In ALS, Respiratory Measure Predicts Pace of Disease

Rate of decline on a single test of respiratory function predicted how quickly respiratory failure would occur in ALS patients, and how long they would survive. In the November 27 JAMA Neurology, researchers led by Jinsy Andrews at Columbia University in New York reported that slow vital capacity (SVC)—the amount of air expelled from the lungs during a slow, gentle breath—correlated with clinically meaningful events such as use of assisted ventilation, tracheostomy, and ultimately, death. Patients with slightly slower decline in SVC could breathe unassisted, and survived longer than patients whose SVC declined faster. The findings suggest that SVC could be used as a prognostic marker in the clinic, and may also serve as a primary endpoint for clinical trials.

  • Slow vital capacity (SVC), a measure of respiratory function, declines more quickly in ALS patients who are older or have advanced disease.
  • SVC decline correlates with slippage in other respiratory measures, time to tracheostomy, and even death.
  • People who better maintain SVC have less risk of respiratory failure, and live longer.

Respiratory failure is the most common cause of death in ALS patients. Different measures of respiratory function are used to gauge respiratory strength as the disease progresses. The most common, forced vital capacity (FVC), measures the volume of air expelled from the lungs during a quick, forceful breath. While FVC reportedly predicts survival (Baumann et al., 2010), the maneuver can be difficult for patients in advanced stages, and can induce bronchospasms that may lead to an underestimation of lung capacity (Cheung and Cheung, 2015). In contrast, even ALS patients with loss of muscle function in the face and mouth can perform the gentler SVC test. Studies have reported a tight correlation between FVC and SVC, yet FVC is still the measure of choice for a majority of clinics, Andrews told Alzforum (Pinto and de Carvalho, 2017).

That is changing in the context of clinical trials, Andrews said. Many recent studies use SVC as a secondary endpoint or exploratory measure, she said. Andrews and colleagues set out to determine whether SVC could be used to predict ALS progression, and ultimately serve as a primary endpoint.

The researchers conducted retrospective analyses on data from 893 patients in three clinical datasets. These included 456 patients randomized to the placebo group of the EMPOWER study, a Phase 3 trial of dexpramipexole that tracked participants for at least a year; 210 placebo-randomized patients from the BENEFIT-ALS study, a Phase 2b trial that tested tirasemtiv in patients over 12 weeks; and 227 patients from the PRO-ACT database, which includes several clinical studies.

The researchers found that the average slope of SVC decline was similar among the studies, dropping by 2.73–2.9 percentage points per month. Relying primarily on data from the longer EMPOWER study, the researchers reported that patients who were older than 65, or who had an ALS functional rating scale-revised (ALSFRS-R) score below 39 at baseline, had a steeper decline in SVC than younger or less-advanced patients.

The researchers next asked how rate of decline in SVC would correlate with clinically meaningful events. Again, drawing on data from the EMPOWER trial, they correlated the slope of SVC decline from baseline to six months for each patient with his or her clinical status, then generated a model to estimate how variations in that slope would affect time to various clinical outcomes after those initial six months. According to the model, slowing the rate of decline from 2.73 percent per month (the rate of average decline in the EMPOWER trial) to 1.23 percent lowered the risk of several outcomes over the next six months. Time to first assisted ventilation, to first occurrence of tracheostomy, and to death all increased by about 23 percent. The risk of poorer scores on any of the three parts of the ALSFRS-R that address respiratory function fell by 19 percent. The researchers also modeled the influence of SVC decline on length of survival. They found that while 80 percent of people with average SVC decline of 1.23 percentage points per month were predicted to survive for 63 weeks, 80 percent of those who declined by 2.73 or 4.23 percentage points per month were predicted to survive for 57 or 52 weeks, respectively.

The findings suggest that SVC can be used as a surrogate biomarker for disease progression, respiratory insufficiency, and survival, Andrews told Alzforum. This is important in the ALS field, she added, where validated fluid biomarkers are lacking, and most clinical studies rely upon changes in survival and/or ALSFRS-R scores to gauge benefits of treatment. “You need big changes in your breathing to make a difference on this scale,” Andrews said. SVC is clearly a more sensitive measure, and now the findings suggest it is also a clinically meaningful one, she said. “If we used SVC as a primary endpoint, we could run shorter, smaller trials because the change is more sensitive,” she added.

Susana Pinto of the University of Lisbon, who previously reported a tight correlation between FVC and SVC, agreed. She pointed out that the authors only found a weak correlation between SVC and scores on the respiratory section of the ALSFRS-R. She interpreted this not as a failure of SVC, but rather of the ALSFRS-R. “We should consider re-evaluating ALSFRS-R and its sub-scores as they probably do not accurately reflect the real functional status of the patients, or at least of all patients,” she wrote to Alzforum.

Pinto added that the results should be interpreted with some caution, as data was combined from multiple studies conducted in several countries, and variability exists not only in how clinicians measure SVC, but also in guidelines for respiratory interventions. For example, European physicians put patients on noninvasive ventilation earlier than their American counterparts do, she wrote, and this is known to improve respiratory function.

In a joint comment to Alzforum, Joost Raaphorst and Jonne Doorduin of Radboud University Medical Center in the Netherlands questioned the findings. They pointed to other reports that vital capacity measures often do not decline significantly until patients are in dire straits: either in need of emergency ventilation, or within three months of death (Raaphorst et al., 2013; Polkey et al., 2017). This makes vital capacity a poor tool for assessing change in earlier disease stages, they wrote. Instead, Raaphorst and Doorduin suggested that another measure—the Sniff Nasal Inspiratory Pressure test—more sensitively detects early changes in respiratory problems, and better predicts survival (Morgan et al., 2005).—Jessica Shugart 

Comments

  1. It is not clear in ALS that the SVC decline is linear during the full course of the disease. One may expect ceiling and floor effects. Nevertheless, and although it is surely difficult to evaluate SVC in patients with moderate to severe bulbar involvement and in late stages of the disease, SVC is, in fact, a good biomarker of respiratory involvement and respiratory function decline in ALS.

    The significant decline when patients are only "in need of emergency ventilation or within three months of death" suggests either a poor follow-up of the patients or patients with extremely fast disease progression.

    View all comments by Susana Pinto

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References

Therapeutics Citations

  1. Dexpramipexole

Paper Citations

  1. Baumann F, Henderson RD, Morrison SC, Brown M, Hutchinson N, Douglas JA, Robinson PJ, McCombe PA. Use of respiratory function tests to predict survival in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2010;11(1-2):194-202. PubMed.
  2. Cheung HJ, Cheung L. Coaching patients during pulmonary function testing: A practical guide. Can J Respir Ther. 2015;51(3):65-8. PubMed.
  3. Pinto S, de Carvalho M. Correlation between Forced Vital Capacity and Slow Vital Capacity for the assessment of respiratory involvement in Amyotrophic Lateral Sclerosis: a prospective study. Amyotroph Lateral Scler Frontotemporal Degener. 2017 Feb;18(1-2):86-91. Epub 2016 Dec 4 PubMed.
  4. Raaphorst J, Tuijp J, Verweij L, Westermann EJ, van der Kooi AJ, Gaytant MA, van den Berg LH, de Visser M, Kampelmacher MJ. Treatment of respiratory impairment in patients with motor neuron disease in the Netherlands: patient preference and timing of referral. Eur J Neurol. 2013 Dec;20(12):1524-30. Epub 2013 Feb 9 PubMed.
  5. Polkey MI, Lyall RA, Yang K, Johnson E, Leigh PN, Moxham J. Respiratory Muscle Strength as a Predictive Biomarker for Survival in Amyotrophic Lateral Sclerosis. Am J Respir Crit Care Med. 2017 Jan 1;195(1):86-95. PubMed.
  6. Morgan RK, McNally S, Alexander M, Conroy R, Hardiman O, Costello RW. Use of Sniff nasal-inspiratory force to predict survival in amyotrophic lateral sclerosis. Am J Respir Crit Care Med. 2005 Feb 1;171(3):269-74. Epub 2004 Oct 29 PubMed.

Further Reading

Primary Papers

  1. Andrews JA, Meng L, Kulke SF, Rudnicki SA, Wolff AA, Bozik ME, Malik FI, Shefner JM. Association Between Decline in Slow Vital Capacity and Respiratory Insufficiency, Use of Assisted Ventilation, Tracheostomy, or Death in Patients With Amyotrophic Lateral Sclerosis. JAMA Neurol. 2018 Jan 1;75(1):58-64. PubMed.

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