Jul 182013
Biomarkers Predict COPD Exacerbations (Sort Of)

In addition to daily breathlessness, people with chronic obstructive pulmonary disease (COPD) often experience exacerbations of shortness of breath and coughing. Those with more severe COPD tend to have more frequent and severe exacerbations, lower enjoyment of life, and more rapid loss of lung function.

The strongest predictor of whether someone with COPD will experience future exacerbations is a previous pattern of COPD exacerbations. But just as yearly rainfall doesn't predict rain on a given day very well, looking at past patterns hasn't proved useful in predicting any particular COPD exacerbation.

Researchers have long sought biomarkers to identify impending bad events like COPD exacerbations, seizures, heart attacks, strokes, etc. at a point at which they can be prevented, or their severity reduced. COPD exacerbations are frequently caused by infections of the respiratory system or disruptions of its microbiome, and this microbial and immune activity causes perturbations of acute phase reactants and inflammatory cells and their signaling, which could be measured in the blood. Previous investigations among people with stable COPD suggest that those with elevated white blood cell counts, circulating fibrinogen and C-reactive protein (when they are feeling relatively well) have worse outcomes on average.

What They Did

Mette Thomsen of the Copenhagen University Hospital in Denmark et al explored whether CRP, fibrinogen and WBC could be used as biomarkers to predict COPD exacerbations in people with stable COPD. Fortunately for them, they already had samples and spirometry available from 6,574 people with COPD in the Copenhagen City Heart Study and another study (pulmonary researchers often have to get their data as hand-me-downs from better-funded cardiology researchers -- call it certified pre-owned data).

After recording their fibrinogen, CRP, WBC, and FEV1, patients were followed for 5 years, during which time 3,083 exacerbations occurred (about 0.5 per patient per year), defined as oral corticosteroid treatment with or without antibiotics, or hospital admission for COPD. Cutoff high values were 3 mg/L for CRP, WBC of 9,000/mL, and 14 micromoles / L for fibrinogen.

What They Found

People with 3 of 3 elevated biomarkers at baseline were four times more likely to experience 2 or more COPD exacerbation within one year than people with similar risk profiles (age, FEV1, past exacerbation history, etc) but who had normal biomarkers. People with 1 or 2 elevated biomarkers were at elevated but lesser risk for COPD exacerbations.

Over five years, the predictive power of these elevated biomarkers fell, but people with 3 of 3 positive biomarkers were still 3 times more likely to have COPD exacerbations than those with normal biomarkers.

The predictive value of elevated biomarkers for COPD exacerbations was independent of the rest of the risk profile (history of previous exacerbations and severity of COPD being the most robust). People with a history of severe COPD and frequent exacerbations, but no biomarker elevations, had a 62% chance of having another COPD exacerbation in 5 years, while almost all (98%) of those with 3 biomarkers elevated had another COPD exacerbation within 5 years.

People with less severe COPD (GOLD 1-2 or GOLD A-B) comprised more than 90% of the sample, and experienced very few exacerbations. Only about 1 in 7 people with mild/moderate COPD and 3 elevated biomarkers had an exacerbation in 5 years, compared to about one in 10 of those with 0 of 3 biomarkers elevated.

What It Means

The question all we physicians want to answer is, is my patient with COPD who tells me she feels a little worse than usual (which she does fairly frequently) about to have a COPD exacerbation in the next few days? And can I do something to prevent it or lessen its severity? As you've surely guessed, this study doesn't begin to offer a method to answer that.

What it does offer is a step toward risk stratification of patients with severe COPD -- certainly for future research trials, and possibly in the average pulmonary clinic or health system. That could prove to be a significant step forward from our current approach -- what I would call intuition-based medicine -- when it comes to anticipating and intervening on COPD exacerbations.

Because these signals are still so diffuse and poorly predictive in individual patients (especially those with 1 or 2 biomarkers elevated, and anyone with mild-moderate COPD), I don't think this defines a new "COPD lab panel" for pulmonology practice.

I can certainly foresee Pharma using these biomarkers as enrollment criteria or prespecified stratification criteria in clinical trials, to help find benefit of tested therapies. If other troves of CRP, fibrinogen, WBC and spirometry can be unearthed and matched to pharmacy data for COPD patients, another observational trial suggesting that treatment has extra benefit at preventing COPD exacerbations in people with high biomarkers.

For health systems, collecting biomarkers from patients with severe COPD could potentially identify those most at risk for COPD exacerbations, and enroll them in COPD disease management programs or give them extra attention otherwise. Biomarkers could also help identify who might be the best candidates for azithromycin to prevent COPD exacerbations.

Another recent tentative step toward improving the prognosis and risk stratification of COPD exacerbations was the so-called DECAF score to predict survival from COPD exacerbations.

As for what we all really want -- realtime decision support tools at (or near) the point of care that can help us prevent COPD exacerbations and hospitalizations before they occur? If you follow the money, the next big hope is in biomonitoring devices like this real-world Star Trek-like tricorder, which patients would apply to their forehead at home, zap their biodata wirelessly to Command Central, and an algorithm could theoretically then trigger a rapid medical evaluation or home self-treatment. Get in now and you can still get your very own tricorder for $199. (The biggest market for these things, of course, are healthy, affluent hypochondriacs -- wait, how did I get on the mailing list?)

Mette Thomsen et al. Inflammatory Biomarkers and Exacerbations in Chronic Obstructive Pulmonary Disease.  JAMA 2013;309(22):2353-2361.

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Biomarkers help predict COPD exacerbations