Updated 2020

COPD and Bronchitis

September 7, 2020 By Dr. G, PharmD

Chronic obstructive pulmonary disease (COPD) causes a significant amount of morbidity and mortality. It’s the fourth leading cause of death in the world.

COPD produces anatomical changes in the lungs that lead to narrowing of small airways, destruction of lung tissue, overproduction of mucous, reduced ciliary function, and airflow limitation.

Smoking is the most common cause. Other risk factors include pollution, second-hand smoke, occupational exposure, and lead poisoning. Other factors include age, frequent respiratory infections as a child, and genetic factors.

Asthma is a disease of inflammation. COPD is a disease of obstruction. Goblet cells make mucous to get particles out of the lungs, but cilia are paralyzed and can’t move it out. The mucous obstructs the airway. That’s why we use steroids in asthma as the first line to reduce inflammation, but not in COPD. Patients with COPD tend to get worse as the disease progresses.

Diagnosis by pulmonary function testing. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines are the accepted guidelines.

Comorbidities: pneumonia, stroke, lung cancer, heart disease
Chronic bronchitis usually degrades to emphysema with age.
Use Beta-blockers with caution (carvedilol is preferred)
Vaccinate for the flu and pneumonia, consider things like Tamiflu (oseltamivir) in this population
Consider smoking cessation.

Severity Scale:

A post-bronchodilator Fev1/FVC ratio of less than 0.7 (70%) confirms COPD. Patients are then classified as below.

Gold 1 (mild): Fev1 >=80% of predicted
Gold 2 (moderate): Fev1 between 50% and 79% of predicted
Gold 3 (severe): Fev1 between 30% and 49% of predicted
Gold 4 (very severe): Fev1 less than 30% of predicted

Remember, these are post-bronchodilator.

Assessment Tools:

CAT (COPD Assessment Test) is the best test to assess medications.
mMRC (Modified Medical Research Council dyspnea scale) is simple and not usually enough information. The scale is from 0 to 4 and assesses breathlessness
St George’s Respiratory Questionnaire (SGRQ) is too complex and not feasible in most clinical settings.
After assessment, use the ABCD tool to determine treatment
History of exacerbations is the most important factor in determining care.

ABCD Assessment:

Exacerbation History	Patient Symptoms mMRC 0-1 or CAT <10	Patient Symptoms mMRC 2 or CAT >=10
<=1 moderate excerabation (no hospitlization)	A	B
>= 2 moderate exacerbations or >- 1 leading to hospitilzation	C	D

COPD Gold Score	Initial Treatment Choices
A	Short-acting bronchodilator (SABA – short-acting beta-agonist or SAMA – short-acting muscarinic-agonist or combo)
B	LABA (long-acting beta-agonist) or LAMA (long-acting muscarinic-agonist)
C	LAMA or LAMA plus LABA or ICS (inhaled corticosteroid) plus LABA (LAMA is preferred: See POET trial)
D	LAMA or LABA (LAMA is preferred here too) *If CAT score is super high (~20) can start with LAMA + LABA, if eosinophil count is above 300 um, consider LABA + ICS (eosinophils mean inflammatory processes involved)

All patients should have short acting bronchodilator for rescue.

Long-acting bronchodilators should be used in anyone in B or above because they are superior to short-acting bronchodilators. You can use two different classes if you need more control. LAMAs are superior to LABAs in some groups See POET trial. ICS have very little to no benefit in patients without eosinophilia. If blood eosinophilias are less than 100 cells/um, don’t use them.

Unlike asthma, patients need a SABA and/or SAMA for rescue therapy. COPD is obstructive, so you don’t really need to reduce inflammation as you do in asthma (that recommends an ICS + formoterol for rescue). You need to dry secretions and dilate airways. A combo like Combivent is better than either alone.

If the response to initial treatment is appropriate, maintain it. If initial treatment is not appropriate, you need to consider the treatable trait to target. GOLD has two: dyspnea and exacerbations. They are very similar.

Gold considers LABA + LAMA the best combo in most cases. See FLAME trial. LAMA + LABA was superior to LABA + ICS.

Escalation for Dyspnea:

If on single long-acting bronchodilator (LABA or LAMA) add second from the other class OR consider changing to a more appropriate inhaler type (here is a good article on assessing what inhaler is right for which patient).
If on LABA + ICS, add LAMA or change to LABA + LAMA (especially if no indication for ICS)
If on LABA + LAMA + ICS, consider changing to a more appropriate inhaler type (here is a good article on assessing what inhaler is right for which patient) and/or removing ICS (especially if no indication for ICS)

Escalation for Exacerbations:

If on single long-acting bronchodilator (LABA or LAMA) and blood eosinophils are >300 cells/um or >100 cells/um and the patient has had at least 2 exacerbations or one hospitalization can change to LABA + ICS OR change to LABA + LAMA if they don’t meet the guidelines for ICS.
If on LABA + ICS, add LAMA or change to LABA + LAMA (especially if no indication for ICS)
If on LABA + LAMA, consider adding ICS if eosinophil count is >100 OR add roflumilast** if the patient has chronic bronchitis and FEVz <50% and eosinophil count <100 OR consider adding azithromycin if the patient is a former smoker* and eosinophil count <100
If on LABA + LAMA + ICS, consider removing ICS (especially if no indication for ICS) OR add roflumilast** if the patient has chronic bronchitis and FEVz <50% or R consider adding azithromycin if the patient is a former smoker*

*Benefit is the greatest in patients who don’t currently smoke. Former smokers can be colonized with h.influenza, azithromycin has some anti-inflammatory effects too
**Patients with a history of hospitalizations benefit most from roflumilast. Phosphodiesterase 4 inhibitor. COPD increases cyclic AMP levels. Decreases exacerbations, but no mortality benefit.

Corticosteriods in acute exacerbations only (not long term, bursts or acute).

This chart of medications can be found in the Gold Pocket Guide, Page 18

Acute bronchitis:

Usually caused by virus: rhinovirus, coronavirus, influenza virus, RSV
Can be caused by bacteria: mycoplasma pneumonia, chlamydia, pneumonia, bordetella, pertussis
Treatment:
- Bedrest, increase fluids
- APAP, NSAIDS, use cautions with antihistamines and decongestants (they increase the viscosity of secretions), dextromethorphan, codeine, Tessalon, and Tussionex
- If flu, can give Tamiflu or Relenza (Relenza causes bronchospasm) within 48 hours of symptoms.

Asthma

September 7, 2020 By Dr. G, PharmD

Asthma is pretty common. Over 25 million people in the US have it, and over 3500 people died from it in 2017. Hispanics and blacks suffer disproportionately. It’s a disease of chronic airway inflammation causing expiratory limitations including wheezing, chest tightness, shortness of breath, and cough. It can be spontaneous or triggered by exercise, allergens and irritants, or infections. Patients usually have more than one symptom. Isolated cough is usually not asthma. Exercise-related chest pain and shortness of breath need a cardiac workout.

The “Biodiversity hypothesis” states that exposure to microbes early in life provides protection against allergic and autoimmune diseases like asthma. Decreasing biodiversity is associated with increases in human immune disfunction.

Diagnosis is based on symptoms and pulmonary function tests and is most accurate before controller meds are initiated. Patients who have already been initiated should hold long-acting beta-agonists (LABA) for up to 2 days before PFTs and hold short-acting beta-agonists (SABA) for at least 6 hours. The FEV1/FVC ratio is a measurement of the amount of air you can forcefully exhale from your lungs. FEV1, or forced expiratory volume in one second, is the volume of breath exhaled with effort in that timeframe. FVC, forced vital capacity, is the full amount of air that can be exhaled with effort in a complete breath.

There are several different phenotypes of asthma: allergic asthma, non-allergic asthma, adult-onset asthma, asthma with persistent airflow limitation, and asthma with obesity.

Some guidelines break it into only two types: T-helper cell type 2 asthmas (Th2) and non-Th2. Th2 asthma is associated with poorer outcomes due to elevated immunoglobin. They also tend to have eosinophilia, elevated exhaled nitric oxide (FeNO), and more oral corticosteroid use. FeNo levels relate to eosinophils in the blood, but FeNO can be elevated for other reasons. Check for skin conditions like eczema first.

The Global Initiative for Asthma (GINA) recommends using FeNO >20 ppb as a factor when increasing ICS or considering a biologic. The American Thoracic Society (ATS) recommends using <25 ppb (20 for kids) as a determinant that eosinophilic inflammation is not likely. ICS response is less likely. A value of >50 ppb (30 for kids) means eosinophilic inflammation and ICS response are likely.

Asthma and COPD often overlap. They call this ACOS (asthma-COPD overlap syndrome). Here is a good pocket guide to the stepwise diagnose of all three syndromes.

The GINA guidelines are the most popular guidelines, but EPR-3 Guidelines are also used (I like this EPR-3 Pocket Guide).

GINA VS EPR-3

GINA has 2 treatment goals (risk reduction and symptom control), EPR-3 has 4 (reduce impairment, reduce risk of exacerbation, controlling symptoms, and preventing asthma-related death)
GINA has 5 treatment steps for 2 age groups (ages 5 and under and 6 and older), EPR-3 has 6 treatment steps for 3 age groups (0-4, 5-11, 12+)
GINA has 3 levels of severity, EPR-3 has 4
GINA favors formoterol as the long-acting beta-agonist (LABA) and requires lower doses of inhaled corticosteroids (ICS) than EPR-3.
In 2019, GINA changed to no longer prefer LABA-only rescue. They now prefer low-dose ICS plus formoterol (a LABA)

Levels of Control in EPR-3
Components	Well Controlled	Not Well Controlled	Very Poorly Controlled
Frequency of Symptoms	<2 days/week	> 2 days a week, but less than daily	Multiple times daily
Nighttime Awakenings	<2 times a month	1-3 times a week	>4 times a week
SABA used	<2 days a week	> 2 days a week	several times daily
Interferes with Normal Activities	none	minor	extremely limited
FeV1 / FVC	normal	normal or reduced <=5%	reduced >5%
FeV1 % of normal	> 80% normal	60-80% normal	< 60% of normal
Exacerbation requiring steroids	0 or 1/yer	>=2 / year	>=2 / year
Recommended step of therapy	Step 1 or Maintain current step Reasses in 1-6 month Consider Step Down If controlled for 3 mo	Step 2 or Step up 1 step Reassess in 2-6 wks	Step 3 and consider oral steroids or Consider oral steroids step up 1 to 2 steps Reassess in 2 weeks
Levels of Control in GINA
	Well Controlled	Partly Controlled	Uncontrolled
Daytime Asthma symptoms > 2 times per week, any nightime symptoms, reliever needed >2 times per week, any limits on activity	None in past 4 weeks	1 or 2 in past 4 weeks	3 or 4 in past 4 weeks
	Reasses in 2-3 months Can step down if well controlled	Step up one step Reassess in 2-3 months	Step up Reasses in 2-3 months unless exacerbation, then reassess in 1 week.

The preferred rescue inhaler is no longer albuterol with GINA 2019 (I know I already said this, but it flies against everything most of us were taught, so I’ll say it over and over again). An ICS formoterol combination is the rescue. Why formoterol? It takes 3-7 minutes to take affect (similar to albuterol). It’s a LABA (long-acting beta-agonist) that has the onset of a SABA (short-acting beta-agonist). You can’t just use any LABA as a rescue. It was also the studied drug.

Previously, it was believed that PRN LABAs could cause premature patient death. The SMART trial is responsible for this original black box warning. The AUSTRI (adults) and VESTRI (kids) studies showed no increase in asthma-related deaths. LABAs upregulate corticosteroid receptors and ICSes upregulate Beta receptors. They work synergistically (and that helps decrease steroid requirements). LABAs alone may cause Beta receptor downregulation. NO LABAs ALONE FOR ASTHMA.

Step 1:

GINA (Mild Asthma):

Low dose PRN inhaled corticosteroid (ICS) plus formoterol PRN or *Previous guidelines have not had PRN use of LABA.
Low dose ICS when SABA is taken
**You don’t schedule LABA until Step 3*** Controller is the same as rescue inhaler, everything is PRN.

EPR-3 (Intermittent):

SABA as needed

Step 2:

GINA (Mild Asthma):

Preferred rescue is ICS/formoterol still PLUS
Low dose ICS/formoterol PRN (same as step 1) OR
Low dose ICS alone OR
Leukotriene modifier OR
Low dose ICS when SABA is taken

EPR-3 (Mild Persistant):

Low dose ICS or
Leukotriene modifier
Theophylline
Cromolyn

Step 3:

GINA (Moderate Asthma)

Low dose ICS/LABA OR
Medium dose ICS OR
Low dose ICS + leukotriene modifier
Consider house dust mite sublingual immunotherapy for patients with allergic rhinitis and FEV1 >70% of expected
Preferred rescue is ICS/formoterol still, but you can use albuterol.
Patient shouldn’t be on two different ICS/LABA combos (ie: if you want to schedule a different LABA/ICS combo than ICS/formoterol, you would change the rescue inhaler to albuterol). You can use ICS/formoterol scheduled and PRN though.

EPR-3 (Moderate Persistant):

Low dose ICS + LABA or
Medium dose ICS or
Leukotriene modifier
Theophylline
Zileuton

Step 4:

GINA (Severe Asthma):

Medium dose ICS/LABA OR
High dose ICS (add on tiotropium or leukotriene modifier) *Tiotropium is only LAMA studied in asthma (bronchodilation and dries up secretions so more useful in COPD)
Consider house dust mite sublingual immunothearphy for patients with allergic rhinitis and FEV1 >70% of expected
Preferred rescue is ICS/formoterol still

EPR-3 (Moderate Persistant):

Medium dose ICS + LABA
Leukotriene modifier
Theophylline
Zileuton

Step 5:

GINA (Severe Asthma)

High dose ICS/LABA OR
Refer for phenotypic assessment (TH2 Asthma)
Can add add on tiotropium, anti-IgEm anti IL-5/5R, anti IL-4R
Consider low dose oral corticosteriods
Preferred rescue is ICS/formoterol still

EPR-3 (Severe Persistant):

High dose ICS + LABA
Consider omalizumab in patients with allergies

Step 6:

EPR-3 (Severe Persistant):

High dose ICS + LABA + oral steriods AND
Consider omalizumab in patients with allergies

Considerations when stepping up:

Inhaler technique. Is the patient getting their dose? Most MDIs must be shaken before use, pressurized MDIs require deep and steady inhalation, patients may breathe too slow or too fast or forget to hold their breath. Some inhalers are breath activated by they still require slow and steady inhalation. Spacers sometimes help. MDIs are just as effective as updrafts and offer fewer side effects. Watch the patient use the inhaler before stepping up. Consider switching types.
Adherence. Are they skipping doses?
Comorbidities (see below)
Overuse of SABA
Mood effects
Modifiable risk factors like smoking

Comorbities

GERD: some asthma medications (Beta-agonists and theophylline) worsen GERD leading to cough. Patients should be treated with PPI before stepping up.
Obesity: obese patients may have harder to control asthma due to lung strain and other comorbidities associated with obesity.
Sinusitis: Patients with T2 asthma tend to have sinusitis frequently. Treatment with nasal corticosteroids can help.
Pregnancy: Asthma worsens due to hormonal fluctuations during pregnancy. Budesonide is preferred in pregnancy. Pregnancy and asthma: Keeping vitamin D levels above 30 mg/mL decreases asthma risk in the fetus. Breastfeeding mothers should avoid broad-spectrum antibiotics during the first year of life.
Exercise-Induced Asthma: Patients should warm-up for 10-15 minutes, breathe through the nose, and use a facemask to create warmth and humidity to breathe.
Medications: NSAIDs can make asthma worse
Infections: Viruses like influenza can worsen asthma

Acute Asthma Exacerbations:

Steroids: no difference in oral vs IV – 80 mg of methylprednisone.
Magnesium sulfate if not responding to steroids (IV)
Racemic epinephrine either subQ or by nebulizer, use IV is not responding to initial albuterol.
Antibiotics are not usually given
Non-invasive ventilation with largest tube possible.

Step Down – Reduce steroid dose by 50% at 3-month intervals or switch to daily dose if on low dose.
Step Up – Increase ICS temporarily or add formoterol.
Exercise induced asthma: B-2 agonist, LABA for prevention
Use bronchodilator first and then ICS (open the bronchi for steroid)

Step Down

Once patient is controlled for 3 months of more, step down to see the lowest step where they remain control. You can decrease ICS dose by 25-50% every 2 to 3 months until they are back to step 1 or at the best level for the patient.

Medications:

GINA has moved away from SABAs (albuterol and levalbuterol) since SABAs do not reduce airway inflammation.

LABA:

formoterol
arformoterol
indracontrol
olodaterol
salmeterol

ICS:

You should probably be able to tell if an ICS dose is a low dose (all < 200) or high dose (all > 400) so you can recommend therapy changes.

Oral Corticosteroids: Oral corticosteroids should be the last option. Use 7.5 mg of prednisone equivalent or less for the shortest time possible.

Anticholinergics: Evidence shows that adding tiotripium to a ICS + LABA improves lung function and reduces exacerbations

aclindinium
glycopyralate
tiotropium
umeclidium

Leukotriene Modifiers: Useful in patients who can’t tolerate higher doses of ICS (maybe kids) or have allergic rhinitis. They can also help with exercise induced asthma.

montelukast sodium – Blackbox warning: suicidal ideations, mood changes.
zafirlukast
zileuton

Monoclonal Antibodies/Biologics: mostly reserved for patients with T2 Asthma, but can be used in step 4 and 5

expensive
Anti-IgE mAb for childhood-onset and allergen driven symptoms
Anti-IL-5/anti-IL 5R and anti-IL-4R for T2 type asthma
If patients don’t meet the criteria for a biologic or can’t afford one, adding tiotropium is an option.
Most common side effects are injection site reactions, headache, and antibody development.
Mepolizumab, benralizumab, and dupilumab can be given at home.

IgE:

Omalizumab (XOLAIR) inhibits IgE binding to receptors on mast cells and basophils.
Indicated in patients 6 years and older with moderate to severe asthma (can be used in child-onset).
Need a positive skin test to an allergen (looking for a specific IgE antibody and levels) and inadequate control with ICS.
Risk of anaphylaxis. It must be given in a health care setting. There is a slight increase in cardiovascular events associated with the drug, so screening is necessary.
Given every 2-4 weeks.

IL5/IL5RA:

Mepolizumab (NUCALA), reslizumab (CINQAIR), and benralizumab (FASENRA)
These target pathways that affect eosinophils, so are indicated only in patients who have elevated eosinophil count. Patients must have had an exacerbation in the past year and eosinophil count 300 per microliter of blood or more. Better responses if eosinophil count is higher or more exacerbations.
Better for adult-onset asthma and patients with nasal polyps present.
Mepolizumab can reactivate herpes zoster.
Benralizumab is only given every 8 weeks after 3 doses (others every 4 weeks)

IL4:

Dupilumab (DUPIXENT – also for atopic dermatitis) targets a receptor for two molecules that drive allergic inflammation.
Indicated for moderate to severe uncontrolled asthma.
The Liberty Asthma QUEST trial foundThe most benefits was in the patients who needed maintenance oral corticosteroids.
They need eosinophil count > 150 ul, a least one exacerbation in the past year.
Can cause hypereosinophilia
Given every 2 weeks

Clostridium/Clostridiodes Difficile

August 26, 2020 By Dr. G, PharmD

Clostridiodes difficile is a pretty big problem, causing quite a bit of morbidity and mortality every year, and it’s becoming more and more common. It can be pretty tricky to treat. C. diff is an anaerobic, spore-forming rod and it makes a toxin that contributes to the severity of the disease. It causes diarrhea and can end up in toxic megacolon/fulminant colitis requiring bowel resection, complete removal of the colon, or causing death. It contributes to tens of thousands of deaths a year.

Risk Factors:

Exposure to Antibiotics: This is the biggest risk factor. The ones that cause it the most are CLINDAMYCIN, FLUOROQUINOLONES, CARBAPENEMS, and 3RD or 4th GEN CEPHALOSPORINS. Even one dose in the past 8 weeks seems to increase risk. Exposure to more than 1 antibiotic increases risk.
Hospitalization (especially longer stays)
Age over 65
Cancer
IBD
Kidney Disease
Organ transplant
Liver disease
Immunodeficiency
Exposure to proton pump inhibitors

It’s not recommended to test everyone with diarrhea. You should only test patients with unexplained and new-onset ≥3 unformed stools in 24 hours who have risk factors. If you use screening criteria such as this, a nucleic acid amplification test (NAAT) is fine. Otherwise, you want to a multistep algorithm for testing (ie, GDH plus toxin; GDH plus toxin, arbitrated by NAAT; or NAAT plus toxin) rather than a toxin test alone. See the SHEA guidelines for treatment and testing.

C. diff is spread via the fecal oral route. Alcohol based cleaners don’t remove the spores. You need soap and water and a thorough hand cleaning.

Disease Severity:
Non-severe: WBC <= 15,000 and SCr < 1.5
Severe Disease: WBC 15,000-20,000 or more or SCr > 1.5
Fulminant: Presence of shock, hypotension, ileus or megacolon

Treatment Depends on Disease Severity.
It’s important to note that metronidazole used to be first-line therapy. It has fallen out favor in the 2017 guidelines. Vancomycin is considered the drug of choice, with some exceptions, now. Also, treatments used to be recommended for 14 days, however now most are only recommended for 10 days.

Discontinue therapy with the inciting antibiotic agent(s) as soon as possible.
First Episode:
- Non-severe
  - vancomycin 125 mg PO four times a day for 10 days OR
  - fidaxomicin 200 mg PO BID for 10 days OR
  - metronidazole 500 mg PO TID for 10 days (only if other two aren’t available)
- Severe
  - vancomycin 125 mg PO four times a day for 10 days OR
  - fidaxomicin 200 mg PO BID for 10 days
- Fulminant
  - vancomycin 500 mg PO four times a day AND 500 mg metronidazole IV every 8 hours for 10-14 days
First recurrence
- If previously treated with metronidazole: vancomycin 125 mg PO four times a day for 10 days
- If previously treated with vancomycin:
  - vancomycin 125 mg PO four times a day for 10 days THEN taper vancomycin 125 mg BID for 7 days then daily for 7 days, vancomycin once every 2-3 days for 2 to 8 weeks OR
  - fidaxomicin 200 mg PO BID for 10 days
- Consider adding bezlotoxumab 10 mg/kg IV one time dose to any of the above
Second or third recurrence
- vancomycin 125 mg PO four times a day for 10 days THEN taper vancomycin 125 mg BID for 7 days then daily for 7 days, vancomycin once every 2-3 days for 2 to 8 weeks OR
- vancomycin 125 mg PO four times a day for 10 days THEN rifaximin 400 mg BID for 20 days
- Consider fidaxomicin if not already given (fidaxomicin 200 mg PO BID for 10 days)
- Fecal transplant is an option
- Consider adding bezlotoxumab 10 mg/kg IV one time dose to any of the above

Bezlotoxumab is a newer agent. It’s a monoclonal antibody that neutralizes the toxin produced by C. diff. It can prevent damage to the colon, but it should not be used alone as treatment.

Fecal transplants are only reccomennded for those who have 2 or more reoccurances. Enemas are less effective than capsules or NG administration.

Proton Pump Inhibitors: The SHEA guidelines state: “Although there is an epidemiologic association between proton pump inhibitor (PPI) use and CDI, and unnecessary PPIs should always be discontinued, there is insufficient evidence for discontinuation of PPIs as a measure for preventing CDI.” Histamines receptor antagnoists have less association with C. diff.

Prophylaxis with vancomycin has been recommended in past guidelines, but the 2017 guidelines say there is insufficient evidence to recommend routine prophylaxis.