Modern Management of Respiratory Infections Ralph Gonzales, MD, MSPH Associate Professor of Medicine; Epidemiology & Biostatistics University of California,

Modern Management of Respiratory Infections

Ralph Gonzales, MD, MSPH

Associate Professor of Medicine; Epidemiology & BiostatisticsUniversity of California, San Francisco

August 16, 2006

General Approach

Making the Diagnosis Excluding Serious Illness Do I need a Diagnostic Test?

Determining Treatment Symptomatic Therapy Antimicrobial Therapy

Communicating Prognosis When to Return for Evaluation

Management Principles for Uncomplicated Acute Bronchitis

Bronchitis-CDC; ACP; AAFP; IDSA… 2001

“The evaluation of adults with acute cough illness… should focus on ruling out serious illness, particularly pneumonia” In healthy, nonelderly adults, pneumonia is

uncommon in the absence of vital sign abnormalities or asymmetrical lung sounds, and CXR is usually not indicated.

When cough>3 weeks, CXR may be warranted in absence of other known causes.

Gonzales et al, 2001

Acute Cough Illness-Ruling Out Pneumonia

Likelihood Ratio Ranges

LR + LR -

Fever 1.7-2.1 0.6-0.7

Chills 1.3-1.7 0.7-0.9

Tachypnea 1.5-3.4 0.8

Tachycardia 1.6-2.3 0.5-0.7

Hyperthermia 1.4-4.4 0.6-0.8

Dullness to Percussion 2.2-4.3 0.8-0.9

Crackles 1.6-2.7 0.6-0.9

Rhonchi 1.4-1.5 0.8-0.9

Egophany 2.0-8.6 0.8-1.0

Leukocytosis 1.9-3.7 0.3-0.6

Metlay et al,

Pneumonia Post Test Probabilities

8

6

8

10

0

20

0 10 20 30 40 50 60 70 80 90 100

Probability of Pneumonia

Tachycardia

Fever

Crackles

Dullness to Percussion

Cough + Nl Vital Signs

Cough, Fever, Tachycardia and Crackles

Metlay et al.

PreTest Prob

When to consider zebras…

• Cough > 3 weeks and normal CXR• Meds, asthma, GERD, postnasal drip,

pertussis

• Nocturnal Cough• GERD/postnasal drip, cough-variant

asthma, CHF

Pertussis…not just for children anymore

• DPT-related immunity wanes as early as 3 years… and absent after 10-12 years

• attack rates as high as 100%• 10-15% adults seeking care for persistent

cough have evidence of pertussis• No clinical features distinguish pertussis in

previously immunized adults

Pertussis

• Diagnosis• Dacron nasopharyngeal swab or wash• PCR is now standard… much better sensitivity

than culture or DFA• Coordinate with public health dept

• Treatment• Erythromycin, azithromycin or clarithromycin• Probably won’t help cough duration, which can

last 3-6 months• Reasonable to provide empirical Abx treatment

to contacts with cough, and close contacts/household members as prophylaxis.

Pertussis Boosters for Adolescents

• Adolescents and adults believed to be vectors of increasing pertussis incidence in young children.

• DTaP and Tdap: FDA approval 2005• Boostrix (GSK; age 10-18 yrs)• Adacel (Sanofi Pasteur; age 11-64 yrs)

• ACIP/NIP Recommendations: 2006• Single DTaP/Tdap instead of dT at age 11-18

Cough-Variant Asthma

Cough > 2-3 weeks Lack of wheezing Normal PFTs Features

Worse at night Worse with exercise/cold

Diagnosis Improved symptoms with bronchodilator Positive methacholine challenge test

Acute Bronchitis-Therapeutic Objectives

Symptoms Pathophysiology TreatmentCough -bronchial RAD -bronchodilators

-mucus production -decongestants

-post-nasal drip -sinus therapy -acid reflux -H2B; PPI

-cough suppressants

Wheezing/SOB -bronchial RAD -bronchodilators

Resolution of Acute Bronchitis

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18

Days with cough

% P

ati

en

ts

No Antibiotic

(+) Antibiotic

Stott, BMJ 1976

Uncomplicated Acute Bronchitis-azithromycin vs. vitamin C (Lancet 2002;359;1648-54)

Return to Usual Activities

Acute Bronchitis:-bronchial hyperresponsiveness

Airflow obstruction in acute bronchitis without underlying lung disease

020406080

100

<=80 >80

FEV1, % predicted

Eur Resp J 1994;7:1239

Acute cough illness treatment-bronchodilator treatment

Melbye bronchitis 73 fenoterol aerosol Decrease symptoms 1991 Improved FEV1

Hueston bronchitis 34 oral albuterol vs. Decrease cough @ 1 week1991 erythromycin (41% vs. 82%)

Hueston bronchitis 46 albuterol aerosol vs. Decrease cough @ 1 week1994 (placebo + erythro) (61% vs. 91%)

Littenberg nonspecific 104 albuterol aerosol No benefit1996 cough

Randomized, placebo controlled trials

OTC Cough Therapies-Cochrane Review, 2004

• Antitussives• codeine: 2 trials; no differences• dextromethorphan: 2 of 3 trials show benefit

• Expectorants (guaifenesin): 1 of 2 trials benefit

• Mucolytics: 1 trial inconsistent benefit• Antihistamine-Decongestant Combinations

• 1 of 2 trials show benefit• Dextro-salbutamol: reduced nocturnal cough

only

Acute Cough Illnesswith or w/o phlegm Patient

Characteristics

ElderlyImmunosuppression

COPD or CHFVital Sign

Abnormalities

HR > 100 bpmRR > 24 br/min, or

T > 38o C

Is Influenza Likely?

PEx Findings

Consolidation, or Pleural Effusion

Treatment Options*

Consider CXR

Treat Pneumonia

YesNo

Yes

No

Positive

Negative

Acute cough illness: evaluation

summary

Yes

No

Acute Exacerbations of COPDAnn Intern Med 2001;134:595-99

Assessing Severity of Exacerbationworsening dyspnea

increased sputum purulenceincreased sputum volume

“severe” = all 3 present“moderate” = 2 of 3 present“mild” = 1 finding + (recent URI; unexplained fever;

increased cough/wheeze; or 20% increase in RR or HR from baseline)

AECB: Treatment Recs (1)Ann Intern Med 2001;134:595-99

• All AECB• CXR utility high among hospitalized and ED

patients with AECB; ? Role in outpatient setting.

• Inhaled bronchodilator therapy• beta-2 agonist and anticholinergic equal in

efficacy, but anticholinergic have fewer/benign side effects

• Use 2nd bronchodilator class only after 1st is at max dose

AECB: Treatment Recs (2)Ann Intern Med 2001;134:595-99

• Moderate-severe AECB• pulse steroids up to 2 weeks if not currently taking• oxygen, with caution, in hypoxemic patients

• Severe AECB• initial narrow-spectrum antibiotics• no RCTs show superiority of broad-spectrum agents

• UPDATED MARCH 31, 2005

• Not recommended for AECB:• mucolytic agents; chest physiotherapy;

methylxanthine bronchodilators

AECB-Therapeutic Objectives

Symptoms Pathophysiology Treatment Cough -bronchial RAD -bronchodilators

-mucus production -decongestants/sinus

-bronchial; post-nasal drip -acid reflux -H2B; PPI

-cough suppressants

Wheezing/SOB -bronchial RAD -bronchodilators -inflammation -oral steroids

-? Bacterial infection -? antibiotics

-BiPAP

AECB-Who’s at greatest risk for relapse?

Miravitlles et al. Ischemic heart disease Degree of dyspnea # office visits previous year

Asthma Exacerbations and Telithromycin Johnston SL, NEJM 2006;354:1632-4.

• N=278; age 18-55; 90% white; mod-severe exacerbation• 1/3 oral steroids

Telith Placebo P-valueBaseline asthma score 3.0 2.8

∆ asthma score 1.3 1.0 0.004

∆ peak exp flow 78 l/m 67 l/m 0.28

Nausea 5% 0% 0.01

Diarrhea 10% 4% 0.09

No difference according to Chlamydia or Mycoplasma infection status…

The ERA of Clinical Trials Registry… must report all prespecified outcomes

Rhinosinusitis: Diagnosis (1)

“The clinical diagnosis of acute bacterial rhinosinusitis should be reserved for…” [B](1) rhinosinusitis symptoms > 7 days

+(2) purulent nasal secretions

+(3) maxillary pain/tenderness in face/teeth

Rhinosinusitis: Diagnosis (2)

“…rarely some patients with acute bacterial rhinosinusitis present with dramatic symptoms of severe unilateral maxillary pain, swelling and fever”

Bacterial Sinusitis? Tough Call

0 20 40 60 80 100

sinus symptoms

high clinical suspicion

Xray (b)

CT scan (a)

purulent sinus aspirate

Cx (+) sinus aspirate

Bacterial Sinusitis, %

(a) CT scan criteria of air-fluid level or complete opacification.(b) Xray criteria of mucosal thickening, air-fluid level or complete opacification.

Rhinosinusitis: Rx Studies Author Pat ient

Select ionTreatment

ArmsAntib iot ic Rx* Placebo Rx*

Lindbaek , 1996 c l i n i ca l susp ic ion+

CT Scan Dx

amox ic i l l i n ;pen ic i l l i n V ;p lacebo

D1086% 57%

van Buchem1997

c l i n i ca l susp ic ion+

Xray Dx

amox ic i l l i n ;p lacebo

D1483% 77%

Sta lman, 1997 c l i n i ca l c r i te r i a doxyc yc l i ne ;p lacebo

D1085% 85%

Bucher , 2003 c l i n i ca l c r i te r i a(on ly 32% Sx > 7

days )

amox-c lavu lana te ;p lacebo

D1475% 75%

Merenste in ,2005

c l i n i ca l c r i te r i a(100% Sx > 7

days )

amox ic i l l i n ;p lacebo

D1448% 37%

*Percent improved or cured

Rhinosinusitis: Abx Rx

“Acute rhinosinusitis resolves without antibiotic treatment in most cases” [A] Antibiotic treatment should be reserved

for patients with moderately severe symptoms who meet criteria for clinical diagnosis of acute bacterial rhinosinusitis and for those with severe symptoms…regardless of duration of illness.

Acute Sinusitis-Therapeutic Objectives

Symptoms Pathophysiology Treatment Pain -increased sinus pressure due - sinus drainage

inflammation & obstruction -nasal saline wash -nasal decongestant-if >7-10 days of Sx -NSAIDs - bacterial infection risk -Antibiotics

Congestion -increased mucus production -oral decongestants

-infection; recurrent; allergic-nasal steroids

Pharyngitis: Diagnosis

• “Clinically screen all adult patients with pharyngitis for the presence of 4 criteria:”

• history of fever• tonsillar exudates• tender anterior cervical LAN• absence of cough

• “Do not test or treat patients with none or only 1 of these criteria…”

Spectrum Bias in GAS Test

Sensitivity of RAT Pediatrics Adults

Centor Score0 47 61*1 65 61*2 82 763 90* 904 90* 97

*groups combined in studyPeds Ref: Hall MC et al. Pediatrics 2004;114:182Adult Ref: Dimatteo LA et al. Ann Emerg Med 2001;38:648

Pharyngitis: Abx Rx

• “Test patients with 2-4 criteria using a rapid antigen test, and limit Abx to patients with positive test results [D]”, OR

• “Test patients with 2 or 3 criteria, and limit Abx to patients with positive test results or patients with 4 criteria” [D], OR

• “Do not use any diagnostic tests, and limit Abx to patients with 3 or 4 criteria [B]”

Streptococcal Pharyngitis-Therapeutic Objectives

Symptoms Pathophysiology Treatment sore throat -inflammation -NSAIDs

-infection -antibiotics

Prednisone for Pharyngitis (Bacterial)-Kiderman A et al, Br J Gen Pract 2005;55:218.

-18-65 years; primary care

-2+ Centor criteria

-50% Strep Cx +

-Oral Prednisone 60 mg for 1 or 2 days

Delayed Antibiotic Prescriptions

Systematic Review: approx 50% decrease in antibiotic treatment Br J Gen Pract. 2003 Nov;53(496):871-7.

Delayed Antibiotic Treatment of Otitis media (AAP; AAFP)…. Definition of AOM (ie. “definite AOM”):

recent, usually abrupt, onset of sx and signs, AND presence of middle ear effusion, AND distinct tympanic erythema or otalgia

Management of AOMGuideline (AAP;AAFP 2004)

Child Age 2 mo to 12 yrs with uncomplicated AOM

Assess and Treat Pain

Observe 48-72 hr with assurance and appropriate

f/u

Age Definite Diagnosis Uncertain Diagnosis< 6 mo Abx Abx6 mo - 2 yr Abx Abx if severe illness (T>39 or severe

otalgia; else observe>2 yr Abx if severe; else observe Observe

AND*Caregiver informed/agrees/monitors/returns; System in place for communication

Amoxicillin 80-90 mg/kg/day; unless T>39 C. or severe otalgia or treatment failure, then amox/clavulanate

observe Abx

How to help patients say “no” to antibiotics for viral ARIs

Illness labeling: use “chest cold”, not “bronchitis”

Validate illness severity; focus on symptom relief Provide a contingency plan Discuss downside of unnecessary antibiotic use

risk of carriage/spread of antibiotic-resistant bacteria

Patient-physician communication Explain the illness Spend “enough” time Treat with respect

Therapeutic Windows in ARI Treatments

Influenza 2 days GAS pharyngitis 2 days

To prevent ARF 10 days Pertussis 7-10 days

CDC/ACP/AAFP/IDSA-Antibiotic Principles for ARIs

• Gonzales R, Bartlett JG, Besser RE, Cooper RJ, Hickner JH, Hoffman JR, Sande MA. Principles of appropriate antibiotic use for treatment of acute respiratory tract infections in adults: Background, Specific Aims and Methods. Ann Intern Med 2001;134:479-86.

• Cooper RJ, Hoffman JR, Bartlett JG, Besser RE, Gonzales R, Hickner JH, Sande MA. Principles of appropriate antibiotic use for acute pharyngitis in adults: background. Ann Intern Med 2001;134:509-17

• Hickner JH, Bartlett JG, Besser RE, Gonzales R, Hoffman JR, Sande MA. Principles of appropriate antibiotic use for acute rhinosinusitis in adults: background. Ann Intern Med 2001;134:498-505.

• Gonzales R, Bartlett JG, Besser RE, Cooper RJ, Hickner JH, Hoffman JR, Sande MA. Principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: background. Ann Intern Med 2001;134:521-29.

Bronchitis References

• Stott NC, West RR. Randomised controlled trial of antibiotics in patients with cough and purulent sputum. BMJ. 1976;2(6035):556-9.

• Melbye H, Kongerud J, Vorland L. Reversible airflow limitation in adults with respiratory infection. Eur Respir J. 1994;7:1239-45.

• Gonzales R, Steiner JF, Lum A et al. Decreasing antibiotic use in ambulatory practice: impact of a multidimensional intervention on the treatment of uncomplicated acute bronchitis in adults. JAMA. 1999;281:1512-9.

• Evans AT, Husain S, Durairaj L, et al. Azithromycin for acute bronchitis: a randomised, double-blind, controlled trial. Lancet. 2002;359(9318):1648-54).

• Schroeder K, Fahey T. Over-the-counter medications for acute cough in children and adults in ambulatory settings. Cochrane Database Syst Rev. 2004(4):CD001831.

• Nennig ME, Shinefield HR, Edwards KM, et al. Prevalence and incidence of adult pertussis in an urban population. JAMA 1996;275:1672-4.

• Metlay JP, Fine MJ. Testing strategies in the initial management of patients with community-acquired pneumonia. Ann Intern Med. 2003;138:109-18.

AECB References

• Anthonisen NR, Manfreda J, Warren CP et al. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 1987;106:196-204

• Snow V, Lascher S, Mottur-Pilson C; ACCP/ACP-ASIM. Evidence base for management of acute exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 2001;134:595-9.

• Wilson R, Allegra L, Huchon G, et al. Short-term and long-term outcomes of moxifloxacin compared to standard antibiotic treatment in acute exacerbations of chronic bronchitis. Chest 2004;125:953-64.

• Miravitlles M, Torres A. No more equivalence trials for antibiotics in exacerbations of COPD, please. Chest 2004;125:811-13.

Acute Rhinosinusitis Refs

• Lindbaek M, Hjortdahl P, Johnsen UL. Randomized, double blind, placebo controlled trial of penicillin V and amoxycillin in treatment of acute sinus infections in adults. BMJ 1996;313(7053):325-9.

• Stalman W, van Essen GA, van der Graaf Y, de Melker RA. The end of antibiotic treatment in adults with acute sinusitis-like complaints in general practice? A placebo-controlled double-blind randomized doxycycline trial. Br J Gen Pract 1997;47(425):794-9.

• van Buchem FL, Knottnerus JA, Schrijnemaekers VJ, Peeters MF. Primary-care-based randomized placebo-controlled trial of antibiotic treatment in acute maxillary sinusitis. Lancet 1997;349(9053):683-7.

• Bucher HC, Tschudi P, Young J, et al. Effect of amoxicillin-clavulanate in clinically diagnosed acute rhinosinusitis: a placebo-controlled, double-blind, randomized trial in general practice. Arch Intern Med. 2003;163:1793-8.

• Merenstein D, Whittaker C, Chadwell T, et al. Are antibiotics beneficial for patients with sinusitis complaints? A randomized double-blind clinical trial. J Fam Pract. 2005;54:144-51.

Acute Pharyngitis Refs

• Centor RM, Witherspoon JM, Dalton HP, et al. The diagnosis of strep throat in adults in the emergency room. Med Decis Making 1981; 1:239-246.

• Zwart S, Sachs APE, Ruijs GJHM, et al. Penicillin for acute sore throat: randomised double blind trial of seven days versus three days treatment or placebo in adults. BMJ 2000; 320:150-154.

• DiMatteo L, Lowenstein SR, Brimhall B, et al. The relationship between the clinical features of pharyngitis and the sensitivity of a rapid antigen test: evidence of spectrum bias. Ann Emerg Med. 2001;38:648-52.

• Bulloch B, Kabani A, Tenenbein M. Oral dexamethasone for the treatment of pain in children with acute pharyngitis: a randomized, double-blind, placebo-controlled trial. Ann Emerg Med. 2003;41:601-8.