Asthma Diagnosis and Management

19% asthma

21% of African American students has asthma

40% of kids with asthmatic parents will develop asthma

Asthma is the most prevalent childhood chronic disease

A chronic inflammatory disease of the airways
- Chronic respiratory disease
- Inflammation and narrowing of small airways
- Airway hyper-responsiveness
-Reversible obstructive disease
*(Must be at least partially reversible)

- Wheezing
- Breathlessness
- Chest tightness
- Nighttime or early morning coughing
- Episodes or attacks

Cortisol levels drop 2 am, asthma worsens

- Environmental and genetic risk factors→
- Inflammation
a) Airway hyper-responsiveness→
b) Mucus and edema
- Obstruction
- Symptoms of breathlessness, feel like cant get enough air (previous slide)

Acute changes include:
- Plasma exudation (exudes- get more plasma and liquid part of blood causing the swelling)
- Desquamation of epithelium, cellular debris – (shed whole first layer)
- Edema (swelling)
- Mucus hyper-secretion and plugging (starting to secrete mucus)

Airway Remodeling - Pathological changes (Chronic changes) include:
- *Hyperplasia of mucus glands
- * Hyperplasia of smooth muscle (asking for more work so get more of us around)
- Hypertrophy and contraction
- Basement membrane thickening
- Subepithelial fibrosis (fibrotic = less flexible)
Angiogenesis (more blood vessels to the airway then more avail. And vicious cycle)

- Airway remodeling has significant role
- Prolonged inflammation in small airways →
a) Structural changes in airway wall → Airflow limitation
b) Changes are permanent
- 2 years of untreated or under-treated asthma → irreversible damage
- Occurs in mild → severe disease
a) Extreme variability of the disease
b) This point emphasized in EPR-3

2 years of untreated or under-treated asthma causes --> IRREVERSIBLE DAMAGE

Inflammation causes:
- Structural alteration
- Functional changes

Structural alterations include:
- Collagen deposition (bulking of the tissue)
- Airway smooth muscle hyperplasia

Functional changes include:
- Bronchospasm
-Hyper-responsiveness

Mast cells + Eosinophils- → Mediators- →
Histamine
Leukotrienes
Prostaglandins
Platelet activating factor
Enzymes
Cytokines

- African American
-White non-Hispanic
- Hispanic

African Americans are 3-4 x more likely to be hospitalized with asthma

African Americans are 4-6 x more likely to die

1) Genetic characteristics
- *Atopy, gender, race
2) Environmental exposures
- Indoor and outdoor allergens, drugs, occupational sensitizers
3) Contributing factors
- Smoking, infection
4) Triggers
- Allergens, infection, exercise

- > 3 episodes of wheezing in past year that lasted > 1 day and affected sleep
- Parent w/asthma
- Atopic dermatitis (excema)
- Allergic rhinitis (runny nose, baggy eyes)
- Wheezing apart from colds
- Peripheral blood eosinophilia (more eosinophils)
- GERD

1) Assessment and monitoring
2) *Control of contributing factors and risk factors (minimize)
3) Pharmacological therapy
- Stepwise approach
- Quick relievers
- *Long term controllers – Important understand rescue inhaler and controlled inhaler. Albuterol vs naso-crom
4) Patient Education

- Wheezing
- Coughing
- SOB
- Chest tightness

1) Symptoms
- Wheezing
- Coughing
- SOB
- Chest tightness
2) Pattern of symptoms
3) Severity
a) urgent care/ER visits
4) Family history

1) Cough, particularly at night
2) Awakened by coughing
3) Coughing or wheezing after physical activity
4) Breathing problems during particular seasons
5) Coughing, wheezing, or chest tightness after exposure to allergens
6) Colds that last more than 10 days
Why exacerbate? More cyclical response & snowball effect
7) Gold standard when making diagnosis **Relief when medication is used

- Audible wheezing
- Hyper-expansion of the thorax (muscles trying to move air through)
- Allergic rhinitis or nasal polyps
- Atopic dermatitis, eczema, or other allergic skin conditions

1) Allergic rhinitis
2) Cystic Fibrosis
3) Foreign body
4) Heart Disease
5) Tumor
6) Bronchiolitis
7) Vocal cord dysfunction
8) GERD

1) COPD
2) CHF
3) Ace Inhibitors
4) Mechanical airway obstruction
5) Pulmonary Embolism
6) Pulmonary infiltration
7) GERD
8) Alpha antitrypsin deficiency

Cough

Is the airway flow at least partially reversible --> because then give the medication!

Objective measure of lung function
Indirect measure of caliber size of airway lumen

Used to establish airflow obstruction:
- FEV1 < 80% predicted
- FEV1/FVC < 65% or below the lower limit of normal

*FEV1 increases > 12% and at least 200ml after using a short-acting beta2-agonist or short course of oral steroids  then yes, person has asthma/airway disease

Over time in EPR-3

1) At initial assessment- Pulmonary Function Test (PFT)
2) After treatment has stabilized symptoms- get a baseline
3) Every 6-12 months and PRN
a) Objective measurement of lung function
b) Patients typically under report symptoms and poor correlation to disease control as young kids have gotten use to symptoms

PEFR
PF
PFR
PEF
Wright’s PEFR

- Measure PEF upon awakening, before taking bronchodilator
- Use personal best

A PEF < 80% of personal best --> needs additional medication

- Check incentive spirometer and adjust as needed.
- Use the same peak flow meter over time

- Have patient stand
- Take big breath
- Close mouth over mouthpiece
- Blow out as hard and fast as possible
- Repeat 3 X
- Take the best measurement

- After stable
- *Measure in morning before meds
- Again in afternoon or evening
- Two weeks
- Average

- Spirometry not feasible for kids < 5 years
- Assessment is the same
- R/O alternative diagnoses
1) AR
2) CF
3) Foreign Body
4) Heart Disease
5) Tumor
6) Bronchiolitis
7) Vocal cord dysfunction
8) GERD

- *History- > 3 episodes of wheezing in past year
a) Lasted > 1 day
b) Affected sleep
- Parental history asthma or atopic dermatitis
- Allergic rhinitis, wheezing not associated w/URI
- Treat presumptively if unconfirmed
- Long term ~ ⅓ of kids who wheeze with respiratory infections develop asthma that persist > age 6

1) Determine and eliminate triggers when possible (talk w/young preg. Teen moms)
a) Review at each visit
b) Consider partnerships for patient education in community and schools (educate all parents)
2) Assess co-morbid conditions that affect asthma and attempt to eliminate or manage these
a) GERD (esp. in pregn. Like prilosec), sleep apnea, rhinitis/sinusitis, obesity, chronic stress/depression
A lot of swimmers have asthma not in dusty gym, or in fields

- Dust mites
- Cats, dogs
- Fungi/mold
- Cockroaches
- Tobacco smoke
- Formaldehyde, fragrances, cooking vapors, household cleaners
- Sulfite containing foods (bacon high in sulfites & nitrates)
- Fireplaces, wood burning stoves
- Humidifiers and swamp coolers

1) URI/viruses (RSV)
2) Cold air temperature (causing bronchospasm)
3) Exercise
4) Pollen, trees, weeds
5) Tobacco smoke

1) Use bedding encasements
2) Wash bed linens weekly
3) Avoid down fillings
4) Limit stuffed animals to those that can be washed
5) Reduce humidity level

Evidence exists of a causal relationship between environmental tobacco smoke exposure and exacerbations of asthma. (even if mom not smoking around kid can still cause reaction

Remove as many water and food sources as possible to avoid cockroaches.

1) People allergic to pets should not have them in the house.
2) At a minimum, do not allow pets in the bedroom.

Eliminating mold may help control asthma exacerbations.

1) Quick relievers (Rescue meds)
2) Long-term controller (Controllers or maintenance meds)

- Bronchospasm --> Relievers

- Inflammation --> Controllers

- Guides management
- Categorizing disease severity or control determines treatment course
- Based on clinical features
- Lung function
- Asthma control test scores

1) How often do you have daytime symptoms?

2) How often do you have nighttime symptoms?

Measured by:
1) Peak expiratory flow rate (PEF)
2) Forced expiratory volume in 1 second (FEV1)
3) Peak expiratory flow variability
4) Most asthmatics know personal best

- Classifying Asthma Severity and Initiating Treatment
- Assessing Asthma Control and - Adjusting treatment** new
- Stepwise Approach for Managing Asthma
- Children Aged ≤ 4 years
- Children Ages 5-11 years
- Youths Ages ≥ 12 Years and Adults

Intermittent:
Symptoms: 2 days/wk
Nighttime awakening: ≤ 2x/month
SABA use for sxs: ≤ 2 days/wk
Inference with normal activity: None
Lung Function: FEV1> 80% predicted
Risk needed oral steroids: 0-1/yr
STEPS: STEP 1

Mild persistent:
Symptoms: >2 days/wk, not qd
Nighttime awakening: 3-4 x/month
SABA use for sxs: > 2 days/wk not qd, no more than 1x/qd
Inference with normal activity: Minor limitation
Lung Function: FEV1 > 80% predicted
Risk needed oral steroids: ≥2/year
STEPS: STEP 2

Moderate persistent: QD
Symptoms: >1x/wk, not QD
Nighttime awakening: QD
SABA use for sxs: Some limitations
Inference with normal activity: Some limitations
Lung Function: FEV1>60% but <80%
Risk needed oral steroids: ≥2/yr
STEPS: STEP 3

Severe persistent:
Symptoms: Through the day
Nighttime awakening: Often 7x/wk
SABA use for sxs: Several times per day
Inference with normal activity: Extremely limited
Lung Function: FEV1<60% predicted
Risk needed oral steroids: ≥2/yr
STEPS: Step 4-5

Step 1= INTERMITTENT
Preferred:
1) Inhaled Short Acting Beta Agonist (SABA) (relaxes mucles)
a) Albuterol inhaler
(Albuterol vasodilates and increase HR and makes you feel like you have had 3 cups of coffeee)
Severe asthmatic and pushing often makes you feel like you are short of breath when pushing. Have them use rescue inhaler and when pushing they bled like stink afterwards.
Think about prostaglandins reverse the effect and reason they are bleeding out - when asthmatic.

Step 2 = MILD PERSISTENT
Preferred: Low-dose inhaled steroids (ICS)

Alternative is:
- Cromolyn
- Leukotriene modifier
- Nedocromil or theophylline

Step 3 = PERSISTENT
Preferred:
- Low dose inhaled steroids (ICS)+ long-acting beta2 agonist (LABA)
OR
- Medium dose ICS

Alternative:
- Low-dose ICS + leukotriene mod
- theophylline or zileuton

Step 4= Moderate Persistent
Preferred:
- Medium-dose ICS + long acting beta2- agonists LABA

Alternative:
- Medium-dose ICS + leukotriene receptor agonists (LTRA)
- Theophylline or zileuton

Step 5 & 6 = SEVERE PERSISTENT
(Not going to maintain these and this is primary care and we stay with Step 1 & 2 and beyond we refer.)

- NPs refer to pulmonologist or allergist
- High-dose ICS
- + LABA
- Consider omalizumab if patients have allergies
- Oral steroids

Yes, because patient needs them to breathe

1) Classify severity
2) Gain control

1) Classify severity: assign patient to most severe step in which feature occurs
- PEF is % of personal best
- FEV1 is % predicted

1) Gain control as quickly as possible, then step down to the least med needed to maintain control after 2-3 months
- Re-evaluate every 2 weeks
- May be able to step down sooner

Rules of two assess level of control
If they had to:
- Use of rescue inhaler 2 X a WEEK or less
- Awakened by asthma symptoms at night 2 times a month or less?
- Refill rescue inhaler 2 times per year or less?

If not done more then this then considered stable. How many times a week and how many times refilled. 4 or 5 because using it everyday then NOT in good control!

No, because they are using it everyday and not considered stable. Stable is when:
a) Rescue inhaler 2x/wk or less
b) Awakened by asthma sx 2x/month or less
c) Refill rescue inhaler 2x/yr or less

Patient self report-screening tool:
- Validated instrument, adults and peds version
- 5 questions with points
- Goal is score of 20
- EPR-3 new strategy

Metered dose inhaler (MDI)
Dry powder inhaler (DPI)
- Space-holding chamber
- Space-holding chamber and face mask
- Nebulizer

No, there is no evidence of significant difference in efficacy

- WHAT IS PATIENT MOST COMFORTABLE WITH?
- Consider patient preference
- Compliance
- Drug reimbursement
- Cost

The agent that forces the med from the inhaler when it is actuated

1) CFC
2) HFA
3) Advair
4) Albuterol inhaler
5) Nebulizer

CFC: chlorofluorocarbon
- Safe for people
- Harmful to ozone layer
- Removal from market in ? 2008

HFA: hydrofluoroalkane- (doesn’t have taste)
- Replacing CFC
- Will not change med or dose
- Different taste or feel
- Effectiveness not changed
- ? Cost

**Albuterol inhaler- 200 puffs per canister inhaler should LAST 6 MONTHS AND USING MORE THAN 6 MONTHS THAN NOT IN GOOD CONTROL

No, Albuterol inhaler- 200 puffs per canister inhaler should LAST 6 MONTHS AND USING MORE THAN 6 MONTHS THAN NOT IN GOOD CONTROL

1) Remove the cap from the end of the inhaler device.
2) Shake the inhaler device and ensure it is "primed" (sprays freely).
3) Hold the inhaler in front of your mouth but not inside of your mouth. 4) See image for correct spacing.
5) Exhale comfortably.
6) While depressing the silver canister within the inhaler device, take as deep of a breath as possible through your mouth.
7) Hold your breath for 5 to 10 seconds.
8) Repeat steps 2 through 6 if instructed by your doctor to take 2 puffs of medication from the spacer.

That the patient:
Shake make primed and in front of mouth. Inhale depress and inhale. Hold breathe for 5-10 SECONDS and repeat and take full 2 puffs

1) Spacers can help patient who have difficulty with technique and can reduce potential side effects
2) Wash spacers out because it aerolizes medication

1) Uses compressed air machine to deliver medicine as a mist
2) Good for small children or for severe asthma episodes

Used in acute asthma episodes and PRN

1) Generally they are short-acting beta₂- agonists
2) Anticholinergics
3) Systemic corticosteroids

Used as a quick relief (rescue med)
- Most effective med for relief of acute bronchospasm
- More than 2 times/week suggest inadequate control
- Regular use is not recommended-
- May lower effectiveness
- May increase airway hyper-responsiveness

- More than 2 times/week suggest inadequate control

Meds: Long-Term Control
Inhaled corticosteroids (ICS)
Fluticasone (Flovent), etc.
Long-acting beta₂-agonists (LABA)
Salmeterol (Serevent), Formoterol
Combination medication
Advair (Flovent and Serevent)
Leukotriene modifiers
Leukotriene receptor agonists (LTRA)
Montelukast (Singulair)
Leukotriene synthesis inhibitors (LTSI)
Zileuton (Zyflo)
Caution drug interactions, liver problems
Cromolyn/Nedocromil
(Tilade, Intal)
Methylxanthines
Theophylline

- Most effective long-term control for persistent asthma, vs
Cromolyn, nedocromil, theophyline, leukotriene modifiers

(Be aware of sm. risk for adverse events)

Reduce potential for adverse events by:
- Using spacer and rinse mouth
- Do not brush teeth immediately after use
- Using lowest possible dose
- Using in combination w/long-acting beta₂-agonists
a) Improved lung function
b) Improved symptoms
c) Less beta₂-agonists used

- Decreased growth velocity (1 cm)
a) Not sustained in subsequent years, not progressive, may be reversible, final predicted height attained in 10 year cohort study
b) Monitor growth

Children with mild or moderate persistent asthma due to Improved health outcomes

1) Bone mineral density: no adverse effects
2) Subcapsular cataracts: no effect
3) Glaucoma: no effect
4) Hypothalamic-pituitary-adrenal axis suppression: clinically insignificant effects

Benefits of daily use (3 months):
1) Fewer symptoms
2) Fewer severe exacerbations
3) Reduced use of quick reliever meds
4) Improved lung function
5) Reduced airway inflammation
6) Less urgent care visits and hospitalization
7) Less mortality (SMART Trial)

1) Not a substitute for anti-inflammatory therapy
2) Not appropriate for mono-therapy
3) Beneficial when added to corticosteroids
a) Advair diskus
4) Not for acute symptoms or exacerbations

Indications:
1) Long-term control therapy in mild persistent asthma
a) Improved lung function
b) Prevent need for short-acting beta₂-agonist
c) Prevent exacerbations

1) Regular follow-up visits
2) Review treatment every 1-6 months
3) Use the Asthma Control Test and PFT’s
4) A gradual step down may be possible

1) How many times in the past WEEK did you use albuterol?
a) Does the patient know which med is albuterol (Ventolin, Proventil)?
2) How many times in the past MONTH did you awaken with asthma (sxs)?
3) How many canisters of albuterol did you use in the past YEAR?

1) Step up if control is not maintained, check “ICE” first
I = inhaler technique
C = compliance
E = environment factors review
2) Consider infection
a) CAP, ABRS, viral
3) Patient education
4) Avoid or control triggers
5) Use of beta₂-agonist > 2/week =
a) Add controller med

1) Antibiotics are not recommended to treat acute asthma exacerbation
(In addition to regular meds)
2) No benefit when administered routinely
3) No benefit when suspicion of bacterial infection is low
4) Use to treat co-morbid conditions: ABRS, CAP, fever and purulent sputum

Step up therapy if patient:
- Awakens at night w/symptoms
- Has an urgent care visit
- Has increased need for quick reliever meds
- Uses beta₂-agonist > 2/week or 1/canister/month

Breathless at rest

Hunched forward

Talking in words rather than sentences

Agitated

Peak flow rate is less than 60% of normal

- Inhaled beta₂-agonist 2-4 puffs
- Nebulized albuterol
- Systemic corticosteroids
a) Burst therapy, 1 mg/kg/day
b) Usually 5-7 days, no taper needed
c) Take w/food, morning
- O2 sat monitoring → O2
- Serial PEF measurements
- MD consult/ ER

1) False, Asthma is the #1 cause of school absence for a chronic disease
AND
2) the most common disease addressed by school nurses

Mold and mildew
Animals in the classroom
Carpets in the classroom
Cockroaches
Air quality
Fumes and vapors
Smoke

- Policies and procedures for managing children with asthma
- Make medications available at all times:
a) During school hours
b) During pre-school and after-school programs
c) On field-trips or when away from campus

- Diagnosis unclear, need more testing
- Co-morbid complicating conditions
- Severe persistent in adults, consider for moderate persistent
- Kids < 3 years with moderate or severe persistent
- For patients not well controlled after 1 month (3 weeks-6 months)
- Candidate for immunotherapy
- Needed > 2 courses of steroids in 1 year
- Life threatening exacerbation

Who to refer to?
allergist, Pulmonologist

Who to refer to?
Allergist, Pulmonologist

The goal of all patient education is to help patients take the actions needed to control their asthma and have a normal life

- Control symptoms
- Prevent exacerbation
- Maintain lung function as close to normal as possible
- Maintain normal activity levels
- Avoid adverse effects from medications
- Prevent irreversible airway obstruction
- Prevent asthma mortality
- Manage co-morbid conditions affecting asthma (AR, GERD, obesity)

1) Basic facts about asthma
a) Normal vs. asthmatic airways

2) Role of meds
a) Long-term control vs. quick reliever meds

3) Skills
a) MDI, DPI, spacers, PEF

4) Triggers, Environmental control measures

5) How and when to take rescue actions

1) National asthma education & prevention program
2) Asthma and allergy foundation of american
3) American Lung Association
4) American Academy of Allergy, asthma & Immunology

- Genetic characteristics
a) Atopy (predisposition toward developing certain allergic hypersensitivity reactions)
b) Gender M > F
c) Race (African American)

- Environmental exposures
a) Indoor & outdoor allergens, drugs, occupational sensitizers

- Contributing Factors
a) Smoking, infection

- Triggers
a) Allergens, infection, exercise

- Wheezing
-Breathelessness
-Chest tightness
- Nighttime or early morning coughing
(Occurs at night because cortisol levels drop 2 am, asthma worsens)
- Episodes or "attacks"

INDOOR ASTHMA TRIGGERS:
Dust mites
Cats, dogs
Fungi/mold
Cockroaches
Tobacco smoke
Formaldehyde, fragrances, cooking vapors, household cleaners
Sulfite-containing foods
Fireplaces, wood burning stoves
Humidifiers and swamp coolers

Initial Assessment & Diagnosis
- Clinical diagnosis
- Is airway flow at least PARTIALLY REVERSIBLE?

1) Meds: Rescue & Controller
2) Assessment & Monitoring
3) Control of risk factors and triggers

40% of kids with asthmatic parents will develop asthma

False, Asthma IS the #1 cause of school absence

False, Asthma is the most prevalent childhood CHRONIC disease

Asthma is:
- Chronic respiratory disease
- Inflammation and narrowing of small airways
a) Airway hyper-responsiveness
b) Mucus and edema
- Reversible obstructive disease
a) Must be @ least partially reversible

URI/viruses (RSV)
Cold air temperature
Exercise
Pollen, trees, weeds
Tobacco smoke

Airway remodeling.
- Prolonged inflammation in small airway causing structural changes in airway wall which then effects airflow limitation
- Changes are permanent
- 2 years of untreated or under-treated asthma causes remodeling which causes irreversible damage
- Airway remodeling Ooccurs in mild to severe disease
a) These is extreme variability of the disease and this point is emphasized in EPR-3

- > 3 episodes of wheezing in past year that lasted > 1 day and affected sleep
- Wheezing apart from colds
- Atopic dermatitis (long-term (chronic) skin disorder that involves scaly and itchy rashes)
- Allergic rhinitis (rhinorrhea, sneezing, pruritus)
- GERD (heartburn)

True, spirometry is NOT feasibel for kids <5 years

House Dust Mites
Encase bedding, wash linens, no stuffed toys, clutter, “dust collectors”, reduce humidity
No smoking
No cockroaches
No pets in bedroom
No mold or damp areas

Acute exacerbation, sever

- Burst Therapy
- Short Course
a) Usually 507 days, no taper needed
b) 1 mg/kg/day
c) Take w/food, morning

1) Most effective long-term control for persistent asthma, vs. other controller meds

2) Small risk for adverse events
a) Growth, bone density, cataracts

3) Using spacer and rinse mouth
a) Do not brush teeth immediately after use

4) Using lowest possible dose

5) Using in combination w/long-acting beta₂-agonist

- Long-term control therapy
a) Improved lung function
b) Prevent need to short acting beta2 agonist
c) Prevent exacerbations

1) Basic facts about asthma
a) Normal vs. asthmatic airways

2) Role of meds
a) Long-term control vs. quick reliever meds

3) Skills
a) MDI, DPI, spacers, PEF

4) Triggers, Environmental control measures

5) How and when to take rescue actions

Control symptoms
Prevent exacerbation
Maintain lung function as close to normal as possible
Maintain normal activity levels
Avoid adverse effects from medications
Prevent irreversible airway obstruction
Prevent asthma mortality
Manage co-morbid conditions affecting asthma (AR, GERD, obesity)

Step up therapy if patient:
Awakens at night w/symptoms
Has an urgent care visit
Has increase need for quick reliever meds
Uses beta₂-agonist > 2/week or 1/canister/month
Always re-check “ICE”

At every visit: check “ICE”
I = inhaler technique
C = compliance
E = environmental factors review
Consider infection
CAP, ABRS, viral
Patient education
Avoid or control triggers
Use of beta₂-agonist > 2/week =
Add controller med

Use of rescue inhaler 2 X a WEEK or less
Awakened by asthma symptoms at night 2 X a month or less?
Refill rescue inhaler 2 times per year or less?

Classify severity: assign patient to most severe step in which feature occurs
Gain control as quickly as possible, then step down to the least med needed to maintain control after ~ 2 months
Re-evaluate every 2 weeks
May be able to step down sooner

Classifying Asthma Severity and Initiating Treatment
Assessing Asthma Control and Adjusting Treatment** new
Stepwise Approach for Managing Asthma
Children Aged ≤ 4 years
Children Ages 5-11 years
Youths Ages ≥ 12 years and Adults

Measured by:
- Peak expiratory flow rate (PEF)
- Peak expiratory flow variability
- Forced expiratory volume in 1 second (FEV1)
- PFTs:
a) Baseline and periodically

How often do you have daytime symptoms?

How often do you have nighttime symptoms?

Most effective med for relief of acute bronchospasm
More than 2 times/week suggests inadequate control
Regular use is not recommended-
May lower effectiveness
May increase airway hyper-responsiveness

Rescue meds:
Used in acute asthma episodes and PRN
Generally they are short-acting beta₂-agonists
Anticholinergenics
Systemic corticosteroids

Two major categories of medications:
1) Quick relievers
a) Rescue meds
b) Treat bronchospasm

2) Long-term controllers
a) Control symptoms
b) Treat inflammation