Managing COPD with Bronchodilators

Treatment of Persistent Breathlessness or Exercise Limitation

• For patients with persistent breathlessness or exercise limitation on bronchodilator monotherapy, using two long-acting bronchodilators is recommended.

Managing Exacerbations

• For patients with persistent exacerbations on bronchodilator monotherapy:
  • If blood eosinophil count ≥ 300 cells/μL, escalation to LABA+LAMA+ICS may be considered.
  • If blood eosinophil count < 300 cells/μL, escalation to LABA+LAMA is recommended.

Escalation Options for Persistent Exacerbations

• In patients on LABA+LAMA and still having exacerbations:
  • If eosinophil counts ≥ 100 cells/ml, escalation to LABA+LAMA+ICS may be considered.
• In patients on LABA+LAMA and eosinophil counts < 100 cells/μL who still have exacerbations, or patients treated with LABA+LAMA+ICS and still having exacerbations:
  • Adding roflumilast may be considered in patients with an FEV1 < 50% predicted and chronic bronchitis.
  • Adding azithromycin may be considered, especially in those who are not current smokers.

Treatment of COPD Symptoms

• For patients with occasional symptoms, either short- or long-acting bronchodilators are recommended initially.
• Short-acting bronchodilators are recommended for all patients as rescue or as-needed therapy to manage symptoms, regardless of category (A-E).

Short-Acting Bronchodilator Options

• Short-acting β2-agonists (SABAs) and short-acting muscarinic antagonists (SAMAs) are both effective options.
• Both SABAs and SAMAs have a rapid onset of action, relieve symptoms to a similar degree, and improve exercise tolerance and lung function.

Limitations of Short-Acting Bronchodilators

• Short-acting bronchodilators do not reduce the frequency or severity of COPD exacerbations.

Combining Short-Acting Bronchodilators

• If a patient does not achieve adequate symptom control with one agent, combining a SABA with a SAMA is a reasonable approach.

SABA Options and Administration

• Albuterol and levalbuterol are SABA options.
• Inhalation is the preferred route for SABAs.
• Administration via metered-dose or dry powder inhalers (MDIs, DPIs) is at least as effective as nebulization therapy and is more convenient and less costly.

Adverse Effects

• Rhythm disturbances can occur in predisposed patients, but are rare
• Skeletal muscle tremors can occur initially, but generally subside as tolerance develops
• Older patients may be more sensitive to the medication, experiencing palpitations, tremors, and “jittery” feelings

Ipratropium Bromide

Characteristics

• Ipratropium bromide is the most commonly prescribed SAMA
• Improvements in pulmonary function are similar to inhaled SABAs

Pharmacokinetics

• Slower onset of action (15–20 minutes) compared to albuterol (5 minutes)
• More prolonged effect compared to albuterol

Clinical Use

• May be less suitable for as-needed use due to slower onset, but is often prescribed in this manner

Side Effects

• Dry mouth is a frequent patient complaint
• Nausea is a frequent patient complaint
• Metallic taste is an occasional patient complaint

Long-Acting Bronchodilators

• Long-acting bronchodilators can be administered as either an inhaled long-acting β2-agonist (LABA) or muscarinic antagonist (LAMA).
• There is no dose titration for LABA or LAMA, meaning the starting dose is the effective and recommended dose for all patients.

LABA Formoterol

• Formoterol has an onset of action similar to albuterol.

Corticosteroids in COPD Treatment

• Combination therapy with ICS is beneficial for patients with COPD, while ICS monotherapy is not recommended.
• Short-term systemic corticosteroids may be used for acute exacerbations, but chronic systemic corticosteroids should be avoided due to high risk of toxicity and questionable benefits.

Roflumilast in COPD Treatment

• Roflumilast is a phosphodiesterase 4 (PDE4) inhibitor that relaxes airway smooth muscle.
• Roflumilast is recommended for patients with recurrent exacerbations despite treatment with triple inhalation therapy (LAMA/LABA/ICS) or dual therapy (LAMA/LABA) who are not candidates for ICS (eosinophil count <100cells/μL).

Chronic Azithromycin in COPD

• Chronic azithromycin is associated with a lower rate of COPD exacerbations, but also with increased colonization of macrolide-resistant bacteria and hearing deficits.
• Azithromycin product labeling includes a precaution about QT prolongation.

COPD Exacerbations

• A COPD exacerbation is defined as a change in a patient's baseline symptoms, such as worsening dyspnea, increased sputum volume, or increased sputum purulence, that warrants a change in management.
• Classification of COPD exacerbations:
  • Mild: managed with short-acting (SA) bronchodilators only
  • Moderate: managed with SA bronchodilators plus antibiotics and/or oral corticosteroids
  • Severe: requires hospitalization or emergency department (ED) visits

Guidelines for Chronic Azithromycin Use

• Current guidelines recommend considering chronic azithromycin only for patients with recurrent exacerbations despite optimal therapy, particularly in non-smokers.

Goals of Treatment

• Minimize negative consequences of acute exacerbation: reduce symptoms, prevent hospitalization, shorten hospital stay, prevent acute respiratory failure or death
• Prevent future exacerbations

Nonpharmacologic Therapy

• Provide oxygen therapy for patients with significant hypoxemia
• Use noninvasive positive-pressure ventilation (NPPV) for ventilatory support with oxygen using a face or nasal mask without endotracheal intubation
• Consider intubation and mechanical ventilation for patients failing NPPV or who are poor candidates for NPPV

Pharmacologic Therapy

• Three classes of medications commonly used for COPD exacerbations: bronchodilators, corticosteroids, and antibiotics

Bronchodilators for COPD Exacerbation

• Inhaled SABAs are recommended as the initial bronchodilators for acute treatment of COPD exacerbation due to their rapid onset of action.
• Muscarinic antagonists can be added to SABAs if symptoms persist despite increased doses of β2-agonists.

Administration of Bronchodilators

• Bronchodilators can be administered via MDI, DPI, or nebulization with equal efficacy.
• Nebulization is recommended for patients with severe dyspnea who are unable to hold their breath after actuation of an MDI.

Methylxanthines

• Methylxanthines are not recommended for COPD exacerbation due to their increased side effect profiles.
• I.V methylxanthines (theophylline or aminophylline) are not recommended due to significant side effects.

Corticosteroids in COPD Exacerbations

• The optimal corticosteroid dose and duration are unknown, but 40 mg of prednisone orally daily for 5 days is effective for many patients.

Antimicrobial Therapy in COPD Exacerbations

• Antibiotics should be initiated in patients with: • Three cardinal symptoms of acute exacerbation: worsening dyspnea, increased sputum volume, or increased sputum purulence. • Two cardinal symptoms, as long as one is increased sputum purulence. • Mechanical ventilation requirement, regardless of symptoms.
• The most common pathogens in COPD exacerbations include Streptococcus pneumoniae.

Empirical Treatment of COPD Exacerbations

• Initial empirical treatment typically involves an aminopenicillin with clavulanic acid, macrolide, tetracycline, or quinolone (in selected patients).

Duration of Antimicrobial Therapy

• Continue antimicrobial therapy for at least 5–7 days.

Monitoring Patient Response

• If the patient deteriorates or fails to improve as anticipated, hospitalization may be necessary, and more aggressive efforts should be made to identify responsible pathogens.

Evaluating Therapeutic Outcomes

In Chronic Stable COPD

• Assess pulmonary function tests annually and with any treatment additions or discontinuations.

In Acute Exacerbations of COPD

• Monitor white blood cell count, vital signs, chest x-ray, and changes in frequency of dyspnea, sputum volume, and sputum purulence at the onset and throughout treatment.

In More Severe Exacerbations

• Monitor ABG and SaO2 in addition to the above.

Tuberculosis (TB) Basics

• TB is a communicable infectious disease caused by Mycobacterium tuberculosis.
• TB can produce silent, latent infection, as well as progressive, active disease.

Epidemiology of TB

• In 2019, there were approximately 10 million new cases of TB and 1.2 million deaths from TB reported.

Transmission and Risk Factors

• M. tuberculosis is transmitted from person to person by coughing or other activities that cause the organism to be aerosolized.
• Close contacts of TB patients are most likely to become infected.
• Human immunodeficiency virus (HIV) is the most important risk factor for progressing to active TB.
• An HIV-infected individual with TB infection is over 100-fold more likely to develop active disease than an HIV-seronegative patient.

Complications of TB

• A massive inoculum of organisms may be introduced into the bloodstream, causing widely disseminated disease and granuloma formation known as miliary TB.

Clinical Presentation of TB

• Typical symptoms of TB include cough, weight loss, fatigue, fever, and night sweats, with gradual symptom onset.
• Frank hemoptysis is a late-stage symptom, but can occur earlier in the disease course.

Diagnosis of TB

• Sputum smear and chest radiograph are essential for TB diagnosis.
• Extrapulmonary TB clinical features vary depending on the affected organ system, but typically involve a slow decline in organ function, low-grade fever, and constitutional symptoms.

TB in HIV-Positive Patients

• HIV-positive patients may have an atypical TB presentation, with fewer skin test positives and fever.
• They have a higher incidence of extrapulmonary TB and are more likely to present with progressive primary disease.

Screening and Testing for TB

• The tuberculin skin test, using purified protein derivative (PPD), is the most widely used screening method for tuberculous infection.
• To isolate M. tuberculosis, attempts should be made to collect daily sputum samples over 3 consecutive days.
• Interferon-γ release assays can provide quick and specific results for identifying M. tuberculosis in the patient's blood in response to TB antigens.

Goals of Treatment

• Rapid identification of new TB cases
• Initiation of specific anti-TB treatment
• Eradication of M.tuberculosis infection
• Achievement of a noninfectious state in the patient, ending isolation
• Prevention of resistance development
• Patient adherence to treatment regimen
• Quick cure of patient (at least 6 months)

Isolation and Treatment

• Active disease patients should be isolated to prevent disease spread
• Drug treatment is the cornerstone of TB management
• Minimum of two drugs, generally three or four, must be used simultaneously
• Directly observed therapy (DOT) by a healthcare worker ensures treatment completion, considered the standard of care
• Treatment duration: at least 6 months, 18-24 months for multidrug-resistant TB (MDR-TB)

Additional Interventions

• Surgery may be necessary to remove destroyed lung tissue, space-occupying lesions, and some extrapulmonary lesions

Pharmacologic Therapy for Latent Tuberculosis Infection

• Chemoprophylaxis is recommended to reduce the risk of progression to active disease in patients with latent tuberculosis infection (LTBI).
• Three treatment regimens are recommended for LTBI:
  • 3 months of once weekly isoniazid plus rifapentine
  • 4 months of daily rifampin
  • 3 months of daily isoniazid plus rifampin
• The Centers for Disease Control and Prevention (CDC) recommends the 12-week isoniazid/rifapentine regimen as an equal alternative to 9 months of daily isoniazid for treating LTBI in otherwise healthy patients aged 12 years or older with a higher likelihood of developing active TB.
• Special considerations for patient populations:
  • Pregnant women, alcoholics, and patients with poor diets treated with isoniazid should receive pyridoxine (10-50 mg daily) to reduce the incidence of CNS effects or peripheral neuropathies.

Treatment of Culture-Positive Pulmonary TB

• Options for treatment of culture-positive pulmonary TB caused by drug-susceptible organisms are listed in Table 1.

Standard TB Treatment Regimen

• The standard treatment regimen consists of isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifampin for 4 months.
• Total treatment duration is 6 months.
• Ethambutol can be stopped if the patient is susceptible to isoniazid, rifampin, and pyrazinamide.

Initial Therapy and Drug Selection

• Appropriate samples should be sent for culture and susceptibility testing prior to initiating therapy for all patients with active TB.
• The data from these tests should guide the initial drug selection for the new patient.

Retreatment of TB

• If the patient is being evaluated for the retreatment of TB, it is essential to know what drugs were used previously and for how long.

Managing Drug Resistance

• When dealing with drug-resistant organisms, the goal is to introduce two or more active agents that the patient has not received previously to combat the resistance.

Avoiding Monotherapy

• It is crucial to avoid monotherapy or adding only a single drug to a failing regimen to prevent further resistance.

Suspecting Drug Resistance

• Drug resistance should be suspected in patients who have received prior therapy for TB.
• Geographic areas with high prevalence of resistance include South Africa, Mexico, Southeast Asia, the Baltic countries, and the former Soviet states.
• Patients with high-risk factors, such as being homeless, institutionalized, IV drug abusers, and/or infected with HIV, should be suspected of having drug resistance.
• Patients who still have acid-fast bacilli–positive sputum smears after 2 months of therapy may have drug resistance.
• Patients who still have positive cultures after 2–4 months of therapy may indicate drug resistance.
• Patients who fail therapy or relapse after retreatment may have drug resistance.
• Patients known to be exposed to MDR-TB cases should be suspected of having drug resistance.

MDR-TB

• There is no standard regimen for MDR-TB.

Special Populations

Tuberculous Meningitis and Extrapulmonary Disease

• Isoniazid, pyrazinamide, ethionamide, cycloserine, and linezolid penetrate the cerebrospinal fluid readily.
• Patients with CNS TB require longer treatment periods, typically 9-12 months.
• Extrapulmonary TB of soft tissues can be treated with conventional regimens.
• TB of the bone is typically treated for 9 months, with occasional surgical debridement.

Children

• Children with TB can be treated with regimens similar to those used in adults.
• Treatment duration may be extended to 9 months in some cases.
• Pediatric doses of drugs should be used.

Pregnant Women

• The standard treatment for pregnant women is 9 months of isoniazid, rifampin, and ethambutol.
• Pregnant women with TB should be cautioned against becoming pregnant again, as the disease poses risks to the fetus and mother.
• Isoniazid and ethambutol are relatively safe during pregnancy.
• Supplementation with B vitamins is crucial during pregnancy.
• Rifampin has been linked to rare birth defects, including limb reduction and CNS lesions, although these are occasionally severe.

Pregnancy and TB Medications

• Pyrazinamide: limited studies, but anecdotal evidence suggests it may be safe during pregnancy
• Ethionamide: associated with premature delivery, congenital deformities, and Down syndrome, and thus not recommended during pregnancy
• Cycloserine: not recommended during pregnancy
• Fluoroquinolones: should be avoided during pregnancy and nursing

Renal Failure and TB Medications

• Isoniazid and rifampin: do not require dose modifications in renal failure
• Pyrazinamide and ethambutol: typically require a reduction in dosing frequency from daily to three times weekly in renal failure

Evaluation of Therapeutic Outcomes

• Nonadherence to the prescribed regimen is the most serious problem with TB therapy
• Directly Observed Therapy (DOT) is the most effective way to ensure adherence
• Baseline and periodic monitoring of blood urea nitrogen, serum creatinine, aspartate transaminase or alanine transaminase, and complete blood count is recommended
• Hepatotoxicity should be suspected if transaminases exceed five times the upper limit of normal or total bilirubin exceeds 3 mg/dL, and the offending agent(s) should be discontinued and alternatives selected

Anemia Definition and Diagnosis

• Anemia is a group of diseases characterized by a decrease in hemoglobin (Hb) or the volume of red blood cells (RBCs), leading to decreased oxygen-carrying capacity of blood.
• The World Health Organization (WHO) defines anemia as:
  • Hemoglobin (Hb) less than 13 g/dL in men
  • Hemoglobin (Hb) less than 12 g/dL in women

Morphologic Classifications of Anemia

• Based on cell size, anemia can be classified into macrocytic, microcytic, or normocytic anemia

Macrocytic Anemia

• Characterized by larger than normal red blood cells
• Associated with deficiencies of vitamin B12 or folic acid

Microcytic Anemia

• Characterized by smaller than normal red blood cells
• Associated with iron deficiency

Normocytic Anemia

• Characterized by normal-sized red blood cells
• May be associated with recent blood loss or chronic disease

Iron-Deficiency Anemia (IDA)

• Characterized by decreased levels of ferritin (most sensitive marker) and serum iron, and decreased transferrin saturation
• Can be caused by:
  • Inadequate dietary intake
  • Inadequate gastrointestinal (GI) absorption
  • Increased iron demand (e.g., pregnancy)
  • Blood loss
  • Chronic diseases

Vitamin B12- and Folic Acid-Deficiency Anemias

• Characterized by macrocytic anemia
• Can be caused by:
  • Inadequate dietary intake
  • Malabsorption syndromes
  • Inadequate utilization

Vitamin Deficiency Anemia

• Deficiency of intrinsic factor leads to decreased absorption of vitamin B12, causing pernicious anemia.

Folic Acid Deficiency Anemia

• Folic acid deficiency can be caused by hyperutilization due to:
  • Pregnancy
  • Hemolytic anemia
  • Malignancy
  • Chronic inflammatory disorders
  • Long-term dialysis
  • Growth spurt
• Certain drugs can cause anemia by:
  • Reducing absorption of folate (e.g., phenytoin)
  • Folate antagonism (e.g., methotrexate)

Anemia of Inflammation (AI)

• Anemia of inflammation (AI) is a newer term encompassing both anemia of chronic disease and anemia of critical illness.
• AI is typically associated with:
  • Malignant processes
  • Infectious processes
  • Inflammatory processes
  • Tissue injury
  • Conditions releasing proinflammatory cytokines
• Serum iron levels are decreased in AI, but unlike iron deficiency anemia (IDA), serum ferritin concentration is normal or increased.

Clinical Presentation of Anemia

• Acute-onset anemia presents with cardiorespiratory symptoms, including palpitations, angina, orthostatic light-headedness, and breathlessness.
• Chronic anemia presents with weakness, fatigue, headache, orthopnea, dyspnea on exertion, vertigo, faintness, cold sensitivity, and pallor.
• IDA is characterized by glossal pain, smooth tongue, reduced salivary flow, pica, and pagophagia.
• Vitamin B12 deficiency can cause neurologic effects, such as numbness and paraesthesias, which may precede hematologic changes.
• Vitamin B12 deficiency can also cause psychiatric findings, including irritability, depression, and memory impairment.
• Anemia with folate deficiency is not associated with neurologic symptoms.

Diagnosis of Anemia

• Rapid diagnosis is essential because anemia is often a sign of underlying pathology.
• The severity of symptoms does not always correlate with the degree of anemia.
• Initial evaluation of anemia involves a complete blood cell count (CBC), reticulocyte index, and examination of the stool for occult blood.
• The earliest and most sensitive laboratory change for IDA is decreased serum ferritin (storage iron).

Macrocitic Anemias

• Mean corpuscular volume is usually elevated in macrocytic anemias
• Vitamin B12 and folate concentrations can be measured to differentiate between the two deficiency anemias

Iron-Deficiency Anemia (IDA)

• Serum iron is usually decreased in AI
• Serum ferritin is normal or increased in AI, unlike IDA
• Peripheral smear reveals normocytic anemia in AI

Treatment of Iron-Deficiency Anemia

• Goals: return hematologic parameters to normal, restore normal function and quality of life, and prevent long-term complications
• Oral iron therapy:
  • Recommended daily dosage: 150-200 mg elemental iron in 2-3 divided doses
  • Use soluble ferrous iron salts that are not enteric coated or slow/sustained release
• Iron absorption:
  • Best absorbed from meat, fish, and poultry
  • Administer at least 1 hour before meals, as food interferes with absorption
  • May administer with food to improve tolerability
• Parenteral iron:
  • Consider for patients with iron malabsorption, intolerance of oral iron therapy, or nonadherence
  • Available preparations: iron dextran, sodium ferric gluconate, iron sucrose, ferumoxytol, and ferric carboxymaltose
  • Similar efficacy, but different pharmacokinetics, bioavailability, and adverse effect profiles

Vitamin B12 Deficiency Anemia

• Oral vitamin B12 supplementation is as effective as parenteral supplementation, even in patients with pernicious anemia, due to the alternate vitamin B12 absorption pathway being independent of intrinsic factor.
• Parenteral therapy acts more rapidly than oral therapy and is recommended if neurologic symptoms are present.
• Vitamin B12 supplementation should be continued for life in patients with pernicious anemia.
• Daily oral cobalamin administration should be initiated after symptoms resolve.

Folate-Deficiency Anemia

• Oral folic acid supplementation of 1 mg daily for 4 months is usually sufficient for treatment, unless the underlying etiology cannot be corrected.
• If malabsorption is present, a higher dose of 1-5 mg daily may be necessary.
• Parenteral folic acid is available but rarely necessary.

Anemia of Inflammation

• Treatment should focus on correcting reversible causes, as it is less specific than that of other anemias.
• Iron therapy should be reserved for established iron deficiency anemia (IDA), as it is not effective when inflammation is present.
• Red blood cell (RBC) transfusions are effective but should be limited to cases where hemoglobin (Hb) levels are 7-8 g/dL.

Erythropoiesis-Stimulating Agents (ESAs)

• ESAs can be considered in anemia of inflammation (AI), but response may be impaired.
• Iron, cobalamin, and folic acid supplementation may improve response to ESA treatment.

Potential Toxicities of ESAs

• Increases in blood pressure, nausea, headache, fever, bone pain, and fatigue are potential toxicities.
• Hemoglobin (Hb) must be monitored during ESA therapy.

Hb Monitoring and Mortality

• Hb increases >12 g/dL with treatment or >1 g/dL every 2 weeks are associated with increased mortality and cardiovascular events.

Anemia of Critical Illness

• Parenteral iron may be used, but it carries a theoretical risk of infection.

Anemia in Pediatric Populations

Infants Aged 9-12 Months

• Ferrous sulfate: 3-6 mg/kg/day (elemental iron), divided once or twice daily between meals for 4 weeks.
• Continue for two additional months in responders to replace storage iron pools.

Vitamin B12 and Folic Acid

• Vitamin B12 dose and schedule should be titrated according to clinical and laboratory response.
• Folic acid: 1 mg daily.

Evaluation of Therapeutic Outcomes

Iron Deficiency Anemia (IDA)

• Positive response to oral iron therapy: Hb increase at 2 weeks.
• Hb should return to normal after 2 months; continue iron therapy until iron stores are replenished and serum ferritin normalized (up to 12 months).

Megaloblastic Anemia

• Signs and symptoms usually improve within a few days after starting vitamin B12 or folic acid therapy.