Clinical Manifestations

General Comments

Clinical Asthma Phenotypes

• Cross-Sectional Study of Clinical Features in Adult Asthmatics (J Allergy Clin Immunol Pract, 2022) [MEDLINE]: n = 175 (57.5 ± 17.1 y/o)
  • 77/175 (44%) subjects had Early-Onset Asthma, 98 (56%) had Late-Onset Asthma and comorbidities had a differential impact in the two groups
  • Rhinitis was more frequent in EOA (76 vs 53%;p=0.02) and was associated with uncontrolled asthma (p<0.001), reduced FEV1/FVC (p=0.01), increased eosinophils (p = 0.003) and total IgE (p <0.01)
  • Conversely, in LOA rhinitis was associated with more controlled asthma and higher FEV1/FVC (both p<0.01)
  • In Early-Onset Asthma only IgE levels were directly related to blood eosinophils (r=0.42;p<0.001) and inversely to FEV1/FVC (r=- 0.35;p=0.002)
  • Obesity was present in 20% of patients in both groups, but only in Late-Onset Asthma obesity was associated to uncontrolled disease (p=0.009), reduced FEV1/FVC (p=0.009) and blood neutrophils (p = 0.03)
  • In multivariable regression analysis rhinitis in Early-Onset Asthma and obesity in Late-Onset Asthma were the risk factor most closely associated with poor control; GERD, cardiovascular and bronchiectasis did not affect control
  • Early-onset persistent and late-onset asthma are distinct phenotypes, with different underlying inflammatory patterns and different comorbidities which impact on symptom control

Infectious Manifestations

Risk of Bacterial Respiratory Infection

• Epidemiology
  • XXXX
• Clinical
  • XXXXX

Risk of Viral Respiratory Infection

• Epidemiology
  • Influenza Virus (see Influenza Virus)
  • Respiratory Syncytial Virus (RSV) (see Respiratory Syncytial Virus)
  • Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2, COVID-19) (see Severe Acute Respiratory Syndrome Coronavirus-2)
    • Acquisition
      • Asthma Does Not Increase the Risk of Acquiring Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2, COVID-19) (Global Initiative for Asthma, Global Strategy for Asthma Management and Prevention, Updated 2022) [MEDLINE]
    • Severity of Infection
      • Patients with Well-Controlled Asthma Do Not Have an Increased Risk of SARS-CoV-2 Infection-Related Death (Global Initiative for Asthma, Global Strategy for Asthma Management and Prevention, Updated 2022) [MEDLINE]
      • However, the Risk of SARS-CoV-2 Infection-Related Death is Increased in Asthma Patients WHo Have Recently Required Oral Corticosteroids for Their Asthma (Global Initiative for Asthma, Global Strategy for Asthma Management and Prevention, Updated 2022) [MEDLINE]

Neurologic Manifestations

Circadian Rhythm Disruption

• Epidemiology
  • XXX
• Association of rest-activity circadian rhythm with chronic respiratory diseases, a cross-section survey from NHANES 2011-2014. Respir Med. 2023 Feb 6;209:107147. doi: 10.1016/j.rmed.2023.107147 [MEDLINE]
  • A total of 7412 participants from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 were included in this study. The rest-activity circadian rhythm indices were calculated using accelerometer data and were divided into quartiles to perform logistic regression.
  • Results: Participants in the highest quartile of Relative amplitude (RA) had a lower prevalence of emphysema, chronic bronchitis and asthma, compared to those in the lowest quartile. Participants in the highest quartile of Intradaily variability (IV) was associated with a higher prevalence of emphysema relative to those in the lowest quartile. Compared to those in the lowest quartile, participants in the highest quartile of the average activity of the most active continuous 10-h period (M10) had a lower prevalence of emphysema. Additionally, compared to those in the lowest quartile of the average activity of the least active continuous 5-h period (L5) and L5 start time, participants in the highest quartile had a higher prevalence of asthma.
  • Conclusions: This study demonstrated that in general US adult population, disrupted rest-activity circadian rhythm was associated with a higher prevalence of chronic respiratory diseases

Otolayngologic Manifestations

Paradoxical Vocal Fold Motion (Vocal Cord Dysfunction) (see Paradoxical Vocal Fold Motion)

• Epidemiology
  • Up to 75% of Asthma Patients Have Coexistent Vocal Cord Dysfunction
• Diagnosis
  • Flexible Laryngoscopy (see Flexible Laryngoscopy)
• Management
  • XXXX

Pulmonary Manifestations

Allergic Bronchopulmonary Aspergillosis (ABPA) (see Allergic Bronchopulmonary Aspergillosis)

• Epidemiology
  • Allergic Bronchopulmonary Aspergillosis is Present in 2-32% of Asthmatics (Int J Tuberc Lung Dis, 2009) [MEDLINE]
• Diagnostic Features
  • Aspergillus Fumigatus-Specific Antibodies
  • Asthma-Like Presentation
  • Central Bronchiectasis (see Bronchiectasis)
  • Elevated Serum IgA (see see Serum Immunoglobulin A)
  • Elevated Serum IgE (see Serum Immunoglobulin E)
  • Peripheral Eosinophilia (see Peripheral Eosinophilia)
  • Positive Skin Test to *Aspergillus Fumigatus
  • Precipitating Antibodies Against Aspergillus Fumigatus Antigen

Cough (see Cough)

• Epidemiology
  • XXXX

Dyspnea (see Dyspnea)

• Epidemiology
  • XXXX

Severe Asthma with Fungal Sensitization (SAFS)

• Epidemiology
  • Subgroup of Asthmatics
• Clinical
  • Severe Asthma
    • ATS Definition of Severe Asthma: need for oral steroids ≥50% of time and need for high-dose inhaled steroid (belcomethasone ≥1200 mg/day or equivalent) and ≥1 other controller (e.g. long-acting bronchodilator, montelukast, etc.) to achieve control at level of mild persistent asthma
  • Positive Immediate Skin Test or In Vitro Specific IgE to ≥1 Filamentous Fungi
  • Exclusion of Allergic Bronchopulmonary Aspergillosis (ABPA) (see Allergic Bronchopulmonary Aspergillosis)
    • SAFS patients do not meet the necessary constellation of clinical, serological and radiological criteria for a diagnosis of ABPA, usually because total IgE levels are <1000 IU/mLand/or key radiographic findings, such as mucoid impaction or bronchiectasis, are lacking

Other Manifestations

• xxxx

Classification: – Mild: 4.0 PD20FEV1/inhaled steroid need <0.5 mg per day – Moderate: symptoms most days/25% variation in PEFR/ <1.0 PD20FEV1/inhaled steroid need 2.0 mg per day – Very Severe: recent hospitalization/nocturnal BD need/>35% variation in PEFR/ <0.1 PD20FEV1/inhaled steroid need 2.0 mg per day

Persistent Asthma (insidious onset or episodic/symptoms lasting for months-years):

-Symptoms/Signs: H+P does not usually fully elucidate the severity of disease/usually responsive to ß-agonists (typically regular use) 1) Wheezing: 2) Dyspnea: dyspnea correlates poorly with FEV1 (patients who are poor perceivers of airflow obsruction are at increased risk of bad outcomes) 3) Chest Tightness: 4) Prolonged Expiratiory Phase: 5) Cough: this is the only presenting symptom in 57% of cases and is often the prominent symptom -Cough may be the first sign of worsening control (particularly occurring at night) 6) Pulsus Paradoxus (due to high negative intrathoracic pressure):

Nocturnal Asthma

-This is associated with asthma severity (and is an indicator of overall control) -Usually early AM (circadian variation in airway muscle tone, inflammation, catecholamine and cortisol secretion, supine posture, snoring, GERD, or waning medication levels) -In dogs, REM autonomic hyperactivity with fluctuation in airway smooth muscle tone occurs but REM is not clearly associated with nocturnal asthma in humans

Episodic (Seasonal) Asthma (episodic exacerbations lasting days-weeks, symptom-free intervals without therapy):

-Seasons: Spring (grass or tree pollen)/ Fall (ragweed pollen) -Allergic rhinitis may also be present

Occupational Asthma: See Occupational Asthma

-Known asthmatics that develop symptoms at work (due to dust, etc.) are classified as having Work-Aggravated Asthma (not Occupational Asthma)

Cough-Variant Asthma

-Common type in children and elderly

Exercise-Induced Asthma (aka Exercise-Induced Bronchoconstriction): this is typically viewed as an indicator of the adequacy of asthma control

-Exercise-induced bronchoconstriction occurs in 70-80% of patients with actively symptomatic asthma (it is more likely to occur in patients with moderately-severely increased airway responsiveness) -Nasal breathing decreases exercise-induced bronchoconstriction -Repeated exercise usually decreases exercise-induced bronchoconstriction (exercise refractoriness usually lasts around 4 hrs)

Aspirin-Sensitive Asthma: ASA produces airway narrowing in 2-10% of adult (most have severe chronic asthma) and childhood asthmatics

-Associated with (nasal symptoms are less prominent in children): hyperplastic rhinitis/nasal polyps/sinusitis -Epidemiology: having both nasal polyps + asthma = 40% risk of having ASA-sensitivity –Most patients have history of perennial rhinitis dating back to 20 s, often after a viral illness -Pathogenesis: due to decreased PG production -Clinical: some asthmatics patients actually improve with ASA (unclear why) –Samter’s Syndrome (most patients are adults): asthma + vasomotor rhinitis/nasal polyposis + ASA sensitivity –Diagnosis is usually made by history + ASA challenge: ASA ingestion results in asthma exacerbation, rhinitis, facial flushing, periorbital edema, and conjunctival injection -Treatment: 1) ASA Avoidance: best treatment -NSAIDs with minimal COX-inhibition may be safely used: sodium salicylate, salicylamide, choline magnesium trisalicylate -Although lower doses of acetaminophen are safe in these patients, higher doses (>1000 mg) may manifest cross-reactivity with ASA -Selective COX-2 inhibitors have not been studied in this setting 2) ASA Desensitization: improves both asthma and nasal polyps -Ideal after polypectomy, as it delays recurrence of polyps up to 6 yrs 3) Cromones: somewhat protective 4) Leukotriene antagonists: protective 5) Diet Screening: ASA sensitivity may predispose sensitivity to tartrazine/benzoates (diet may need to be screened for salicylates, etc.)

Reversible Airway Restriction

• Rare presentation with low lung volumes, normal or near normal expiratory airflow, increased lung elastance, and decreased lung compliance that may reverse with bronchodilators or steroids
• The mechanism of reversible restriction in humans is not known, it likely involves closure of terminal lung units due to alveolar duct constriction (ie, pneumoconstriction ) similar to what has been observed in cats [Kaminsky DA, Irvin CG. Anatomic correlates of reversible restrictive lung disease. Chest. 1993;103:928-931 Hudgel DW, Cooper D, Souhrada J. Reversible restrictive lung disease simulating asthma. Ann Intern Med. 1976;85:328-332]
• International Variation in Severe Exacerbation Rates in Patients With Severe Asthma. Chest. 2024 Jul;166(1):28-38. doi: 10.1016/j.chest.2024.02.029 [MEDLINE]
  • Background: Exacerbation frequency strongly influences treatment choices in patients with severe asthma
  • Research question: What is the extent of the variability of exacerbation rate across countries and its implications in disease management
  • Study design and methods: We retrieved data from the International Severe Asthma Registry, an international observational cohort of patients with a clinical diagnosis of severe asthma. We identified patients aged ≥ 18 years who did not initiate any biologics prior to baseline visit. A severe exacerbation was defined as the use of oral corticosteroids for ≥ 3 days or asthma-related hospitalization/ED visit. A series of negative binomial models were applied to estimate country-specific severe exacerbation rates during 365 days of follow-up, starting from a naive model with country as the only variable to an adjusted model with country as a random-effect term and patient and disease characteristics as independent variables
  • Results: The final sample included 7,510 patients from 17 countries (56% from the United States), contributing to 1,939 severe exacerbations (0.27/person-year). There was large between-country variation in observed severe exacerbation rate (minimum, 0.04 [Argentina]; maximum, 0.88 [Saudi Arabia]; interquartile range, 0.13-0.54), which remained substantial after adjusting for patient characteristics and sampling variability (interquartile range, 0.16-0.39)
  • Interpretation: Individuals with similar patient characteristics but coming from different jurisdictions have varied severe exacerbation risks, even after controlling for patient and disease characteristics. This suggests unknown patient factors or system-level variations at play. Disease management guidelines should recognize such between-country variability. Risk prediction models that are calibrated for each jurisdiction will be needed to optimize treatment strategies

Asthma Clinical Remission

• xxxx
• Consensus of an American College of Allergy, Asthma, and Immunology, American Academy of Allergy, Asthma, and Immunology, and American Thoracic Society workgroup on definition of clinical remission in asthma on treatment. Ann Allergy Asthma Immunol. 2023 Sep 8:S1081-1206(23)01218-8. doi: 10.1016/j.anai.2023.08.609 [MEDLINE]

Complications of Asthma

• Pneumothorax/Pneumomediastinum:
• Respiratory Failure/Death: most asthma deaths are preventable (most asthma deaths occur before they get to the hospital)
• Status Asthmaticus:
• Hypercapnia during status asthmaticus occurs when FEV1 falls <20% predicted and often signals the need for ventilatory support
• Mucous Impaction: usually seen in ABPA cases though
• Pneumonia:
• Bronchiectasis: occurs in a few cases (especially those with mucoid impaction)
• SIADH: occurs during severe prolonged attacks
• Irreversible Airflow Limitation (development is related to severity and duration of disease/asthma does not appear to lead to emphysema): PFT’s are often abnormal during symptom-free intervals
• Symptoms/Signs: wheezing (may be absent in severe disease)/dyspnea/cough (may be only symptom)/pulsus paradoxus (>15 suggests severe attack)
• Difficult to distinguish from acute bronchiolitis in children without asthma history
• Previous life-threatening episode portends poorer prognosis
• Patient is usually better judge of attack severity than physician
• Patients who are poor perceivers of airflow obsruction are at increased risk of bad outcomes (including death)

Asthma in Pregnancy (see Pregnancy, [[Pregnancy]])

• Epidemiology
  • Uncontrolled Asthma Increases the Risk of Perinatal Mortality, Pre-Eclampsia, Preterm Birth, and Low Birthweight Infant
  • Asthma Improves in 33% of Women, Worsens in 33% of Women, and Stays the Same in 33% of Women
• Physiology
  • Asthma May Improve in Approximately 33% of Cases During Pregnancy, Due Predominantly to Progesterone-Induced Bronchodilation and Increased Circulating Histaminase
• Diagnosis

1) ABG: pCO2 is usually <35 with slight metabolic acidosis (pH ranges from 7.4-7.45) and normal pO2 a) Increased VE (begins during first trimester, up to 48% increase by term) with Normal-Mildly Elevated RR: due to progesterone b) Increased VT (30-35% above normal, to around 450-600 ml) with Increased A-P Diameter of Chest 2) Swan: a) PVR decreased (up to 35% by late pregnancy): b) Increased CO and blood volume with normal PCWP and CVP 3) PFT s/Exercise Testing: a) FRC and RV are decreased (with preserved FEV1 and VC) b) Increased oxygen consumption (rises to 40-100% above normal) + Increased CO2 Production (rises to 30-50% above normal by third trimester)

• Clinical
  • Dyspnea (see Dyspnea, [[Dyspnea]])
    • Dyspnea is Common in All Pregnancies: due to progesterone secreted by the placenta

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Specific Clinical Manifestations of Acute Asthma Exacerbation

Epidemiology

• XXXXX
  • International variation in severe exacerbation rates in patients with severe asthma. Chest. Published online February 21, 2024. doi:10.1016/j.chest.2024.02.029 [MEDLINE]
• Background: Exacerbation frequency strongly influences treatment choices in patients with severe asthma
• Research question: What is the extent of the variability of exacerbations rate across countries and its implications in disease management?
• Study design and methods: We retrieved data from the International Severe Asthma Registry, an international observational cohort of patients with a clinical diagnosis of severe asthma. We identified patients aged ≥18 years who did not initiate any biologics prior to baseline visit. A severe exacerbation was defined as the use of oral corticosteroids for ≥3 days or asthma-related hospitalization/emergency room visit. A series of negative binomial models were applied to estimate country-specific severe exacerbation rates during 365 days of follow-up, starting from a naïve model with country as the only variable, to an adjusted model with country as a random-effect term and patient and disease characteristics as independent variables
• Results: The final sample included 7,510 patients from 17 countries (56% from the United States), contributing to 1,939 severe exacerbations (0.27/person-year). There was large between-country variation in observed severe exacerbation rate (min: 0.04 [Argentina], max:0.88 [Saudi Arabia], interquartile range [IQR]: 0.13-0.54), which remained substantial after adjusting for patient characteristics and sampling variability (IQR: 0.16-0.39)
• Interpretation: Individuals with similar patient characteristics but coming from different jurisdictions have varied severe exacerbation risks, even after controlling for patient and disease characteristics. This suggests unknown patient factors or system-level variations at play. Disease management guidelines should recognize such between-country variability. Risk prediction models that are calibrated for each jurisdiction will be needed to optimize treatment strategies.

Risk Factors of Asthma Exacerbation

Clinical (Including Complications)

• xxx
  • Barotrauma
    • Pneumomediastinum (see Pneumomediastinum)
    • Pneumopericardium (see Pneumopericardium)
    • Pneumothorax (see Pneumothorax)
    • Subcutaneous Emphysema
  • Dyspnea (see Dyspnea)
  • Wheezing (see Wheezing)
    • Degree of Wheezing Correlates Poorly with the Degree of Airflow Limitation

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References