'Tis the Season: Pneumonia/Influenza

Educational Objectives

The goal of this program is to improve the management of community-acquired and health care-associated pneumo­nia, and to increase preparedness for an influenza epidemic or pandemic. After hearing and assimilating this program, the clinician will be better able to:

1.   Predict and determine the microbiologic etiology of a patient’s community-acquired pneumonia (CAP).

2.   Assess patients for potential drug resistance and provide appropriate therapy.

3.   Distinguish between unique features of health care-associated pneumonia (HCAP) and CAP.

4.   Implement polices designed to increase preparedness for an influenza epidemic or pandemic.

5.   Describe factors that alter virulence and mortality rates associated with specific influenza strains.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee re­ported nothing to disclose.

Acknowledgments

Dr. Sharpe was recorded at 30th Annual Advances in Infectious Diseases, held May 6-8, 2009, in San Francisco, CA, and sponsored by the Department of Medicine, Division of Infectious Diseases, University of California, San Fran­cisco. Dr. Cinti was recorded at 27th Advances in Infectious Disease: Winter Update, held March 5-7, 2009, in Cap­tiva Island, FL, and sponsored by the Department of Internal Medicine at University of Michigan Medical School. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this pro­gram.

Community-acquired Pneumonia: A Practical Approach

Bradley A. Sharpe, MD, Associate Clinical Professor, Department of Medicine, University of California, San Francisco, School of Medicine

Background: community-acquired pneumonia (CAP) in United States  —  common disease with 5 million cases annu­ally; 80% managed as outpatients; sixth leading cause of death; inpatient mortality rate 10% to 35%; geriatric study  —  patients ³65 yr of age admitted to hospital for pneumonia experienced 40% 1-yr mortality rates (30% for controls); mortality rates low in ambulatory settings; higher mortality rates among whites (reason undetermined); symptoms  —  coughing, shortness of breath, production of sputum, and pleuritic chest pain; only 4% of physician visits related to cough result in diagnosis of pneumonia

Etiology and microbiology: clinical features do not predict organism type (contrary to classic teaching); trends  —  Streptococcus pneumoniae possibly more common in elderly; Mycoplasma pneumoniae possibly more common among younger patients; experts recommend modulating therapy according to severity of illness (predicts microbi­ology more accurately than clinical signs and symptoms) and site of care; ambulatory setting  —  50% of total cases result from S pneumoniae; M pneumoniae, »30%; viral, 10% to 15%; non-ICU inpatients  —  patterns similar to those seen in ambulatory setting, but with additional risk for Legionella; ICU  —  Legionella common cause; Staph­ylococcus aureus (typically, methicillin-sensitive) capable of causing severe pneumonia; influenza-associated methicillin-resistant S aureus (MRSA)  —  25 cases reported by Centers for Disease Control and Prevention (CDC); median patient age 20 yr; majority had no risk factors for MRSA; mortality rate »50%; speaker recommends early prophylaxis with vancomycin in younger patients exhibiting rapidly-progressive pneumonic illness (especially dur­ing influenza season)

Diagnosis: guidelines  —  require visible infiltrate on x-ray to qualify for CAP diagnosis; studies show physical exam­inations not sufficiently sensitive or specific; patients with negative x-ray occasionally require treatment; “blossom­ing pneumonia”  —anecdotal phenomenon in which patients exhibit evidence of progression (eg, fluid, crackles) after fluid administered; blood culture  —  provides specific diagnosis; large database study found blood cultures taken within 24 hr of arrival associated with reduced mortality rate at 30 days; <10% return positive results; inde­pendent predictors of positivity include liver disease, hypotension, fever >40°C, hypothermia, tachycardia, dehy­dration, and hyponatremia; blood cultures typically negative in ambulatory setting (patients with illness severe enough to yield positive results typically admitted to hospital); 5% to 10% of positive results attributed to contami­nants (eg, S aureus); speaker asserts blood cultures not indicated in management of CAP; guidelines state blood cultures optional for inpatients without risk factors (eg, ICU admission, severe liver disease, pleural effusion); spu­tum cultures  —  simple and inexpensive; 80% to 90% specific when gram-positive cocci (GPC) observed; only 10% of patients capable of producing high-quality sputum; sputum culture not indicated in outpatient setting; guidelines recommend inpatient culturing only with 1) immediate lab oratory availability and high-quality samples, or 2) seri­ous illness (eg, ICU admission, cavitary infiltrates, underlying lung disease)

Emerging diagnostics: pneumococcal urinary antigen test  —potentially available within next few years; detects cell wall material from pneumococcal pathogens; fast in-office test with excellent specificity; procalcitonin  —  inflammatory marker specifically increased by sepsis and bacterial infections; standard of care vs management with procalcitonin levels  —  study involving 300 patients divided equally between groups; patients with low procal­citonin levels received no antibiotics (only fluid and supportive care); fewer antibiotics and shorter duration of ther­apy required in procalcitonin-managed group; no difference between groups in overall cure rate

Admission: critical and frequently difficult decision; with similar degree of illness, outpatients resume normal activi­ties more quickly; admission typically multiplies costs »25-fold and associated with additional risks; outpatient management preferred, if possible; guidelines recommend use of severity-of-illness scores or prognostic models; pneumonia severity index (PSI)  —  also known as pneumonia patient outcomes research team (PORT) score; vali­dated prognostic scoring system; infrequently applied due to complexity; confusion, urea, respiratory rate, blood pressure (CURB)-65  —  validated scoring system with 5 features; each symptom assigned 1 point; 1) confusion, 2) blood urea nitrogen (BUN) >20 mg/dL, 3) respiratory rate >30, 4) hypotension, 5) age >65 yr; score yields statisti­cally significant prediction of mortality risk and should inform admission decisions

Therapy: principles for management of outpatient CAP —antibiotics must treat typical and atypical organisms; phy­sicians must assess risk for drug-resistant S pneumoniae; risk factors for drug resistance  — age  >65 yr, any chronic disease, diabetes, alcoholism, active malignancy, immunosuppression, or antibiotics in past 3 mo; macrolides vs doxycycline  —  frequently decided by institutional protocol; better evidence exists for macrolides (azithro­mycin typically preferred); outpatients with risk factors for drug-resistance  —  macrolide resistance in S pneu­moniae increasing; assume drug resistance includes macrolides unless established community prevalence indicates otherwise; therapy typically consists of oral fluoroquinolone or combination regimen (b-lactam plus doxycycline or b-lactam plus macrolide); preferred oral fluoroquinolones include moxifloxacin, gemifloxicin, and levofloxacin; preferred b-lactams typically high-dose amoxicillin or amoxicillin and potassium clavulanate (Augmentin); inpatients  —  also require treatment covering typical and atypical organisms; pneumococcal resistance and Legio­nella more likely; preferred therapies same as for outpatients; ICU  —  patients typically receive intravenous (IV) b-lactam plus macrolide or IV b-lactam plus fluoroquinolone; sepsis  —  may indicate MRSA; speaker recommends vancomycin for 48 hr (or until cultures available); guideline-concordant vs nonconcordant regimens  —  studies uni­formly demonstrate superiority of guideline-concordant antibiotic regimens; concordant treatment associated with shorter admissions, better outcomes, and lower mortality; broad-spectrum antibiotics inferior to ceftriaxone (or similar b-lactams) for standard CAP; short-course antibiotic study  —  meta-analysis of 15 randomized controlled trials (RCTs) with 2800 patients; evaluated clinical failure, bacterial eradication, and mortality associated with short-course (<7-day) vs long-course (>7-day) antibiotic regimens for mild to moderate pneumonia; no statistically significant difference in clinical failure rates, but trends associate short-course regimens with better outcomes; rela­tive risk (RR) for mortality 0.8 with both regimens; guidelines specify minimum course of 5 days; follow-up chest x-rays  —  recommended by previous American Thoracic Society (ACS) guidelines; speaker advises waiting mini­mum of 3 mo (to avoid false positives) and orders only for patients with high risk for malignancy

Health care-associated pneumonia (HCAP): incidence increasing; criteria  —  1) hospitalized for >2 days in past 3 mo, 2) resident of skilled nursing facility, 3) receiving IV antibiotics, chemotherapy, or wound care, 4) receiving hemodialysis; exposure to health care plus risk factors (eg, malnourished or bedridden patient) associated with al­tered oropharyngeal microbiology; aspiration of microorganisms populating oropharynx may alter microbiology of pneumonia; 60-hospital study  —  limited to patients with risk factors for HCAP and positive cultures; microbiology of HCAP patients compared with hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP); S aureus, MRSA, and Pseudomonas rates similar; revised guidelines treat HCAP similar to HAP or VAP (instead of CAP); HCAP associated with significant risk for drug-resistant organisms (eg, Pseudomonas, Acinetobacter, MRSA); HCAP vs CAP microbiology study  —  rates of S pneumoniae approximately equal; more Haemophilus and MRSA in HCAP (2% of total); aspiration rate significantly increased in HCAP group; degree of illness best indica­tor for microbiology of HCAP; nursing home patients in ICU  —  speaker recommends regimen of levofloxacin, van­comycin, piperacillin and tazobactam (Zosyn); dialysis patients  —  more likely to have standard CAP and should receive standard CAP therapy

Prevention: pneumococcal vaccines  —  do not prevent pneumonia, but may prevent invasive pneumococcal disease (eg, pneumococcal bacteremia or pneumococcal meningitis); speaker recommends vaccines, due to potential for re­duction in severity of pneumonia; 3 trials found superior outcomes in vaccinated (vs nonvaccinated) patients with CAP; vaccinated group reported fewer ICU admissions, fewer complications, shorter lengths of stay, and lower mortality; influenza vaccine  —prevents influenza; associated with decreased rates of hospitalization and pneumo­nia, and lower mortality (per 1995 and 2007 studies); smoking cessation  —  smoking represents risk factor for pneu­monia and pneumococcal disease; both passive and active smoking increase risk for invasive S pneumoniae; risks dose-respondent; proton pump inhibitors (PPIs)  —observational studies correlate PPI use with increased risk for CAP; decreased levels of gastric acid encourage bacterial proliferation; may increase risk for aspiration-related pneumonia

Anti-inflammatory agents: speaker discourages steroids without clear evidence of wheezing; apply indications for exacerbation of asthma or chronic obstructive pulmonary disease

Influenza: Epidemics and Pandemics

Sandro K. Cinti, MD, Clinical Associate Professor, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor; Staff, Department of Infectious Diseases, University of Michigan Hospitals/Veter­ans Affairs Ann Arbor Health Systems

Background: seasonal influenza  —  associated with pandemic influenza; 122 United States cities reported increased prevalence of influenza, with associated increases in pneumonia and mortality; vaccine correlation  —  for 2007 to 2008 influenza season, correlation poor (66% for H1N1, 23% for H3N2, and 2% for influenza B); H3N2 strain pre­dominant in 2008; H1N1 predominant in 2009; drug resistance in 2008  —  some resistance to oseltamivir (Tamiflu) observed in H1N1, but not in strain in common circulation; rimantadine and amantadine remained effective; drug resistance in 2009  —  oseltamivir resistance increasing; H1N1 demonstrates nearly complete resistance; stockpiling oseltamivir for biopreparedness potentially rendered useless

Proteomics: surface proteins  —  hemagglutinin and neuraminidase; influenza naming conventions derived from vari­ations in surface proteins; vaccine development remains problematic; influenza A  —  only type capable of causing pandemic; H5N1  —  little immunity in population due to recent emergence; sialic acid a-2,6-galactose-linked receptors  —  site of surface recognition and preferential binding of human influenza viruses; allows penetration of cell and replication; oseltamivir and zanamivir (Relenza) interfere with cleavage of sialic acid by viral nucleic acid; preventing cleavage halts neuraminidase activity

Epidemics and pandemics: epidemics occur approximately annually; pandemics occur every 30 to 40 yr; 1918 pandemic  —worst during previous century; caused 40,000,000 to 50,000,000 deaths worldwide; viral mutation from H3N8 to H1N1 caused severe illness; deaths occurred predominantly during 12-wk period; cytokine storm  —  massive cytokine release from diverse cellular sources induces fatal response; viruses with uniquely novel or un­recognized protein configurations (eg, H1N1 in 1918) produce abrupt cytokine storms in humans; possible explana­tion for unusual mortality rate and demographics (deaths predominantly in those 17-40 yr of age) during 1918 pandemic; Taubenberger study  —  reconstructed gene sequences of 1918 influenza; based on analysis of lung core samples taken from pandemic victims buried in Alaskan permafrost and cultures preserved by Armed Forces Insti­tute of Pathology; animal model  —  reconstructed viral sequences and infected rodents; goal of modeling 1918 in­fluenza; hemagglutinin associated with high rate of infiltrates; related cytokine storms induced severe pulmonary edema; secondary pneumonia  —  possible major cause of death during 1918 pandemic; 58 preserved culture sam­ples exhibited characteristics consistent with bacterial pneumonia; secondary pneumonia as primary cause of mor­tality necessitates new strategies for pandemic preparedness; commonly stockpiled antibiotics (eg, ciprofloxacin) not ideal for treating pneumonia; influenza plus S aureus  —  associated with increased mortality among children; in­creasing prevalence of S aureus observed in cultures from sterile sites; death frequently occurs rapidly (2-4 days)

Pandemic response: Department Health and Human Services influenza plan  —  warns that thousands of communi­ties could encounter influenza simultaneously, with little or no community or government assistance; internet surveillance  —  studies correlate internet searches for influenza-related keywords with prevalence of infection; data from internet search engine 2 wk ahead of CDC, with nearly matching curves; “flu market”  —experts invited to place imaginary bets on date of influenza season or predominant viral genotype; implementation in Iowa yielded successful predictions; vaccines  —currently require incubation in chicken eggs; since H5N1 fatal to chickens (and embryonated chicken eggs), viruses require reconfiguration; production of vaccines for new influenza variants re­quires minimum 4 to 6 mo; speaker advises physicians to assume vaccines unavailable during next pandemic; Sci­ence Express study  —  compared antibodies in patients infected with H5N1 to those with standard influenza; new vaccines may stimulate activation of CR6261 antibodies (capable of universally inhibiting influenza); antivirals  —  CDC stockpiling created overabundance of oseltamivir; resistance remains significant issue; expensive treatment (averages $60 per course); masks  —  ineffective unless worn univerally; protects others (does not provide personal protection); community mitigation  —  includes closing schools and discouraging social aggregation; decisions fre­quently made at hospital level (public health department uninvolved); outpatient setting  —  current plans call for closing small clinics and aggregating patients in larger clinic areas; phone triage effectively screens patients with less severe illness

Suggested Reading

Christ-Crain M et al: Procalcitonin-guidance of antibiotic therapy in community-acquired pneumonia - a randomized trial. Am. J. Respir. Crit. Care Med 174:84, 2006; Ekiert DC et al: Antibody recognition of a highly conserved influenza virus epitope. Science 324:246, 2009; Garcia-Vazquez E et al: Assessment of the usefulness of sputum culture for diagno­sis of community-acquired pneumonia using the port predictive scoring system. Arch Intern Med 164:1807, 2004; Hidron A et al: Emergence of community-acquired meticillin-resistant Staphylococcus aureus strain USA300 as a cause of necro­tising community-onset pneumonia. The Lancet Infectious Diseases 9:384, 2009; Kollef MH et al: Epidemiology and out­comes of health-care–associated pneumonia. Chest 128:3854, 2005; Kyaw MH et al: Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant streptococcus pneumoniae. N Engl J Med 355:638, 2006; Li J et al: Ef­ficacy of short-course antibiotic regimens for community-acquired pneumonia: a meta-analysis. The American Journal of Medicine 120:783, 2007; Mandell LA et al: Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clinical Infectious Diseases 44:S27, 2007; Morens DM et al: Predominant role of bacterial pneumonia as a cause of death in pandemic influenza. The Journal of In­fectious Diseases 198:962, 2008; Myint PK et al: Severity assessment criteria recommended b