INFECTIOUS DISEASES
Educational Objectives
| The goal of this program is to improve the management of influenza and sepsis. After hearing and assimilating
this program, the clinician will be better able to:
|
 | 1. Explain the difference between antigenic drift and antigenic shift.
|
| 2. Utilize the appropriate influenza antiviral drug in a timely way.
|
| 3. Review the indications for and contraindications to influenza vaccine.
|
| 4. Distinguish between sepsis, severe sepsis, and septic shock.
|
| 5. Apply early goal-directed therapy for sepsis.
|
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.
Acknowledgements
Dr. Winston was recorded at Topics in Emergency Medicine, held October 1-4, 2007, in San Francisco, CA, and sponsored
by the University of California, San Francisco, School of Medicine, Division of Emergency Medicine. Dr. Torbati
was recorded at the 5th Annual Emergency Medicine Symposium—A Practical Update, held December 7, 2007, in
Los Angeles, CA, and sponsored by the Cedars-Sinai Medical Center. The Audio-Digest Foundation thanks Drs.
Winston and Torbati and the sponsors for their cooperation in the production of this program.
| INFLUENZA SEASON— Lisa Winston, MD, Assistant Clinical Professor, University of California, San Francisco, School of
Medicine, Interim Vice Chief, Medical Service, and Hospital Epidemiologist, San Francisco General Hospital, San Francisco,
CA
|
| Influenza biology: influenza viruses single-stranded enveloped RNA viruses; influenza A viruses—most commonly
seen (name includes year and place isolated); hemagglutinin (HA) and neuraminidase (NA) types of influenza A virus;
influenza B viruses—only infect humans; typically do not make people as sick as influenza A viruses; do not cause pandemic
influenza; influenza C viruses—do not infect humans; influenza A viruses—also infect animals (pigs, horses, sea
mammals, and birds); concern about reassortment of viruses and how humans become infected with new viruses; 16 HA
subtypes; 9 NA subtypes; most types infect birds; only 4 true human influenza A viruses (H1N1, H1N2, H2N2, and
H3N2); H1N1 and H3N2 circulating at present; HA attaches to cellular sialic acid receptors (reason for different influenza
A viruses infecting different species); NA cleaves sialic acid, releasing infectious virus particles; segmented genome
with 8 RNA fragments (reassort in patients infected with >1 influenza type)
|
| Influenza drift and shift: antigenic drift—occurs every year; due to point mutations; reason vaccine changed each
year; antigenic shift—responsible for pandemics; major changes due to reassortment of RNA segments; pandemics occur
when little immunity to circulating virus; 1919 “Spanish flu” probably avian virus that got into human population,
with ability to spread from person to person; 1957 to 1958 “Asian flu” and 1968 to 1969 “Hong Kong flu” probably due
to reassortment
|
| Antiviral therapy: 2 classes; adamantanes—not presently used for influenza, due to resistance; effective only against
influenza A; target virus M2 ion channel protein and inhibit virus uncoating; 2 drugs amantadine and rimantadine; NA
inhibitors—inhibit cleavage of influenza A and B viruses from host cell surface; 2 drugs zanamivir (inhaled) and oseltamivir
(Tamiflu; more commonly used; oral)
|
| Adamantanes: given ≤48 hr after symptom onset; decrease viral shedding; reduce clinical illness by ≈1 day; used effectively
for chemoprophylaxis, particularly in hospitals and nursing homes; amantadine—approved for many age
groups; associated with gastrointestinal (GI) and central nervous system (CNS) side effects; rimantadine—more commonly
used, especially in older individuals, because of fewer CNS side effects; resistance—surfaced during 2005-
2006 influenza season; most of virus circulating H3N2, with 92% of isolates tested resistant, prompting Centers for
Disease Control and Prevention (CDC) to order discontinuation of use of adamantanes for influenza until further notice;
for 2006-2007 season, H1N1 predominant virus circulating, with only one-third of H3N2 virus resistant
|
| NA inhibitors: zanamivir (Relenza)—orally inhaled, powdered drug; not approved for prophylaxis; approved for treatment
of patients ≥7 yr of age; not recommended if underlying respiratory disease present (eg, asthma); dose 2 inhalations
q12h for 5 days; start early (within 48 hr); reduces duration of symptoms by ≈1 day; oseltamivir (Tamiflu)—
capsule or oral suspension; approved for prophylaxis and treatment of patients ≥1 yr of age; main side effects nausea
and vomiting (decreased if taken with food); no data showing drugs effective at >48 hr after symptom onset; reduces
duration of symptoms by ≈1 day; treatment dose for adults 75 mg bid for 5 days; prophylactic dose for adults 75 mg
daily; meta-analysis—modest decreases in lower respiratory tract complications, overall antibiotic use, and hospitalization
for any cause found in patients with confirmed influenza; good data on efficacy of prophylaxis; no clinical trial
data on treatment after complications develop; resistance—less common than with adamantanes; incidence <0.5% in
recent survey; probably more common after treatment; resistant virus possibly less fit and less transmissible; viruses
resistant to oseltamivir possibly still inhibited by zanamivir, and novel NA inhibitors in development
|
| Influenza vaccine: always trivalent; has 2 strains of influenza A and one strain of influenza B; same strains in inactivated
(flu shot) and live attenuated vaccines (nasal spray); immunity wanes; most individuals maintain immunity for ≈6
mo; need influenza vaccine every year to maintain elevated antibody levels; individuals vaccinated regularly do better
than those who do not; indications—all adults ≥50 yr of age; in United States, success much better with age indications
than disease indications; last year, ≈89% of patients ≥65 yr of age vaccinated; children between 6 mo and 5 yr of age;
anyone >6 mo of age with chronic medical condition; residents of long-term care facilities; women pregnant during influenza
season; health care workers; healthy persons with high-risk contacts; ≈218 million people targeted in United States
(73% of population)
|
| Injectable inactivated vaccine: grown in eggs; few contraindications; severe egg allergy only absolute contraindication;
relative contraindications include recent history of Guillain-Barré syndrome (although no evidence of association);
cannot get influenza from vaccine; sore arm only common side effect, compared with placebo
|
| Live attenuated intranasal vaccine (nasal spray): same strains as inactivated vaccine; attenuated, heat-sensitive,
and cold-adapted; approved for healthy individuals 2 to 49 yr of age, including health care workers and contacts of most
high-risk patients; not recommended if working in bone marrow transplantation unit or with profoundly neutropenic patients,
unless absent from work for 1 wk after vaccination; who should not get vaccine—those outside recommended age
ranges (recommended age ranges likely to skew younger in future); those with chronic medical conditions; pregnant
women; people with history of Guillain-Barré syndrome or anaphylaxis to eggs; those who have contact with highly immunosuppressed
patients; side effects—runny and stuffy nose (common); efficacy—very efficacious in children (85%-
90% effective in preventing influenza A, compared to placebo); in children, several studies suggest better efficacy than
inactivated vaccine; study of adults in Michigan from 2004-2005, comparing live attenuated vaccine to inactivated injectable
vaccine, found live attenuated vaccine inferior, especially against influenza B
|
| Vaccination of health care workers: multiple organizations working on recommendations and regulations, including
Joint Commission and California Department of Health Services; tracking of health care workers required; declination
forms
|
| Diagnosis: 2 most helpful symptoms during influenza season fever and cough, but not ideally sensitive or specific; nasal
washing specimens preferred; yield from nasopharyngeal swab not as good as from nasal washing; rapid antigen test—
ready in ≈30 min; determines whether patient has influenza; distinguishes between influenza A or B; negative rapid test
does not rule out influenza; not specific, especially if influenza not circulating in community (false-positive results possible);
helpful if positive during influenza season; for patients admitted to hospital, culture recommended if rapid test negative
and suspicion moderate to high; call Infectious Disease, Infection Control, Department of Public Health, and
laboratory if H5N1 suspected
|
| Institutional infection control: patients infectious from 24 hr before until 5 days after symptom onset; mostly spread
by respiratory droplets; droplet and body substance precautions indicated (eg, surgical masks, keeping patients 3 ft apart
from each other, using partitions, private room with closed door)
|
| SEPSIS AND CRITICAL CARE —Sam Torbati, MD, Attending Physician and Medical Director of Quality and Safety,
and Clinical Instructor of Medicine, David Geffen School of Medicine at the University of California, Los Angeles
|
| Demographics of severe sepsis: >750,000 cases annually; 10% of intensive care unit (ICU) admissions; almost
250,000 people die annually from severe sepsis; average hospital length of stay almost 20 days; costly for medical centers
and hospitals (≈$16.7 billion); mortality same as that for acute myocardial infarction; more common than AIDS, colon
cancer, and breast cancer combined; impact of severe sepsis—higher mortality rate; longer length of stay; higher ventilator
usage; higher cost; close to 50% mortality; mortality increases with number of dysfunctional organs
|
| Case 1: nursing home patient, 76 yr of age, has diabetes, renal insufficiency, previous stroke, coronary artery disease, indwelling
Foley catheter, and sacral decubiti; referred for fever and altered mental status (AMS); vital signs temperature of
103°F, pulse of 130 bpm, systolic blood pressure (BP) of 76 mm Hg, with mean arterial pressure (MAP) of 48, tachypneic
with respiratory rate of 30/min, and O2 saturation of 85%; patient appears acutely and chronically ill, unresponsive,
and looks dry; urine purulent; decubiti on back; white blood cell (WBC) count 30,000/µL, with 30% bands; sodium elevated;
acute renal failure and acute hepatic dysfunction; blood gases show severe metabolic acidosis; lactic acid elevated;
infiltrates found on chest x-ray; patient septic
|
| Case 2: woman, 81 yr of age, presented at emergency department (ED) with 2-day fever, chills, anorexia, and nausea;
temperature of 101°F; BP and MAP within normal limits; pulse 99 bpm; respiratory rate 20/min; good saturation; patient
appears mildly ill; ambulatory; WBC count 18,000/µL; some renal insufficiency (serum urea nitrogen [BUN] 48 mg/dL
and creatinine of 2.2 mg/dL, compared to baseline BUN of 18 mg/dL and creatinine of 1.0 mg/dL); chest x-ray clear;
urine “dirty”; patient meets criteria for severe sepsis
|
| Definition of sepsis: presence of systemic inflammatory response syndrome (SIRS) and presumed or documented infection;
criteria for SIRS include 2 of following, ie, high or low temperature, pulse >90 bpm, increased respiratory rate, and
increased or low WBC count or >10% bands; severe sepsis—sepsis with 1 organ dysfunction, eg, acute lung injury, coagulopathy,
thrombocytopenia, AMS, new renal insufficiency, new hepatic or cardiac failure, and systemic hypoperfusion
(lactic acidosis); septic shock—severe sepsis with refractory hypotension (unresponsive to fluid challenge of 20-40
mL/kg bolus of normal saline); bacteremia—50% of patients with severe sepsis and septic shock do not have positive
blood cultures; 20% to 30% have no microbial cause from any source
|
| Case 3: woman, 61 yr of age, presented to ED 2 wk after gastric banding procedure, with 1 wk of worsening abdominal
pain, vomiting, and low-grade fever; vital signs temperature of 99.2°F, BP 110/40 mm Hg, MAP of 63 mm Hg, pulse of
110 bpm, respiratory rate of 28/min; patient appears pale, with pain in her abdomen (tender), and slightly tachypneic;
WBC count of 24,000/µL, with 40% bands, acute renal dysfunction, and lactic acid of 4.1 mg/dL; chest x-ray clear, and
computed tomography (CT) pending; patient meets criteria for severe sepsis; 7 L of fluid given before patient able to urinate
|
| Pathogenesis: not disease of particular tissue, but physiologic state with endothelial dysfunction of every organ; eliciting
problem bacterial, viral, fungal, or parasitic infection leading to inflammation, hypercoagulation, fibrinolysis, and endothelial
dysfunction, with formation of clots in small vessels, leading to tissue hypoperfusion and end-organ dysfunction
|
| Time-sensitive interventions: trauma has “golden hour”; in stroke, 3-hr tissue plasminogen activator (tPA) window;
in sepsis 6-hr critical period to identify and carry out early goal-directed therapy (EGDT); in sepsis, time equals tissue
|
| General principles of sepsis management: recognize sepsis; order appropriate tests and cultures; establish likely
microbial cause (statistically, lungs number one source, followed by genitourinary [GU] tract, GI tract, skin, and indwelling
lines); initiate early appropriate antibiotics; remove source of infection (drain abscesses, debride devitalized
tissue, remove infected lines or Foley catheters); optimize hemodynamics and oxygenation to restore tissue perfusion
|
| Recognizing sepsis: febrile or hypothermic patient; watch for fever developing in ED; observe presenting vital signs and
pattern in ED; ill appearance; cold clammy skin; AMS
|
| Laboratory examination: highly elevated or low WBC count; bandemia; new organ dysfunction (renal insufficiency, liver
failure, or coagulopathy); metabolic acidosis; high lactic acid level; appropriate tests—blood cultures; lactic acid; lactic
acid assessment—measure of overall tissue perfusion; level >4 mg/dL in and of itself risk factor for poor prognosis
|
| Antibiotics: important to start ≤3 hr after ED admission; study by Kumar—retrospective; ≈2000 hypotensive patients
with severe sepsis or septic shock; those started on antibiotics ≤1 hr after ED arrival had 80% survival rate; every 1-hr
delay in administration associated with 7.6% increase in mortality
|
| Optimizing hemodynamics: ensure adequate volume; measure central venous pressure (CVP); no benefit of colloids over
crystalloids; manipulate afterload if required by low BP; administer vasopressors (no data to suggest that dopamine
better than norepinephrine or phenylephrine); manipulate contractility (overworked heart in older patient may induce
myocardial ischemia or infarction); optimize oxygenation—to provide adequate perfusion to end organs (measured by
lactic acid levels; if lactic acid elevated, not enough perfusion to tissues); measure mixed venous O2 saturation (by
sampling blood from superior vena cava or right atrium from high-placed central line); the more tissues “starving,” the
more O2 extracted before venous return of blood to heart; if patient anemic, give blood for more O2 -carrying capacity;
put on high-flow O2 and intubate if necessary (for positive-pressure ventilation); if intubated patient still has low
mixed venous O2 saturation, decrease work of breathing by paralyzing and sedating patient, allowing ventilator to do
work
|
| EGDT: shown that if done within first 6 hr in ED, mortality reduced from 46% to 30%; 28-day and 60-day mortality also
decreased; group who received EGDT got more fluids (5 L vs 3.5 L); cardiovascular collapse most common pathway to
death for patients with severe sepsis; EGDT group had lower rate of cardiovascular collapse; less use of vasopressors in
ICU; shorter length of hospital stay; now standard of care; components of early resuscitation bundle—measure serum
lactate; early blood cultures; early antibiotics (empiric broad-spectrum; goal within 3 hr); fluid boluses; use vasopressors
if necessary; more aggressive if fluid-refractory hypotension or high lactic acid level present
|
| Components of 24-hr bundle: next stage of care; protective ventilation—literature suggests that patients do better, especially
those with lung injury associated with sepsis, with low tidal volumes (6 mL/kg; aimed at reducing airway plateau
pressure); issue of whether to use drotrecogin alfa (activated protein C; Xigris), corticosteroids, or intensive insulin
therapy
|
Suggested Reading
Braun MM et al: Effectiveness of influenza vaccination. N Engl J Med 357:2730; author reply 2730, 2007; Carlet J et
al: Sepsis: time to reconsider the concept. Crit Care Med 36:964, 2008; Dailey MP: Pandemic influenza and community
medical care. South Med J 101:215, 2008; Dellinger RP et al: Surviving Sepsis Campaign: international guidelines for
management of severe sepsis and septic shock: 2008. Crit Care Med 36:296, 2008; Erratum in: Crit Care Med. 2008; Doshi
P: Trends in recorded influenza mortality: United States, 1900-2004. Am J Public Health 98:939, 2008; Hatakeyama S
et al: Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors. JAMA 297:1435, 2007; Kortgen
A et al: Implementation of an evidence-based "standard operating procedure" and outcome in septic shock. Crit Care
Med 34:943, 2006; Kumar A et al: Duration of hypotension before initiation of effective antimicrobial therapy is the critical
determinant of survival in human septic shock. Crit Care Med 34:1589, 2006; Laohaburanakit P: Resource utilization
in patients undergoing early goal-directed therapy for severe sepsis and septic shock. Chest 133:315; author reply 316,
2008; Rivers EP et al: The influence of early hemodynamic optimization on biomarker patterns of severe sepsis and septic
shock. Crit Care Med 35:2016, 2007; Shorr AF et al: Economic implications of an evidence-based sepsis protocol:
can we improve outcomes and lower costs? Crit Care Med 35:1257, 2007; Smith J et al: Antivirals for influenza in
healthy adults. Lancet 367:1571; author reply 1573, 2006; Talmor D et al: The costs and cost-effectiveness of an integrated
sepsis treatment protocol. Crit Care Med 36:1168, 2008; Tosh PK et al: Flu myths: dispelling the myths associated
with live attenuated influenza vaccine. Mayo Clin Proc 83:77, 2008; Trzeciak S et al: Early microcirculatory perfusion
derangements in patients with severe sepsis and septic shock: relationship to hemodynamics, oxygen transport, and survival.
Ann Emerg Med 49:88, 2007; van Riel D et al: Human and avian influenza viruses target different cells in the lower respiratory
tract of humans and other mammals. Am J Pathol 171:1215, 2007; Weiss MM et al: Disrupting the transmission
of influenza a: face masks and ultraviolet light as control measures. Am J Public Health 97 Suppl 1:S32, 2007.
|
