Asthma Management Guidelines PDF

PULMONARY AND CRITICAL CARE MEDICINE Asthma Management of exacerbation of asthma: NAEPP guidelines Initial Evaluation: 1. H&P (chest auscultation, accessory muscle usage, HR/RR evaluation) 2. Recording of Peak Flow or FEV1 3. O2 sat. 4. Laboratory work-up...

PULMONARY AND CRITICAL CARE MEDICINE Asthma Management of exacerbation of asthma: NAEPP guidelines Initial Evaluation: 1. H&P (chest auscultation, accessory muscle usage, HR/RR evaluation) 2. Recording of Peak Flow or FEV1 3. O2 sat. 4. Laboratory work-up as indicated Based on the initial assessment, patients are grouped into 3 categories: 1. Group I: FEV1 or peak flow ≥ 40% of baseline. Mild to moderate exacerbation 2. Group II: FEV1 or peak flow < 40% Severe exacerbation 3. Group III: Impending or actual respiratory arrest: Intubation and mechanical ventilation. Admit to ICU. Management of Group I: First Hour: 1. Nebulized SABA or SABA by MDI with valved holding chamber: 3 doses in 1 hour 2. Oxygen to achieve O2 sat ≥ 90% 3. PO steroid if there is no quick response or if the patient completed steroid recently. After 1 hour, again assess symptoms, examine patient, peak flow, O2 sat, and other tests as needed: a. Moderate exacerbation on repeat assessment: 1. Peakflow 40 – 69% of predicted or personal best, 2. Moderate symptoms per exam Administer SABA q1 hour, PO steroid (if not given earlier), treatment is continued 1 – 3 hours if there is continuous improvement. Decide admit Vs discharge in < 4 hours. b. Good response on repeat assessment: 1. FEV1 or Peak flow ≥ 70%, 2. Response persists 1 hour after last treatment 3. No distress Then, D/C home. D/C meds: 1. Inhaled SABA 2. Tapered PO steroid 3. Consider starting inhaled corticosteroid, continue inhaled steroid if already on © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 647  4. Patient education: Medication review, inhaler technique, asthma action plan, close medical follow up. c. Incomplete response after the second treatment period: 1. FEV1 or PEF still 40 – 69% 2. Mild to moderate symptoms Individualize decision: – D/C home vs. hospital floor admission. If admitted to floor: Oxygen, inhaled SABA, systemic (oral or IV) steroid, and adjunct therapies, if needed are given. Monitor vital signs, FEV1 or PEF, and O2 sat. If they improve, then D/C instructions as above are followed. Prior to D/C, follow up appointment with PCP or Pulmonologist in 1 – 4 weeks. Management of Group II: 1. O2 to get O2 sat ≥ 90% 2. Nebulized high dose inhaled SABA + ipratropium or MDI with valved holding chamber, q20 minutes or continuously for 1 hour, and 3. PO steroids. Repeat evaluation in 1 hour. Symptoms, exam, peakflow, O2 sat, other tests as needed. a. Moderate exacerbation (Peakflow 40 – 69%) on repeat assessment: Managed as above. b. Severe exacerbation on repeat assessment: (FEV1 or peak flow < 40%, examination shows severe at rest symptoms, accessory muscle use, chest retraction, or by history, a high risk patient, and show no improvement after initial treatment) 1. Oxygen is continued 2. Nebulized SABA + ipratropium q1 hour 3. PO steroids 4. Adjunct therapies (magnesium and heliox) can be given. c. Good response (PEF > or + 70%) on repeat assessment: Discharged as described above. If patients continue to show poor response even after this second period of treatment, with FEV1 or peak flow < 40%, ABG PCO2 > 42 mmHg, and severe symptoms on exam, drowsiness, or confusion, then they are admitted to ICU. Management in ICU: 1. O2 2. Inhaled SABA q1 hour or continuously (no ipratropium after admission, whether floor or ICU) 3. IV steroid 4. Adjunct therapies (magnesium and heliox) can be given. 5. May need intubation and mechanical ventilation. Upon improvement, patients can be moved to hospital ward. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 648 Intubated patients: Permissive hypercapnia, high inspired O2, high flow rate, and IV sodium bicarbonate to treat respiratory acidosis are recommended. Tidal volume, rate, and inspiration to expiration ratio must be adjusted to minimize airway pressure. SABA is continued for ventilated patients. NAEPP Guidelines do not recommend methylxanthines, antibiotics unless there is indication (fever and purulent sputum, suspected bacterial sinusitis or pneumonia), aggressive hydration, chest PT, mucolytics or sedation. Ipratropium is not recommended after hospitalization. Higher dose of SABA and ipratropium are given for severe exacerbations, while in ED. Continuous administration of SABA is most effective. Albuterol, levalbuterol and pirbuterol are SABAs. Nebulization is preferred for patients in severe exacerbation, agitation, or using MDI inappropriately. Equivalent bronchodilatation can be achieved by nebulization or high dose (4 – 12 puffs) of SABA by MDI with valved holding chamber. Ipratropium dose is 0.5 mg nebulized or 8 puffs by MDI in adults in ED management. There is no benefit to adding ipratropium for hospitalized patients. Oral steroid and IV methylprednisolone have equal efficacy. A 5 – 7day course of steroid is recommended after ED discharge. Global Initiative for Asthma (GINA) gives global asthma guidelines. GINA guidelines have recommendations for stable asthma and asthma exacerbation. Management of Asthma exacerbation recommended by GINA classifies patients as: Mild-moderate exacerbation: Peak flow (> 50%), talking in phrases, tachypnea, and tachycardia (HR: 100-120/min) and O2 saturation ≥ 90% without accessory muscle use. Start treatment: 1. SABA 4-10 puffs by MDI with spacer every 20 minutes x 3, 2. Prednisolone 40-50 mg and 3. O2 for saturation 93-95% the first hour Assess response in 1 hour and if this is in the office setting, if worsening, patient should be transferred to acute care setting. If improving/doing well, continue SABA and plan discharge. Discharge can be planned when symptoms improve, have adequate home resources and peak flow is > 60-80%. If in ED for mild to moderate exacerbation: SABA (+ consider ipratropium), O2 (93-95% saturation), oral steroid. Severe exacerbation: Only able to talk in words, RR > 30/min, using accessory muscles, HR > 120, O2 sat < 90%, peak flow ≤ 50%) need urgent transfer to the hospital. While waiting, start treatment: SABA + SAMA, prednisolone and oxygen. In ED: O2 (93-95%), SABA + SAMA, oral or IV steroid, and consider magnesium sulphate IV. Use of high dose ICS: - High dose ICS within 1 hour of presentation to ED reduces need for admission in patients not receiving systemic steroids. GINA guidelines recommend to continue/start ICS in the hospital. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 649 Evidence for NIV is weak in asthma per GINA, if started should be monitored closely. Discharge: Follow up within 2-7 days; ongoing ICS containing treatment (MART – see below), prednisolone or equivalent 40-50 mg/day for 5-7 days (dexamethasone only 1-2 days), asthma action plan, inhaler technique. Asthma – Definition, types, diagnosis, management (outpatient setting) GINA definition of asthma: “Asthma is a heterogenous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms, such as wheeze, shortness of breath, chest tightness and cough, that vary over time and in intensity, together with variable expiratory airflow limitation”. Immunohistopathologic feature: Inflammatory cell infiltration. The inflammation leads to hyperresponsiveness of the airways. There is inflammation by activated eosinophils and type 2 helper cells. Neutrophil infiltration, instead of eosinophils causes less reversibility, and less response to steroids and bronchodilators. In some patients with asthma, airway remodeling occurs - sub-basement membrane fibrosis, hypersecretion of mucus, epithelial cell injury, smooth muscle hypertrophy and angiogenesis. Airway remodeling leads to irreversible airflow obstruction. Asthma phenotypes: Allergic asthma: Associated with a personal or family history of allergic diseases (rhinitis, urticaria, or eczema, food allergy). There is eosinophilic inflammation of airways. Good response to inhaled corticosteroid (ICS) Non-allergic asthma has no allergic features. The inflammatory infiltrate can be eosinophilic, neutrophilic, or only a few inflammatory cells. Less short term response to steroid. Late onset asthma: Starts in adult life. Usually, non-allergic and may not respond to ICS or require higher doses of ICS. R/O Occupational asthma in this group. Asthma with persistent airflow limitation: Due to airway remodeling (see above) Asthma with obesity: Patients have prominent symptoms but little eosinophilic airway inflammation. The bronchial hyper-responsiveness can be measured by bronchoprovocation challenge. Bronchoprovocation challenge is used to assess the presence of hyper-responsive airways in a patient with symptoms of asthma, but with normal exam and normal pulmonary function test. Lung function is measured by spirometry after each incremental concentration of methacholine. The test is stopped when FEV1 decreases by ≥ 20% from baseline or after a maximal concentration of methacholine has been given. Negative bronchoprovocation challenge in a patient not taking any anti-asthma therapy excludes a diagnosis of asthma with 95% certainty (high negative predictive value). Positive results confirm bronchial hyper-responsiveness. 10 to 15% of general population © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 650 and 20 to 25% of patients with hay fever may have a positive result, so the bronchoprovocation test is not specific to asthma. Mannitol is also used for bronchoprovocation. Stimuli (Asthma triggers): Allergens – Respiratory allergens activate IgE bound mast cells causing immediate bronchoconstriction that is relieved by bronchodilators. Grass (summer) and tree pollen (spring), rag weed (fall), and fungal spores are seasonal. Non-seasonal forms of allergens include feathers, animal dander, dust mite, cockroach, and mold. Viruses: Rhinovirus (most common), RSV, influenza virus, and corona virus trigger exacerbation Pharmacological stimuli: Aspirin Exacerbated Respiratory Disease (AERD, aspirin sensitive asthma): Starts as perennial vasomotor rhinitis à hyperplastic rhinosinusitis with nasal polyps à progressive asthma. There is cross reactivity between aspirin and other NSAIDs. The mechanism of aspirin sensitive asthma is leukotriene overproduction. Aspirin sensitive asthma usually occurs in asthmatics. Samter’s triad: Asthma, sinus inflammation with nasal polyps, aspirin sensitivity. Treatment: Avoidance of aspirin and NSAIDs. Aspirin desensitization is done in some specialized centers. ICS is the main treatment. Leukotriene inhibitors may be useful. Surgery for polyps, biological agents (e.g. dupilumab) may be needed. Beta-blockers including selective beta 1 blockers at high doses and beta-blocker eye drops can provoke wheezing in an asthmatic. Sulfating agents, e.g., potassium metabisulfite, etc., used in food/drug industry can cause wheezing. Occupational asthma: Sensitizing antigens in the workplace can lead to new onset of asthma, e.g. cereal in bakers and millers, animal allergens in animal handlers, enzymes in detergent users, bakers, and pharmaceutical workers, formaldehyde in hospital employees, metal salts in solderers and refiners etc. Once sensitization occurs, symptoms develop after exposure to the antigen. Wheezing occurs during or hours after work exposure and worsens throughout the workweek. There is relief during weekends and days off from work. With continued exposure, symptoms become persistent and chronic with irreversible airway changes. Workplace Spirometry shows obstruction with reduced FEV1/FVC. Removal from the environment within 6 months of symptom onset can lead to full recovery. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 651 Exercise: Exercise can precipitate acute episode of wheezing in asthmatics. Hyperventilation increases osmolality of airway fluids. This triggers mast cell release. Cold dry air is implicated. Adequate warm-up prior to exercise, covering mouth with cloth in cold weather, SABA or ICS/SABA prior to exercise can prevent it, regular inhaled steroids/leukotriene antagonists are best for prevention in patients with underlying asthma. SABA is given 15 minutes prior to exercise. Emotional stress, changes in weather, perfumes also trigger asthma. GERD may trigger bronchoconstriction. There was no improvement in asthma symptoms when asthmatics with no symptoms of reflex were treated with PPI. Only asthmatics with GERD symptoms should be treated for GERD. Asthma should be controlled well during pregnancy. Inhaled steroids are first line for long-term control. Oral steroid is safe for exacerbations. Allergic bronchopulmonary aspergillosis (ABPA): ABPA accounts for less than 1% of asthma. ABPA is due to an immediate hypersensitivity reaction to the presence of aspergillus fumigatus, in the airway. Features: Central bronchiectasis, migratory pulmonary infiltrates, cough with plugs of dirty brown sputum, and peripheral eosinophilia. Diagnostic criteria: International Society for Human and Animal Mycology 1. Presence of predisposing condition: Asthma or Cystic fibrosis + 2. Elevated IgE against aspergillus or positive skin test + elevated total IgE + 3. Any 2 of the 3: Elevated IgG antibody to aspergillus, Xray features consistent with ABPA, total eosinophil count > 500/mcL while not on steroid ABPA is treated with systemic steroids. Adjunctive therapy with itraconazole or voriconazole Reactive Airways Dysfunction Syndrome: Accidental massive exposure of irritant stimuli (bleach, ammonia) can lead to persistent inflammation and dysfunction of the airways leading to cough, dyspnea and bronchospasm. Cough variant asthma: Asthma manifesting as chronic cough. Diagnosis: Spirometry. If negative, methacholine challenge test can be done. D/D: GERD, Postnasal drip. Vocal cord dysfunction (VCD): Mimicker of asthma, presenting as recurrent stridor and wheezing. VCD can occur in patients with and without asthma. Exercise and stress are important precipitating factors. VCD can also be precipitated by irritants, irritant © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 652 associated VCD (inhaled noxious irritants, laryngeal acid reflux, rhinitis etc). During symptomatic periods, vocal cords undergo involuntary adduction, leading to stridor and flattening of inspiratory loop of the flow-volume loop. Treatment: Acute attack: Heliox and NIPPV. Long-term: Behavioral modification, speech therapy. Diagnosis of Asthma: Patient with symptoms (dyspnea, wheezing, chest tightness, cough) suggestive of asthma: Do spirometry/PEF with reversibility testing 1. Spirometry to confirm airflow limitation (reduced FEV1, FEV1/FVC ratio, and PEF). In a patient already on ICS-SABA/ICS-LABA, if spirometry is negative, repeat after withholding bronchodilator therapy to confirm asthma. 2. Demonstrate reversibility by > 12% and > 200 ml increase in FEV1 15 minutes after SABA. 3. Flow-volume loop, if done, shows reduced PEF and reduced maximum expiratory flow. 4. Methacholine challenge may be needed if spirometry is negative in the presence of suspicious symptoms. Post exercise bronchoconstriction may be demonstrated in exercise induced asthma; workplace spirometry is done for occupational asthma. 5. In patients in whom asthma diagnosis is not clear-cut after history, exam, disease course and spirometry with bronchodilator response (or when spirometry cannot be done), FeNO (Fractional exhaled nitric oxide) measurement may support asthma diagnosis. FeNO indicates Type 2 bronchial (eosinophilic) inflammation of airways. FeNO < 25 ppb à Lack of evidence for T2 inflammation, so unlikely to be asthma or the patient has non eosinophilic or non-T2 inflammation asthma or they are on steroids. FeNO > 50: Supports Asthma as diagnosis (evidence for T2 inflammation) FeNO 25-50: Grey zone, clinical correlation. 6. CXR is normal in asthma or may show hyperinflation during exacerbation 7. Skin prick or scratch allergen testing for respiratory allergens may be done in patients with persistent grade asthma to emphasize allergen avoidance or for immunotherapy. Treatment for asthma: The currently preferred definitions of mild, moderate, and severe asthma is based on “difficulty to treat” – the level of treatment required to control symptoms and exacerbations after several months of treatment. Mild Asthma: Asthma well controlled with low intensity treatment (as needed low dose ICS-formoterol or low dose ICS + as needed SABA) Moderate Asthma: Asthma well controlled with step 3 or 4 treatment (low or medium dose ICS-LABA) Severe asthma: Asthma that stays uncontrolled despite optimized high dose ICS-LABA or asthma that requires high dose ICA-LABA to prevent from being uncontrolled. Poor inhaler technique, nonadherence, symptoms due to alternative diagnoses such as vocal cord dysfunction, comorbidities such as GERD/OSA/obesity/rhinosinusitis, © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 653 continuous exposure to irritants at home/work should be ruled out before severe asthma diagnosis. Definition based on symptoms and SABA frequency, night waking, lung function, and exacerbation - before ICS containing regimen has been started: Mild intermittent asthma: 1. Daytime symptoms ≤ 2 days/week 2. Nighttime symptoms ≤ 2 nights/month 3. FEV1 > 80% predicted, FEV1/FVC normal, normal FEV1 between exacerbations 4. No interference with daily activity 5. Exacerbation that needs oral steroid: 0-1/year 6. Short acting beta agonist use to control symptoms: ≤ 2 days/week 7. Treatment step: Step 1 Mild persistent asthma: 1. Day symptoms: 3 - 6 days per week (not daily) 2. Nighttime symptoms: 3-4 nights per month 3. FEV1 > 80% predicted, FEV1/FVC normal 4. Minor limitation in daily activity 5. Exacerbations that need oral steroid: ≥ 2/year 6. Short acting β agonist to control symptoms: > 2 days/week, not daily, not > 1x/day 7. Treatment step: Step 2 Moderate Persistent Asthma: 1. Daytime symptoms occur daily 2. Nighttime symptoms > 1x/week, but not every night 3. FEV1 is > 60%, but < 80%, FEV1/FVC reduced 5% 4. Some limitation of daily activity 5. Exacerbations that need oral steroid: ≥ 2/year 6. Short acting β agonist to control symptoms: Daily 7. Treatment step: Step 3 (and consider short course oral steroid) Severe Persistent Asthma 1. Daytime symptoms continuously throughout the day 2. Nighttime symptoms: nightly, 7x/week 3. FEV1 < 60% predicted, FEV1/FVC reduced > 5% 4. Severe limitation of daily activity 5. Exacerbations that need oral steroid: ≥ 2/year 6. Short acting β agonist to control symptoms: Many times/day 7. Treatment step: Step 4 - 6 (and consider short course oral steroid) STEPWISE therapy of asthma as recommended by NAEPP 2020 STEP 1: SABA PRN. For patients with mild intermittent asthma only. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 654 For persistent grade asthma, step 2 – 6 is given based on response. STEP 2: Preferred: Low dose ICS daily + PRN SABA and ICS (or) PRN SABA Alternative: Daily LTRA + PRN SABA or Cromolyn or nedocromil or Zileuton or theophylline + PRN SABA (ICS: Inhaled corticosteroid; LTRA Leukotriene antagonist) STEP 3: Preferred: Daily and PRN Low dose ICS + formoterol combination Alternative: Daily medium dose ICS and PRN SABA (or) daily low dose ICS- LABA or daily low dose ICS + LAMA or daily low dose ICS + LTRA and PRN SABA or daily low dose ICS + theophylline or zileuton and PRN SABA. ICS + LABA is preferable rather than ICS + LAMA, use LAMA if LABA cannot be used. In black patients, LAMA may increase risk of harm. Glaucoma and risk of urinary retention are contraindications for LAMA in asthma. Daily maximum dose of formoterol: 12 puffs (54 mcg) STEP 4: Preferred: Daily and PRN Medium dose ICS + formoterol combination Alternative: Daily medium dose ICS-LABA or daily medium dose ICS-LAMA and PRN SABA or Daily medium dose ICS + LTRA or daily medium dose ICS + theophylline or Zileuton and PRN SABA Daily maximum dose of formoterol: 12 puffs (54 mcg) STEP 5: Preferred: Daily medium-high dose ICS-LABA + LAMA and PRN SABA Alternative: Daily medium-high dose ICS-LABA or daily high dose ICS + LTRA and PRN SABA STEP 6: Preferred: Daily high dose ICS-LABA + oral steroid + PRN SABA Omalizumab for patients with allergies. STEPS 2 – 4: SC Immunotherapy as an adjunct to standard pharmacological treatment. STEPS 5 – 6: Consider addition of biologics (Anti-IgE, anti-IL5, anti-IL5R, anti- IL4/IL13) Refer to specialist if step 4 or higher is needed. Albuterol 180 mcg/budesonide (160 mcg) fixed dose inhaler as the rescue inhaler along with ICS daily maintenance inhaler was shown to be associated with decreased rate of severe exacerbations compared to albuterol only as rescue. FDA has approved albuterol/budesonide combination inhaler to be used as rescue inhaler. Formoterol does not have FDA approval as rescue/reliever, only for long term maintenance. Assess asthma control: Check adherence to therapy, inhaler technique, environmental factors, and comorbidities. If indicated, Step-up therapy and reassess in 2-6 weeks. If well controlled for 3 months, consider step down. FeNO can be included as a strategy for monitoring response to treatment and for choosing medications in patients with persistent allergic asthma. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 655 In patients without sensitization to indoor allergens, allergen mitigation interventions are not recommended. In patients with symptoms from indoor allergen exposure confirmed by history or allergy testing, allergen mitigation intervention is recommended. For cockroach/rodent sensitization, pest management alone is recommended. For dust mite sensitivity, impermeable pillow/mattress covers should be part of a multicomponent allergen mitigation intervention. In each step: Patient education, environment control and management of comorbidities are needed in addition to step care. GINA guidelines for outpatient asthma management: GINA no longer recommends as needed SABA only for anyone with asthma. Step Care per GINA: GINA gives 2 treatment tracks for asthma: Definitions: AIR (anti-inflammatory reliever; never SABA alone) and MART: ICS- formoterol as maintenance and reliever (Maintenance and reliever therapy) First track: Symptom Reliever: As needed low dose ICS-formoterol. Steps 1-2: Low dose ICS-formoterol as needed only - Use in patients with symptoms age 40 with risk factors and symptoms. COPD is diagnosed by a post bronchodilator © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 658 FEV1/FVC < 70%. COPD leads to persistent symptoms (dyspnea, cough, sputum, wheezing) and airflow limitation due to a combination of disease of the small airways and destruction of lung parenchyma. Some patients have symptoms and/or structural lung disease (emphysema) and/or abnormalities in spirometry (low FEV1, air trapping, reduced diffusion capacity etc) but post bronchodilator FEV1/FVC is ≥ 70. These patients have pre-COPD. Preserved ratio Impaired Spirometry (PRISM) is the term proposed. PRISM/pre-COPD patients are at risk of developing airflow obstruction. Diagnosis: Risk factors, symptoms, and then spirometry to diagnose. Initial Evaluation steps: Assess symptoms, exacerbations, GOLD grade, smoking status, address comorbidities, check α1 antitrypsin, eosinophil count. Initial Management: Smoking cessation, vaccinations, lifestyle/exercise, initial management per stage: Bronchodilator(s), inhaler technique, self-management education, risk factor management, written action plan, and comorbidity management. Then review and adjust management steps. COPD has important comorbidities: Concomitant CVD, skeletal muscle dysfunction, osteoporosis, depression and anxiety, metabolic syndrome, and lung cancer, which should be diagnosed and managed aggressively to improve outcomes. WHO recommends all patients with COPD diagnosis to be screened for alpha1 AT deficiency once, particularly in areas of high prevalence. Patients with symptoms and/or structural lung disease (emphysema) and/or physiological abnormalities (low normal FEV1, hyperinflation, air trapping, decreased diffusion capacity and/or fast decline in FEV1) but without airflow obstruction (FEV1/FVC is ≥ 0.7) are called Pre-COPD, and Preserved Ratio Impaired Spirometry (PRISm) is the proposed name for the condition of normal ratio, but otherwise abnormal spirometry. Pre- COPD/PRISM patients are at risk of progressing to airflow obstruction (COPD). Smoking cessation is the most effective step to reduce risk of development of COPD, slow it’s progression, and improve survival. Ask (identify smokers), Advice (to quit), Assess (willingness to quit), Assist (help the patient to quit – social support & pharmacotherapy) and Arrange (schedule follow up). FDA approved drugs for smoking cessation are nicotine replacements (recently found to be associated with increased CVD events), varenicline and bupropion (no increased CVD risk so far). Varenicline is the most effective. FDA has removed the boxed warning on bupropion and varenicline since changes in mood, behavior and thinking were found to be much lower than previously thought after the results of recent clinical trial. Emphysema: Permanent destruction and enlargement of air spaces distal to the terminal bronchioles without fibrosis. Normal architecture is lost. Advanced emphysema in CXR is seen as hyperlucent, hyperinflated lung fields with flattening of the domes of the diaphragm. Lateral view shows retrosternal air space. High resolution CAT scan can © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 659 accurately diagnose emphysema. The severity of emphysema in CAT scan does not correlate with the degree of obstruction. Chronic bronchitis: Cough with sputum, not due to other causes on most days for at least 3 months/year for 2 consecutive years. CXR is usually normal. Sometimes thickened bronchi cut in the cross section known as ring shadows or increased bronchial markings at the lung bases called dirty chest x-ray can be seen. Persistent, severe, hypoxia due to COPD (PAO2 less than 60 mmHg) leads to pulmonary hypertension, erythrocytosis, limited exercise capacity, and impaired mentation. Significant hypercapnia can cause delirium and respiratory depression. Avoid hypnotic agents, anxiolytics, and narcotic agents in hypercapnic patients. Significant hypercapnia can be ruled out if the O2 sat is normal on room air (> 96%) If hypoxemia is present, then ABG is required to diagnose and quantify hypercapnia. Hypercapnia is seen when FEV1 falls below 1 liter in the absence of respiratory depressants. Alpha-1 antitrypsin deficiency: COPD developing at young age, i.e., < 45 years of age, with strong family history without significant cigarette smoking suggests this disorder. Z-allele causes production of protein that is not transported out of the liver. Homozygous ZZ has a serum alpha-1 antitrypsin level of 10 to 15% of normal and predisposes the patient to emphysema. Cirrhosis of the liver develops in some patients. Heterozygotes with MZ have serum alpha-1 antitrypsin level at 50% of normal and they are not predisposed to development of emphysema. Weekly infusion of alpha-1 antitrypsin at a dose of 60 mg/kg has been shown to slow the rate of decline of lung function and improve survival. Candidates for this infusion are patients with alpha-1 antitrypsin deficiency with moderate airflow obstruction. WHO recommends screening all patients diagnosed with COPD for alpha 1 antitrypsin deficiency, especially in areas with high prevalence. D/D of COPD: Asthma, CHF, bronchiectasis, TB, obliterative bronchiolitis, diffuse panbronchiolitis Management of COPD per GOLD guidelines: REFER TO GOLD GUIDELINES GOLD guidelines recommend assessing various aspects of COPD separately: 1. Symptoms: Use COPD assessment test (CAT) or COPD Control Questionnaire (CCQ). 2. Spirometric Grade. FeV1/FVC must be < 70% GOLD 1: Mild - FEV1 ≥ 80% of predicted. GOLD 2: Moderate - FEV1 ≥ 50%, but < 80% of predicted. GOLD 3: Severe - FEV1 ≥ 30% but < 50% of predicted. GOLD 4: Very severe - FEV1 < 30% of predicted 3. Exacerbations: ≥ 2 or ≥ 1 that led to admission to hospital/year (E) or 0-1 © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 660 exacerbations that did not need hospital admission/year (A and B) 4. Comorbidities: Cardiovascular disease, anxiety/depression, osteoporosis, metabolic syndrome, skeletal muscle dysfunction, and lung cancer. Diagnose COPD by Spirometry (FeV1/FVC < 70%). The severity of airflow limitation is assessed by spirometry FeV1 (grade). Symptoms are assessed by the CCQ or CAT. Then history of exacerbations should be assessed. Patients are then classified into 3 groups: A, B, E using the symptom scale and exacerbations, and their Grade is based on airflow limitation (GOLD 1, 2, 3 and 4) Exacerbations Combined assessment based on symptom score and exacerbations ≥ 1 that led to hospitalization (or) E ≥ 2/year 0-1/year No hospital A B admissions CAT < 10 CAT ≥ 10 (Symptom Score by CAT) Management of COPD can be divided into management of stable COPD and management of acute exacerbations of COPD (per GOLD guidelines). Management of stable COPD: 1. Vaccinations: Influenza vaccination yearly reduces the risk of lower respiratory infections requiring admission and reduce mortality in COPD. Pneumovac is recommended for COPD patients (reduces CAP and exacerbations, Prevnar 20 or Prevnar 15 + PPSV 23). Tdap: COPD patients not vaccinated as adolescents. Zoster vaccine for age ≥ 50, COVID-19 vaccine per recommendations. RSV vaccine for age over 60. 2. Smoking Cessation (All stages) 3. Pulmonary rehabilitation: Decrease symptoms and improves quality of life (stages B-E) 4. Pharmacological therapy: Systematic review has shown that bronchodilators/ICS used to treat COPD decrease decline in FEV1, compared to placebo. Inhaled bronchodilators are the mainstay of treatment. 1. Group A: A bronchodilator - short or long acting, preference to long acting. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 661  2. Group B: LABA + LAMA. 3. Group E: LABA + LAMA (LABA + LAMA + ICS if Eosinophil ≥ 300) Short acting bronchodilator to be prescribed for all patients for symptom relief. After starting treatment – Review (symptoms, exacerbation), assess (inhaler technique, adherence, non-pharmacological aspects), adjust (pharmacological therapy – escalation/de-escalation). Assess whether the predominant problem is dyspnea or exacerbation. 1. Dyspnea: LABA or LAMA should be made LAMA + LABA. Consider inhaler device switch/molecule switch. Implement/escalate nonpharmacological therapy. W/U and management of other causes of dyspnea. 2. Exacerbations: 1. If on LAMA or LABA à Switch to LABA + LAMA or to LABA + LAMA + ICS for eosinophils ≥ 300. 2. If eosinophils ≥ 100 + exacerbations on LABA + LAMA, switch to LABA + LAMA + ICS. 3. If eosinophils < 100, after LAMA + LABA, proceed to add roflumilast (for FEV1 < 50% + chronic bronchitis) or proceed to add azithromycin (former smokers). Difference: No ICS if eosinophils < 100. 4. If eosinophils ≥100 or ≥300 also, after LABA + LAMA + ICS add roflumilast/azithromycin for the same indications. After each step, assess the response to treatment, adjust medications and review. ICS should always be given if COPD patients have h/o asthma. While on LABA + LAMA + ICS, de-escalate ICS if pneumonia or other significant side-effects occur. H/O mycobacterial infections: No ICS. In COPD, ICS is always part of triple therapy (LAMA+LABA+ICS), and single triple therapy inhaler is preferred. If a COPD patient has been on LABA + ICS, and well controlled (no dyspnea/exacerbations), then continuing LABA+ICS is an option, but if they have symptoms à switch to LABA+LAMA, if they have exacerbations, escalate to LABA+LAMA+ICS if eosinophils ≥100, and change to LABA+LAMA if eosinophils are < 100. Non pharmacological treatments in COPD per group: Group A: Smoking cessation, physical activity, vaccinations as above. Groups B-E: Smoking cessation, physical activity, vaccines + Pulmonary Rehabilitation © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 662 Medications available to treat COPD: BRONCHODILATORS: Anticholinergics: Short acting (SAMA): Ipratropium, oxitropium Long acting (LAMA): Tiotropium, Umeclidinium, Aclidinium, Glycopyrronium bromide, Glycopyrrolate, Revefenacin Beta agonists: Short acting (SABA): Albuterol, Levalbuterol, Fenoterol, Terbutaline Long acting (LABA): Salmeterol, Formoterol, Indacaterol, Arformoterol, Olodaterol Short acting combination bronchodilators: Albuterol + ipratropium Fenoterol + ipratropium Combination LABA + LAMA (long acting muscarinic agonists): Indacetrol + Glycopyrronium, Vilanterol + Umeclidinium, Formoterol + Aclidinium Formoterol + Glycopyrronium, Olodaterol + tiotropium Methylxanthines: Theophylline, Aminophylline Combination LABA + inhaled steroid: Formoterol + Budesonide, Formoterol + Mometasone, Formoterol + Beclomethasone Salmeterol + Fluticasone, Vilanterol + Fluticasone furoate Triple Combination (LABA + LAMA + ICS): Fluticasone + Umeclinidium + Vilanterol Beclomethasone + Formoterol + Glycopyrronium Budesonide + formoterol + glycopyrrolate PDE4 inhibitor: Roflumilast Mucolytics: Erdosteine, Carbocysteine, N-acetylcysteine Oral steroids Monotherapy with ICS should not be used in COPD. SABA + SAMA are superior to either of them alone in improving FEV1 and symptoms. LAMA reduces exacerbations/hospitalizations better than LABA. LABA + LAMA decreases exacerbations and hospitalizations better than monotherapy with either of them. Tiotropium increases exercise performance in pulmonary rehabilitation, improving its effectiveness. If there is an indication for ICS, use LABA + LAMA + ICS (single inhaler triple therapy) PDE 4 inhibitor, roflumilast has been shown to reduce COPD exacerbations requiring © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 663 systemic steroids in GOLD 3 and 4 patients with h/o exacerbations and chronic bronchitis. Roflumilast has side effects such as diarrhea, headache, weight loss, nausea. It is also associated with anxiety, insomnia and depression, and is contraindicated in liver impairment, and should not be used with cytochrome P450 inducers. UPLIFT study found that tiotropium appears to improve lung function and quality of life in moderate to severe COPD, and significantly reduced risk of COPD exacerbation without an impact on rate of FEV1 decline. UPLIFT study did not show an increase in cardiovascular risk or stroke. Azithromycin (250 mg/day or 500 mg 3x/week) was found to decrease exacerbations of COPD in moderate to severe COPD with h/o exacerbations. Azithromycin was associated with higher incidence of bacterial resistance, prolonged QT and decreased hearing. Less benefit in active smokers. No data to show benefit beyond 1 year. Pulmonary rehabilitation (stages B-E) includes exercise training, education, behavioral modification, and outcome assessment. Pulmonary rehabilitation has been shown to improve dyspnea and fatigue, reduce anxiety and depression, reduce hospital admissions, and improve health status and exercise capacity. Outpatient use of N acetylcysteine in stable COPD patients may reduce exacerbations (HIACE study). Regular mucolytic use reduces exacerbation in selected COPD patients. Treatments with evidence for reduction in mortality in COPD patients: LABA + LAMA + ICS (single inhaler triple therapy, IMPACT and ETHOS trials involving symptomatic patients with frequent and/or severe exacerbations), smoking cessation (Lung health study, asymptomatic or mildly symptomatic patients), Pulmonary rehabilitation (Systematic review of RCTs, in patients in whom rehab was started during or ≤ 4 weeks of discharge compared to no rehab), long term O2 (NOTT and MRC trials in patients with PaO2 ≤ 55 or < 60 with cor pulmonale), long term orNIPPV (Patients with marked hypercapnia with stable COPD, higher IPAP levels), lung volume reduction surgery (severe COPD with upper lobe emphysema with low functional capacity) Acute exacerbation of COPD: Exacerbation is diagnosed when dyspnea and/or cough and sputum worsen in < 2 weeks. Consider pneumonia, PE, heart failure (most common), MI/arrhythmia, pneumothorax/pleural effusion (less common). Exacerbation classification: Mild - Needs short acting bronchodilators only. Moderate: Needs short acting bronchodilators + antibiotics +/- oral steroids. Severe: Needs hospitalization or ER visit. Indications for hospitalization for exacerbation: Severe symptoms (confusion, drowsiness, decreased O2 saturation and significant dyspnea), acute respiratory failure, cyanosis, new peripheral edema, outpatient treatment failure of exacerbation, serious comorbidities, inadequate support at home. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 664 Hospitalized patients are classified as follows: 1. No respiratory failure: RR ≤24/min, HR < 95/min, without accessory muscle use, no encephalopathy, hypoxemia improves with O2 by mask at 24-35% FiO2, and no increase in PCO2. 2. Non-life threatening acute respiratory failure: RR > 24/min, use of accessory muscles, no encephalopathy, hypoxemia improves with supplemental O2 by mask > 35% FiO2, and presence of hypercarbia, PCO2 increased from baseline or PCO2 50-60 mm Hg. 3. Life threatening acute respiratory failure: RR > 24/minute, use of accessory muscles, acute encephalopathy, hypoxemia not improving with supplemental O2 by mask or FiO2 needed is > 40%, and hypercarbia with PCO2 > 60 mmHg or pH ≤ 7.25. Severe but non-life threatening exacerbation management: Assess: Severity of symptoms, CXR, ABG. Give O2, and measure serial ABG, VBG and pulse oximetry. Bronchodilators (combination SABA/SAMA with spacers or nebulizers), consider long acting bronchodilators when patient becomes stable, consider systemic steroids, antibiotics when signs of bacterial infection are present, need for NIPPV, and monitor fluid balance. VTE prophylaxis, treatment of associated conditions such as heart failure, PE etc. Duration of steroid and antibiotic: 5 days. Non-invasive ventilation (NIV) is the recommended first method of ventilation for acute respiratory failure when there are no contraindications. NIV improves gas exchange, and decreases work of breathing, need for intubation and length of stay. It improves survival. Antibiotic should be given for exacerbation of COPD when there is increase in dyspnea, increased sputum quantity and purulence (all 3 cardinal symptoms) or if increased purulence is one of the symptoms or if on NIPPV or mechanically ventilated. Choice: Based on local resistance. Usual initial empiric therapy is with Amoxicillin clavulanate, macrolide or tetracycline. If severe airflow limitation or mechanically ventilated, pseudomonas or other resistant gram negative may be present - then cefepime/ceftazidime or fluoroquinolone and culture sputum. Risk factors for death due to COPD exacerbation: Development of respiratory acidosis, associated significant comorbidities, and mechanical ventilation need. Admit to ICU: 1. Severe shortness of breath without adequate response to initial treatment 2. Altered mentation – lethargy, confusion, coma 3. Persistent or worsening hypoxemia (PaO2 < 40 mmHg) and/or severe/worsening respiratory acidosis (pH < 7.25) in spite of O2 and NIPPV 4. Mechanical ventilation 5. Unstable hemodynamically © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 665 NIPPV, Indications and exclusion criteria: INDICATIONS (Any one of the following) 1. Severe shortness of breath using accessory muscles, paradoxical abdominal motion, intercostal retraction 2. Respiratory acidosis (pH ≤ 7.35 and PaCO2 > 45 mmHg) 3. Persistence of hypoxemia in spite of O2 supplementation CONTRAINDICATIONS FOR NIPPV: 1. Respiratory arrest, refractory hypoxemia 2. Cardiovascular instability (hypotension/arrhythmia/MI) 3. Change in mental status, uncooperative patient 4. Increased aspiration risk 5. Thick or high amount of secretions 6. Recent facial or gastroesophageal surgery/trauma 8. Abnormalities of nasopharynx 9. Burns 10. Extremely obese patient Intubation is done if: 1. NIPPV failure/intolerance 2. Resuscitated cardiac/respiratory arrest 3. Decreased consciousness, agitation not controlled by sedation 4. Life threatening hypoxemia and cannot tolerate NIV 5. Significant aspiration or intractable vomiting 6. Unable to remove respiratory secretions 7. Hemodynamic compromise without response to fluids/pressors 8. Severe supraventricular and ventricular arrhythmias Measures to prevent further exacerbations after an acute exacerbation: Optimize bronchodilators (LAMA, LAMA, LABA+LAMA), ICS containing regimens (LABA + ICS + LAMA), roflumilast (per indication), vaccinations, long term macrolide antibiotic, use of N acetyl cysteine/carbocysteine in selected patients, smoking cessation, pulmonary rehab, lung volume reduction when applicable. F/U after discharge: 1-4 weeks, treatment regimen review and understanding, inhaler technique, O2 therapy reassessment, assess physical activity ability and if pulmonary rehab is needed, symptom severity, comorbidity status. When to consider CT chest in COPD: Patients with persistent exacerbations, disproportion between PFT findings and symptoms (other differential diagnoses), significant hyperinflation and air trapping with FEV1 < 45% (lung volume reduction and other interventions), meet criteria for lung cancer screening. Evaluate pulse oximetry or ABG prior to D/C to see if patient needs O2. Criteria for long-term oxygen therapy for stable COPD: © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 666 1. PaO2 ≤ 55 mmHg or oxygen saturation ≤ 88% on room air at rest with or without hypercapnia, confirmed twice over 3 weeks. 2. PaO2 > 55 but < 60 mmHg or O2 sat 88% + pulmonary HTN, edema suggesting CHF or hematocrit > 55% (right heart failure or erythrocytosis) Reevaluate after starting O2 in 60-90 days to see if O2 sat is therapeutic and if O2 is still needed. Goal for O2 therapy is O2 saturation ≥ 90%. For patients with stable COPD and only moderate resting oxygen desaturation (O2 sat 89-93%) or only moderate exercise induced desaturation (O2 sat 80-89%), O2 should not be routinely prescribed. Patients with moderate exertional desaturation (80-89%) had no survival benefit when given oxygen in the LOTT trial. The INOX trial showed that nocturnal O2 supplementation had no survival benefit in patients with isolated nocturnal hypoxemia (OSA patients excluded), but the trial was underpowered, so cannot definitively rule out benefit. Noninvasive positive pressure ventilation + O2: Improves survival and decreases hospitalization after recent hospital admission in patients with persistent daytime hypercapnia (PaCO2 ≥ 53 mmHg) Other treatments: Lung volume reduction surgery: Only for patients with upper lobe emphysema with low baseline exercise capacity. Surgical bullectomy (for large bulla), and bronchoscopic interventions to decrease end expiratory lung volume, improve exercise tolerance, quality of life and lung function (endobronchial valves, lung coils, vapor ablation) are other options. Lung transplant is an option in the management of very severe COPD USPSTF does not recommend screening for COPD in asymptomatic adults. Emerging concepts/treatments in COPD: Eosinophil directed prednisolone treatment for acute exacerbation of COPD, anti-eosinophil monoclonal antibody for COPD, other Phosphodiesterase inhibitors. Bronchiectasis Bronchiectasis: Abnormal, permanent dilatation of bronchi. This may be focal or diffuse. Bronchiectasis is due to infection destroying bronchial wall structural components. Clinical presentation: Persistent or recurrent cough and purulent sputum. 50% to 70% of the patients with bronchiectasis have hemoptysis. Physical exam: Leathery crackles, rhonchi, and wheezes. Clubbing occurs. Diagnosis is by high resolution CT scan. If there is central bronchiectasis, the diagnosis to consider is ABPA. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 667 Treatment of bronchiectasis: Eliminate an identifiable underlying problem, e.g., treatment of hypogammaglobulinemia with immunoglobulin, ABPA with steroids, and tuberculosis with anti-TB drugs. Improve clearance of secretions by chest physical therapy. Aerosolized recombinant DNAase is used for cystic fibrosis only. Control of infection and reversal of airflow obstruction: For patients with frequent exacerbations and daily cough and congestion, continuous antibiotics are used, frequently macrolides. Massive hemoptysis is treated with bronchial artery embolization or surgery. Lung Abscess: Necrosis and cavitation of lung parenchyma due to infection. Risk factors: Aspiration, periodontal disease, and alcoholism. Anerobic bacteria are the most common cause. Clinical features: Cough, purulent sputum, fever, chest pain and hemoptysis. Patients may be asymptomatic in slowly evolving anerobic abscess. Acute presentation is usually seen with aerobic bacteria (staph, klebsiella, gram-negatives). CXR and CT are useful for diagnosis. Treatment: IV ampicillin/sulbactam or carbapenem, for at least 4 – 6 weeks. If allergic to PCN, clindamycin or levofloxacin + metronidazole, deescalate per culture, if available. Surgery indications: No response to medical treatment, refractory hemoptysis or suspicion for malignancy. Cystic fibrosis Cystic fibrosis is the most common disorder that limits life expectancy in Caucasians. It is autosomal recessive. About 7% are diagnosed after age 18. About 40% of CF patients in US are adults. It is a multisystem disorder due to abnormal ion transport across the epithelial cells in various organs. Primary defect: Mutation in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene in chromosome 7 Features: Respiratory system: Chronic sinusitis, nasal polyposis, bronchiectasis, obstructive lung disease, pneumothorax, hemoptysis, chronic infections, clubbing, eventually respiratory failure/cor pulmonale GI: Distal bowel obstruction, exocrine pancreatic insufficiency leading to steatorrhea, cholestasis, cirrhosis Genitourinary: Azoospermia due to bilateral obliteration of vas deference Endocrine: Glucose intolerance/diabetes mellitus, premature osteroporosis Sputum microbiology in patients with cystic fibrosis: Initially: Haemophilus influenzae and Staphylococcus aureus, later Pseudomonas aeruginosa. After repeated antibiotic exposure, mucoid form of Pseudomonas aeruginosa Other organisms include Burkholderia cepacia, Alcaligenes xylosoxidans, Xanthomonas, © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 668 and Burkhloderia gladioli. Rarely, mucoid Proteus, E. coli, and Klebsiella are seen. ABPA can occur in CF. Nontuberculous mycobacteria are also identified. PFT: Initially increased ratio of residual volume to TLC. Later reversible and irreversible changes in FEV1 and FVC. Chest x-ray early on shows hyperinflation, in late stages shows bronchiectasis (ring shadows). Diagnosis: Made based on clinical suspicion, sweat chloride testing, CFTR mutation analysis, and nasal PD measurement (done when sweat chloride is borderline). Sweat chloride ≥ 60 mEq/L is abnormal. Treatment: Clearance of pulmonary secretion by chest percussion, high frequency oscillator vests, aerobic exercise, active cycle breathing, and flutter devices. Inhaled hypertonic saline has been found to restore mucus clearance and pulmonary function. Antibiotics are given for infection. Infection is suspected when there is increased cough and mucus production. Chronic suppressive antibiotic therapy with inhaled tobramycin or oral azithromycin, inhaled aztreonam for pseudomonas are used. Nebulized recombinant human DNAase is used to reduce the sputum viscosity, since 10% of secretions of CF patients is made up of DNA Patients frequently require inhaled beta-adrenergic agonist and inhaled anticholinergics. Inhaled steroids and chromolyn sodium are given. For pancreatic insufficiency, pancreatic enzyme replacement and fat-soluble vitamin supplementation is given. Bisphosphonates are prescribed for osteoporosis. CFTR modulator therapy is recommended for patients with CF with suitable mutations. Elexacaftor-Tezacaftor-Ivacaftor is a CFTR modulator to improve production and function of CFTR protein. These drugs improve lung function, quality of life and are well tolerated. Bronchiolitis Bronchiolitis is an acute or chronic cellular inflammation of the bronchioles. Acute bronchiolitis due to respiratory syncytial virus (RSV) is seen in infants. In adults, acute bronchiolitis can be idiopathic or related to infection with parainfluenza or adenoviruses, or drugs (e.g busulphan)/exposures (e.g vaping). The most common symptom is cough with or without airflow obstruction causing shortness of breath. Chest x-ray is often normal. PFT reveals reduced FEV1 and reduced FEV1/FVC. Management includes cough suppression, macrolides, and steroids. Bronchiolitis obliterans is a major life threatening complication after lung transplant (50% incidence). It is associated with high mortality. It is a form of chronic rejection. Risk factor: Frequency and severity of episodes of acute rejection. Treatment includes azithromycin, and immunosuppressive agents. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 669  Pulmonary hypertension Resting mean pulmonary artery pressure ≥ 20 mm Hg at right heart catheterization, with pulmonary vascular resistance ≥ 3 wood units and mean PCWP < 15 mmHg is pulmonary arterial HTN. WHO Classification of Pulmonary Hypertension: Group 1: Pulmonary arterial hypertension (PAH) Idiopathic Familial (e.g. BMPR2 mutation) Associated with PAH: Connective tissue diseases (e.g. scleroderma, RA, SLE) Congenital systemic to pulmonary shunt HIV Portal hypertension Drug and toxin induced (cocaine, amphetamine, fenfluramine) Other (Thyroid disorder, glycogen storage disease, Gaucher’s Hereditary hemorrhagic telangiectasia, hemoglobinopathies Chronic myeloproliferative disorders, splenectomy) Associated with significant venous or capillary involvement Pulmonary veno-occlusivedisease Pulmonary capillary hemangiomatosis Persistent pulmonary hypertension of newborn Group 2: Pulmonary hypertension due to left heart disease (pulmonary venous HTN) Left sided atrial or ventricular heart disease Left sided valvular heart disease Group 3: Pulmonary hypertension due to lung disease &/or hypoxemia COPD ILD Sleep disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities Group 4: Chronic thromboembolic pulmonary hypertension (CTEPH) Thromboembolic obstruction to proximal pulmonary artery Thromboembolic obstruction to distal pulmonary artery Non thrombotic pulmonary embolism (tumor/parasite/ foreign material) Group 5: Miscellaneous Sarcoid/histiocytosis X/LAM Compression of pulmonary vessels (tumor/adenopathy fibrosing mediastinitis) © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 670 Pulmonary hypertension due to intrinsic pulmonary vascular disease is pulmonary arterial hypertension-PAH (no left heart disease, chronic hypoxemic lung disease or thromboembolic disease). Clinical features: Gradual onset of dyspnea on exertion, fatigue, angina due to right ventricular ischemia, syncope/near syncope, and peripheral edema. Physical examination: Elevated JVD, decreased carotid pulse, palpable right ventricular lift, loud P2, right-sided S3 and S4, and tricuspid regurgitation, with congestive hepatomegaly. In late stages, there is peripheral cyanosis and edema. There is usually no clubbing. Features of underlying disease also can be seen. Chest x-ray shows enlarged central pulmonary arteries and clear lung fields. EKG shows right axis deviation and right ventricular hypertrophy. Echocardiogram shows right ventricular enlargement, and abnormal septal configuration consistent with right ventricular pressure overload. Work – up: A patient suspected to have PAH will need: Good first test: Echocardiogram CXR (CT/HRCT as per CXR and exam findings), EKG ECHO (good initial test that can suggest pulmonary hypertension) TEE PFT (with ABG), Polysomnography if indicated V/Q scan HIV serology ANA, RF, ANCA Liver function tests Hb electrophoresis if needed/other tests per indication Oxyhemoglobin saturation at rest and exercise BNP (higher level correlates with worse outcomes) Functional tests: 6 minute walk test The final diagnosis is made by Right heart catheterization, with vasoreactivity testing (especially for patients in group 1). Right heart catheterization is not needed in patients with clear cut left heart disease or pulmonary etiology to explain pulmonary HTN. Treatment of pulmonary hypertension: Pulmonary hypertension due to left heart failure should be treated with treatment of heart failure. Pulmonary HTN associated lung disease should be treated with appropriate lung disease treatment (COPD: oxygen/pulmonary rehab/symptomatic treatment of COPD, OSA: CPAP) Pulmonary HTN due to thromboembolic disorder should be treated with surgical thromboendarterectomy and anticoagulation. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 671 Pulmonary arterial hypertension (PAH) is treated with background therapy and disease specific therapy. It is treated by specialists in specialized clinics. Background therapies: Pulmonary rehabilitation, vaccinations (age appropriate, flu/pneumovac), treatment of edema with diuretics, oxygen, warfarin is no longer routinely used. Dihydropyridine CCB or diltiazem are usually given for patients with mild symptoms with excellent vasoreactivity during hemodynamic testing. The effect is not sustained long-term. (CCB are NOT FDA approved for treatment of pulmonary hypertension). Disease specific advanced therapies for PAH: Prostacyclin derivatives, endothelin receptor antagonists, stimulators of guanylate cyclase, phosphodiesterase 5 inhibitors. Prostacyclin analogues: Epoprostenol, treprostinil, iloprost, selexipag Endothelin receptor antagonists: Ambresentan, bosentan, macitentan Phosphodiesterase 5 inhibitors: Sildenafil (20 mg TID) and tadalafil (40 mg once a day) Stimulator of guanylate cyclase: Riociguat stimulates guanylate cyclase regardless of nitric oxide levels and increases cyclic GMP that causes vasodilatation. For Group IV and Group I Patients with progressive disease requiring parenteral therapy are referred for lung transplant. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 672  Interstitial lung disease (ILD) Interstitial lung diseases comprise a heterogenous group of diseases, both acute and chronic. ILD: Idiopathic interstitial pneumonias Idiopathic Pulmonary Fibrosis - IPF (UIP) Respiratory bronchiolitis associated ILD (RBILD) and Desquamative interstitial pneumonia (DIP) ` Nonspecific interstitial pneumonitis (NSIP) Cryptogenic organizing pneumonia (COP) Acute interstitial pneumonia (AIP) Lymphocytic interstitial pneumonia (LIP) Eosinophilic pneumonia Connective tissue disease related ILD (e.g. scleroderma pulmonary fibrosis/GPA RA/Good Pasteur’s/microscopic polyangiitis etc) Drug induced and iatrogenic ILDs (e.g. amiodarone, busulfan, cocaine) Granulomatous disease related ILDs (e.g. sarcoidosis, hypersensitivity pneumonitis) Inherited diseases causing ILD (e.g. familial IPF, tuberous sclerosis, Hermanski-Pudlak) Environmental and occupational exposure related ILDs (e.g. asbestosis, Farmer’s lung, bird fanciers’ lung, silicosis) Other miscellaneous ILDs (LAM, histiocytosis X, alveolar proteinosis etc) Common presentation for interstitial lung disease: Progressive exertional dyspnea and dry cough. (Some have acute presentation like Hamman Rich syndrome) Physical exam: Bilateral inspiratory crackles (this finding is less likely in sarcoidosis). Chest x-ray: Bilateral reticular, nodular, or reticulonodular pattern. Upper lobe predominant infiltrates: Sarcoidosis, hypersensitivity pneumonitis Lower lobe predominant: IPF, asbestosis Central lung: Sarcoidosis, pulmonary alveolar proteinosis Peripheral lung: IPF, COP, chronic eosinophilic pneumonia Detailed occupational, family, hobby, drug, bird, and environmental exposure history is needed for a patient with interstitial lung disease. PFT: Restrictive with diminished DLCO (sarcoidosis may show combined restrictive and obstructive features). There is oxygen de-saturation with exercise. High resolution CT scan: Imaging of choice to diagnose ILD. Lung biopsy (VATS) is required for final diagnosis. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 673 Idiopathic Pulmonary Fibrosis (IPF): IPF is usually seen in middle aged to older age. Up to 75% of patients with IPF are smokers. Presentation: Exertional dyspnea with a non-productive cough. Physical exam: Bilateral inspiratory (Velcro) crackles. Chest x-ray: Lower lobe predominant bilateral interstitial infiltrates. High resolution CAT scan reveals predominantly peripheral, sub-pleural, and reticular opacities in lower lung zones. Traction bronchiectasis and sub-pleural honeycombing can be seen in late stages. PFT: Restrictive pattern, decreased DLCO, hypoxemia worsened by exercise. Diagnosis: VATS lung biopsy. Characteristic clinical and CT findings, with exclusion of other known causes of diffuse parenchymal lung disease can lead to a diagnosis of IPF without lung biopsy. Histopathology: UIP (usual interstitial pneumonia) pattern. IPF is associated with 50% mortality at five years. Acute exacerbation (worsening of previously stable disease with hypoxia and bilateral lung infiltrates) is the common cause of death. IPF patients who develop vent dependent respiratory failure despite empiric therapy and without a reversible cause (infection, PE etc) should be offered comfort care. Lung transplantation has been shown to improve survival. 2 medications are approved for IPF, nintedanib and pirfenidone. Upon diagnosis of idiopathic pulmonary fibrosis, appropriate patients are referred for lung transplant evaluation (only treatment that improves survival in IPF). IPF comorbidities include GERD (manage GERD in IPF), combined pulmonary fibrosis and emphysema (increased risk of death in 5 years) pulmonary arterial HTN and lung cancer. NSIP: Nonspecific interstitial pneumonitis resembles IPF. Usually seen in younger patients with underlying connective tissue disease. Diagnosis is by lung biopsy. Prognosis is better than IPF. Smoking related ILD: Desquamative Interstitial Pneumonitis (DIP) and respiratory bronchiolitis associated ILD (RB-ILD): These are smoking related disorders. DIP: Cough and dyspnea. CXR and HRCT show diffuse ground glass opacity. PFT is restrictive. Treatment is stopping smoking and steroid. RB-ILD: Cough and dyspnea. HRCT shows patchy or diffuse ground glass opacity. PFT is normal or mixed obstructive/restrictive. D/C smoking and give steroids. Pulmonary Langerhans cell Histiocytosis, (histiocytosis X) is also smoking related. (young male smoker). Spontaneous pneumothorax is a frequent presentation. Insidious disease, with fatigue, weight loss, dyspnea, low grade fever, and cough. DI is a rare manifestation. PFT: Reduced DLCO, and a restrictive pattern. HRCT shows nodules and thin walled cysts in an upper lobe distribution. Smoking cessation is needed. AIP: Acute Interstitial Pneumonitis: This is the Hamman - Rich syndrome. Starts over 1- © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 674 3 weeks and it is like ARDS (ARDS of unknown etiology). It is a diagnosis of exclusion. Supportive care, including mechanical ventilation is given. > 50% mortality. Sarcoidosis: Sarcoidosis is a chronic multi-system inflammatory disorder. Affected organs have accumulation of T-lymphocytes and noncaseating granulomas. Predominantly affects the lung. African American women are the highest risk group for developing sarcoidosis. Other granulomatous diseases - TB, histoplasmosis, coccidioidomycosis, hypersensitivity pneumonitis, and berylliosis should be ruled out before sarcoid diagnosis. Two acute presentations: 1. Lofgren’s syndrome: Fever, erythema nodosum, and bilateral hilar lymphadenopathy. This is usually self-limiting. 2. Heerfordt syndrome: Uveitis, fever, and parotid swelling with facial palsy. These 2 classic syndromes of sarcoidosis do not need biopsy for diagnosis. Clinical features of sarcoidosis: Sarcoidosis is asymptomatic in many patients. Presentation can be acute with one to two weeks of symptoms or insidious over several months. Symptoms are usually due to lung involvement. Acute and subacute symptoms may include fever, fatigue, anorexia, weight loss, and pulmonary symptoms such as dyspnea, cough, retrosternal chest discomfort and/or polyarthritis. Lung involvement: Lung involvement is usually an interstitial lung disease. Crackles are infrequent. Large airways can be involved leading to wheezing and obstruction in PFT. Pulmonary arteritis can occur. Pleural involvement is rare (< 5% of the cases of sarcoidosis). If pleural involvement is present it leads to exudative, lymphocyte predominant pleural effusion. Chest x-ray findings are divided into four groups. Stage I: Hilar adenopathy only. Stage II: Hilar adenopathy plus parenchymal opacities. Stage III: Parenchymal opacities without hilar adenopathy. Stage IV: Parenchymal fibrosis Stage I is associated with acute or subacute reversible form of sarcoidosis like Lofgren’s syndrome. Lofgren’s has a benign course and is self-limiting. PFT in sarcoidosis is typical for interstitial lung disease with reduced lung volumes and reduced DLCO. Airflow obstruction can also be present and there may be a combination of findings for both restrictive and obstructive lung disease. BAL shows increased lymphocytes of Th1 subset of CD4 T-lymphocyte type. Biopsy © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 675 shows mononuclear cell granulomatous inflammation leading to noncaseating granulomas. Lymph node involvement: Common in sarcoidosis. Hilar and paratracheal lymph nodes are frequently affected. Peripheral lymphadenopathy can also occur. The nodes are usually non-matted, firm, rubbery, and nontender. Skin involvement: 1. Erythema nodosum: Tender red nodules on the shin. This usually spontaneously resolves leading to hyperpigmentation. 2. Skin plaques – purple raised plaques in the face, buttock, and extremities. 3. Maculopapular eruptions. 4. Subcutaneous nodules. 5. Lupus pernio – bluish purple, swollen, and shiny lesions on the nose, cheeks, lips, ears, fingers, and knees. Eye: Involved in up to 25% of the patients. 75% anterior uveitis and 25% posterior uveitis. Keratoconjunctivitis sicca can occur. Upper respiratory tract: Nasal mucosal involvement leading to nasal stuffiness. Epiglottis and area around the vocal cord can be involved. Bone marrow: Rare involvement leading to anemia, lymphocytopenia, neutropenia, and eosinophilia. Spleen is involved in 50% to 60% of the patients. Splenomegaly can occur. Liver: Isolated granulomatous hepatitis; cholestatic pattern with elevated alkaline phosphatase occurs (mimicking PBC). Renal: Mild proteinuria, sterile pyuria, concentrating and acidifying defects can happen. Noncaseating granulomatous interstitial nephritis is the classic lesion. Hypercalcemia due to elevated 1, 25 dihydroxy vitamin D produced by granuloma can lead to chronic tubulointerstitial nephritis, nephrocalcinosis and nephrolithiasis. Neurological: Seventh nerve palsy is a common feature. Optic nerve dysfunction can occur. Abnormalities of hearing, and pituitary and hypothalamus abnormalities can occur. Chronic meningitis and psychiatric manifestations are other involvements. Musculoskeletal: Bone cysts and arthralgias and frank arthritis mostly of large joints. Cardiac: Occurs in < 10% of the patients with sarcoidosis, but becomes the cause of death for > 50% of patients who develop cardiac sarcoid. Left ventricular wall involvement can lead to systolic dysfunction and congestive heart failure. Heart blocks are characteristic (CHF with heart blocks). Pericarditis can also occur. Endocrine: Central diabetes insipidus, and deficiency of one or more pituitary hormones. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 676 Exocrine gland involvement with parotid enlargement can occur. Diagnosis: For patients with symptomatic progressive disease and lung involvement, biopsy is done for diagnosis. Endobronchial US or transbronchial biopsy combined with EBUS can be used. Biopsy is also required if steroids are needed for treatment. Gallium scan and angiotensin converting enzyme level are not useful for diagnosis or follow up. Spontaneous remission in sarcoidosis: 60% to 80% of patients with stage I and 50% to 60% of stage II disease have spontaneous remission, but < 30% of patients with stage III disease undergo spontaneous remission. Management of sarcoidosis: Observation and follow up is done in patients who do not immediately need steroid therapy. This is due to the high degree of spontaneous remission in stage I and II disease. Treatment, if needed is done with steroids. Immediate treatment indications include severe ocular, neurological or cardiac involvement, severe hypercalcemia, symptomatic stage II or stage III disease, and progressive lung disease. For patients who are dependent on steroids, steroid sparing agents such as methotrexate, mycophenolate mofetil are used. Cutaneous sarcoidosis can be treated with administration of hydroxychloroquine. Acute exacerbation of pulmonary sarcoidosis is treated with low dose/short course (20 mg prednisone over a median of 21 days) steroid therapy. Arthritis and arthralgia are managed with NSAIDs and colchicine/MTX. Cryptogenic organizing pneumonia (COP): It is an idiopathic organizing pneumonia. Can be primary or secondary (related to conn tissue disease, drugs, malignancy) Onset: Fifth to sixth decade usually. Clinical presentation: Cough, fever, malaise, fatigue, and weight loss associated with infiltrates in CXR mimicking pneumonia (ground glass or consolidation). Exam shows inspiratory crackles in two-thirds of the patients. PFT shows restrictive defect and arterial hypoxemia. Recurrent and migratory pulmonary opacities are common, and patients frequently get two to three courses of antibiotics to try to treat typical and atypical pneumonia without response. High resolution CT: Patchy areas of consolidation. Definitive diagnosis is by VATS lung biopsy. Granulation tissue is seen inside small airways, alveolar ducts, air spaces. Surrounding alveoli have chronic inflammation. Once COP is diagnosed, the treatment is with prednisone 1 mg/kg per day for one to three months. This is lowered down to 40 mg per day for three months and then 10 to 20 mg per day for one year. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 677  Hypersensitivity pneumonitis Hypersensitivity pneumonitis: Acute, subacute, or a chronic granulomatous pneumonia due to cell mediated immune response to inhaled organic antigens (bird proteins, fungi, airborne bacteria, etc). Common disorders: 1. Farmer’s lung, 2. Bird fancier's lung, and 3. Chemical worker’s lung. Farmer’s lung is due to inhalation of thermophilic actinomyces. Bird fancier’s lung is due to inhalation of bird protein from feathers and droppings. Mycobacterium avium intracellulare causes hypersensitivity pneumonitis from hot tub exposure Clinical picture: Acute phase: Cough, fever, chills, malaise, and dyspnea 6-8 hours after exposure to antigen. Resolves within a few days if removed from further exposure. (Symptoms may progress to respiratory failure needing hospitalization). There is transient hypoxemia and elevated WBCs. Chest x-ray shows diffuse reticular infiltrates. PFT shows restrictive defect. Subacute phase: Progresses over several weeks. Usual symptoms are cough and dyspnea. This can progress to cyanosis. Severe shortness of breath requiring admission may occur. The subacute phase also resolves in weeks to months if there is no continued exposure. Chronic Phase: The chronic phase is due to continued exposure and is like pulmonary fibrosis. Systemic symptoms such as weight loss, fever, and fatigue, along with characteristic findings of interstitial fibrosis (dyspnea and bilateral crackles). Chest x-ray: Reticulonodular opacities and honeycombing. PFT: Restrictive with reduced DLCO. Serum antibody to inhaled antigens may be negative. Lung biopsy resembles UIP, with multinucleate giant cells Eosinophilia is not seen in hypersensitivity pneumonitis. Diagnosis: 1. Consistent symptoms, physical findings, PFT (restrictive, exercise induced hypoxemia), HRCT (upper lobe predominant opacities with mosaic attenuation and air trapping) 2. Exposure to a recognized antigen Management for acute and subacute phases: Stop the exposure. If symptoms are moderate-to-severe, steroid. Dose is decreased gradually after symptoms and chest x-ray abnormalities resolve. OSHA approved devices (pollen masks, personal dust respirators, air-stream helmets, ventilated helmets) that supply fresh inhaled air is needed if the patient cannot be removed from exposure. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 678 Chronic phase: Trial of prednisone/immunosuppressive agents. Refer for transplant. Pulmonary infiltrates with eosinophilia: ABPA, parasitic infestations, drug reactions, and eosinophilia-myalgia syndrome (known etiology). Loeffler's syndrome, acute and chronic eosinophilic pneumonia, Churg-Strauss syndrome, and hypereosinophilia syndrome. Eosinophilic Pneumonias: Simple eosinophilic pneumonia (Loffler’s syndrome): Episodic migrating lung infiltrates on CXR. Ascaris infection and drugs and fungi are implicated. Resolution occurs typically within 1 month. Acute eosinophilic pneumonia: Fever and respiratory failure, needing mechanical ventilation. BAL shows marked eosinophilia. It responds to steroid. Chronic eosinophilic pneumonia: Cough, fever, weight loss, sweats like pneumonia. Duration of symptoms: Days to weeks. Eosinophilia is seen. CXR: Subpleural, bilateral consolidation, predominantly upper lobe. The classic, “photographic negative of pulmonary edema” occurs in 60% of patients. Responds well to steroids. Radiation pneumonitis presents with fever, cough, and dyspnea. Usually starts 6 weeks after radiation. Symptoms progress over days to weeks. CXR shows alveolar infiltrates of the irradiated part of the lung. Usually resolves within 6 months. Moderate to severe cases are treated with steroids. Radiation fibrosis is an irreversible fibrosis of the lung occurring 1 – 2 years after radiation. E-cigarette and Vaping associated acute lung injury (EVALI) (EVALI can lead to respiratory failure and deaths) is implicated to be due to vitamin E acetate used as thickening agent in cannabinoid products. Pleural Diseases Pleural effusion: The best step in diagnosis of etiology of a pleural effusion is diagnostic thoracentesis, after a detailed H & P and CXR, unless the reason is obvious (typical CHF). This helps in differentiating the pleural effusion into transudate or exudate. Small pleural effusions in association with heart failure, pneumonia, and post cardiac surgery need not be tapped. Unexplained pleural effusions need thoracentesis, when the effusion is > 1cm between lung and chest wall on CXR. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 679 Light criteria for exudates: (Any 1 of the following) 1. Pleural fluid: serum protein ratio > 0.5, 2. Pleural fluid: serum LDH ratio > 0.6 3. Pleural fluid LDH > 2/3rd of normal upper limit If all 3 criteria are absent, then the fluid is a transudate. If the fluid is an exudate, further diagnostic steps include pleural fluid glucose, pleural fluid amylase, cell count and differential, culture and Gram’s stain, cytology, AFB staining, & PCR for TB-DNA. TB diagnosis is established by pleural biopsy. Elevated amylase in an exudative pleural fluid: Esophageal rupture, pancreatic pleural effusion, adenocarcinoma of lung (can secrete salivary like amylase) Exudative pleural fluid with low glucose: RA, empyema, malignancy, TB, Lupus pleurisy, esophageal rupture Lymphocytic exudative pleural effusion: Tuberculosis (characteristic features: high protein, no mesothelial cells), malignancy/lymphoma, chylothorax, RA, post CABG, sarcoid (pleural involvement is rare in sarcoid), trapped lung, yellow nail syndrome Pleural fluid with > 10% eosinophils more than 10%: Benign asbestos effusion, PE, parasitic/fungal diseases, hemothorax, pneumothorax, drugs (e.g. nitrofurantoin, PTU), EGPA, Lymphoma Exudates with high protein: Multiple myeloma/Waldenstrom’s, RA, TB The clinical scenario can often predict the etiology of transudative effusion. If bilateral pleural effusion in decompensated congestive heart failure does not improve with diuresis, thoracentesis is done. If a patient is clinically thought to have a transudate (CHF), but the pleural fluid has a criterion (high protein) for exudate, then the difference between protein or albumin levels in the serum and pleural fluid should be measured. If the protein gradient is > 3.1 g/dL or albumin gradient > 1.2 g/dL, then it is a transudate. A pleural fluid NT-proBNP > 1500pg/mL is diagnostic of effusion due to CHF. 5% of patients with ascites due to liver cirrhosis develop pleural effusion, usually right sided. Left-sided effusion, fever, pleuritic chest pain, or encephalopathy suggests need for thoracentesis and paracentesis to rule out SBP, or spontaneous bacterial empyema. Hepatic hydrothorax reaccumulates rapidly after thoracentesis. VATS to close the diaphragmatic defects or TIPS may be needed. Pleural effusion due to nephrotic syndrome is transudative, bilateral, small, and asymptomatic. In cases of asymmetric effusion, pleural pain, exudative effusion or shortness of breath, then pulmonary embolism must be ruled out. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 680 Exudative Pleural Effusion: Exudative pleural effusion is commonly due to bacterial or viral pneumonia, malignancy, and pulmonary embolism. Bloody effusion suggests malignancy or pulmonary embolism. Elevated neutrophils suggest para pneumonic effusion and elevated lymphocytes suggest tuberculosis or malignancy. If history and pleural fluid analysis do not suggest a specific condition, then pleural biopsy and cytological testing of fluid is done. Malignant effusion is due to metastatic cancer. 75% are caused by lung cancer, breast cancer, and lymphoma. Recurrent malignant effusion not relieved with thoracentesis can be managed by tube thoracostomy with talc (sclerosing agent) to prevent further re- accumulation. Intrapleural catheter can also be done for symptom relief. Talc pleurodesis and intrapleural catheter are equal in providing symptom relief. Talc pleurodesis needs chest tube and 4-7 in patient days. Intrapleural catheter can be done as outpatient, can be used to provide daily drainage based on symptoms, and it is associated with about 46% spontaneous pleurodesis. Mesothelioma: Mesothelioma is a primary tumor of the pleura, associated with asbestos exposure. Patients usually present with chest pain and dyspnea. Chest x-ray shows pleural effusion, pleural thickening, and shrunken hemithorax. Thoracoscopy or open pleural biopsy is usually needed for diagnosis. Surgery with chemotherapy and radiation aimed at cure may be done for young patients with non-metastatic disease. Others are treated for palliation. Tuberculosis: Tuberculous pleural effusion is the 2nd most frequent extrapulmonary site of TB after tuberculous lymphadenitis. Tuberculous pleural effusion is due to delayed hypersensitivity (type IV) reaction to TB protein in the pleural space. Tuberculous empyema is a chronic active infection of pleura due to direct extension of tuberculous infection, rupture of a cavity into the pleural space or by hematogenous spread. Negative PPD and spontaneous resolution of effusion do not rule out tuberculosis - Post primary TB pleuritis can resolve without treatment in several months, but often returns as pulmonary TB; therefore, pursue the diagnosis of TB pleurisy aggressively. Tuberculous pleurisy can present as an acute or subacute disease. Patients typically have pleuritic chest pain and dry cough. TB pleural effusion is usually unilateral and usually is not a large pleural effusion. Tuberculous pleural fluid is a lymphocytic exudate, with high protein. Mesothelial cells and eosinophils are absent. Diagnostic tests for TB include: 1. Pleural fluid adenosine deaminase < 40 IU/liter, virtually rules out TB pleural effusion. It is a good screening test. 2. Positive PCR to tuberculosis. Gold standard for diagnosis is biopsy of the pleura. Standard tuberculous multi-drug therapy is given for tuberculous pleural effusion. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 681 Tuberculous empyema requires surgical drainage in addition to medical therapy. Parapneumonic effusion and empyema: Exudative effusion: Most common is Parapneumonic effusion. Due to bacterial pneumonia, lung abscess or bronchiectasis. Parapneumonic effusions > 1cm (> 1cm between lung and chest wall on CXR) need thoracentesis. Indications for chest tube in parapneumonic effusion: 1. Loculated pleural fluid 2. Fluid pH < 7.2 3. Fluid glucose < 60 mg/dL 4. Fluid Gram’s stain or culture positive 5. Pus. Intrapleural tPA + deoxyribonuclease in empyema has been shown to improve drainage, decrease length of stay and reduce need for decortication. Urinothorax is seen in association with hydronephrosis. Patient has a transudate, but with acidic pH. Empyema with a high pH, e.g., 8 is due to Proteus empyema. Pneumothorax 1. Primary spontaneous pneumothorax (associated with apical subpleural blebs, though said to be no underlying lung disease) 2. Secondary spontaneous pneumothorax (presence of underlying lung disease) is seen in association with COPD, pneumonia, cancer, asthma, tuberculosis, eosinophilic granuloma, sarcoidosis, pulmonary fibrosis, recurrent emesis, rheumatological and immunological disorders, and drug induced disorders. 3. Traumatic pneumothorax 4. Tension pneumothorax has positive intrapleural pressure throughout the respiratory cycle. Initial management of large pneumothorax (regardless of etiology): Oxygen, emergent needle thoracostomy, chest tube placement. Primary spontaneous pneumothorax: Tall thin male smokers/marijuana smokers are the classic patients who develop apical pleural bleb rupture almost exclusively. Small pneumothorax (< 2 cm between lung and chest wall in CXR) can be treated with observation and serial CXR. If > 2 cm and associated with symptoms, simple aspiration is done, and chest tube is placed if it reaccumulates. About 50% of these patients have recurrent episodes. If lung does not expand or there is persistent air leak or if pneumothorax is recurrent, thoracoscopy with stapling of the blebs and pleural abrasion is done. Secondary spontaneous pneumothorax: Most cases are COPD related, causing significant respiratory compromise. Patients © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 682 should be admitted. Small (< 2 cm) and large (> 2 cm) are managed as for primary spontaneous pneumothorax, but even after 1 episode, definitive treatment with chemical pleurodesis, or thoracoscopic pleurodesis is needed. Most patients require tube thoracostomy. There is a high risk of recurrence. If there is inadequate re-expansion or persistent leak beyond 48 hours, VATS with bleb resection and pleurodesis is done. Pneumothorax in a tall, thin, young male smoker without HIV, with normal lung parenchyma after tube thoracostomy drainage is consistent with primary spontaneous pneumothorax. Pneumothorax in a young non-smoking female, consider pulmonary lymphangioleiomyomatosis (LAM). If a patient with pneumothorax has HIV risk factors, consider PCP pneumonia. If the chest x-ray done after resolution of pneumothorax shows lung disease, then high resolution CAT scan is done. Tension pneumothorax: Usually occurs during mechanical ventilation or during resuscitation. In tension pneumothorax, the intrapleural pressure is positive, leading to a decrease in venous return and reduction in cardiac output. The trachea is shifted to the opposite side, there are no breath sounds on the side of pneumothorax, and the percussion note is hyper resonant, hypotension occurs. Both peak and plateau pressures are increased in mechanically ventilated patients. As soon as clinical diagnosis is made, insertion of a large bore needle into the pleural space anteriorly through the second intercostal space is needed. If large amount of gas escapes from the needle, it confirms the diagnosis and provides rapid treatment. Tube thoracostomy should be done immediately. Chylothorax: Chylothorax is due to thoracic duct obstruction due to mediastinal adenopathy or injury due to surgery or trauma resulting in a milky pleural effusion. Pseudochylothorax can be seen in association with chronic tuberculous and rheumatoid effusion. True chylothorax has a triglyceride level > 110 mg/dL (except in malnourished/cirrhotic patients). Pseudochylothorax has high cholesterol. Lipid protein electrophoresis showing chylomicrons is the most sensitive test for diagnosis of chylothorax. Lymphangioleiomyomatosis is an ILD that can present with chylothorax, chylopericardium, chyloperitoneum, or chyluria, in addition to recurrent pneumothorax or chylopneumothorax. It is seen in premenopausal women and often misdiagnosed as asthma or emphysema. It can be associated with tuberous sclerosis. It is considered a low grade metastatic neoplasm that affects the lung. There is atypical pulmonary interstitial smooth muscle proliferation and formation of cyst,. It can cause dyspnea, cough, and chest pain. CXR shows diffuse reticulonodular opacities with hyperinflation. HRCT shows diffuse thin walled cysts. Elevated vascular endothelin growth factor-D is a specific marker for LAM. PFT can be obstructive or mixed. Progesterone and LHRH © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 683 analogues have been used, but lung transplant is done for suitable candidates. The disease can recur in transplanted lungs. Pneumoconiosis Coal worker’s pneumoconiosis: Simple: Asymptomatic. CXR: Bilateral small parenchymal nodules. Pathological finding of black dust macules in respiratory bronchioles. Complicated: Large fibrotic masses causing progressive massive fibrosis (PMF). There is progressive dyspnea, and cough. Crackles are heard on exam. PFT: Restrictive. Supportive care is given. Oxygen for hypoxia. Pneumovac and flu vaccine. Exposure to coal, silica and cadmium are risk factors for COPD. Silicosis: Silica exposure is associated with mining, stone cutting, stone, clay, glass, and cement manufacturing, foundry, and quarrying granite. Simple silicosis: Chest x-ray showing bilateral small nodular opacities. If there is no continued exposure, respiratory symptoms and disability do not develop. Less intense long term exposure causes small round opacities in the upper lobes. There is retraction and hilar adenopathy with eggshell calcification. Complicated silicosis with progressive massive fibrosis leads to disabling symptoms and severe pulmonary function test abnormalities. Symptomatic treatment is given. Diffuse interstitial fibrosis can occur. Silicosis with progressive massive fibrosis is associated with high-risk for TB due to macrophage abnormalities and distorted lung architecture. All patients with silicosis must be screened for latent TB and treated once active TB is ruled out. Acute silicosis can occur secondary to massive exposure acutely. This leads to an alveolar proteinosis like reaction in air spaces. There is sudden onset dyspnea. Chest x- ray shows diffuse haziness and ground glass opacities. Asbestos associated lung disease: Asbestos exposure can lead to pleural plaques, diffuse pleural thickening, rounded atelectasis, benign pleural effusion, mesothelioma, asbestosis, and lung cancer. Asbestosis refers to bilateral interstitial fibrosis of lungs. This is clinically like idiopathic pulmonary fibrosis. The threshold exposure for development of asbestosis is higher than the exposure necessary for development of pleural plaques. Asbestos exposure along with smoking increases the risk of lung cancer. For mesothelioma, smoking is not synergistic. Pleural plaque, the most common manifestation of exposure to asbestos is usually identified incidentally in CXR or CT. Occurs usually 20 years after exposure. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 684 Rounded atelectasis occurs due to in folding of visceral pleura leading to collapse of the adjacent lung. Benign asbestos pleural effusion is hemorrhagic, exudative with eosinophils, and may cause pain. It usually resolves. Berylliosis: Berylliosis is associated with aerospace, computer and electronic applications, and manufacture of dental prosthesis. Berylliosis can be an acute or chronic form. Acute form happens after massive accidental exposure. Chest x-ray shows pulmonary edema pattern. Treated with steroid. Recovery usually occurs in one to six months. Mortality is 5 to 10%. Chronic beryllium disease mimics sarcoidosis. It is a granulomatous disease with skin lesions, granulomatous hepatitis, and hypercalcemia. Beryllium lymphocyte proliferation test is positive. Early treatment with prednisone can lead to regression of chronic beryllium disease. Byssinosis: This is an occupational asthma due to exposure to cotton dust. Treatment of Early stage: bronchodilators, antihistamines, and decrease/eliminate dust exposure. Physicians are frequently asked to assess disability from occupational lung disease in order to get disability payments. One should use already proscribed schema by agencies (e.g. Social Security). If no guidelines exist, use AMA guidelines. Pulmonary alveolar proteinosis: There is excessive accumulation of lipids and proteins in the alveolar space. The alveoli show granular eosinophilic debris. It is commonly an autoimmune disease with antibodies against GM-CSF, though there are other types. CXR shows ‘bat-wing’ distribution of alveolar opacities. HRCT shows crazy paving pattern. Treatment is total lung lavage. Administration of GM - CSF is off-label. Lithium: Hemodialysis is effective for patients with lithium toxicity who are in a coma, have seizures, or have progressive confusion, CNS depression, renal failure, or a lithium level of more than 8 millimoles per liter. Methemoglobinemia: Methemoglobinemia is caused by chemicals that can oxidize the hemoglobin’s ferrous state iron to the ferric state. Oxidation of hemoglobin causes its precipitation, leading to hemolytic anemia with Heinz bodies and bite cells. Aniline dye, nitrates, dapsone, and primaquine may cause methemoglobinemia. Methemoglobin does not carry oxygen, there is hypoxia and anaerobic metabolism. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 685 There is cyanosis but PaO2 measurement is high enough to normally saturate the hemoglobin (Cyanosis disproportionate to pulse ox). The cyanosis is unresponsive to oxygen. Methemoglobin level > 15% of total hemoglobin, leads to brown color of blood. The diagnosis is confirmed by measuring methemoglobin level. Emergency therapy is injection of methylene blue. Methylene blue is contraindicated in G6PD deficiency (causes hemolysis) and in patients taking SSRI (serotonin syndrome). In G6PD deficiency or SSRI, ascorbic acid is given. Salicylate toxicity: Salicylate toxicity results in vomiting, tachycardia, tachypnea, fever, tinnitus, lethargy, and confusion. Progressive toxicity leads to coma, seizures, respiratory, and cardiovascular collapse. Early on, there is respiratory alkalosis only. With moderate toxicity, there is a combination of respiratory alkalosis plus metabolic acidosis. Later, there is only metabolic acidosis. Serum salicylate level is done for diagnosis. There is also hypernatremia, hyperkalemia, and hypoglycemia. Treatment is with charcoal, supportive care, administration of glucose. Alkalization of urine for a pH of 8 is done (sodium bicarbonate) is needed. Hemodialysis also removes salicylates. Community-acquired pneumonia (CAP) Current ATS and IDSA guidelines CAP severity criteria: 1 major or ≥ 3 minor criteria à Severe CAP Major: 1. Septic shock with pressors 2. Mechanical ventilation Minor: 1. RR ≥ 30/min, PaO2/FiO2 ≤ 250, multilobar pneumonia, confusion, uremia (BUN ≥ 20), WBC < 4000, platelets < 100,000, temperature < 36, hypotension needing aggressive fluids. Gram stain and culture of sputum: 1. Not needed for outpatients and non-severe CAP in hospital. 2. Severe CAP, and for patients empirically going to be treated for MRSA/pseudomonas or hospitalized and got IV antibiotic within 90 days: Check pre-treatment sputum gram stain and culture. Blood culture: 1. Not needed for outpatients and non-severe CAP in hospital. 2. Severe CAP, and for patients empirically going to be treated for MRSA/pseudomonas or hospitalized and got IV antibiotic within 90 days: Get blood culture Legionella and Pneumococcal urine antigen test: 1. No need to order pneumococcal urine antigen 2. Legionella: Severe CAP, when epidemiological factors make legionella possible © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 686 Flu test: Get Rapid molecular test during flu season Procalcitonin: Procalcitonin need not be used for decisions. Treat pneumonia based on clinical + radiological diagnosis. Inpatient VS Outpatient treatment decision: Use clinical judgement and PSI (pneumonia severity index) ICU admission for pressors or mechanical ventilation. Antibiotic selection: 1. Outpatient: a. Healthy adults, no comorbidity or risk factors for antibiotic resistance: Amoxicillin 1g TID or Doxycycline 100 mg BID. Azithromycin 500 mg x 1 and 250 mg daily x 4 days only if pneumococcal resistance is known to be < 25% b. Comorbidities present (chronic heart/lung/liver/renal diseases, DM, alcoholism, malignancy, asplenia: Amoxicillin/clavulanate 875/125 BID or Cefpodoxime 200 BID or Cefuroxime 500 mg BID + macrolide (azithromycin or clarithromycin) or doxycycline if macrolide can’t be given. Another choice is Fluoroquinolone alone. 2. Inpatients: a. Non severe CAP w/o risk factors for MRSA/pseudomonas: Ampicillin sulbactam or cefuroxime or ceftriaxone or ceftaroline + Macrolide or doxycycline Another choice is fluoroquinolone alone b. In-patient severe CAP: Beta lactam + macrolide or Beta lactam + fluoroquinolone Aspiration pneumonia: Anerobic coverage is only needed for lung abscess or empyema. Otherwise use above guidelines Risk factors for MRSA/pseudomonas present (prior culture of these bacteria, recent admission to hospital and IV antibiotics within 90 days): Vancomycin or Linezolid + Cefepime or ceftazidime or piperacillin/tazobactam or aztreonam or meropenem or imipenem. If sputum culture does not yield those bacteria, then deescalate antibiotics. If MRSA nasal swab is available and negative, can discontinue MRSA coverage. Steroid in pneumonia: Guideline: Use in septic shock refractory to fluids and vasopressors (per sepsis guidelines from surviving sepsis). ARDS guidelines now recommend steroid in all ARDS severity (see below). A 2023 RCT of hydrocortisone (200 mg/day for 4 or 7 days based on clinical improvement and followed by 8 or 14 day taper Vs placebo) in addition to standard care in severe CAP (respiratory failure with the initiation of at least high-flow oxygen, ICU admission, and the absence of both septic shock and influenza) showed lower mortality by day 28 with hydrocortisone. Steroid (dexamethasone 6mg/day) is proven in COVID-19 pneumonia with hypoxemia. © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 687 Concomitant influenza with pneumonia: Add oseltamivir regardless of the duration of illness before diagnosis, in addition to antibiotic for CAP, if patients test positive for influenza. Duration of antibiotics: Clinical stability (based on HR, RR, BP, O2 sat), able to eat, normal mental status Minimum antibiotic duration: 5 days. Antibiotic given till patient achieves clinical stability, for a minimum duration of 5 days. Longer antibiotic course: Pneumonia + meningitis, endocarditis, or deep seated infections and for less common pathogens like burkholderia, fungi etc. For MRSA or pseudomonas suspected or proven: 7 days Follow up CXR after pneumonia treatment: If symptoms have resolved within 5-7 days, no need for routine follow up CXR. CXR is the first best test for pneumonia diagnosis, and in most patients, the only test needed. CT is useful in suspected post obstructive pneumonia. Ceftaroline is a broad spectrum fifth generation cephalosporin with invitro activity against S.pneumoniae, S.aureus including MRSA, and coliforms. It is now approved for CAP and skin and soft tissue infections. It does not cover pseudomonas or bacteroides fragilis. Pneumococcal vaccination: 2 types of vaccines are available: 1. Pneumococcal conjugate vaccines (PCV15, PCV20) 2. Pneumococcal polysaccharide vaccine (PPSV 23). Pneumococcal vaccination in adults: Average risk adults < 65 without chronic medical conditions do not need pneumococcal vaccine. Adults 19-64 years of age with risk factors: (all the risk factors are together now) 1. Alcoholism, smoking 2. CSF leak 3. Cochlear implant 4. Chronic cardiac conditions (CHF, cardiomyopathies etc) 5. Chronic lung diseases including asthma/COPD/emphysema 6. CKD 7. Chronic liver diseases 8. Asplenia 9. Congenital or acquired immunodeficiencies 10. DM © Geetha Krishnamoorthy 2021 Pulmonary Critical Care | 688 11. Malignancies 12. HIV 13. Lymphoma – NHL and Hodgkin’s and leukemias 14. Iatrogenic immunosuppression (including steroids) 15. Multiple Myeloma 16. Nephrotic syndrome 17. Sickle cell and other hemoglobinopathies 18. Post solid organ transplant If patients in the above categories have not received any previous pneumovac: PCV20 x1 (or) PCV15 followed by PPSV 23 1 year later (minimum 8 weeks between doses – for immunosuppressed patients, post cochlear implant or CSF leak) For patients in the above categories, who already had PPSV 23: Give 1 dose of PCV20 or PCV15 For patients in the above categories, who already had PCV13 +/- PPSV23: Give PPSV 23 per prior guidelines Age ≥ 65: If no prior pneumovac: PCV20 x1 (or) PCV15 followed by PPSV 23 1 year later (minimum 8 weeks between doses – for immunosuppressed pateints, post cochlear implant or CSF leak) If already received PPSV23: Give PCV20 or PCV 15 x 1 (At least 1 year after the PPSV23) If already received only PCV13: PPSV23 x 1 as per prior guidelines or give PCV20 x 1 if PPSV23 is not available Hospital Associated Pneumonia and Ventilator Associated Pneumonia: ATS/IDSA guidelines 2016 Pneumonia is defined as a “new lung infiltrate + clinical evidence that the infiltrate is infectious in origin” (fever, purulent sputum, leukocytosis, and decrease in oxygenation) HAP: Hospital associated pneumonia. Pneumonia ≥ 48 post admission and was not incubating at the time of admission. VAP: V