function in PI patients with reversible airways disease.

The next question that needed to be answered was about patient response to different doses of IVIg. A group of patients with symptoms of asthma underwent spirometry testing or breathing measurement to compare their breathing on a low dose of IVIg versus a somewhat higher dose of IVIg. The study found the patients’ spirometry improved on the higher dose of IVIg and worsened with the lower dose.

While there are approximately 12 million people diagnosed with COPD in the U.S., the American Lung Association estimates there may be as many as 24 million people with the disease who haven’t been diagnosed or treated for it. We estimate that 3-5% of this population has PI, which damaged their airways and caused their COPD. The question, then, is what causes PI at a later age?

PI and COPD emerge in later years due to immune system ‘memory loss’

Just as a developing child’s immune system has to learn to recognize germs, our immune system starts to “forget” germs as we age. This may account for the some of the emergence of PI and COPD in later years. An example of the immune system’s forgetfulness is an older person who had chicken pox as a child, which their immune system identified and fought. In later years, that person’s immune system forgets the virus they had as a child, and it resurfaces as shingles.

Just as a developing child’s immune system has to learn to recognize germs, our immune system starts to “forget” germs as we age.

Today, one of the first things we check in these patients is their immunoglobulin level. Recognizing PI as a treatable underlying contributor to the progression and exacerbations of COPD, and provision of immunoglobulin G replacement therapy, may dramatically decrease infections, lung deterioration, and even COPD. Hundreds of thousands of people could better manage their respiratory condition and avoid or make their COPD less severe.

Correctly diagnosing PI in COPD patients would reduce hospitalizations

Reducing the symptoms that make it more difficult to breathe and be active, and that reduce hospitalizations is huge. A correct diagnosis of PI in patients with a chronic recurrent respiratory disease could markedly reduce the number of hospitalizations and save the health system millions of dollars.

Major steps towards achieving these goals include developing a high index of suspicion, further study of the prevalence and importance of PI in COPD, more frequent application of screening tests such as quantitative immunoglobulins, and prompt institution of IgG replacement therapy when antibody deficiency has been diagnosed.

Note: References available on request.

World PI Week

Dr. Berger is CSL Behring’s Senior Director, Medical Research Strategy, and Adjunct Professor of Pediatrics and Pathology at Case Western Reserve University

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