Infectious Disorders of the Lung Parenchyma

Infectious Infectious Disorders of the Disorders of the

Lung Lung ParenchymaParenchyma

Matthew L. Paden, MDMatthew L. Paden, MDPediatric Critical Care FellowPediatric Critical Care Fellow

Emory UniversityEmory UniversityChildren’s Healthcare of Atlanta Children’s Healthcare of Atlanta

at Eglestonat Egleston

ObjectivesObjectives

Worldwide epidemiology of the Worldwide epidemiology of the problemproblem

Review common etiologiesReview common etiologies Discuss empirical and disease Discuss empirical and disease

specific treatmentspecific treatment

EpidemiologyEpidemiology World wideWorld wide

Leading cause of Leading cause of death in childrendeath in children

More than AIDS, More than AIDS, malaria, and measles malaria, and measles combinedcombined

Most deaths in < 5 yoMost deaths in < 5 yo United statesUnited states

33rdrd leading cause of leading cause of hospitalization for hospitalization for kidskids

2% of deaths (5% 2% of deaths (5% including neonates)including neonates)

http://www.who.int/child-adolescent-health/publications/http://www.who.int/child-adolescent-health/publications/CHILD_HEALTH/ISBN_92_806_4048_8.htmCHILD_HEALTH/ISBN_92_806_4048_8.htm

Worldwide EpidemiologyWorldwide Epidemiology

Cases Cases 150 million150 million

Hospitalizations Hospitalizations 11-20 million11-20 million

DeathsDeaths 2 million2 million

Barriers to careBarriers to care

Recognizing Recognizing there is a there is a problemproblem

Seek appropriate Seek appropriate carecare

Treatment with Treatment with antibioticsantibiotics

PreventionPrevention

Adequate nutritionAdequate nutrition Exclusive breastfeedingExclusive breastfeeding

Less than 1 yo, get any formula – 5 X Less than 1 yo, get any formula – 5 X increased risk of death from pneumoniaincreased risk of death from pneumonia

Zinc supplementationZinc supplementation


ImmunizationImmunization Measles –Measles –

Pneumonia is what they die of – often super-Pneumonia is what they die of – often super-infectioninfection

World-wide coverage rate – 76% in 2004World-wide coverage rate – 76% in 2004 Still having 30-40 million cases a yearStill having 30-40 million cases a year

HIB –HIB – 2-3 million cases of severe disease a year2-3 million cases of severe disease a year In 2003, developed world coverage – 92%In 2003, developed world coverage – 92% Developing world – 42%Developing world – 42% Least developed countries – 8%Least developed countries – 8%


ImmunizationImmunization Strep pneumo –Strep pneumo –

7 –valent vaccine (Prevnar) in the US7 –valent vaccine (Prevnar) in the US 9, 11, or 13 valent vaccine for the rest of 9, 11, or 13 valent vaccine for the rest of

the worldthe world Gambia – 17,000 childrenGambia – 17,000 children

37% reduction in pneumonia37% reduction in pneumonia 15% reduction in hospitalization15% reduction in hospitalization 16% reduction in mortality16% reduction in mortality

Costs involvedCosts involved

More than 1 million deaths a year can be More than 1 million deaths a year can be prevented with treatment and preventionprevented with treatment and prevention

600,000 lives saved by just treatment alone600,000 lives saved by just treatment alone Cost analysisCost analysis

Antibiotic treatment course- Antibiotic treatment course- $ 0.27$ 0.27

$ 600 million total cost including :$ 600 million total cost including : Cost of antibioticsCost of antibiotics Cost of hospital staysCost of hospital stays Increasing training of health care staffIncreasing training of health care staff Increasing physical plants to take care of these Increasing physical plants to take care of these

patients patients

Costs involvedCosts involved

Those costs inflated by Mexico and Those costs inflated by Mexico and BrazilBrazil

85% of deaths are in sub-Saharan 85% of deaths are in sub-Saharan Africa and southeast AsiaAfrica and southeast Asia $200 million dollars will expand $200 million dollars will expand

coverage to those regions only and coverage to those regions only and potentially fix 85% of the problem potentially fix 85% of the problem

Potential solutionsPotential solutions One F-22 fighter - $183 millionOne F-22 fighter - $183 million 1997-2003, Defense Department purchased and then left

unused approximately 270,000 fully refundable commercial airline tickets at a total cost of $100 million.

$4,000,000 for the Northern Line Extension A direct 82 mile train route from North Pole (pop. 1,778 in

2005) to Delta Junction (pop. 840 in 2000) $9,500,000 for the Extended Cold Weather Clothing

System $8,000,000 added by the Senate for special assistance

DOD Dependents Education. $5,500,000 for The Ernest Gallo Clinic and Research

Center at (USCF) to study basic neuroscience and the effects of alcohol and drug abuse on the brain.”

$1,650,000 to improve the shelf life of vegetables “This project will help our troops in the field get fresh tomatoes…”

DiagnosisDiagnosis

TachypneaTachypnea Sensitive but not specificSensitive but not specific

Higher specificityHigher specificity Decreased breath soundsDecreased breath sounds Inspiratory ralesInspiratory rales Chest wall retractionsChest wall retractions Nasal flaringNasal flaring

Absence of fever has high negative Absence of fever has high negative predictive value for bacterial predictive value for bacterial pneumoniapneumonia

EtiologiesEtiologies

Streptococcus pneumoniaeStreptococcus pneumoniae Most common cause outside of neonatal Most common cause outside of neonatal

periodperiod Nasopharyngeal colonization – 50% of Nasopharyngeal colonization – 50% of

kidskids >90 serotypes – majority of invasive >90 serotypes – majority of invasive

disease caused by 10 serotypesdisease caused by 10 serotypes Bacteremia in 25-30% of kidsBacteremia in 25-30% of kids Gram stain – gram positive lancet shaped Gram stain – gram positive lancet shaped

diplococci (“gram positive cocci in pairs”)diplococci (“gram positive cocci in pairs”)

Age differencesAge differences

Adults – lobar Adults – lobar pneumoniapneumonia

Kids – lobar or Kids – lobar or bronchopneumoniabronchopneumonia

Treatment - Streptococcus Treatment - Streptococcus pneumoniaepneumoniae

2002 CDC 2002 CDC Surveillance dataSurveillance data 20% PCN resistant20% PCN resistant 4% Cefotaxime 4% Cefotaxime

resistantresistant 0% Vancomycin 0% Vancomycin

resistantresistant 2003-2004 FAST 2003-2004 FAST

Surveillance dataSurveillance data 56% PCN resistant56% PCN resistant

Geographically-based evaluation of multi-drug resistance trends among Streptococcus pneumoniae in the USA: findings of the FAST surveillance initiative (2003-2004). Int J Antimicrob Agents. 2006 Dec;28(6):525-31.

2006 CHOA Data2006 CHOA Data

OrganisOrganismm

VanVancc

CTX ICTX I CTX RCTX R PCN IPCN I PCN PCN RR

ECH ECH Strep Strep pneumopneumo

0%0% 21/1421/14%%

20/6 20/6 %%

14 %14 % 46 %46 %

SRH SRH Strep Strep pneumopneumo

0 %0 % 26/9 26/9 %%

7/8 %7/8 % 34 %34 % 31 %31 %

Percent of organisms tested that have intermediate or resistant sensitivity patterns

Treatment – Strep Treatment – Strep pneumopneumo

Mechanism of resistance – Mechanism of resistance – PCN and Cephalosporins – change in PCN and Cephalosporins – change in

penicillin binding proteins (NOT beta penicillin binding proteins (NOT beta lactamase)lactamase)

Empiric : 3Empiric : 3rdrd generation generation cephalosporin + vancomycin until cephalosporin + vancomycin until sensitivities are confirmedsensitivities are confirmed


Staphylococcus aureusStaphylococcus aureus Common cause of ventilator associated Common cause of ventilator associated

and nosocomial pneumoniaand nosocomial pneumonia Community acquired disease usually Community acquired disease usually

coincident with viral infection coincident with viral infection (influenza)(influenza) Viral hemagglutinins – inhibit neutrophil Viral hemagglutinins – inhibit neutrophil

and monocyte activationand monocyte activation Gram stain – gram positive cocci in Gram stain – gram positive cocci in

grape like clustersgrape like clusters

Diagnosis – Staphylococcal Diagnosis – Staphylococcal pneumoniapneumonia

Classically a lobar Classically a lobar consolidation on consolidation on CXRCXR

Raise suspicion of Raise suspicion of staphstaph PneumatocelesPneumatoceles Pleural effusionPleural effusion Air fluid levelsAir fluid levels NecrosisNecrosis

Treatment – Staphylococcus Treatment – Staphylococcus aureusaureus

Treatment has changed over the past 5 Treatment has changed over the past 5 years with emergence of caMRSAyears with emergence of caMRSA

Empiric therapy with VancomycinEmpiric therapy with Vancomycin VISA (1996, Japan, 1997 US) VISA (1996, Japan, 1997 US)

Mechanism – thickening of cell membrane – decreased Mechanism – thickening of cell membrane – decreased penetration of vancomycin – unclear mechanism penetration of vancomycin – unclear mechanism

VRSA (2002, US)VRSA (2002, US) Mechanism – VanA from enterococcus – changes d-Mechanism – VanA from enterococcus – changes d-

alanine, d-alanine terminus to d-alanine, d-lactate – alanine, d-alanine terminus to d-alanine, d-lactate – reduces affinity by 1,000 foldreduces affinity by 1,000 fold

VDSA VDSA

2006 CHOA Data2006 CHOA Data

OrganisOrganismm

VanVancc

ClindClinda*a*

BactriBactrimm

RifampRifampinin

GentGent

ECH ECH MRSAMRSA

0%0% 14%14% 1 %1 % 1 %1 % 1 %1 %

SRH SRH MRSAMRSA

0 %0 % 13 %13 % 1 %1 % 1 %1 % 3 %3 %

• ECH total % MRSA 53% SRH total % MRSA 51%

* Not adjusted for inducible resistance

Staph Aureus treatmentStaph Aureus treatment

Get off Vancomycin if MSSAGet off Vancomycin if MSSA MSSA much more susceptible to NafcillinMSSA much more susceptible to Nafcillin Use of Vancomycin or first-generation Use of Vancomycin or first-generation

Cephalosporins for the treatment of hemodialysis-Cephalosporins for the treatment of hemodialysis-dependent patients with methicillin-susceptible dependent patients with methicillin-susceptible Staphylococcus aureus bacteremia. Clin Infect Staphylococcus aureus bacteremia. Clin Infect Dis. 2007 Jan 15;44(2):190-6.Dis. 2007 Jan 15;44(2):190-6.

Treatment failure - Vancomycin 31.2% vs. Ancef 13% ; Treatment failure - Vancomycin 31.2% vs. Ancef 13% ; p=.02p=.02

Multivariable analysis - factors independently associated Multivariable analysis - factors independently associated with treatment failure included Vancomycin use (odds with treatment failure included Vancomycin use (odds ratio, 3.53; 95% confidence interval, 1.15-13.45) ratio, 3.53; 95% confidence interval, 1.15-13.45)

Staph aureus treatmentStaph aureus treatment Get off Vancomycin if MSSAGet off Vancomycin if MSSA

Staphylococcus aureus bacteremia and endocarditis: Staphylococcus aureus bacteremia and endocarditis: the Grady Memorial Hospital experience with the Grady Memorial Hospital experience with methicillin-sensitive S aureus and methicillin-resistant S methicillin-sensitive S aureus and methicillin-resistant S aureus bacteremia. Am Heart J. 2004 Mar;147(3):536-9. aureus bacteremia. Am Heart J. 2004 Mar;147(3):536-9.

MSSA bacteremia is associated with higher rates of MSSA bacteremia is associated with higher rates of endocarditis than MRSA. endocarditis than MRSA.

Comparative activity of cloxacillin and vancomycin Comparative activity of cloxacillin and vancomycin against methicillin-susceptible Staphylococcus aureus against methicillin-susceptible Staphylococcus aureus experimental endocarditis.experimental endocarditis.J Antimicrob Chemother. 2006 Nov;58(5):1066-9.J Antimicrob Chemother. 2006 Nov;58(5):1066-9.

Cloxacillin produced a greater decrease in the number of Cloxacillin produced a greater decrease in the number of staphylococci than vancomycin staphylococci than vancomycin

41% of rabbits had sterile vegetations in comparison with 41% of rabbits had sterile vegetations in comparison with 0% with vancomycin (p=0.035)0% with vancomycin (p=0.035)

New horizonsNew horizons Anti-MRSA beta-lactams in development, with a Anti-MRSA beta-lactams in development, with a

focus on ceftobiprole: the first anti-MRSA beta-focus on ceftobiprole: the first anti-MRSA beta-lactam to demonstrate clinical efficacy. Expert lactam to demonstrate clinical efficacy. Expert Opin Investig Drugs. 2007 Apr;16(4):419-29. Opin Investig Drugs. 2007 Apr;16(4):419-29. Investigational beta-lactam antibiotic against Investigational beta-lactam antibiotic against

methicillin-resistant staphylococci, enterococcus methicillin-resistant staphylococci, enterococcus faecalis, penicillin-resistant streptococci and many faecalis, penicillin-resistant streptococci and many Gram-negative pathogens. Gram-negative pathogens.

Completed Phase III therapeutic trialsCompleted Phase III therapeutic trials PPI0903 - injectable pro-drug of a broad-PPI0903 - injectable pro-drug of a broad-

spectrum cephalosporin with anti-MRSA activityspectrum cephalosporin with anti-MRSA activity RO4908643 - a carbapenem with anti-MRSA RO4908643 - a carbapenem with anti-MRSA

activityactivity


Pseudomonas aeruginosaPseudomonas aeruginosa Common cause of bacterial nosocomial Common cause of bacterial nosocomial

pneumoniapneumonia More common in CF, tracheostomy More common in CF, tracheostomy

dependant, or immunocompromiseddependant, or immunocompromised Oxidase positive gram negative rodOxidase positive gram negative rod

Pseudomonas treatmentPseudomonas treatment

Antibiotic resistance commonAntibiotic resistance common Mechanism – extended spectrum beta-Mechanism – extended spectrum beta-

lactamaselactamase Implication – serious or life-threatening Implication – serious or life-threatening

infections should not be treated with an anti-infections should not be treated with an anti-pseudomonal synthetic pseudomonal synthetic penicillin/cephalosporin/carbapenem alonepenicillin/cephalosporin/carbapenem alone

Empiric therapy – anti-pseudomonal PCN Empiric therapy – anti-pseudomonal PCN + an aminoglycoside+ an aminoglycoside Role of monotherapy has not been well defined.Role of monotherapy has not been well defined.


Antibiotic choicesAntibiotic choices Anti-pseudomonal synthetic penicillinAnti-pseudomonal synthetic penicillin

Ticarcillin +/- clavulanateTicarcillin +/- clavulanate Piperacillin +/- tazobactamPiperacillin +/- tazobactam


Antibiotic choicesAntibiotic choices Anti-pseudomonal synthetic penicillinAnti-pseudomonal synthetic penicillin

Ticarcillin +/- clavulanateTicarcillin +/- clavulanate Piperacillin +/- tazobactamPiperacillin +/- tazobactam

Mechanism of ActionMechanism of Action Inhibits bacterial cell wall synthesis by binding Inhibits bacterial cell wall synthesis by binding

to one or more of the penicillin-binding proteinsto one or more of the penicillin-binding proteins Inhibits the final transpeptidation step of Inhibits the final transpeptidation step of

peptidoglycan synthesis in bacterial cell walls peptidoglycan synthesis in bacterial cell walls Clavulanate and tazobactam prevents Clavulanate and tazobactam prevents

degradation of the PCN by binding to beta-degradation of the PCN by binding to beta-lactamases lactamases


Antibiotic choicesAntibiotic choices Anti-pseudomonal synthetic penicillinAnti-pseudomonal synthetic penicillin 44thth generation cephalosporin – cefepime generation cephalosporin – cefepime

Ceftazidime – 2Ceftazidime – 2ndnd generation with generation with pseudomonas activitypseudomonas activity


Antibiotic choicesAntibiotic choices 44thth generation cephalosporin – cefepime generation cephalosporin – cefepime Mechanism of Action Mechanism of Action

Inhibits bacterial cell wall synthesis by Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding to one or more of the penicillin-binding proteinsbinding proteins

Inhibits the final transpeptidation step of Inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell peptidoglycan synthesis in bacterial cell walls walls


Antibiotic choicesAntibiotic choices Anti-pseudomonal synthetic penicillinAnti-pseudomonal synthetic penicillin 44thth generation cephalosporin – cefepime generation cephalosporin – cefepime Carbapenems – imipenem-cilastatin or Carbapenems – imipenem-cilastatin or

meropenemmeropenem


Antibiotic choicesAntibiotic choices Carbapenems – imipenem-cilastatin or Carbapenems – imipenem-cilastatin or

meropenemmeropenem Mechanism of Action Mechanism of Action

Inhibits cell wall synthesis by binding to Inhibits cell wall synthesis by binding to penicillin-binding proteins (PBPs) with its penicillin-binding proteins (PBPs) with its strongest affinities for PBPs 2, 3 and 4 of strongest affinities for PBPs 2, 3 and 4 of E. E. colicoli and and P. aeruginosaP. aeruginosa and PBPs 1, 2 and 4 of and PBPs 1, 2 and 4 of S. aureusS. aureus

Meropenem reduces valproate levels by Meropenem reduces valproate levels by ~40% ~40%



meropenemmeropenem AztreonamAztreonam


Antibiotic choicesAntibiotic choices AztreonamAztreonam Mechanism of ActionMechanism of Action

Binds to penicillin-binding protein 3 which Binds to penicillin-binding protein 3 which produces filamentation of the bacterium produces filamentation of the bacterium inhibiting bacterial cell wall synthesis and inhibiting bacterial cell wall synthesis and causing cell wall destruction causing cell wall destruction



meropenemmeropenem AztreonamAztreonam Fluroquinolones – ciprofloxacin, Fluroquinolones – ciprofloxacin,

levofloxacin, etc.levofloxacin, etc.


Antibiotic choicesAntibiotic choices Fluroquinolones – ciprofloxacin, Fluroquinolones – ciprofloxacin,

levofloxacin, etc.levofloxacin, etc. Mechanism of Action Mechanism of Action

Inhibits DNA-gyrase and topoisomerase IV Inhibits DNA-gyrase and topoisomerase IV in susceptible organisms; inhibits relaxation in susceptible organisms; inhibits relaxation of supercoiled DNA and promotes breakage of supercoiled DNA and promotes breakage of double-stranded DNA of double-stranded DNA




levofloxacin, etc.levofloxacin, etc. Aminoglycosides – amikacin, gentamicin, Aminoglycosides – amikacin, gentamicin,

tobramycin tobramycin


Antibiotic choicesAntibiotic choices Aminoglycosides – amikacin, Aminoglycosides – amikacin,

gentamicin, tobramycingentamicin, tobramycin Mechanism of Action Mechanism of Action

Inhibits cellular initiation of bacterial Inhibits cellular initiation of bacterial protein synthesis by binding to 30S and 50S protein synthesis by binding to 30S and 50S ribosomal subunits resulting in a defective ribosomal subunits resulting in a defective bacterial cell membranebacterial cell membrane




levofloxacin, etc.levofloxacin, etc. Aminoglycosides – amikacin, gentamicin, Aminoglycosides – amikacin, gentamicin,

tobramycin tobramycin So which to choose?

2006 CHOA Data - 2006 CHOA Data - PseudomonasPseudomonas

SiteSite TimTimentientinn

ZosyZosynn

FortFortazaz

CefeCefepimpimee

MerreMerremm

AztrAztreoneonamam

CiprCiproo

AmiAmikacikacinn

GentGent TobrTobraa

ECECHH

12 12 %%

6 %6 % 13 %13 % 16 16 %%

12 %12 % 24 24 %%

8 %8 % 12 %12 % 20 %20 % 13 %13 %

SRSRHH

6 %6 % 2 %2 % 4 %4 % 11 11 %%

8 %8 % n/an/a 14 %14 % 10 %10 % 29 %29 % 16 %16 %

* No CF patients included

2006 CHOA Data - 2006 CHOA Data - PseudomonasPseudomonas

SiteSite TimTimentientinn

ZosyZosynn

FortFortazaz

CefeCefepimpimee

MerreMerremm

AztrAztreoneonamam

CiprCiproo

AmiAmikacikacinn

GentGent TobrTobraa

ECECHH

12 12 %%

6 %6 % 13 %13 % 16 16 %%

12 %12 % 24 24 %%

8 %8 % 12 %12 % 20 %20 % 13 %13 %

SRSRHH

6 %6 % 2 %2 % 4 %4 % 11 11 %%

8 %8 % n/an/a 14 %14 % 10 %10 % 29 %29 % 16 %16 %

* No CF patients included


““Atypical” PneumoniasAtypical” Pneumonias Mycoplasma pneumoniaeMycoplasma pneumoniae Chlamydia pneumoniaeChlamydia pneumoniae Legionella pneumophiliaLegionella pneumophilia

Common cause of pneumonia in Common cause of pneumonia in school age childrenschool age children Persistent cough (for weeks after Persistent cough (for weeks after

infection has cleared)infection has cleared)

““Atypical” Pneumonia Atypical” Pneumonia diagnosisdiagnosis

Mycoplasma – clinical picture + Mycoplasma – clinical picture + serologic testingserologic testing Cold agglutinins are not specificCold agglutinins are not specific Complications – arthritis, hemolysis, Complications – arthritis, hemolysis,

pericardial effusions, myocarditis, pericardial effusions, myocarditis, encephalitis, Stevens-Johnson syndromeencephalitis, Stevens-Johnson syndrome Antibiotic therapy has not been conclusively Antibiotic therapy has not been conclusively

shown to help non-pulmonary shown to help non-pulmonary manifestationsmanifestations

““Atypical” Pneumonia Atypical” Pneumonia diagnosisdiagnosis

Legionella pneumophiliaLegionella pneumophilia Severe disease in immunocompromisedSevere disease in immunocompromised

Respiratory failure, pericarditisRespiratory failure, pericarditis Classic history triggers – exposure to Classic history triggers – exposure to

travel, hot tubs, or hospitalizationtravel, hot tubs, or hospitalization DFA, culture, and serology availableDFA, culture, and serology available Urinary antigen – good sensitivity and Urinary antigen – good sensitivity and

specificityspecificity

““Atypical” Pneumonia Atypical” Pneumonia treatment treatment

Macrolide antibiotics Macrolide antibiotics ErythromycinErythromycin AzithromycinAzithromycin

Mechanism of Action Mechanism of Action Inhibits bacterial RNA-dependent Inhibits bacterial RNA-dependent

protein synthesis by binding to the 50S protein synthesis by binding to the 50S ribosomal subunit which results in the ribosomal subunit which results in the blockage of transpeptidation blockage of transpeptidation


ViralViral Respiratory syncytial virusRespiratory syncytial virus ParainfluenzaParainfluenza InfluenzaInfluenza AdenovirusAdenovirus Human metapneumovirusHuman metapneumovirus HantavirusHantavirus

Respiratory syncytial Respiratory syncytial virusvirus

Enveloped, single Enveloped, single stranded, negative stranded, negative polarity RNA polarity RNA paramyxovirusparamyxovirus

Seasonality – Seasonality – November through November through MayMay

Respiratory syncytial virus Respiratory syncytial virus diagnosisdiagnosis

Viral culture is gold standardViral culture is gold standard DFA and PCR availableDFA and PCR available

PICU presentationPICU presentation Upper airway obstructionUpper airway obstruction Lower airway obstructionLower airway obstruction PneumoniaPneumonia ApneaApnea


Upper airway obstructionUpper airway obstruction LaryngotracheobronchitisLaryngotracheobronchitis

If fails traditional management (steroids, If fails traditional management (steroids, oxygen, epinephrine, heliox, etc.) and is oxygen, epinephrine, heliox, etc.) and is intubated get endotracheal aspirate for intubated get endotracheal aspirate for bacterial superinfectionbacterial superinfection

Often staph or strep Often staph or strep


Lower airway obstructionLower airway obstruction Clinically bronchiolitisClinically bronchiolitis Increasing airway edema and mucous Increasing airway edema and mucous

secretion worsen the obstructionsecretion worsen the obstruction CXR confirms hyperinflation and patchy CXR confirms hyperinflation and patchy

infiltratesinfiltrates Intubated patients commonly co-Intubated patients commonly co-

infected with moraxellainfected with moraxella

Respiratory syncytial virus Respiratory syncytial virus treatmenttreatment

Lower airway obstructionLower airway obstruction Treatment –Treatment –

OxygenOxygen +/- nebulized B-agonists or epinephrine+/- nebulized B-agonists or epinephrine +/- nasal suctioning+/- nasal suctioning +/- vasoconstrictive nasal drops+/- vasoconstrictive nasal drops +/- NIPPV+/- NIPPV Mechanical ventilation based on reduction Mechanical ventilation based on reduction

of obstructionof obstruction Lower rates and maximizing expiratory time Lower rates and maximizing expiratory time

Respiratory syncytial virus Respiratory syncytial virus treatmenttreatment

Lower airway obstructionLower airway obstruction Treatment –Treatment –

Steroids – RSV alone, no efficacy in Steroids – RSV alone, no efficacy in reducing stayreducing stay

Ribivirin – only FDA approved drug for RSVRibivirin – only FDA approved drug for RSV Many complications and expensiveMany complications and expensive May have a role in the immunocompromisedMay have a role in the immunocompromised


RSV PneumoniaRSV Pneumonia Similar presentation as bronchiolitisSimilar presentation as bronchiolitis Different pathophysiology – alveolar Different pathophysiology – alveolar

filling and consolidationfilling and consolidation CXRCXR

Discrete infiltrate and lack of hyperinflationDiscrete infiltrate and lack of hyperinflation Greater degree of hypoxiaGreater degree of hypoxia More likely to progress to ARDSMore likely to progress to ARDS


RSV ApneaRSV Apnea Not well describedNot well described More common with increasing More common with increasing

prematurityprematurity Polysomnography implies it is central Polysomnography implies it is central

apneaapnea Pathophysiology – signaling from Pathophysiology – signaling from

pulmonary nerves through the GABA and pulmonary nerves through the GABA and substance P pathwayssubstance P pathways Pediatr Res. 2005 Jun;57(6):819-25.Pediatr Res. 2005 Jun;57(6):819-25.



Parainfluenza diagnosisParainfluenza diagnosis

Enveloped, single stranded, negative Enveloped, single stranded, negative polarity RNA paramyxoviruspolarity RNA paramyxovirus

Similar presentations to RSVSimilar presentations to RSV Viral culture is gold standardViral culture is gold standard DFA or PCR availableDFA or PCR available 4 different virus types4 different virus types

Type 1 epidemic every other yearType 1 epidemic every other year

Parainfluenza seasonalityParainfluenza seasonality

Parainfluenza treatmentParainfluenza treatment

Similar supportive care to RSVSimilar supportive care to RSV May be a role for both inhaled and May be a role for both inhaled and

intravenous ribivirin in intravenous ribivirin in immunosuppressed patientsimmunosuppressed patients



Influenza diagnosisInfluenza diagnosis

Negative sense, single stranded RNA Negative sense, single stranded RNA virusesviruses

Type A and B responsible for majority of Type A and B responsible for majority of illnessesillnesses

Hemagglutinin – viral binding to Hemagglutinin – viral binding to respiratory epithelial cells vial sialic acidrespiratory epithelial cells vial sialic acid

Neuroaminidase – cleaves sialic acid Neuroaminidase – cleaves sialic acid residues once virus has multiplied in the residues once virus has multiplied in the cell allowing viral spreadcell allowing viral spread

Influenza Viral Life CycleInfluenza Viral Life Cycle


Clinical markersClinical markers Other manifestationsOther manifestations

LaryngotracheobronchitisLaryngotracheobronchitis MyocarditisMyocarditis RhabdomyolysisRhabdomyolysis Reye’s syndromeReye’s syndrome EncephalitisEncephalitis Staph superinfectionStaph superinfection


Viral culture is gold standardViral culture is gold standard DFA, PCR, and rapid immunoassays DFA, PCR, and rapid immunoassays

availableavailable

Influenza treatmentInfluenza treatment

Amantidine or rimantidineAmantidine or rimantidine Inhibits influenza M2 proteins and Inhibits influenza M2 proteins and

prevent viral uncoatingprevent viral uncoating Need to give early or no benefitNeed to give early or no benefit Resistance is documentedResistance is documented

Oseltamivir and zanamivirOseltamivir and zanamivir Neuroaminidase inhibitors Neuroaminidase inhibitors



Adenovirus diagnosisAdenovirus diagnosis Specifically types 3 and 7Specifically types 3 and 7 Rapidly evolving life threatening Rapidly evolving life threatening

pneumonia with necrosis, pulmonary pneumonia with necrosis, pulmonary hemorrhage and bronchiolitis obliteranshemorrhage and bronchiolitis obliterans

Survival dependant on degree of injurySurvival dependant on degree of injury Viral culture is gold standardViral culture is gold standard DFA, PCR, rapid ELISA are availableDFA, PCR, rapid ELISA are available ECLS an optionECLS an option

Extracorporeal life support for the treatment of Extracorporeal life support for the treatment of viral pneumonia: collective experience from the viral pneumonia: collective experience from the ELSO registry. Extracorporeal Life Support ELSO registry. Extracorporeal Life Support Organization. J Pediatr Surg. 1997 Organization. J Pediatr Surg. 1997 Feb;32(2):232-6.Feb;32(2):232-6.



Human metapneumovirus Human metapneumovirus diagnosisdiagnosis

Also a paramyxovirusAlso a paramyxovirus In children and infants notable cause of lower In children and infants notable cause of lower

respiratory tract infectionsrespiratory tract infections Bronchiolitis (59%)Bronchiolitis (59%) Croup (18%)Croup (18%) Asthma exacerbations (14%)Asthma exacerbations (14%) Pneumonia (8%). Pneumonia (8%).

Symptoms very similar to RSV (cough 90%; Symptoms very similar to RSV (cough 90%; dyspnea 83%; coryza 88%; fever 52-92%)dyspnea 83%; coryza 88%; fever 52-92%)

Can cause severe disease in BMT patientsCan cause severe disease in BMT patients PCR based diagnosis at this pointPCR based diagnosis at this point Supportive treatmentSupportive treatment



Hantavirus diagnosisHantavirus diagnosis

A negative sense, single stranded RNA A negative sense, single stranded RNA virus of the bunyaviridae familyvirus of the bunyaviridae family

Multiple different viruses worldwideMultiple different viruses worldwide Four corners region - Sin Nombre virusFour corners region - Sin Nombre virus All other bunyaviridae have arthropod All other bunyaviridae have arthropod

vectorsvectors Hantavirus – vector is the deer mouseHantavirus – vector is the deer mouse

8% of hantavirus infections in US are 8% of hantavirus infections in US are childrenchildren 33% mortality (similar to adults)33% mortality (similar to adults)

Hantavirus infectionHantavirus infection

Exposure/Travel historyExposure/Travel history Clinical syndromeClinical syndrome

FeverFever Fulminant bilateral pulmonary diseaseFulminant bilateral pulmonary disease Cardiogenic shockCardiogenic shock Pulmonary edemaPulmonary edema


Laboratory syndromeLaboratory syndrome HemoconcentrationHemoconcentration ThrombocytopeniaThrombocytopenia LeukocytosisLeukocytosis Absence of granules in neutrophilsAbsence of granules in neutrophils Immunoblasts on smearImmunoblasts on smear


Laboratory syndromeLaboratory syndrome Testing via serologies, Testing via serologies,

immunohistochemistry, and rapid RNA immunohistochemistry, and rapid RNA PCRPCR

All via New Mexico/CDCAll via New Mexico/CDC

Treatment – Treatment – Study with IV Ribavirin via UNM/CDCStudy with IV Ribavirin via UNM/CDC SupportiveSupportive

Hantavirus treatmentHantavirus treatment

Above all – Consultation with experts Above all – Consultation with experts at University of New Mexico and CDCat University of New Mexico and CDC

From CDC Website :From CDC Website : Take-home Message for Care Take-home Message for Care

ProvidersProviders Rapid transfer to ICURapid transfer to ICUCareful monitoringCareful monitoringFluid balanceFluid balanceElectrolyte balance Electrolyte balance Blood pressure Blood pressure


Management with Swan-Ganz catheter Management with Swan-Ganz catheter essentialessential In contrast to septic shock, HPS patients In contrast to septic shock, HPS patients

have a low cardiac output with a raised have a low cardiac output with a raised systemic vascular resistance. systemic vascular resistance.

Titrate fluid to keep wedge pressure to <12Titrate fluid to keep wedge pressure to <12 Poor prognostic indicators include a plasma Poor prognostic indicators include a plasma

lactate of greater than 4.0 mmol/L or a lactate of greater than 4.0 mmol/L or a cardiac index of less than 2.2 L/min/m2cardiac index of less than 2.2 L/min/m2

Whilst pulmonary edema and pleural Whilst pulmonary edema and pleural effusions are common, multiorgan effusions are common, multiorgan dysfunction syndrome is rarely seen. dysfunction syndrome is rarely seen.


Prior to the use of extracorporeal Prior to the use of extracorporeal membrane oxygenation (ECMO) as a membrane oxygenation (ECMO) as a rescue therapy, a cardiac index of less rescue therapy, a cardiac index of less than 2.5 L/min/m2 predicted 100% than 2.5 L/min/m2 predicted 100% mortality rate.mortality rate.

eMedicine – 15 patients, 9 intact eMedicine – 15 patients, 9 intact survivorssurvivors

Dramatic improvement usually seen in Dramatic improvement usually seen in the first daythe first day

Runs are usually 4-5 daysRuns are usually 4-5 days


Fungal PneumoniasFungal Pneumonias CandidaCandida AspergillusAspergillus

Candida pneumonia Candida pneumonia diagnosisdiagnosis

Essentially a disease of immuno-Essentially a disease of immuno-compromisedcompromised

Common upper airway and oral floraCommon upper airway and oral flora Colonization vs. infectionColonization vs. infection

Translocation across the gut -> Translocation across the gut -> hematogenous spread to the lungs is hematogenous spread to the lungs is another source in neutropenic another source in neutropenic patientspatients


ECH ProcedureECH Procedure Sensitivity done automatically on all Sensitivity done automatically on all

sterile site specimenssterile site specimens Can be done request on others (ETT is Can be done request on others (ETT is

NOT sterile)NOT sterile) Done at SRH – Done at SRH –

48 hour test – must be done on a 48 hour 48 hour test – must be done on a 48 hour old sampleold sample

Must be set up in the morningMust be set up in the morning Don’t set it up on the weekend Don’t set it up on the weekend


Multiple speciesMultiple species C. albicans C. albicans

Most commonMost common Quickest of the yeast to be identified – Quickest of the yeast to be identified –

candida chrome agar (green color change)candida chrome agar (green color change)

Candida Chrome AgarCandida Chrome Agar

Produces species Produces species specific colorful specific colorful colonies of colonies of Candida species.Candida species.

Green: Green: C. C. albicansalbicansBlue: Blue: C. C. tropicalistropicalisPink: Pink: C. kruseiC. krusei


Multiple speciesMultiple species C. albicans C. albicans

Most commonMost common Quickest of the yeast to be identified – Quickest of the yeast to be identified –

candida chrome agar (green color change)candida chrome agar (green color change) C. parapsilosisC. parapsilosis

Second most common at ECHSecond most common at ECH C. glabrata, krusei, lusitanieaC. glabrata, krusei, lusitaniea

More rare, but the ones to worry aboutMore rare, but the ones to worry about

Antifungal TherapyAntifungal Therapy

Not a lot of good, large number Not a lot of good, large number trials in pediatric immuno-trials in pediatric immuno-suppressed patientssuppressed patients

Even less in treating pneumoniaEven less in treating pneumonia Assume systemic spread in neutropenic Assume systemic spread in neutropenic

patientspatients

Antifungal TherapyAntifungal Therapy Mostly Mostly C. albicansC. albicans fungemia in non-neutropenics fungemia in non-neutropenics Flu (400/d) vs. AmB (0.5-0.6 mg/kg/d). Flu (400/d) vs. AmB (0.5-0.6 mg/kg/d). %Success:%Success:

Randomized, N=206, Flu 70%, AmB 79%, Randomized, N=206, Flu 70%, AmB 79%, PP = 0.22 = 0.22 Randomized, N=103, Flu 56%, AmB 60%, Randomized, N=103, Flu 56%, AmB 60%, PP = 0.80 = 0.80 Observational, N=294, Flu 73%, AmB 69%, Observational, N=294, Flu 73%, AmB 69%, PP = 0.58 = 0.58 Observational, N=479, Flu 71%, AmB 73%, Observational, N=479, Flu 71%, AmB 73%, PP > 0.38 > 0.38

ABLC (5 mg/kg/d) vs. AmB (0.6-1 mg/kg/d)ABLC (5 mg/kg/d) vs. AmB (0.6-1 mg/kg/d) Randomized, N=194, ABLC 65%, AmB 61%, Randomized, N=194, ABLC 65%, AmB 61%, PP = 0.64 = 0.64

Rex, 1994; Phillips 1997; Nguyen, 1995; Anaissie, 1998

Candida sensitivitiesCandida sensitivities

Flucon Itra AmB 5-FCFlucon Itra AmB 5-FC

C. albicansC. albicans SS S S S S S S

C. parapsilosisC. parapsilosis SS S S S S S S

C. tropicalisC. tropicalis SS S S S S S S

C. glabrataC. glabrata SSDDDD-R S-R SDDDD-R -R II SS

C. kruseiC. krusei RR SSDDDD-R I-r I-R-R I-r I-R

C. lusitaniae C. lusitaniae SS S- S-SSDDDD R RR R

Aspergillus pneumoniaAspergillus pneumonia

Organism – Aspergillus fumigatusOrganism – Aspergillus fumigatus Increasing incidence in immuno-Increasing incidence in immuno-

compromised patientscompromised patients Solid organ or BMT patientsSolid organ or BMT patients

Mortality approaches 75%Mortality approaches 75%

Aspergillus pneumonia Aspergillus pneumonia diagnosisdiagnosis

Large areas of pulmonary necrosisLarge areas of pulmonary necrosis Can look like staphCan look like staph

Necrosis is because of direct blood Necrosis is because of direct blood vessel invasion by the organism and vessel invasion by the organism and subsequent thrombosissubsequent thrombosis SAME PHYSIOLOGY AS A SAME PHYSIOLOGY AS A

PULMONARY EMBOLUSPULMONARY EMBOLUS Wedge shaped emboli seen on CXRWedge shaped emboli seen on CXR Right heart strain less oftenRight heart strain less often

Aspergillus pneumonia Aspergillus pneumonia diagnosisdiagnosis

Fungal culture Fungal culture from BAL sample from BAL sample is gold standardis gold standard

Aspergillus pneumonia Aspergillus pneumonia treatmenttreatment

Empiric therapy with amphoteracin-Empiric therapy with amphoteracin-B or itraconazoleB or itraconazole

Lobectomy used if caught early and Lobectomy used if caught early and confinedconfined

Mortality remains high despite all Mortality remains high despite all treatmenttreatment


Mycobacterium tuberculosisMycobacterium tuberculosis

TB diagnosisTB diagnosis Aerobic acid-fast bacilliAerobic acid-fast bacilli High index of suspicionHigh index of suspicion Exposure/risk factor history is keyExposure/risk factor history is key

Known TB casesKnown TB cases Incarceration (jail/prison)Incarceration (jail/prison) Health care workersHealth care workers Homeless/Community shelterHomeless/Community shelter Immuno-compromisedImmuno-compromised Travel to/visitation from endemic areas Travel to/visitation from endemic areas

(Grady)(Grady) Ask about BCG in immigrantsAsk about BCG in immigrants

TB diagnosisTB diagnosis

Recovery from culture is gold Recovery from culture is gold standardstandard AFB stain and cultureAFB stain and culture

PCR availablePCR available

TB TreatmentTB Treatment Get ID involved for recs and follow-upGet ID involved for recs and follow-up Isolation in negative pressure roomIsolation in negative pressure room

Patient with surgical mask for any transportPatient with surgical mask for any transport Parents to get CXR (surgical mask)Parents to get CXR (surgical mask)

““When determining TB status on adult family When determining TB status on adult family members of inpatients with diagnosed or members of inpatients with diagnosed or strongly suspected TB, external diagnostic strongly suspected TB, external diagnostic resources (private physician, health department) resources (private physician, health department) are considered first.”are considered first.”

““When circumstances do not allow for this, When circumstances do not allow for this, Children’s will provide diagnostic services only Children’s will provide diagnostic services only and refer, if needed, for treatment of disease.”and refer, if needed, for treatment of disease.”

Write an order – parents register – pay or SW - Write an order – parents register – pay or SW - get CXR – Emory radiologists read itget CXR – Emory radiologists read it

Documents

Infectious Disorders of the Lung Parenchyma