ALTERNATE OVERLAP SYNDROME

The Asthma and OSA

Connection
BONN T. MA, MD
Pulmonary Fellow
 OBJECTIVES
• To present a case of an asthmatic male diagnosed with obstructive
sleep apnea

• To present the epidemiology of Alternate Overlap Syndrome

• To discuss the pathophysiology and risk factors for Asthma-OSA

Overlap syndrome

• To discuss the clinical outcomes and management of Alternate overlap

syndrome
 Day time sleepiness
35 year old Unrefreshing sleep
Male LOUD SNORING Morning headaches
Single Dry throat upon waking up
Fatigue
Asian
LOUD SNORING Choking episodes and gasping,
Day time sleepiness Decreased concentration,
Unrefreshing sleep Irritable
Morning headaches
House mates report breath
Dry throat upon waking up
Fatigue holding spells that sometimes
followed by cough
Sleep History
• Usual time in 10PM usual time out 4 am
• Shift work
• No sleeping aids/medications taken
• Falls asleep in 10 minutes
• Occasionally awakens from choking spells but none to urinate
• Habitually takes short naps even in the morning for 10-15 minutes
• No history of sleep related traffic accidents

• Has occasional bruxism

• No sudden muscle weakness upon laughing, surprise, anger
• No sleep paralysis
• No vivid dreams during naps or when about to sleep
• No restless leg sensation
• No nighttime awakenings via kicking
PAST MEDICAL HISTORY

ASTHMATIC

ALLERGIC RHINITIS

ECZEMA

GERD
NO CARDIAC DISEASE

NO RENAL DISEASE

NO THYROID DISEASE

COVID 19 VACCINATIONS
PAST MEDICAL HISTORY PERSONAL SOCIAL FAMILY HISTORY REVIEW OF SYSTEMS
HISTORY
ASTHMATIC PREVIOUS SMOKER: 3.5PY PARENTS: SNORE NO ORTHOPNEA
ALLERGIC RHINITIS OCCASIONAL ALCOHOL NO CHEST PAIN
HYPERTENSION
DRINKER
ECZEMA NO NEUROLOGIC
NO HISTORY OF ILLICIT
DRUG USE DIABETES SYMPTOMS
GERD
NO CARDIAC DISEASE HEAVY COFFEE DRINKER
ASTHMA
NO RENAL DISEASE PHYSICIAN
NO THYROID DISEASE

COVID 19 VACCINATIONS
 PHYSICAL EXAMINATION
Weight: 89Kg Height:
165 cm BMI:32.72
kg/M2

BP: 130/80 HR: 98 RR:20

O2 Saturation:
sitting 98% supine 95%

Anicteric sclerae, Neck circumference: 44 cm

No cardiac murmur, regular rhythm
Clear breath sounds No wheezing
No pedal edema
 STOP BANG Epworth Sleepiness Scale
Score SITUATION chance

Snoring 1 Sitting and reading 2

Tiredness 1 Inactive in public place 2

Observed Apnea 1 Passenger in a car 2

Rest in the afternoon 3
High Blood Pressure 0
Sitting and talking to someone 1
BMI>30Kg/m2 1
Age > 50 0
Sitting and watching TV 2
Neck Circumference > 40 1
Sitting quietly after lunch 2
cm
Male Gender 1 In a car, stopped a few mins 2

TOTAL 6
TOTAL 16
 BERLIN QUESTIONNAIRE

X
X X

X
X
X

X X

X
 ADMITTING IMPRESSION

T/C OSA high risk T/c Obesity hypoventilation syndrome

Bronchial Asthma not in exacerbation
Obesity class II
 Severe
obstructive sleep apnea
CPAP 13 cm
FINAL IMPRESSION

ALTERNATE OVERLAP SYNDROME

Obesity class II
DISCUSSION
 Obstructive Sleep Apnea Syndrome
• Characterized by abnormal apnea-hypopnea index (AHI)
and symptoms of Excessive Daytime Sleepiness (EDS)

• Suspected: witnessed apneas, chronic snoring and

excessive daytime sleepiness
• Presence of risk factors such as obesity, diabetes, dyslipidemia
and hypertension along with the triad strengthens the suspicion
of OSA.
• Obesity, increased neck circumference, and narrowed pharyngeal
airway

• Associated with increased morbidity and mortality from

cardiovascular causes, or vehicular accidents due to EDS.

Philippine Clinical Practice Guidelines on the Diagnosis and Management of Obstructive Sleep Apnea in Adults 2016
Obstructive Sleep Apnea Syndrome

Ages of 30 to 69 years of age

936 million people worldwide with mild to severe OSA
425 million people worldwide with moderate to severe OSA
Benjafield AV, Ayas NT, Eastwood PR, et al. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med 2019; 7:687.

• More prevalent in African-Americans

• The prevalence of OSA in Asia is similar to that in the
United States, despite lower rates of obesity
 Obstructive Sleep Apnea Syndrome
Philippines there isages
still no prevalence data for OSA
of 30 and 69 years of age
936 million people worldwide with mild to severe OSA,
425 million people worldwide with moderate to severe OSA,
The within-laboratory prevalence of OSA was 62%.
Body mass index, snoring affecting others, and daytime sleepiness
were found to be• significant predictors
More prevalent in Africa for obstructive sleep apnea
• The prevalence of OSA in Asia is similar to that in the
United States, despite lower rates of obesity

Ian Homer Y Cua, Loreto J Codamos, Mercy Antoine Gappi. Validation of the St. Lukes Medical Center-obstructive sleep apnea clinical scoring system. Philippine Journal of Internal
Medicine. July 2003; Vol. 41 ( 4 ) : p. 175-178
 Obstructive Sleep Apnea Syndrome
Physical findings suggestive of the presence of OSA
Increased neck circumference (M: >17 in., F >16)
BMI ≥ 30 (*BMI ≥ 27.5 for Asians)
Modified Mallampati score of 3 or 4
Retrognathia
Lateral peritonsillar narrowing
Macroglossia
Tonsillar hypertrophy/ elongated/enlarged uvula
High arched/narrow hard palate
Overjet defined as the extent of horizontal overlap of the maxillary
central incisors over the mandibular central incisors)

Philippine Clinical Practice Guidelines on the Diagnosis and Management of Obstructive Sleep Apnea in Adults 2016
Adapted from Epstein et al. J Clin Sleep Med 2009;5(3):263- 276.
• Chronic airway inflammation
• History of respiratory symptoms such as wheeze, shortness of breath,
chest tightness, and cough that vary over time and in intensity
• Variable expiratory airflow limitations
– FEV1 increases by > 12% and 200mL
– Average daily diurnal PEF variability > 10%
– FEV1 increases by > 12% and 200mL after 4 weeks of anti-inflammatory treatment
 ESTABLISHING THE CONNECTION OF

ASTHMA AND OSA

ALTERNATE OVERLAP SYNDROME
Patients who had asthma were 1.70 times (95% CI=1.15-
2.51) more likely to develop sleep apnea after eight years.

Childhood-onset asthma was associated with 2.34 times

(95% CI=1.25-4.37) the likelihood of developing sleep
apnea.
Duration of asthma affected the chances of
developing sleep apnea.
For every five-year increase in asthma duration, the chances of
developing OSA after eight years increased by 10 percent.
 Correlating Asthma and OSA

• The overall incidence of OSA was 2.51-fold greater in the asthma cohort
than in the comparison cohort (12.1 vs 4.84 per 1000 person-years).

• Risk of OSA is proportional to asthma control

• Patients with inhaled steroid treatment have a higher risk for OSA than
those without

Shen T-C et al. (2015) Risk of Obstructive Sleep Apnea in Adult Patients with Asthma: A Population-Based Cohort Study in Taiwan. PLoS ONE 10(6): e0128461
 Correlating Asthma and OSA

A high prevalence of OSA among patients with

unstable asthma receiving long-term chronic or
frequent burst of oral corticosteroid therapy

Yiqla M, et al. Difficult-to-control asthma and Obstructive Sleep Apnea. J Asthma 2003 Dec;40 (8) 865-71
 Correlating Asthma and OSA

Effects of oral corticosteroids on the upper airway

A high prevalence of OSA
• Myopathy of the muscles of the pharynx
among patients with
unstable asthma receiving
• Fatty infiltration of the pharyngeal wall long-term chronic or
frequentofburst
• Accumulation liquid inof
theoral
neck corticosteroid therapy

Yiqla M, et al. Difficult-to-control asthma and Obstructive Sleep Apnea. J Asthma 2003 Dec;40 (8) 865-71
 Correlating Asthma and OSA

Inhaled corticosteroid
improves AHI in patients
with allergic rhinitis

Lavigne F, Petrof BJ, Johnson JR, et al. Effect of topical corticosteroids on allergic airway inflammation and disease severity in obstructive sleep apnoea. Clin Exp
Allergy. 2013;43:1124–1133
 ESTABLISHING THE CONNECTION OF

ASTHMA AND OSA

THE PATHOPHYSIOLOGIC LINK
Kryger Principle and practice of sleep medicine 7.ed. P 1334
Interrelationship between Obstructive Sleep Apnea and Asthma
 Neural Receptors and Mechanical Effects
• Patients with OSAS have an increased vagal tone during sleep as a
consequence of partial or complete airway obstruction occurring
during apneas.

• Increased vagal tone occurring during apnea episodes could be a trigger for
nocturnal asthma attacks in sleep apnea patients
• stimulation of muscarinic receptors

Alkhalil M; Schulman E; Getsy J. Obstructive Sleep Apnea Syndrome and Asthma: What Are the Links? J Clin Sleep Med 2009;5(1):71-78.
 Neural Receptors and Mechanical Effects
• Neural receptors at the glottic inlets and larygeal region have
powerful reflex bronchoconstrictive activity.

• Stimulation of the larynx also increases activity in efferent

parasympathetic nerve fibers going to the trachea and bronchi
• Repeated stimulation of these neural receptors during heavy snoring
and obstructive apneas could stimulate neural reflex-induced
bronchoconstriction.

Alkhalil M; Schulman E; Getsy J. Obstructive Sleep Apnea Syndrome and Asthma: What Are the Links? J Clin Sleep Med 2009;5(1):71-78.
 Neural Receptors and Mechanical Effects
• Hypoxia may modulate the airway response to
constricting stimuli through a vagal pathway
• Likely initiated by stimulation of the peripheral carotid body
chemoreceptors

Alkhalil M; Schulman E; Getsy J. Obstructive Sleep Apnea Syndrome and Asthma: What Are the Links? J Clin Sleep Med 2009;5(1):71-78.
 Gastroesophageal Acid Reflux (GER)
The prevalence of GER is high in OSAS

• GER occurring during sleep is a well-known trigger for

nocturnal asthma
• Vagal reflexes induced by exposure of the esophagus to
acid

Harding SM. Gastroesophageal reflux and asthma: insight into the association. J Allergy Clin Immunol. 1999;104:251–259
 Local Airway Inflammation
• OSAS has been shown to be associated with inflammation of both the
upper and lower respiratory tracts
• Inflammatory and Oxidative stress markers are present in expired air
in OSAS
• Pentane
• Exhaled nitric oxide,
• IL-6
• 8-isoprostane

Alkhalil M; Schulman E; Getsy J. Obstructive Sleep Apnea Syndrome and Asthma: What Are the Links? J Clin Sleep Med 2009;5(1):71-78.
 Local Airway Inflammation
Strong inspiratory effort produced by snoring and obstructive apneas

High negative pressures transmitted against a closed airway passage

Mechanical stress exerted on the mucosa

Alkhalil M; Schulman E; Getsy J. Obstructive Sleep Apnea Syndrome and Asthma: What Are the Links? J Clin Sleep Med 2009;5(1):71-78.
 Local Airway Inflammation
• Local inflammation of the nasal and pharyngeal mucosa
• PMNs, Bradykinin, VIP
• Chronic inflammation of the soft palate with increased
interstitial edema
• Uvula shows mucous gland hypertrophy and infiltration of
the lamina propria with T cells

Inflammatory changes  Asthma trigger

Alkhalil M; Schulman E; Getsy J. Obstructive Sleep Apnea Syndrome and Asthma: What Are the Links? J Clin Sleep Med 2009;5(1):71-78.
 Systemic Inflammation
• Chronic, low-grade systemic inflammation in OSAS
• Increased serum cytokines and chemokines

• Severity of OSAS is proportional to the CRP level

• 1 month of effective treatment for OSAS with CPAP  ecease in CRP level

• The origin of this systemic inflammation appears to be the oxidative

stress induced by oxygen desaturation during sleep apneas.
• OSAS-induced oxidative stress and elevation of IL-8 might contribute to
bronchial inflammation

Alkhalil M; Schulman E; Getsy J. Obstructive Sleep Apnea Syndrome and Asthma: What Are the Links? J Clin Sleep Med 2009;5(1):71-78.
 Cardiac Dysfunction
• OSAS contributes to the development of systemic
hypertension, a precursor of CHF

• Elevated sympathetic nerve activity, which is known to be

cardiotoxic in patients with CHF
• Recurrent hypoxemia: independently lead to oxidative vascular wall
injury.
• Hypercapnia
• Baroreflex inhibition resulting from repetitive surges in nocturnal
blood pressure
Alkhalil M; Schulman E; Getsy J. Obstructive Sleep Apnea Syndrome and Asthma: What Are the Links? J Clin Sleep Med 2009;5(1):71-78.
 Cardiac Dysfunction
• CHF causes airway obstruction
• Hyperresponsiveness to cholinergic stimuli with constriction of airway
smooth muscles
• Pulmonary edema-induced airway constriction by vagal reflexes
• Nonspecific bronchial C-fiber activation
• Thickening of bronchial walls
• Changes in epithelial sodium and water transport
• Increased endothelin levels

Alkhalil M; Schulman E; Getsy J. Obstructive Sleep Apnea Syndrome and Asthma: What Are the Links? J Clin Sleep Med 2009;5(1):71-78.
Vascular endothelial growth factor (VEGF)
and airway angiogenesis
• Correlation has been found between increased VEGF levels in
asthmatic patients and the degree of airway obstruction
• VEGF may contribute to bronchial inflammation and
hyperresponsiveness
• OSAS patients have elevated concentrations of VEGF that correlate
with the severity of the syndrome:
• AHI levels
• Degree of nocturnal oxygen desaturation

Alkhalil M; Schulman E; Getsy J. Obstructive Sleep Apnea Syndrome and Asthma: What Are the Links? J Clin Sleep Med 2009;5(1):71-78.
 Leptin Hypothesis
• Leptin : produced by adipose tissue acting on the
hypothalamus to induce satiety and increase metabolism.
• Increased in obese patients suggesting leptin resistance
• Proinflammatory: Stimulating release of IL-6 and TNF-a by
adipocytes

• Role of leptin in activation of mast cells:

• Increased airway hyperresponsiveness to inhaled
methacholine
• Increased serum IgE levels,

Alkhalil M; Schulman E; Getsy J. Obstructive Sleep Apnea Syndrome and Asthma: What Are the Links? J Clin Sleep Med 2009;5(1):71-78.
 Weight Gain
• Repetitive episodes of hypoxia and sleep fragmentation in OSAS have
been shown to induce glucose intolerance and an increase in insulin
resistance
• Increase in insulin resistance in OSAS:
• stimulation of the sympathetic nervous system
• stimulation of the Hypothalamic-Pituitary-Adrenal axis
• release of adipocyte-derived inflammatory cytokines IL-6, TNF-α, and leptin

• OSAS patients have decreased Growth Hormone (GH) secretion.

• Suppression of secretion of GH in untreated OSAS results in impaired
lipolysis  Promotes the storage of fat and weight gain.

Alkhalil M; Schulman E; Getsy J. Obstructive Sleep Apnea Syndrome and Asthma: What Are the Links? J Clin Sleep Med 2009;5(1):71-78.
 Weight Gain

• Asthma is more prevalent in obese individuals, and obesity

appears to contribute to severe asthma
• Obese or overweight patients account for 75% of emergency
department visits for asthma

Alkhalil M; Schulman E; Getsy J. Obstructive Sleep Apnea Syndrome and Asthma: What Are the Links? J Clin Sleep Med 2009;5(1):71-78.
Alkhalil M; Schulman E; Getsy J. Obstructive Sleep Apnea Syndrome and Asthma: What Are the Links? J Clin Sleep Med 2009;5(1):71-78.
 Nasal Obstruction
• Increased incidence of nasal obstruction in asthmatic patients

• Majority of patients with asthma have rhinitis

• Rhinitis and chronic sinusitis may cause nasal congestion and

consequently contribute to upper airway obstruction in OSAS

Alkhalil M; Schulman E; Getsy J. Obstructive Sleep Apnea Syndrome and

Asthma: What Are the Links? J Clin Sleep Med 2009;5(1):71-78.
 Nasal Obstruction
Increased nasal obstruction

Increase in nasal resistance

Increases the negative pressure in the upper airway during

inspiration
a key factor for developing OSAS
Decrease in Pharyngeal Cross-Sectional Area
• Permanent airway mucosal inflammation observed in asthmatic
patients

• Significant reduction of upper airway dimension during

inspiration and expiration during asthma flares

Prasad B, et al. Obstructive sleep apnea and asthma: associations and

treatment implications. Sleep Med Rev. 2014 Apr;18(2):165-71
 Increased Upper Airways collapsibility
• Increased fat deposits in the pharyngeal wall from weight
gain
• Weight gain may continue with time, due to a limited ability to exercise,
sleep deprivation with increased insulin resistance, depression, and the
use of oral steroids.

• Chronic sleep deprivation and especially sleep fragmentation

increase upper airway collapsibility, contributing to the
development of OSAS

Prasad B, et al. Obstructive sleep apnea and asthma: associations and

treatment implications. Sleep Med Rev. 2014 Apr;18(2):165-71
 Clinical Outcomes and Treatment in
ASTHMA AND OSA
ALTERNATE OVERLAP SYNDROME
There are no long term studies of comorbid OSA and
asthma and thus no current specific guidelines

Data do exist documenting that CPAP treatment for

comorbid OSA improves asthma symptoms,
decreases the use of rescue medication, and improves
asthma specific quality of life
 Second Line Treatments for OSA
have not been prospectively evaluated in patients with asthma/OSA overlap

Bariatric Surgery
For patients with OSA and morbid obesity may be effective not only
for OSA resolution but also for improving asthma
 Asthma in patients with OSA
should be treated according to current asthma
treatment guidelines in addition to optimizing
treatment of the comorbid OSA
 ESTABLISHING THE CONNECTION OF ASTHMA AND OSA

ALTERNATE OVERLAP SYNDROME

IMPORTANT POINTS TO PONDER
• OSA and Bronchial Asthma have demonstrated a number of
pathophysiologic mechanisms

• Patients with Asthma (especially those who are difficult to treat asthma)
should be screened for OSA

• Management of both conditions is necessary since one may further

potentiate the other, leading to a vicious cycle

• Large scale population-based cohort study can be done since studies on this
entity is limited