RESPIRATORY INFECTIONS








Influenza (flu)
  • Epidemiology - influenza is a virus that infects people of all ages. In the U.S., influenza typically circulates between October and May, with the peak incidence occurring between December and March. Symptomatic influenza infection occurs in approximately 8% of the U.S. population each year, with a range of 3 - 11%, depending on the season.
  • Pathology - influenza is a respiratory infection caused by the influenza A, B, and C viruses. In the fall, winter, and spring of each year, influenza A and B spread as epidemics across the U.S., while influenza C causes sporadic, less frequent outbreaks. The virus is easily spread from person to person through the inhalation of infected air droplets (e.g. coughing, sneezing), direct contact with infected secretions (e.g. kissing, sharing drinks), and touching of infected surfaces (e.g. doorknobs). Once the virus gains access to the upper airway, it infects and destroys epithelial cells, and an inflammatory reaction ensues. In most cases, the virus remains in the upper airway, but it can spread to the lower airways and cause bronchiolitis, croup, and pneumonia. The virus is shed in respiratory secretions for 5 - 10 days from the first onset of symptoms.
  • Symptoms - influenza infection has an incubation period of 1 - 2 days, after which any of the following may develop: cough, congestion, fever, body aches, decreased appetite, headache, and sore throat. GI symptoms including nausea, vomiting, and diarrhea are more common in children, as is conjunctivitis. Systemic symptoms usually last 3 - 7 days, but a cough can persist for weeks. Risk factors for severe disease are listed below (see whom to test/treat).
  • Diagnosis - influenza can be diagnosed clinically when a person has typical symptoms during a seasonal outbreak. Rapid influenza tests are widely available that detect the presence of viral antigens or nucleic acids in upper airway swabs. Antigen tests have sensitivities ranging from 40 - 60% in adults to 70 - 90% in children; specificities for antigen tests are very high (> 95%), which means that there are few false positives. Nucleic acid tests have much higher sensitivities (> 90%), but they require special equipment that is usually only available in labs.
  • Treatment - antiviral medications are available that can decrease the length of flu symptoms. The CDC and IDSA recommendations on who should be treated are listed below (see whom to test/treat). There is no conclusive evidence that antivirals reduce the incidence of clinically meaningful outcomes like hospitalization, pneumonia, and death.
  • Prevention - new influenza vaccines are produced annually that are designed to protect against viral strains predicted to be most active. Because the effectiveness of the influenza vaccine varies widely from very little protection in poorly-matched seasons to 40 - 60% protection in well-matched seasons, patients who have received the vaccine should still be considered susceptible to influenza. [14,15,17,18]

Whom to test / treat

  • The list below is a summary of recommendations from the CDC and IDSA on which patients should be tested and/or treated for influenza infection

  • The following patients are at high-risk of complications from influenza infection and should be tested / treated for infection
    • Children aged < 5 years (especially those < 2 years)
    • Adults aged ≥ 65 years
    • Persons with certain chronic medical conditions (asthma, COPD, DM, CAD, stroke, kidney disease, liver disease, hematologic disorders, neurological and neurodevelopmental conditions, intellectual disability, developmental delay, muscular dystrophy)
    • Immunosuppressed patients (e.g. HIV, medications, cancer)
    • Pregnant or postpartum (within 2 weeks after delivery)
    • Patients ≤ 18 years old who are receiving chronic aspirin or salicylate therapy (may be at increased risk of Reye syndrome with influenza infection)
    • Morbid obesity (BMI ≥ 40)
    • American Indians/Alaska Natives
    • Nursing home residents and other chronic-care facilities [14,15]

Treatment

Children
  • Oseltamivir (Tamiflu®)
    • Age 14 days - 1 year: 3 mg/kg/dose twice daily for 5 days
    • Age > 1 year (dose based on weight)
      • ≤ 15 kg: 30 mg twice a day for 5 days
      • > 15 to 23 kg: 45 mg twice a day for 5 days
      • > 23 to 40 kg: 60 mg twice a day for 5 days
      • > 40 kg: 75 mg twice a day for 5 days ($$)
  • Zanamivir (Relenza®)
    • Age ≥ 7 years: 10 mg (inhalation powder) twice a day for 5 days ($$)
  • Baloxavir (Xofluza®)
    • Age ≥ 12 years:
      • 88 lbs (40 kg) to < 176 lbs (80 kg): single dose of 40 mg
      • ≥ 176 lbs (80 kg): single dose of 80 mg ($$$$)
      • Should be taken within 48 hours of symptom onset
Adults

Postexposure prophylaxis

Whom to treat
  • Asymptomatic exposed persons
    • Treat asymptomatic adults and children aged ≥ 3 months who are at very high risk of developing complications from influenza (eg, severely immunocompromised persons) and for whom influenza vaccination is contraindicated, unavailable, or expected to have low effectiveness, after household exposure to influenza
    • Treat and give vaccine to adults and children aged ≥ 3 months who are unvaccinated and are household contacts of a person at very high risk of complications from influenza (eg, severely immunocompromised persons), after exposure to influenza
    • Clinicians should not administer once-daily postexposure antiviral chemoprophylaxis if > 48 hours has elapsed since exposure. If exposed persons develop symptoms, full-dose treatment should be used. [15]
  • Institutional setting outbreaks
    • For outbreaks in institutional settings, the CDC recommends antiviral chemoprophylaxis for a minimum of 2 weeks, and continuing for 10 days after the last known case is identified. Antiviral chemoprophylaxis should be considered for all exposed residents, including those who have received influenza vaccination, and for unvaccinated institutional employees. [14]
Prophylaxis (Children)
  • Oseltamivir (Tamiflu®)
    • Age 3 months - 1 year: 3 mg/kg/dose once daily for 7 days
    • Age > 1 year (dose based on weight)
      • ≤ 15 kg: 30 mg once a day for 7 days
      • > 15 to 23 kg: 45 mg once a day for 7 days
      • > 23 to 40 kg: 60 mg once a day for 7 days
      • > 40 kg: 75 mg once a day for 7 days ($$)
  • Zanamivir (Relenza®)
    • Age ≥ 5 years: 10 mg (inhalation powder) once daily for 7 days ($$)
Prophylaxis (Adults)

Studies

Baloxavir vs Oseltamivir vs Placebo for Uncomplicated Influenza , NEJM (2018) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=1064) in adults with uncomplicated influenza
  • Treatment: Baloxavir 40 or 80 mg vs Oseltamivir 75 mg twice daily vs Placebo
  • Primary outcome: Time to alleviation of influenza symptoms in the intention-to-treat infected population
  • Results:
    • Baloxavir - 53.7 hours
    • Oseltamivir - 53.8 hours
    • Placebo - 80.2 hours
  • Findings: Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed.
Safety of Neuraminidase Inhibitors during Pregnancy, BMJ (2017) [PubMed abstract]
  • Design: Retrospective cohort study and meta-analysis (N=698,056) in women with singleton births
  • Exposure: Neuraminidase inhibitor (oseltamivir or zanamivir) vs None
  • Primary outcome: Low birth weight, low Apgar score, preterm birth, small for gestational age birth, stillbirth, neonatal mortality, neonatal morbidity, and congenital malformations.
  • Findings: This large multinational register study found no increased risks of adverse neonatal outcomes or congenital malformations associated with exposure to neuraminidase inhibitors during embryo-fetal life. The results support previously reported findings that the use of neuraminidase inhibitors is not associated with increased risks of adverse fetal or neonatal outcomes.

Community-acquired pneumonia (Adults)

Etiology

A study published in 2015 found the following etiologies of community-acquired pneumonia in 2259 hospitalized adults:
  • No pathogen detected - 62%
  • Rhinovirus- 9%
  • Influenza virus - 6%
  • Streptococcus pneumoniae - 5%
  • Human metapneumovirus - 4%
  • Respiratory syncytial virus - 3%
  • Parainfluenza virus 1,2,3 - 2%
  • Coronaviruses- 2%
  • Mycoplasma pneumoniae - 2%
  • S. aureus - 2%
  • Adenovirus- 1%
  • L. pneumophila - 1%
  • Enterobacteriaceae - 1% [10]

Prevention

Pneumococcal vaccines
  • There are currently four pneumococcal vaccines available that contain 13 - 23 different serotypes of Streptococcus pneumoniae, the most common cause of bacterial pneumonia.
    • Pneumovax (PPSV23) - PPSV23 is a vaccine from Merck that covers 23 serotypes of Streptococcus pneumoniae. PPSV23 has been available since 1983.
    • Prevnar 13 (PCV13) - PCV13 is a conjugate vaccine from Pfizer that covers 13 serotypes of Streptococcus pneumoniae. PCV13 has been available since 2010 and is part of the recommended childhood immunization schedule.
    • Prevnar 20 (PCV20) - PCV20 is a conjugate vaccine from Pfizer that covers 20 serotypes of Streptococcus pneumoniae. The vaccine was FDA-approved in 2021.
    • Vaxneuvance (PCV15) - PCV15 is a conjugate vaccine from Merck that covers 15 serotypes of Streptococcus pneumoniae. The vaccine was FDA-approved in 2021.

CDC recommendations
Efficacy
  • PCV13 - A large randomized trial performed in the Netherlands compared the efficacy of PCV13 to placebo in 84,496 adults aged 65 years or older (mean age 73 years). After an average follow-up of 3.97 years, 0.32% of patients who received PCV13 had confirmed pneumococcal community-acquired pneumonia (CAP) compared to 0.41% in the placebo group (p=0.05). The PCV13 group had a lower incidence of CAP caused by pneumococcal strains covered in the vaccine (0.15% vs 0.25%, p=0.003), but there was no significant difference in overall cases of CAP (1.8% vs 1.9%, p=0.32) or all-cause mortality (7.1% vs 7.1%). [PubMed abstract]
  • PPSV23 - No large randomized trials involving the general public have been published. Small studies that have examined its effects in high-risk patients have been mostly disappointing - PMID 28122642, PMID 28122642, PMID 28122642, PMID 28122642.
  • PCV15 and PCV 20 - There is currently no real-world data on the efficacy of PCV20 and PCV15 in preventing pneumonia, as their approvals were based on antibody titers, a surrogate endpoint.

Symptoms

  • Cough
  • Fever
  • Sputum production
  • Shortness of breath
  • Hypoxia
  • Tachycardia
  • Pleuritic chest pain

Diagnosis

Overview
  • Chest X-ray is usually performed to confirm the diagnosis
  • For outpatient treatment, sputum cultures, blood cultures, and urinary pneumococcal and Legionella antigen testing are not recommended
  • In 2017, the FDA approved the procalcitonin (PCT) blood test to help distinguish bacterial vs viral pneumonia. High levels of PCT suggest a bacterial infection, while low levels suggest a viral infection or noninfectious causes. [FDA press release]
ACCP and ACP pneumonia rule out criteria
  • For healthy adults < 70 years old, the absence of all the following makes the diagnosis of pneumonia very unlikely and a chest X-ray is not indicated:
    • Tachycardia (heart rate > 100 beats/min)
    • Tachypnea (respiratory rate > 24 breaths/minute)
    • Fever (oral temp > 38° C or 100.4° F)
    • Abnormal findings on chest exam including egophony (increased resonance of voice sounds heard when auscultating the lungs), fremitus (voice vibrations transmitted to the chest wall that are heard or felt with the hands), and rales (rattling sound) [11,12]

Inpatient vs outpatient treatment

Overview
  • The IDSA recommends using a validated clinical prediction tool to help determine if patients should be treated in an outpatient or inpatient setting
  • The preferred tool of the IDSA is the Pneumonia Severity Index (see online PSI calculator). This tool requires laboratory information that is only likely to be available in an emergency room setting.
  • The CURB-65 tool (see below) is mentioned as an alternative and may be more practical in a clinic setting
CURB-65 criteria
  • The CURB-65 criteria can be used to help guide decision-making regarding inpatient vs outpatient treatment
  • Patients receive one point for each criteria they meet
  • Patients with a score of 0 - 1 can be treated as outpatients
  • patients with a score ≥ 2 should be hospitalized [1]
  • CURB-65 criteria include:
    • Confusion - disorientation to person, place, or time
    • BUN - > 20 mg/dl (may be excluded in office settings)
    • Respiratory rate - ≥ 30 breaths/min
    • Low Blood pressure - systolic < 90 mmHg or diastolic ≤ 60 mmHg
    • Age ≥ 65 years
  • 30-day mortality based on CURB-65 score:
    • 0 - 0.7%
    • 1 - 2.1%
    • 2 - 9.2%
    • 3 - 14.5%
    • 4 - 40%
    • 5 - 57%

Treatment (2019 IDSA)

Healthy adults (outpatient treatment)
  • One of the following:
    • Amoxicillin 1000 mg three times a day ($)
    • Doxycycline 100 mg twice daily ($)
    • Azithromycin✝ 500 mg on the first day followed by 250 mg once daily ($)
    • Clarithromycin✝ 500 mg twice daily ($)
    • Clarithromycin (extended-release)✝ 1000 mg once daily ($)
    • Duration of treatment: The IDSA does not give specific recommendations for therapy duration, but they state that therapy should last for at least 5 days and until clinical stability is achieved. Clinical stability is defined as normal vital signs, normal mentation, and ability to eat.
  • ✝ Only recommended in areas where pneumococcal resistance to macrolides is < 25% [16]
Adults with comorbid conditions (outpatient treatment)
  • Recommended treatment regimens in patients with any of the following conditions:
    • Chronic heart, lung, liver, or kidney disease
    • Diabetes mellitus
    • Alcoholism
    • Malignancies
    • Asplenic
    • Immunosuppressing conditions or use of immunosuppressing drugs
  • Monotherapy regimens
  • Combination therapy (Beta-lactam + a macrolide or doxycycline)
    • Beta-lactams
    • Macrolide or doxycycline
    • Duration of treatment: The IDSA does not give specific recommendations for therapy duration, but they state that therapy should last for at least 5 days and until clinical stability is achieved. Clinical stability is defined as normal vital signs, normal mentation, and ability to eat.
Influenza season
  • When influenza is circulating in the community, the IDSA recommends testing for influenza (nucleic acid tests preferred) and treating patients who are positive with antiinfluenza medications in addition to antibiotic therapy. Influenza treatment is recommended in positive patients regardless of symptom duration. [16]
Corticosteroids
  • The IDSA recommends against the routine use of corticosteroids in patients with pneumonia [16]

Studies

Beta lactam for 3 days vs 8 days in Adults Hospitalized with CAP, Lancet (2021) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=310 | length = 15 days) in adults hospitalized with moderate-to-severe CAP who had completed 3 days of Augmentin or parenteral third-generation cephalosporin and were clinically stable (afebrile, heart rate < 100, respiratory rate < 24, O2 sat ≥ 90%)
  • Treatment: Augmentin (amoxil 1000 mg/clavulanate 125 mg three times daily) for 5 days vs Placebo
  • Primary outcome: Cure 15 days after the start of antibiotic treatment with beta-lactam therapy. Cure was defined by the following criteria: afebrile; resolution or improvement of clinical signs or symptoms (coughing frequency or severity, sputum production, dyspnea, crackles); and no additional antibiotic treatment (for any reason) since the last follow-up visit
  • Results:
    • Primary outcome: Augmentin - 68%, Placebo - 72% (difference of 9.42%, 95%CI [–0.38 to 20.04])
  • Findings: Among patients admitted to hospital with community-acquired pneumonia who met clinical stability criteria, discontinuing Beta-lactam treatment after 3 days was non-inferior to 8 days of treatment. These findings could allow substantial reduction of antibiotic consumption.
Beta-lactam vs Beta-lactam + Macrolide vs Fluoroquinolone in CAP, NEJM (2015) [PubMed abstract]
  • Design: Cluster-randomized, controlled trial (N=2283 | length = 90 days) in adults with clinically suspected CAP
  • Treatment: Beta-lactam vs Beta-lactam + Macrolide vs Fluoroquinolone. Preferred beta-lactam therapy was amoxicillin, amoxicillin plus clavulanate, or a third-generation cephalosporin.
  • Primary outcome: 90-day mortality
  • Results:
    • Primary outcome: Beta-lactam - 9%, Beta-lactam + macrolide - 11.1%, Fluoroquinolone - 8.8%
  • Findings: Among patients with clinically suspected CAP admitted to non-ICU wards, a strategy of preferred empirical treatment with beta-lactam monotherapy was noninferior to strategies with a beta-lactam–macrolide combination or fluoroquinolone monotherapy with regard to 90-day mortality.
Adjuvant Prednisone vs Placebo for CAP, Lancet (2015) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=785) in hospitalized adults with CAP
  • Treatment: Prednisone 50 mg once daily for 7 days vs Placebo
  • Primary outcome: Time to clinical stability defined as time (days) until stable vital signs for at least 24 hours
  • Results:
    • Primary outcome: Prednisone - median 3 days, Placebo - median 4.4 days (p<0.0001)
  • Findings: Prednisone treatment for 7 days in patients with community-acquired pneumonia admitted to hospital shortens time to clinical stability without an increase in complications. This finding is relevant from a patient perspective and an important determinant of hospital costs and efficiency.
Prednisolone + Evidence-based Care vs Usual Care, JAMA Internal Medicine (2019) [PubMed abstract]
  • Design: Randomized controlled trial (N=917) in hospitalized adults with CAP
  • Treatment: Prednisolone 50 mg once daily for 7 days + evidence-based care vs Usual care
  • Primary outcome: Hospital length of stay, mortality, readmission, and intervention-associated adverse events (eg, gastrointestinal bleeding and hyperglycemia)
  • Results:
    • No significant difference was found between the groups for length of stay, mortality, or readmission
    • In the steroid group, a higher incidence of GI bleeding was observed (2.2% vs 0.7%)
  • Findings: This bundled intervention including adjunctive corticosteroids demonstrated no evidence of effectiveness and resulted in a higher incidence of gastrointestinal bleeding. Efficacy of individual interventions demonstrated in clinical trials may not necessarily translate into effectiveness when implemented in combination and may even result in net harm.

Pneumonia, (Pediatric)

Etiology

Overview
  • In preschool-aged children (2 - 5 years), viruses are responsible for the vast majority of pneumonias, and antibiotics are not routinely required
  • Streptococcus pneumoniae is the most common cause of bacterial pneumonia. Haemophilus influenzae is uncommon since the advent of the H. flu vaccine.
  • Mycoplasma pneumonia is marked by slowly progressing cough, malaise, sore throat, and low-grade fever developing over 3 – 5 days. It's unclear if antibiotics are beneficial in children with Mycoplasma pneumonia. [8]
  • A study published in 2015 found the following etiologies of community-acquired pneumonia in 2222 hospitalized children (median age 2 years):
    • Respiratory Syncytial Virus (RSV) - 28%
    • Human rhinovirus - 27%
    • Human metapneumovirus (HMPV) - 13%
    • Adenovirus - 11%
    • M. pneumoniae - 8%
    • Parainfluenza virus - 7%
    • Influenza virus - 7%
    • Coronavirus - 5%
    • S. pneumoniae - 4%
    • S. aureus - 1%
    • S. pyogenes - 1% [9]

Symptoms

General
  • Cough
  • Fever
  • Sputum production
  • Respiratory distress (see below)
  • Hypoxia
  • Pleuritic chest pain
Signs of respiratory distress in children include:
  • Tachypnea
    • Defined as respiratory rate (breaths/min):
      • Age 0–2 months: > 60
      • Age 2–12 months: > 50
      • Age 1–5 Years: > 40
      • Age > 5 Years: > 20
  • Dyspnea
  • Retractions (suprasternal, intercostals, or subcostal)
  • Grunting
  • Nasal flaring
  • Apnea
  • Altered mental status
  • Pulse oximetry measurement < 90% on room air

Diagnosis

  • Routine chest X-ray is not necessary in children well enough to be treated as outpatients. Patients with signs of respiratory distress should have a chest X-ray.
  • Infants < 6 months old with suspected bacterial pneumonia should be hospitalized
  • Blood and sputum cultures should not be routinely obtained for outpatient treatment
  • In children who recover uneventfully from pneumonia, follow-up chest X-ray is not necessary
  • Patients with respiratory distress should be hospitalized [8]

Treatment (children ≥ 3 months)

NOTE: Recommendations are for previously healthy, appropriately-immunized patients with presumed bacterial pneumonia
First-line (2011 IDSA)
Alternatives
  • Cefpodoxime 10 mg/kg/day given in 2 divided doses for 7 - 10 days ($$-$$$)
  • Cefuroxime 30 mg/kg/day (max 1000 mg/day) given in 2 divided doses for 7 - 10 days ($-$$)
  • Cefprozil 30 mg/kg/day (max 1000 mg/day) given in 2 divided doses for 7 - 10 days ($-$$)
  • Ceftriaxone 50 - 100 mg/kg/day IM (max 2000 mg/day) given once daily for 7 - 10 days ($)
  • Levofloxacin ($$-$$$ for suspension, $ tablet)
    • 6 months - 5 years old: 16 - 20 mg/kg/day given in 2 divided doses for 7 - 10 days
    • 5 - 16 years old: 8 - 10 mg/kg/day (max 750 mg/day) given once daily for 7 - 10 days
  • Linezolid ($$)
    • < 12 years old: 30 mg/kg/day given in 3 divided doses for 7 - 10 days
    • ≥ 12 years old: 20 mg/kg/day (max 1200 mg/day) given in 2 divided doses for 7 - 10 days
For suspected Mycoplasma pneumoniae or Chlamydophila pneumoniae:

Studies

Five vs Ten Days of High-dose Amoxicillin for Pediatric CAP, JAMA Pediatrics (2021) [PubMed abstract]
  • Design: Randomized controlled trial (N=281 | length = 21 days) in children 6 months to 10 years of age (median age 2.6 years) who presented to the ER with CAP and did not require hospitalization
  • Treatment: Five days of high-dose amoxicillin vs Ten days of high-dose amoxicillin
  • Primary outcome: Clinical cure at 14 to 21 days
  • Results:
    • Primary outcome: Five days - 85.7%, Ten days - 84.1%
  • Findings: Short-course antibiotic therapy appeared to be comparable to standard care for the treatment of previously healthy children with CAP not requiring hospitalization. Clinical practice guidelines should consider recommending 5 days of amoxicillin for pediatric pneumonia management in accordance with antimicrobial stewardship principles.


Pricing legend
  • $ = 0 - $50
  • $$ = $51 - $100
  • $$$ = $101 - $150
  • $$$$ = > $151
  • Pricing based on one month of therapy at standard dosing in an adult
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  • Pricing may vary by region and availability