Infectious Disorders of the Lung Parenchyma Matthew L. Paden, MD Pediatric Critical Care Fellow Emory University Children’s Healthcare of Atlanta at Egleston Objectives Worldwide epidemiology of the problem Review common etiologies Discuss empirical and disease specific treatment Epidemiology World wide Leading cause of death in children More than AIDS, malaria, and measles combined Most deaths in < 5 yo United states 3rd leading cause of hospitalization for kids 2% of deaths (5% including neonates) http://www.who.int/child-adolescenthealth/publications/CHILD_HEALTH/ISBN_92_806_4048_8.htm Worldwide Epidemiology Cases 150 million Hospitalizations 11-20 million Deaths 2 million Barriers to care Recognizing there is a problem Seek appropriate care Treatment with antibiotics Prevention Adequate nutrition Exclusive breastfeeding Less than 1 yo, get any formula – 5 X increased risk of death from pneumonia Zinc supplementation Prevention Immunization Measles – Pneumonia is what they die of – often super-infection World-wide coverage rate – 76% in 2004 Still having 30-40 million cases a year HIB – 2-3 million cases of severe disease a year In 2003, developed world coverage – 92% Developing world – 42% Least developed countries – 8% Prevention Immunization Strep pneumo – 7 –valent vaccine (Prevnar) in the US 9, 11, or 13 valent vaccine for the rest of the world Gambia – 17,000 children 37% reduction in pneumonia 15% reduction in hospitalization 16% reduction in mortality Costs involved More than 1 million deaths a year can be prevented with treatment and prevention 600,000 lives saved by just treatment alone Cost analysis Antibiotic treatment course $ 0.27 $ 600 million total cost including : Cost of antibiotics Cost of hospital stays Increasing training of health care staff Increasing physical plants to take care of these patients Costs involved Those costs inflated by Mexico and Brazil 85% of deaths are in sub-Saharan Africa and southeast Asia $200 million dollars will expand coverage to those regions only and potentially fix 85% of the problem Potential solutions One 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…” Diagnosis Tachypnea Sensitive but not specific Higher specificity Decreased breath sounds Inspiratory rales Chest wall retractions Nasal flaring Absence of fever has high negative predictive value for bacterial pneumonia Etiologies Streptococcus pneumoniae Most common cause outside of neonatal period Nasopharyngeal colonization – 50% of kids >90 serotypes – majority of invasive disease caused by 10 serotypes Bacteremia in 25-30% of kids Gram stain – gram positive lancet shaped diplococci (“gram positive cocci in pairs”) Age differences Adults – lobar pneumonia Kids – lobar or bronchopneumonia Treatment - Streptococcus pneumoniae 2002 CDC Surveillance data 20% PCN resistant 4% Cefotaxime resistant 0% Vancomycin resistant 2003-2004 FAST Surveillance data 56% 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 Data Percent of organisms tested that have intermediate or resistant sensitivity patterns Organism Vanc CTX I ECH Strep pneumo CTX R PCN I PCN R 0% 21/14% 20/6 % 14 % 46 % SRH Strep 0 % 26/9 % 7/8 % pneumo 34 % 31 % Treatment – Strep pneumo Mechanism of resistance – PCN and Cephalosporins – change in penicillin binding proteins (NOT beta lactamase) Empiric : 3rd generation cephalosporin + vancomycin until sensitivities are confirmed Etiologies Staphylococcus aureus Common cause of ventilator associated and nosocomial pneumonia Community acquired disease usually coincident with viral infection (influenza) Viral hemagglutinins – inhibit neutrophil and monocyte activation Gram stain – gram positive cocci in grape like clusters Diagnosis – Staphylococcal pneumonia Classically a lobar consolidation on CXR Raise suspicion of staph Pneumatoceles Pleural effusion Air fluid levels Necrosis Treatment – Staphylococcus aureus Treatment has changed over the past 5 years with emergence of caMRSA Empiric therapy with Vancomycin VISA (1996, Japan, 1997 US) VRSA (2002, US) Mechanism – thickening of cell membrane – decreased penetration of vancomycin – unclear mechanism Mechanism – VanA from enterococcus – changes d-alanine, d-alanine terminus to d-alanine, d-lactate – reduces affinity by 1,000 fold VDSA 2006 CHOA Data • ECH total % MRSA 53% Organism SRH total % MRSA 51% Vanc Clinda* Bactrim Rifampin Gent ECH MRSA 0% 14% 1% 1% 1% SRH MRSA 0% 13 % 1% 1% 3% * Not adjusted for inducible resistance Staph Aureus treatment Get off Vancomycin if MSSA MSSA much more susceptible to Nafcillin Use of Vancomycin or first-generation Cephalosporins for the treatment of hemodialysis-dependent patients with methicillin-susceptible Staphylococcus aureus bacteremia. Clin Infect Dis. 2007 Jan 15;44(2):190-6. Treatment failure - Vancomycin 31.2% vs. Ancef 13% ; p=.02 Multivariable analysis - factors independently associated with treatment failure included Vancomycin use (odds ratio, 3.53; 95% confidence interval, 1.15-13.45) Staph aureus treatment Get off Vancomycin if MSSA Staphylococcus aureus bacteremia and endocarditis: the Grady Memorial Hospital experience with methicillin-sensitive S aureus and methicillinresistant S aureus bacteremia. Am Heart J. 2004 Mar;147(3):536-9. MSSA bacteremia is associated with higher rates of endocarditis than MRSA. Comparative activity of cloxacillin and vancomycin against methicillinsusceptible Staphylococcus aureus experimental endocarditis. J Antimicrob Chemother. 2006 Nov;58(5):1066-9. Cloxacillin produced a greater decrease in the number of staphylococci than vancomycin 41% of rabbits had sterile vegetations in comparison with 0% with vancomycin (p=0.035) New horizons Anti-MRSA beta-lactams in development, with a focus on ceftobiprole: the first anti-MRSA beta-lactam to demonstrate clinical efficacy. Expert Opin Investig Drugs. 2007 Apr;16(4):419-29. Investigational beta-lactam antibiotic against methicillinresistant staphylococci, enterococcus faecalis, penicillinresistant streptococci and many Gram-negative pathogens. Completed Phase III therapeutic trials PPI0903 - injectable pro-drug of a broad-spectrum cephalosporin with anti-MRSA activity RO4908643 - a carbapenem with anti-MRSA activity Etiologies Pseudomonas aeruginosa Common cause of bacterial nosocomial pneumonia More common in CF, tracheostomy dependant, or immunocompromised Oxidase positive gram negative rod Pseudomonas treatment Antibiotic resistance common Mechanism – extended spectrum beta-lactamase Implication – serious or life-threatening infections should not be treated with an anti-pseudomonal synthetic penicillin/cephalosporin/carbapenem alone Empiric therapy – anti-pseudomonal PCN + an aminoglycoside Role of monotherapy has not been well defined. Pseudomonas treatment Antibiotic choices Anti-pseudomonal synthetic penicillin Ticarcillin +/- clavulanate Piperacillin +/- tazobactam Pseudomonas treatment Antibiotic choices Anti-pseudomonal synthetic penicillin Ticarcillin +/- clavulanate Piperacillin +/- tazobactam Mechanism of Action Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins Inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls Clavulanate and tazobactam prevents degradation of the PCN by binding to beta-lactamases Pseudomonas treatment Antibiotic choices Anti-pseudomonal synthetic penicillin 4th generation cephalosporin – cefepime Ceftazidime – 2nd generation with pseudomonas activity Pseudomonas treatment Antibiotic choices 4th generation cephalosporin – cefepime Mechanism of Action Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins Inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls Pseudomonas treatment Antibiotic choices Anti-pseudomonal synthetic penicillin 4th generation cephalosporin – cefepime Carbapenems – imipenem-cilastatin or meropenem Pseudomonas treatment Antibiotic choices Carbapenems – imipenem-cilastatin or meropenem Mechanism of Action Inhibits cell wall synthesis by binding to penicillin-binding proteins (PBPs) with its strongest affinities for PBPs 2, 3 and 4 of E. coli and P. aeruginosa and PBPs 1, 2 and 4 of S. aureus Meropenem reduces valproate levels by ~40% Pseudomonas treatment Antibiotic choices Anti-pseudomonal synthetic penicillin 4th generation cephalosporin – cefepime Carbapenems – imipenem-cilastatin or meropenem Aztreonam Pseudomonas treatment Antibiotic choices Aztreonam Mechanism of Action Binds to penicillin-binding protein 3 which produces filamentation of the bacterium inhibiting bacterial cell wall synthesis and causing cell wall destruction Pseudomonas treatment Antibiotic choices Anti-pseudomonal synthetic penicillin 4th generation cephalosporin – cefepime Carbapenems – imipenem-cilastatin or meropenem Aztreonam Fluroquinolones – ciprofloxacin, levofloxacin, etc. Pseudomonas treatment Antibiotic choices Fluroquinolones – ciprofloxacin, levofloxacin, etc. Mechanism of Action Inhibits DNA-gyrase and topoisomerase IV in susceptible organisms; inhibits relaxation of supercoiled DNA and promotes breakage of double-stranded DNA Pseudomonas treatment Antibiotic choices Anti-pseudomonal synthetic penicillin 4th generation cephalosporin – cefepime Carbapenems – imipenem-cilastatin or meropenem Aztreonam Fluroquinolones – ciprofloxacin, levofloxacin, etc. Aminoglycosides – amikacin, gentamicin, tobramycin Pseudomonas treatment Antibiotic choices Aminoglycosides – amikacin, gentamicin, tobramycin Mechanism of Action Inhibits cellular initiation of bacterial protein synthesis by binding to 30S and 50S ribosomal subunits resulting in a defective bacterial cell membrane Pseudomonas treatment Antibiotic choices Anti-pseudomonal synthetic penicillin 4th generation cephalosporin – cefepime Carbapenems – imipenem-cilastatin or meropenem Aztreonam Fluroquinolones – ciprofloxacin, levofloxacin, etc. Aminoglycosides – amikacin, gentamicin, tobramycin So which to choose? 2006 CHOA Data - Pseudomonas Site Time Zosyn Fortaz Cefep Merrem Aztre Cipro ntin ime onam Amik acin Gent Tobra ECH 12 % 6% 13 % 16 % 12 % 24 % 8% 12 % 20 % 13 % SRH 6% 2% 4% 11 % 8% n/a 14 % 10 % 29 % 16 % * No CF patients included 2006 CHOA Data - Pseudomonas Site Time Zosyn Fortaz Cefep Merrem Aztre Cipro ntin ime onam Amik acin Gent Tobra ECH 12 % 6% 13 % 16 % 12 % 24 % 8% 12 % 20 % 13 % SRH 6% 2% 4% 11 % 8% n/a 14 % 10 % 29 % 16 % * No CF patients included Etiologies “Atypical” Pneumonias Mycoplasma pneumoniae Chlamydia pneumoniae Legionella pneumophilia Common cause of pneumonia in school age children Persistent cough (for weeks after infection has cleared) “Atypical” Pneumonia diagnosis Mycoplasma – clinical picture + serologic testing Cold agglutinins are not specific Complications – arthritis, hemolysis, pericardial effusions, myocarditis, encephalitis, Stevens-Johnson syndrome Antibiotic therapy has not been conclusively shown to help non-pulmonary manifestations “Atypical” Pneumonia diagnosis Legionella pneumophilia Severe disease in immunocompromised Respiratory failure, pericarditis Classic history triggers – exposure to travel, hot tubs, or hospitalization DFA, culture, and serology available Urinary antigen – good sensitivity and specificity “Atypical” Pneumonia treatment Macrolide antibiotics Erythromycin Azithromycin Mechanism of Action Inhibits bacterial RNA-dependent protein synthesis by binding to the 50S ribosomal subunit which results in the blockage of transpeptidation Etiologies Viral Respiratory syncytial virus Parainfluenza Influenza Adenovirus Human metapneumovirus Hantavirus Respiratory syncytial virus Enveloped, single stranded, negative polarity RNA paramyxovirus Seasonality – November through May Respiratory syncytial virus diagnosis Viral culture is gold standard DFA and PCR available PICU presentation Upper airway obstruction Lower airway obstruction Pneumonia Apnea Respiratory syncytial virus diagnosis Upper airway obstruction Laryngotracheobronchitis If fails traditional management (steroids, oxygen, epinephrine, heliox, etc.) and is intubated get endotracheal aspirate for bacterial superinfection Often staph or strep Respiratory syncytial virus diagnosis Lower airway obstruction Clinically bronchiolitis Increasing airway edema and mucous secretion worsen the obstruction CXR confirms hyperinflation and patchy infiltrates Intubated patients commonly co-infected with moraxella Respiratory syncytial virus treatment Lower airway obstruction Treatment – Oxygen +/- nebulized B-agonists or epinephrine +/- nasal suctioning +/- vasoconstrictive nasal drops +/- NIPPV Mechanical ventilation based on reduction of obstruction Lower rates and maximizing expiratory time Respiratory syncytial virus treatment Lower airway obstruction Treatment – Steroids – RSV alone, no efficacy in reducing stay Ribivirin – only FDA approved drug for RSV Many complications and expensive May have a role in the immunocompromised Respiratory syncytial virus diagnosis RSV Pneumonia Similar presentation as bronchiolitis Different pathophysiology – alveolar filling and consolidation CXR Discrete infiltrate and lack of hyperinflation Greater degree of hypoxia More likely to progress to ARDS Respiratory syncytial virus diagnosis RSV Apnea Not well described More common with increasing prematurity Polysomnography implies it is central apnea Pathophysiology – signaling from pulmonary nerves through the GABA and substance P pathways Pediatr Res. 2005 Jun;57(6):819-25. Etiologies Viral Respiratory syncytial virus Parainfluenza Influenza Adenovirus Human metapneumovirus Hantavirus Parainfluenza diagnosis Enveloped, single stranded, negative polarity RNA paramyxovirus Similar presentations to RSV Viral culture is gold standard DFA or PCR available 4 different virus types Type 1 epidemic every other year Parainfluenza seasonality Parainfluenza treatment Similar supportive care to RSV May be a role for both inhaled and intravenous ribivirin in immunosuppressed patients Etiologies Viral Respiratory syncytial virus Parainfluenza Influenza Adenovirus Human metapneumovirus Hantavirus Influenza diagnosis Negative sense, single stranded RNA viruses Type A and B responsible for majority of illnesses Hemagglutinin – viral binding to respiratory epithelial cells vial sialic acid Neuroaminidase – cleaves sialic acid residues once virus has multiplied in the cell allowing viral spread Influenza Viral Life Cycle Influenza diagnosis Clinical markers Other manifestations Laryngotracheobronchitis Myocarditis Rhabdomyolysis Reye’s syndrome Encephalitis Staph superinfection Influenza diagnosis Viral culture is gold standard DFA, PCR, and rapid immunoassays available Influenza treatment Amantidine or rimantidine Inhibits influenza M2 proteins and prevent viral uncoating Need to give early or no benefit Resistance is documented Oseltamivir and zanamivir Neuroaminidase inhibitors Etiologies Viral Respiratory syncytial virus Parainfluenza Influenza Adenovirus Human metapneumovirus Hantavirus Adenovirus diagnosis Specifically types 3 and 7 Rapidly evolving life threatening pneumonia with necrosis, pulmonary hemorrhage and bronchiolitis obliterans Survival dependant on degree of injury Viral culture is gold standard DFA, PCR, rapid ELISA are available ECLS an option Extracorporeal life support for the treatment of viral pneumonia: collective experience from the ELSO registry. Extracorporeal Life Support Organization. J Pediatr Surg. 1997 Feb;32(2):232-6. Etiologies Viral Respiratory syncytial virus Parainfluenza Influenza Adenovirus Human metapneumovirus Hantavirus Human metapneumovirus diagnosis Also a paramyxovirus In children and infants notable cause of lower respiratory tract infections Bronchiolitis (59%) Croup (18%) Asthma exacerbations (14%) Pneumonia (8%). Symptoms very similar to RSV (cough 90%; dyspnea 83%; coryza 88%; fever 52-92%) Can cause severe disease in BMT patients PCR based diagnosis at this point Supportive treatment Etiologies Viral Respiratory syncytial virus Parainfluenza Influenza Adenovirus Human metapneumovirus Hantavirus Hantavirus diagnosis A negative sense, single stranded RNA virus of the bunyaviridae family Multiple different viruses worldwide Four corners region - Sin Nombre virus All other bunyaviridae have arthropod vectors Hantavirus – vector is the deer mouse 8% of hantavirus infections in US are children 33% mortality (similar to adults) Hantavirus infection Exposure/Travel history Clinical syndrome Fever Fulminant bilateral pulmonary disease Cardiogenic shock Pulmonary edema Hantavirus diagnosis Laboratory syndrome Hemoconcentration Thrombocytopenia Leukocytosis Absence of granules in neutrophils Immunoblasts on smear Hantavirus diagnosis Laboratory syndrome Testing via serologies, immunohistochemistry, and rapid RNA PCR All via New Mexico/CDC Treatment – Study with IV Ribavirin via UNM/CDC Supportive Hantavirus treatment Above all – Consultation with experts at University of New Mexico and CDC From CDC Website : Take-home Message for Care Providers Rapid transfer to ICU Careful monitoring Fluid balance Electrolyte balance Blood pressure Hantavirus treatment Management with Swan-Ganz catheter essential In contrast to septic shock, HPS patients have a low cardiac output with a raised systemic vascular resistance. Titrate fluid to keep wedge pressure to <12 Poor prognostic indicators include a plasma lactate of greater than 4.0 mmol/L or a cardiac index of less than 2.2 L/min/m2 Whilst pulmonary edema and pleural effusions are common, multiorgan dysfunction syndrome is rarely seen. Hantavirus treatment Prior to the use of extracorporeal membrane oxygenation (ECMO) as a rescue therapy, a cardiac index of less than 2.5 L/min/m2 predicted 100% mortality rate. eMedicine – 15 patients, 9 intact survivors Dramatic improvement usually seen in the first day Runs are usually 4-5 days Etiologies Fungal Pneumonias Candida Aspergillus Candida pneumonia diagnosis Essentially a disease of immuno-compromised Common upper airway and oral flora Colonization vs. infection Translocation across the gut -> hematogenous spread to the lungs is another source in neutropenic patients Candida pneumonia diagnosis ECH Procedure Sensitivity done automatically on all sterile site specimens Can be done request on others (ETT is NOT sterile) Done at SRH – 48 hour test – must be done on a 48 hour old sample Must be set up in the morning Don’t set it up on the weekend Candida pneumonia diagnosis Multiple species C. albicans Most common Quickest of the yeast to be identified – candida chrome agar (green color change) Candida Chrome Agar Produces species specific colorful colonies of Candida species. Green: C. albicans Blue: C. tropicalis Pink: C. krusei Candida pneumonia diagnosis Multiple species C. albicans Most common Quickest of the yeast to be identified – candida chrome agar (green color change) C. parapsilosis Second most common at ECH C. glabrata, krusei, lusitaniea More rare, but the ones to worry about Antifungal Therapy Not a lot of good, large number trials in pediatric immuno-suppressed patients Even less in treating pneumonia Assume systemic spread in neutropenic patients Antifungal Therapy Mostly C. albicans fungemia in non-neutropenics Flu (400/d) vs. AmB (0.5-0.6 mg/kg/d). %Success: Randomized, N=206, Flu 70%, AmB 79%, P = 0.22 Randomized, N=103, Flu 56%, AmB 60%, P = 0.80 Observational, N=294, Flu 73%, AmB 69%, P = 0.58 Observational, N=479, Flu 71%, AmB 73%, P > 0.38 ABLC (5 mg/kg/d) vs. AmB (0.6-1 mg/kg/d) Randomized, N=194, ABLC 65%, AmB 61%, P = 0.64 Rex, 1994; Phillips 1997; Nguyen, 1995; Anaissie, 1998 Candida sensitivities Flucon Itra AmB C. albicans S S S C. parapsilosis S S S C. tropicalis S S S C. glabrata SDD-R SDD-R I C. krusei R SDD-R I-r C. lusitaniae S S-SDD R 5-FC S S S S I-R R Aspergillus pneumonia Organism – Aspergillus fumigatus Increasing incidence in immuno-compromised patients Solid organ or BMT patients Mortality approaches 75% Aspergillus pneumonia diagnosis Large areas of pulmonary necrosis Can look like staph Necrosis is because of direct blood vessel invasion by the organism and subsequent thrombosis SAME PHYSIOLOGY AS A PULMONARY EMBOLUS Wedge shaped emboli seen on CXR Right heart strain less often Aspergillus pneumonia diagnosis Fungal culture from BAL sample is gold standard Aspergillus pneumonia treatment Empiric therapy with amphoteracin-B or itraconazole Lobectomy used if caught early and confined Mortality remains high despite all treatment Etiologies Mycobacterium tuberculosis TB diagnosis Aerobic acid-fast bacilli High index of suspicion Exposure/risk factor history is key Known TB cases Incarceration (jail/prison) Health care workers Homeless/Community shelter Immuno-compromised Travel to/visitation from endemic areas (Grady) Ask about BCG in immigrants TB diagnosis Recovery from culture is gold standard AFB stain and culture PCR available TB Treatment Get ID involved for recs and follow-up Isolation in negative pressure room Patient with surgical mask for any transport Parents to get CXR (surgical mask) “When determining TB status on adult family members of inpatients with diagnosed or strongly suspected TB, external diagnostic resources (private physician, health department) are considered first.” “When circumstances do not allow for this, Children’s will provide diagnostic services only and refer, if needed, for treatment of disease.” Write an order – parents register – pay or SW - get CXR – Emory radiologists read it