======Asthma======

=====Background=====
  * Definition: Chronic inflammatory disease of airways → episodes of airflow limitation → classic triad of sx (wheezing, cough, & dyspnea); over time can → airway remodeling (fibrosis, smooth muscle hypertrophy) → fixed obstructive component
  * “Asthma-plus” syndromes: Atopy (asthma + allergic rhinitis + atopic dermatitis), Samter’s triad (asthma + ASA sensitivity + nasal polyps), Allergic Bronchopulmonary Aspergillosis (ABPA) (asthma + bronchiectasis+ allergic reaction to aspergillus), Churg–Strauss (asthma + eosinophilia + granulomatous vasculitis) (Lancet 2002;360:1313)
  * Pathophysiology: Genetic (predisposition for IgE-mediated/Th2 response) & environmental factors (pollution, tobacco, allergens) → altered immune response → airway hyperresponsiveness, bronchoconstriction, ↑ edema/mucus → airflow obstruction
  * Epidemiology: Affects ~8% of US adults, ♀ > ♂; African-American > Caucasian > Hispanic; onset in majority of pts occurs by age 40 y
  * Risk factors: Atopy, smoking, obesity, occupational exposure (adult onset), dust mite exposure (childhood onset); rural upbringing protective (thought to be 2/2 ↑ diversity of microbial exposure) (NEJM 2013;369:549)

=====Diagnosis=====
  * Hx/PE and spirometry used to diagnose and assess comorbidities, triggers and severity
  * History: Classic sx: Intermittent episodes of dyspnea, chest tightness, wheezing, cough, frequently w/ identifiable triggers (below), often early-AM or nighttime coughing
    * PMHx: Atopy (atopic dermatitis, allergic rhinitis), seasonal allergies, rhinitis/sinusitis, GERD, CHF, OSA, obesity, depression/anxiety, vocal cord dysfunction
    * Meds: ASA/NSAIDs (use or hx sensitivity), βB, ACEI
    * FHx: Asthma, atopy, other pulm diseases
    * Social hx: Tobacco exposure, occupational & home exposures, incl pets
  * Exam: Often unremarkable exam if not in acute exacerbation; HEENT (nasal polyps, allergic “shiners” or rhinitis), skin (atopic dermatitis), full chest & pulm exam
  * Spirometry: Recommended in all pts in whom asthma is considered; documents obstruction (FEV1/FVC <70%) & its potential reversibility (FEV1 ↑ by 200 mL & 12% w/ bronchodilator); however, spirometry can be nl in mild disease btw episodes; pts may fail to show reversibility if asthma very poorly controlled; see “Pulmonary Function Tests”
  * Labs: Not routinely indicated; if severe asthma, consider serum IgE, CBC w/ diff (↑eos), skin testing/RAST (typically by allergy/immunology specialist)
  * Other: Methacholine challenge: Induced bronchospasm demonstrates airway hyperresponsiveness; occasionally used if PFTs nl and/or cough-variant asthma suspected; Se >90% (ARJCCM 2000;161:309), trial of empiric tx typically preferred; Sputum: >3% eosinophils has Se 86%, Curschmann spirals (mucous casts), Charcot–Leyden crystals (eosinophil lysophospholipase); CXR/advanced imaging if indicated by Ddx
  * Differential diagnosis: COPD, PE, CHF, bronchiectasis, hypersensitivity pneumonitis, eosinophilic lung disease, tracheobronchomalacia, mechanical airway obstruction, (tumor), ABPA, med-induced cough (ACEI), vocal cord dysfunction (see “Hoarseness”)

=====Evaluation=====
  * General approach: Patients w/ asthma should be assessed for symptom control, medication/tx adherence, and trigger exposure to determine management plan
  * Asthma history: age of onset, exacerbations (PO steroids, ED, inpatient, intubation); recent poor control/hx intubation assoc w/ ↑ asthma mortality (Chest 2003;124:1880), peak flow

^  Potential Asthma Triggers (cdc.gov/asthma/healthcare)  ^^
| Allergens | Persistent: Dust mites, cockroaches, pets, Seasonal (some regional variability): trees (spring), grass (summer), weed pollen (fall) |
| Occupational | Smoke, irritants, mold |
| Meds/toxins | Tobacco smoke exposure, outdoor air pollution, perfumes, ASA, NSAIDs, nonselective βB (though some controversy) |
| Infections | Viral upper respiratory infections |
| Other | Stress, cold air, strenuous physical activity, food additives (sulfites), hard laughing/crying |
  
  * Current control: For pts already on treatment, review current inhaler adherence and technique, as well as current symptoms, can use Asthma Control Test (qualitymetric.com/act; score >20 indicates control)
  * Exam: often unremarkable; wheezing on routine exam suggests poor control/exacerbation
  * Peak flow: Used to assess control (comparing current test against personal best), but improvement by 20% w/ bronchodilator can be used to support dx; n.b. reduced peak flow ≠ airway obstruction

=====Treatment=====
  * Nonpharmacologic treatment: Indicated for all pts, multifaceted approach beneficial
    * Allergen avoidance: Dust mites: Use bedding encasements, wash sheets weekly in hot water, avoid down, HEPA vacuum or air filter, no carpet in bedroom; pets: ↓ pet exposure (pet-free home or at least keep out of bedroom); eliminate mold/moist conditions when possible (↓ indoor humidity); Cockroach: Extermination, no exposed food or garbage; Pollens (indoors w/ windows closed during peak season); consultation with allergy specialist may be helpful
    * Irritant avoidance: Avoid outdoor exercise during periods of ↓ air quality (airnow.gov/ offers US air quality forecasts), avoid exposure to wood stoves, tobacco smoke
    * Smoking: Smoking & 2nd-hand smoke may ↓ response to asthma medication, ↓ lung function, & trigger exacerbations; counsel all pts & family members to quit (see “Tobacco Use”) & ask housemates to smoke outside (AJRCCM 2007;175:783)
    * Immunizations: Influenza & pneumococcal vaccines recommended; see “Immunizations”
    * Patient education: Key to trigger avoidance, effective inhaler use; see “Tip Sheets” at www.nhlbi.nih.gov/health/public/lung/asthma/asthma_tipsheets.pdf
    * Asthma action plan: Pts & providers should establish an asthma action plan, using sx or peak flow: sample at www.nhlbi.nih.gov/health/public/lung/asthma/asthma_actplan.pdf
  * Pharmacologic Treatment
    * General Approach: Initial tx dictated by severity; subsequent tx dictated by degree of control; all pts should have “rescue” inhaler Rx; All other Rx’s are “controller”: effective in preventing/reducing sx over long-term, not useful in acute management of sx
    * Initiating treatment: For pts not currently treated, determining which “step” to start on determined by severity assessment (below); pt category determined by most severe sx
    * Continuing treatment: For pts currently treated, assess control (see above) and then step up, down, or maintain as indicated; pt & provider judgment of tx efficacy should be guide; if asthma not well controlled, assess inhaler adherence & technique before modifying tx

^   Classification of Asthma Severity   ^^^^^
^ ^ ^  Persistent  ^^^
^ ^  Intermittent  ^  Mild  ^  Mod  ^  Severe  ^
| Sx frequency | ≤2 d/wk | >2 d/wk | Daily | Daily |
| Nighttime awakenings | ≤2×/mo | 3–4×/mo | >1/wk | Nightly |
| SABA use for sx control | ≤2 d/wk | >2 d/wk  | Daily | Several times/d |
| Interference w/ nl activity | None | Minor | Some | Extreme |
| Spirometry (% predicted) | Nl btw exacerbations | Nl btw exacerbations | FEV1: 60–80% pred; FEV1/FVC: ↓ | FEV1: <60% pred; FEV1/FVC: ↓ |
| Exacerbations | <1/y | ≥2/y | ≥2/y | ≥2/y |
| Initial Tx | Step 1 | Step 2 | Step 3 | Step 4 or 5 |

^ Asthma Treatment Steps ^^
^ Step ^  Controller Medication  ^
| Step 1 | None indicated (should receive SABA PRN) |
| Step 2 | Low-dose ICS, consider allergen immunotherapy \\ Alt: Antileukotriene, theophylline, cromolyn |
| Step 3 | Low-dose ICS & LABA \\ Alt: Medium-dose ICS, low-dose ICS + (LTRA, theophylline, or zileuton); consider adjunct tiotropium, allergen immunotherapy |
| Step 4 | Med-dose ICS & LABA, specialist referral \\ Alt: Med-dose ICS & (LTRA, theophylline, or zileuton); consider adjunct tiotropium, allergen immunotherapy |
| Steps 5, 6 | High-dose ICS + LABA ± oral corticosteroids, specialist referral, consider anti-IgE therapy or anti-IL5 therapy if appropriate phenotype |

^  Features of Well-Controlled Asthma  ^^
| No limitation of activities \\  No nocturnal sx/awakenings \\ Validated survey indicating control (see above) | PEF or FEV1 nl \\ Reliever/rescue tx ≤2 d/wk \\ Daytime sx ≤2 d/wk |

^  Treatment Plan by Level of Control  ^^
| Well-controlled: All control criteria met or n/a | <3 mo: maintain regimen; ≥3 mo: consider step-down \\ reassess in 1-6 mo |
| Partially controlled: 1–2 of the listed criteria not met | Step-up 1 step \\ Reassess in 2–6 wk |
| Poorly controlled: ≥3 of the listed criteria not met | Step-up 1–2 steps: Consider short course PO corticosteroids (40–60 mg QD × 3–10 d) \\ Reassess in 2 wk |

  *  When to Refer
    * Patients with “asthma-plus” syndromes; pts w/ mod–severe asthma or poorly controlled/frequent exacerbations despite escalation of Rx; dx uncertain, prior hospitalization for asthma → specialist (pulm or allergy/immunology)
    * Patients with /prominent allergic component → allergy/immunology for allergy testing, consideration of allergen immunotherapy

=====ASTHMA MEDICATIONS=====
  * Inhalers: Multiple devices (below); pt education key, as many use inhalers incorrectly (AJRCCM 1994;150:1256); inhaler how-to videos at cdc.gov/asthma/inhaler_video/default.htm

^  Inhaled Medication Delivery Systems (nhlbi.nih.gov)  ^^
| Metered-dose inhaler (MDI) | Aerosolized Rx; must be “primed” (discarded sprays) before 1st use; requires coordination of actuation & breath \\ Deep slow breath × 3–5 s, then hold × 10 s; repeat after 1 min if dose is “2 puffs” |
| Spacer | Used w/ MDI; turns aerosol into finer droplets for ↑ delivery to lungs; ineffective if pt exhales into spacer; requires separate Rx |
| Valved holding chamber (VHC) | Similar to spacer but prevents pt exhaling into device, may be more expensive; requires Rx |
| Dry powder inhaler (DPI) | Powdered Rx drawn into lungs w/ inhalation; can clump w/ ↑ humidity; use fast, deep breath & hold for 10 s |
| Nebulizer | Requires nebulizer machine to deliver Rx; no more effective at Rx delivery, but does not require pt effort/coordination |
  
  * “Quick-relief” or “rescue” inhaler: Should be prescribed for all pts; to be used PRN or as ppx prior to anticipated exposure (e.g., exercise)
    * Short-acting beta agonists (SABA, e.g., albuterol): Mainstay and should be prescribed for all pts; onset <5 min, peak 30–60 min, duration 4–6 h; S/e: Tremor, tachycardia, anxiety, palpitations
    * Short-acting anticholinergics (e.g., ipratropium): less-effective alternative in pts w/ mild sx who do not tolerate SABA or as adjunct in pts w/ severe sx; not FDA-approved
  * Inhaled corticosteroids (ICS): controller Rx
    * Mechanism: ↓ airway inflammation & bronchial hyperresponsiveness → fewer asthma sx, ↑ lung function, ↑ QoL, ↓ exacerbations & ↓ mortality (JAMA 1997;277:887; NEJM 2000;343:332)
    * S/e: Hoarseness, sore throat, oral candidiasis; can → systemic s/e in ↑ doses (e.g., >1000 μg beclomethasone/d)
    * Dosing: Delivered by DPI or HFA (see above) and divided into low, medium, or high dose: determined by individual steroid’s potency, concentration (“dose/puff”), and number of inhalations (“puffs”)
    * Example Rx: fluticasone offered at 3 strengths (44 mcg/inh, 110 mcg/inh, and 220 mcg/inh); low dose = 88–264 mcg/d, med dose = 264–440 mcg/d, high dose >440 mcg/d
    * Best to pick one agent and step up/down; use conversion chart to switch agents
    * Pt education: rinse mouth after use, if delivery vehicle is MDI, use w/ spacer or VHC
  * Combination ICS + long-acting beta agonist (LABA): In asthma, LABA always used in combination w/ ICS 2/2 risk of ↑ asthma-related deaths (Chest 2006;129:15), though some believe risk may be overstated (NEJM 2016;375:850)
    * Benefits: Combination tx → sustained improvement in lung function, ↓ in sx, exacerbations, ICS dose (Cochrane Database Syst Rev 2010;4:CD005533)
    * Dosing: In combination inhalers, LABA dose constant but ICS may come in different strengths; most inhalers are BID, although some newer agents (e.g., Breo, fluticasone-vilanterol) are QD; may have to Rx LABA and ICS as separate inhalers (to be used together) depending on insurance formulary
    * Example Rx: Fluticasone/salmeterol 100 mcg/50 mcg inh BID, 200/50 mcg inh BID, or 500 mcg/50mcg inh BID
    * S/e: Usually mild; muscle cramps, ↑ HR
  * Leukotriene modifiers: Used as adjunct/alternative to ICS; also effective for AR, may be preferable to ICS in pts w/ mild sx and allergic component; also consider in obese, smokers, ASA hypersensitivity; additive benefit to ICS in exercise-induced bronchospasm (AJRCCM 2007;175:783; AJRCCM 2006;173:379; JACI 2012;130:535)
    * Dosing: PM dosing preferred for montelukast; onset is hours, peak few days
    * Example Rx: Montelukast 10 mg PO QPM (leukotriene receptor antagonist); Zileuton XR 1200 mg BID (leukotriene formation inhibitor)
    * S/e: Hepatitis (zileuton 2–4%, requires LFT monitoring), possible mood/behavior sx
  * Long-acting muscarinic antagonists (LAMA): Adjunct to ICS ± LABA; Not FDA-approved for asthma; adding tiotropium superior to doubling ICS dose re: ↑ asthma control days, PEF, & ↓ daily sx (NEJM 2010;363:1715); Can ↓ exacerbation freq when added to pts w/ sx despite LABA/ICS (NEJM 2012;367:1257) example Rx: tiotropium 18 mcg inh QD
  * Other: Typically Rx’ed by specialist for pts w/ severe or refractory disease
    * Omalizumab: Anti-IgE; SC q2–4wk; >$10K/y; must have ↑ IgE & sensitization to perennial aeroallergen (e.g., dust mite, pet) S/e: Local reaction, anaphylaxis (rare)
    * Mepolizumab: Anti-IL5; pts w/ poorly controlled asthma on high-dose ICS with ↑eos; found to ↓exacerbation rate, ED visits/hospitalizations (NEJM 2014; 371:1198)
    * Theophylline: Can be useful in refractory disease; narrow therapeutic window (can → arrhythmia, N/V, HA, sz)
    * Mast-cell stabilizer: Cromolyn sodium, Nedocromil: Specific benefit for ASA-sensitive pts or exercise-induced asthma; few s/e (AJRCCM 2002;165:9; Ann Intern Med 2000;132:97)

=====EXACERBATIONS=====
  * Definition: Acute onset/worsening of asthma symptoms (AFP 2011;84:40)
  * Presentation: hx: Cough, wheeze, chest tightness, some limitation of activity; Exam: ↑ work of breathing on exam, wheezing, tachypnea; Peak flow: <80% (<40% consistent w/ severe exacerbation)
  * Red flags: Severe SOB, failure for peak flow to improve after quick-acting rx used, sx not improving 24 h after step-up → severe exacerbation → ED
  * Management of mild–mod exacerbation: (Some limitation of activity, peak flow 50–80% personal best): SABA 2–6 puff (or neb) now then Q2–4h PRN; step-up to next level of care; low threshold for short-course oral corticosteroids (40–60 mg prednisone QD × 3–10 d), esp if sx fail to improve w/ initial rescue Rx