Comment on: use of blood biomarkers to screen for obstructive sleep apnea

Dear editor

The recently published paper in Nature and Science of Sleep¹ describes a combination of blood biomarkers for obstructive sleep apnea (OSA) screening which is shown to have better sensitivity and selectivity than any one individually. The combination comprises elevated levels of glycated hemoglobin (HbA1c), C-reactive protein, and erythropoeitin. The combination algorithm alluded to in the paper requires a sufficiently elevated level above a threshold of the combination of the three constituents for further diagnostic testing to be recommended. Of course, OSA would have to have been present long enough for the elevated levels to occur in order for the proposed biomarker to indicate its likely presence. My comment on this paper questions not whether this screening tool is valid, but whether it is valid early enough in the development of OSA to initiate diagnosis and treatment before some irreversible life-threatening consequence of OSA develops.

In particular, I focus on HbA1c, which when elevated above 5.7% indicates prediabetes or diabetes, a recognized common consequence of OSA which risks the quality and length of life. The meta-analyses in^2,3 conclude that overcoming OSA does not generally reduce HbA1c, although it may improve insulin sensitivity. Insulin insufficiency from beta cell dysfunction and mass reduction remains to keep HbA1c elevated, and diabetes is still a threat.

There is another biomarker, although not a blood biomarker, which appears earlier in the development of OSA. It is the formation of monosodium urate crystals on patellar, biceps, or quadriceps tendons, where they are detectable by ultrasonic means.⁴ The intermittent hypoxemia which results from OSA causes three effects which quickly elevate the concentration of serum uric acid, often leading to the precipitation of monosodium urate crystals: 1) intermittent cell catabolism which culminates irreversibly in the generation of excess uric acid fed into the blood; 2) concurrent intermittent serum acidosis and hypercapnia which reduces the solubility of uric acid in the blood; and 3) gradual reduction of the kidneys’ glomerular filtration rate which slows removal of serum uric acid. Once formed, the crystals dissolve very slowly, which allows for their detection at any time convenient for OSA screening.

Disclosure

The author reports no conflicts of interest in this communication.

References

1.		Fleming WE, Holty JC, Bogan RK, et al. Use of blood biomarkers to screen for obstructive sleep apnea. Nat Sci Sleep. 2018;10:159–167.
2.		Feng Y, Zhang Z, Dong ZZ. Effects of continuous positive airway pressure therapy on glycaemic control, insulin sensitivity and body mass index in patients with obstructive sleep apnoea and type 2 diabetes: a systematic review and meta-analysis. NPJ Prim Care Respir Med. 2015;25:15005.
3.		Labarca G, Reyes T, Jorquera J, et al. CPAP in patients with obstructive sleep apnea and type 2 diabetes mellitus: systematic review and meta-analysis. Clin Respir J. 2018. In press.
4.		Abrams B. Monosodium urate as a biomarker for obstructive sleep apnea. J Sleep Disord: Treat Care. 2017;6(2).

Authors’ reply

Wesley Elon Fleming¹, Jon-Erik C Holty², Richard K Bogan³, Dennis Hwang⁴, Aliya S Ferouz-Colborn⁴, Rohit Budhiraja⁵, Susan Redline⁵, Edith Mensah-Osman⁶, Nadir Ishag Osman⁶, Qing Li⁷, Armaghan Azad¹, Susann Podolak¹, Michael K Samoszuk⁸, Amabelle B Cruz⁸, Yang Bai⁸, Jiuliu Lu⁸, John S Riley⁸, Paula C Southwick⁸

¹Sleep Center Orange County, Irvine, CA, USA; ²Stanford Medical School, VA Palo Alto Health Care System, Pulmonary, Critical Care and Sleep Medicine Section, Palo Alto, CA, USA; ³SleepMed Inc., Bogan Sleep Consultants, LLC, Columbia, SC, USA; ⁴Sleep Medicine Department, Southern California Permanente Medical Group, Kaiser Permanente, Fontana Medical Center, Fontana, CA, USA; ⁵Division of Sleep Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA; ⁶EENA Comprehensive Neurology and Sleep Center, Boynton Beach, FL, USA; ⁷South Bend Medical Foundation, New Technology and Test Development, South Bend, IN, USA; ⁸Clinical Research Department, Beckman Coulter, Inc., Brea, CA, USA

Correspondence: Wesley Elon Fleming, Sleep Center Orange County, 4980 Barranca Pkwy, Ste 170, Irvine, CA 92604, USA
Tel +1 949 679 5510
Fax +1 949 679 1080
Email [email protected]

Dear editor

We would like to thank Burton Abrams, MS, for the letter in response to our recently published article.

Mr Abrams questions whether our new screening tool is valid early enough in the development of OSA to initiate diagnosis and treatment before irreversible life-threatening consequences of OSA develop. We would like to reiterate that the algorithm score derived from a combination of three biomarkers correlated with severity of disease (none, mild, moderate, severe), allowing sleep centers to identify and triage lower- to higher-risk patients for sleep study testing and treatment. In addition, the combination of biomarkers performed significantly better than current screening methods. Given that up to 90% of individuals with obstructive sleep apnea (OSA) remain undiagnosed and untreated, this new screening tool represents a substantial improvement in early identification of OSA.

Mr Abrams’ work on ultrasonic detection of monosodium urate is interesting, and we commend any effort to improve upon the early detection of OSA.

Acknowledgment

This work was supported by research grant funding from Beckman Coulter, Inc. (Brea, CA, USA) provided to the respective institutions of Drs Fleming, Holty, Bogan, Hwang, Ferouz-Colborn, Budhiraja, Redline, Mensah-Osman, Osman, and Li.

Disclosure

Drs Samoszuk, Riley, and Southwick, as well as Ms Cruz, Mr Bai, and Mr Lu are employed by Beckman Coulter. The authors report no other conflicts of interest in this communication.

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