Do We Know How to Diagnose and Treat Pneumonia in

Children?B. Keith English, M.D.

Chair, Pediatrics and Human Development

Pneumonia –

“The Captain of the Men of Death”– (William Osler)

Case Presentation

• Previously healthy 13 yo athlete, began to complain of sore throat at football practice 9/1/09

• Fever and cough that evening; seen by PCP early 9/2/09: begun on oseltamivir and azithromycin

• Evening of 9/2/09: respiratory distress and chest pain

• Walked into Memphis ED at 10:30 pm; appeared ill but O2 sats reportedly 99% on room air

Case Presentation

• Rapidly deteriorated in outside ED; required intubation and then had blood and copious frothy pink secretions suctioned from ETT

• Transported to Le Bonheur Children’s Hospital

• Treated with oseltamivir, vancomycin, azithromycin, meropenem

• Required oscillating ventilator, then ECMO; died four days later

Diagnosis

• Rapid antigen test on admission positive for influenza A; confirmed as the 2009 novel H1N1 influenza A virus by PCR

• Admission blood and tracheal aspirate cultures yielded methicillin-resistant Staphylococcus aureus (MRSA)

• Necrotizing, hemorrhagic pneumonia at autopsy

Influenza Epidemics2006-2009 (4/11/09)

In March 2009, something unusual was occuring in Mexico

VeracruzVeracruz

Novel H1N1 Virus Identified in Two Children in U.S. 4/15/09-4/17/09

In late March, 2009, two children in California had viral Cx that grew influenza A that could not be typed with standard reagents

April 15-17, 2009, CDC received the two isolates and identified a novel H1N1 swine-origin influenza A virus --similar viruses quickly identified from patients from the Mexico outbreak

Emergence of a pandemic S-OIV strain

Segments

1 PB22 PB13 PA4 HA5 NP6 NA7 M8 NS

Human

N.A. Avian “Classic” orEurasian Swine

“Triple reassortant” Swine-origin influenza virus (S-OIV)

Influenza Epidemics and a Pandemic: 2006-2009 (8/13/09)

Influenza Epidemics and a Pandemic: 2006-2009 (10/24/09)

346 patients admitted (210 between 8/25/09 and 10/25/09)

50 admissions to PICU; 5 deaths (4/5 with definite or probable secondary bacterial pneumonia)

Admissions to Le Bonheur Children’s Hospital with confirmed Novel H1N1 influenza: August 2009 – April 2010

Pneumonia in Children

1. Leading cause of death in children less than 5 years of age: estimated 1.6 million deaths each year (98% in the developing world)* -- more than AIDS, malaria and measles combined *(Dagan et al, “The Remaining Challenge of Pneumonia, PIDJ 30: 1-2, 2011)

2. More than 11 million children hospitalized with pneumonia worldwide each year

3. We should know more about it than any other infection ….. but ….

What we DON’T know about pneumonia in children

1. Which children with a clinical diagnosis of bacterial pneumonia actually have bacterial infection?

2. How common is “co-infection” or “secondary infection” in children with pneumonia -- and does this matter?

3. What is the best antibiotic treatment for children (or adults) with bacterial pneumonia caused by specific pathogens? (e.g., Streptococcus pneumoniae)

What we DON’T know about pneumonia in children

Bacterial Pneumonia in Children

• Bacterial pneumonia long presumed to be distinct from viral or “atypical” pneumonia (mycoplasmal, chlamydial) on clinical and radiological grounds

• However, there is considerable overlap; expert radiologists disagree with each other (and with the microbiology results!)

• Recent studies using more sensitive techniques document frequent co-infection (especially viral and bacterial co-infection)

Bacterial Causes of Pneumonia in Children

• Lung puncture studies from 60s and 70s identified Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus as causes of severe bacterial pneumonia in children in the developing world

• Group A streptococcus and enteric gram-negative bacteria also implicated

Etiology of Pneumonia in Children Often Unknown

• Difficult to identify the specific etiology of presumed bacterial pneumonia in children

• -- Collection of sputum samples unreliable

• -- Blood cultures usually negative

• -- Thoracentesis may not be diagnostic after antibiotic therapy

• Only a minority of cases “confirmed” (e.g., positive blood or pleural fluid Cx or PCR)

What we DON’T know about pneumonia in children

Bacterial Pathogens in Pediatric Pneumonia: Dallas (2000)

48 of 154 children (31%) hospitalized with Dx of pneumonia had a single bacterial pathogen identified* (Michelow et al, Pediatrics, 113: 701, 2004)

– Streptococcus pneumoniae 73% (35/48)

– Mycoplasma pneumoniae 23% (11/48)

– Chlamydia pneumoniae 13% (6/48)

– Mycobacterium tuberculosis 2% (1/48)

(* overall 60% of patients had a bacterial pathogen identified while 45% had documented viral infection)

Co-Pathogens in Pediatric Pneumonia: Dallas

Michelow et al, Pediatrics 113: 701, 2004.

Etiology of Pneumonia in Hospitalized Children

o DALLAS

– 154 pts (6 wks -18yrs)

– 60% with documented bacterial infection

– 45% with documented viral infection:

Pneumococcus 44%

Mycoplasma 14%

Chlamydia 9%(Michelow et al, Pediatrics, 113: 701,

2004)

o ATHENS

– 75 pts (5-14 yrs)

– 40% with documented bacterial infection

– 65% with documented viral infection)

o Mycoplasma 35%

Pneumococcus 7%

Chlamydia 3%(Tsolia, et al, Clin Infect Dis 39: 681, 2004)

CDC EPIC Study

“Etiology of Pneumonia in the Community (EPIC)” study funded by the CDC (2009-2012)

Memphis was 1 of 4 national sites for this study – enrolling pediatric patients only (other sites: Vanderbilt, Northwestern, Salt Lake City)

Jain et al NEJM 372: 835, 2015

CDC EPIC Study Aims

Main purposes were to determine:

1. Incidence of hospitalized pneumonia

2.Etiology of pneumonia in hospitalized patients: by evaluating blood, sputum and nasal/throat swabs for respiratory viruses, typical and atypical bacteria --using culture, molecular diagnostics and serology

CDC EPIC Study– Le Bonheur Arm

Study personnel enrolled patients approximately 18 hours/day, 7 days/wk

Le Bonheur enrolled 988 pts in 30 months (most of any site)

CDC EPIC Study

Huge cohort of patients with clinical and radiologic evidence of pneumonia

Testing algorithm likely much more sensitive than any published experience re: identification of viral pathogens

BUT it remains uncertain whether these tests can/will detect most cases of bacterial pneumonia

Etiology of Pneumonia in Children: Le Bonheur Cohort (n=742)

Etiology Number

Typical bacterial 5

Typical bacterial-viral coinfection 26

Atypical bacterial 19

Atypical bacteria-viral coinfection 17

Viral 553

Total number of subjects with etiology identified

620 (84% of cohort)

Arnold et al, IDSA, October, 2012

CDC EPIC Study: Results Most children hospitalized and treated for

pneumonia have viral pneumonia

Less than 10% have documented bacterial pneumonia (pyogenic bacteria plus mycoplasma)

Question remains – what percent of hospitalized children with viral pneumonia have bacterial co-infection that we are unable to document?

What we DON’T know about pneumonia in children

Impact of Beta-Lactam Resistance on Outcome of Bacterial Pneumonia?

• High rates of resistance to penicillins/cephalosporins in Streptococcus pneumoniae -– rare failures

• Community-acquired pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA) – universal failures*

*(ceftaroline clinical trials underway in children)

Cephalosporin Treatment Failures in Pneumococcal Meningitis

Bradley et al - Reported first case of extended spectrum cephalosporin failure in meningitis caused by multi-resistant S. pneumoniae (Pediatr Infect Dis J, 1991;10:871).

Sloas et al - Reported 3 cases of cephalosporin treatment failure in penicillin and cephalosporin resistant S. pneumoniae meningitis in Memphis (cefotaxime MICs 8-32 g/ml) (Pediatr Infect Dis J, 1992;11:662).

Impact of Antibiotic Resistance on Rx of Other Invasive Pneumococcal Infections

Most patients without meningitis will respond to therapy with intravenous beta-lactams, especially if the isolate’s MIC is < 2 g/ml.

Two treatment failure with bone/joint infection due to highly-resistant pneumococci in Memphis (Abbasi et al, PIDJ, 15: 78, 1996)

Possible treatment failures in pneumonia, especially if MIC > 4 g/ml

Beta-Lactams *Usually Adequate Therapy for Pneumonia due to “Non-Susceptible” Pneumococci Barcelona study (Adults): “R” to Pen or Ceph: no effect on

outcome (Pallares, et al, N Engl J Med 333: 474, 1995)

Two large pediatric studies: No increased morbidity or mortality assc with “R” strains

• (A) PMPSSG Study (U.S.) Tan, et al, Pediatrics 102: 1369, 1998

• (B) South American Study Deeks, et al, Pediatr 103: 409, 1999

International Multicenter study (prospective) in adults “R” to Pen/Ceftx/Cefotax: discordant Rx had no effect on outcome (but R to cefuroxime assc with Rx failure) Yu, et al, Clin Infect Dis 37: 230, 2003.

*However, these studies included few infections caused by pneumococci with with Pen/Ceph MICs ≥ 4 g/ml

Beta-Lactam Failures in Rx of pneumococcal pneumonia?

Buckingham et al reported breakthrough bacteremia and meningitis in an 18 mo old treated for pneumonia with cefotaxime/cefuroxime (MICs 2/8 g/ml)

(J Pediatr 132: 174, 1998)

Dowell et al reported cefuroxime failure in 18 mo old with pneumonia (MIC 8 g/ml) (Clin Infect Dis 29:462, 1999)

Beta-Lactam Failures in Rx of pneumococcal pneumonia? II

“Mortality from Invasive Pneumococcal Pneumonia in the Era of Antibiotic Resistance, 1995-1997”

(Feikin, et al, Amer J Public Health 90: 223-9, 2000)

CDC multi-state surveillance project: 5837 cases of pneumococcal pneumonia (98% + BCx, 2% + pl. fluid)

93% of cases were in adults

Beta-Lactam Failures in Rx of pneumococcal pneumonia?

CDC surveillance 95-97

• Case Fatality Rate 12.6% adults; 2.4% children

• Overall mortality not related to Penicillin or Cefotaxime MIC (OR 2.3/1.3)

However, Deaths occurring after 4th hospital day strongly associated with Pen/Cef resistance:

Pen MIC > 4 g/ml: OR 7.1 (95% CI 1.7-30.0)

Cef MIC > 2 g/ml: OR 5.9 (95% CI 1.1-33.0)

But treatment information not available (effect of discordant Rx not examined)

EFFECT OF PENICILLIN ON SURVIVAL IN PATIENTS WITH BACTEREMIC PNEUMOCOCCAL

PNEUMONIA

(Austrian and Gold, Ann Intern Med, 60:759, 1964)

PENICILLIN ( 298 )

SERUM ( 93 )

UNTREATED ( 384 )

DAY OF ILLNESS

%

SU

RV

IVO

RS

Treatment “failures” with beta-lactams are rare

BUT documented failures may be rare because very few infections are caused by isolates with Pen MIC > 8 g/ml (<1%)

Is the Focus on Antibiotic Resistance Missing the Point?

Beta-lactams (and other cell-wall active agents) may not be optimal therapy for severe infections caused by susceptible bacteria

Therapy with alternative agents (alone, or in combination with beta-lactams) that trigger less rapid bacterial lysis and less inflammation may be superior (clear consensus for group A strep necrotizing fasciitis – “Eagle Effect”; strong evidence in experimental pneumococcal meningitis)

Combination Therapy for Severe Pneumococcal Pneumonia ?

Baddour et al reported markedly reduced mortality (23.4 vs. 55.3%) in critically ill adults with bacteremic pneumococcal pneumonia who received combination antibiotic therapy (usually macrolide + beta-lactam) vs beta-lactam alone)(prospective) (Am J Resp Crit Care Med 2004; 15: 440)

Martinez et al reported comparable benefit in adults with pneumococcal pneumonia in two large retrospective studies -- in the 2nd study, benefit was also noted in all patients with CAP

(Clin Infect Dis 2003; 15:396; Eur J Clin Microbiol Infect Dis 2005; 24: 190)

Why Might Combination Therapy Be Superior?

1. Not likely to be synergistic killing based on in vitro or animal model data

2. Anti-inflammatory effects of macrolides ?

3. Indirect effects on host response because of reduced/delayed bacterial lysis?

4. Modulation of bacterial virulence factor expression?

5. Effect on co-pathogens? (unlikely)

Combination Therapy for Severe Pediatric Pneumonia?

Much lower mortality rate in children with pneumococcal pneumonia

Macrolide frequently part of empiric therapy for older children (to cover mycoplasma/chlamydia)

High rates of macrolide resistance in pneumococci causing pediatric infections make these drugs poor options for monotherapy

Predominant Role of Bacterial Pneumonia as a Cause of Death in Pandemic Influenza: Implications for Pandemic Influenza Preparedness

David M. Morens, Jeffery K. Taubenberger, and Anthony S. Fauci

National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland

Journal of Infectious Diseases 2008; 198:962–70

“If grippe condemns, the secondary infections execute”

Louis Cruveilhier, 1919

Influenza-Pneumococcus Synergy In Mice

McCullers, J Infect Dis 190: 519, 2004

Days 1 3 5 7 8 2 4 6 0

# Mice withPneumonia /

Total

8/8

# Mice Dead /Mice with Pneumonia

8/8

Influenza-Pneumococcus Synergy:Mice Treated with Ampicillin Alone Die

Mouse #1

2

3

4

5

McCullers, J Infect Dis 190: 519, 2004

Azithromycin superior to ampicillin in mouse model of

post-influenzal pneumococcal pneumonia

-

p < 0.05 by log rank test compared to all other groups

Karlström, Boyd, English and McCullers, J Infect Dis 2009;199:311.

Macrolides as Adjunctive Rx of Pneumonia?

• Is the effect non-specific (as seen in cystic fibrosis, in Asian patients with panbronchiolitis) or specific – e.g, would it be seen on Azithromycin-Resistant bacteria?

• (40-50% of pneumococci isolated at Le Bonheur are macrolide-resistant)

Kar

Karlstrom et al, Infect Dis. 2011, 204:1358-66

2011 PIDS/IDSA Pneumonia Guidelines

Clinical Infectious Diseases 2011; 53: 617-630.

2011 PIDS/IDSA Pneumonia Guidelines: Outpatients

Amoxicillin still best outpatient agent (90 mg/kg/day recommended)

Amoxicillin-clavulanate alternative

Clindamycin or levofloxacin or linezolid recommended for infections caused by highly-beta-lactam resistant pneumococci (PCN MIC >/= 4)

2011 PIDS/IDSA Pneumonia Guidelines: Inpatients

IV ampicillin or ceftriaxone/cefotaxime best choice for most hospitalized children

Add clindamycin or vancomycin if Staph aureus suspected (e.g., severe or complicated pneumonia)

Role of combination therapy uncertain – possible benefit in severe cases

Duration of Therapy for Complicated Pneumonia?

10 days of therapy recommended for uncomplicated pneumonia

Shorter courses likely effective in mild disease; longer treatment “may be required” for infections caused by MRSA, etc (weak evidence)

Longer courses – 2-4 weeks – recommended for patients with pneumonia complicated by parapneumonic effusion/empyema (weak evidence)

Route of Therapy for Complicated Pneumonia?

Oral vs IV choice –

– Depends on …

– Patient factors (age, home situation, availability of followup),

– The pathogen (e.g., Staph vs pneumococcus)

– Susceptibility results (e.g., clindamycin, linezolid. or levofloxacin highly bioavailable given by mouth)

No “one size fits all” recommendation

Prevention of Pneumonia I

Vaccines directed at influenza (and, eventually, other respiratory viruses) and pneumococcus can prevent many cases of pneumonia in children

Efforts to develop a Staph vaccine remain problematic; a promising group A strep vaccine is in clinical trials

Prevention of Pneumonia II

• First generation conjugated pneumococcal vaccine (PCV7) associated with 25-30% reduction in all pneumonia (CXR-confirmed, per WHO criteria (Hansen et al, PIDJ 25: 779, Sept, 2006)

• However, 44% of complicated pneumonias in one large U.S. study* were caused by pneumococcal serotypes not in PCV7

*Tan et al, Pediatrics, 2002: 110: 1-6.

Prevention of Pneumonia III

• PCV13 includes serotypes 1 and 3 and more than 80% of the serotypes causing complicated pneumonia in the U.S.

• Synergy between influenza vaccine and pneumococcal vaccine in preventing pneumonia