Acute infections of the lower airways in children

1. Acute infections of the lower airways in children Aleksandra Szczawińska-Popłonyk Department of Pediatric Pneumonology, Allergology and Clinical Immunology Karol Marcinkowski University of Medical Sciences Poznań

2. Infection • The specific and nonspecific defense mechanisms keep the bronchial tree sterile beyond the first bronchial bifurcation • A certain amount of microorganisms must both avoid mucociliary clearance and resist destruction by the humoral or cellular defense mechanisms • Large amounts of the organisms reach the LRT through aspiration • The invading microorganisms have particular characteristics- eg. a marked capacity to adhere to epithelium (Influenza virus, other viruses, Mycoplasma pneumoniae, Bordetella pertussis)

3. Infection • Microorganisms avoid immune defence system: • Encapsulated bacteria (pneumococci, Klebsiella pneumoniae, Haemophilus influenzae) are resistant to phagocytosis • Some bacteria are resistant to mechanisms of intracellular killing, other (Haemophilus influenzae, Neisseria, streptococci) produce IgA protease, which degrades IgA antibodies • There is a defect in mucociliary clearance by the inhalation of number of irritants (industrial pollution, tobacco smoke), microorganisms (viruses: Influenza, Morbilli, bacteria: B.pertussis, H.influenzae)

4. Lower respiratory tract infectionsepidemiological data • A global health problem: four milion children die each year for respiratory tract infections (98-99% in the developing countries) • Children aged 1-5 yrs in an urban area have 6-8 episodes of RTI each year, in the country 3-5 • Only a small proportion of these infections concern the lower respiratory tract; the difference between industrialized and developing countries doesn’t concern the incidence but the severity of infections • Even if only in exceptional cases infections lead to serious complications, they cause suffering and impairement of the individual child

5. Lower respiratory tract infectionssocial problems • Respiratory tract infections account for a large proportion of physician consultations • The significant proportion of the resources of out-patient care expand on RTI • Sickness absence and medicine cost society a lot of money: 57% of acute illnesses 50% number of days restricted activity 42% of the lost working days 60% of the lost school days

6. Pneumonia • Definition Pneumonia is defined as inflammation in the lung parenchyma, the portion distal to the terminal bronchioles and comprising the respiratory bronchioles, alveolar ducts, alveolar sacs and alveoli • Pathogenesis Organisms reach the lung to cause pneumonia by one of four routes: - inhalation of microbes present in the air - aspiration of organisms from the naso- or oropharynx (the most common cause of bacterial pneumonia) - hematogenous spread from a distant focus of infection - direct spread from a contiguous site of infection or penetrating injury

7. Pneumonia - classification • By anatomic distribution: lobar, lobular, segmental, bronchopneumonia • By dominant histological lesions: alveolar exudation, involvement of interstitial tissue or both • By etiological factor: infections (viral, bacterial, mycotic, other), aspiration, drug / radiation pneumonia, Loeffler syndrome, hypersensitivity pneumonitis • By the place where infection is acquired: community-acquired pneumonia, hospital-acquired (nosocomial) pneumonia

8. Community-acquired pneumonia • In the United States CAP remains an important cause of morbidity and mortality: -more than 3 million cases occur annually -results in more than 900 000 hospitalizations and more than 60 000 deaths • Only 20-30% of CAP occur in young, previously healthy individuals without comorbidities • Mortality is high (15-30%) in patients with predisposing risk factors including: -old age -history of cigarette smoking and COPD -chronic ethanol abuse -cardiac disease -diabetes mellitus -malignancy -renal insufficiency -corticosteroid or immunosuppressive therapy

9. Etiology of pneumonias

10. Pneumonia of unknown etiology • The newborn Group B Streptococcus Escherichia coli Staphylococci Listeria monocytogenes Tuberculosis Herpes simplex virus TORCH agents

11. Pneumonia of unknown etiology • Infants 1-3 months of age Group B Streptococcus Escherichia coli Haemophilus influenzae type b Streptococcus pneumoniae Chlamydia trachomatis Ureaplasma urealyticum Pneumocystis carinii Cytomegalovirus Respiratory syncytial virus Parainfluenzae virus Adenovirus

12. Pneumonia of unknown etiology • Children 3 months to 5 years of age -respiratory viruses 75% Respiratory syncytial virus Adenovirus Parainfluenzae virus Influenzae virus Streptococcus pneumoniae Haemophilus influenzae type b Klebsiella pneumoniae Staphylococcus aureus

13. Pneumonia of unknown etiology • Children 6 years of age to adults Mycoplasma pneumoniae Respiratory viruses: Parainfluenzae virus, RSV, Adenovirus Influenzae virus Streptococcus pneumoniae Staphylococcus aureus Haemophilus influenzae Klebsiella pneumoniae Chlamydia pneumoniae

14. Mycoplasmal respiratory infection • The most commonly recognized clinical syndrome following Mycoplasma pneumoniae infection is bronchopneumonia Additional respiratory illnesses include pharyngitis, sinusitis, croup, bronchitis, bronchiolitis Superinfection with typical bacteria is infrequent • Treatment: because of the absence of the cell wall, Mycoplasma is resistant to beta-lactams, but is exceptionally sensitive to: • macrolids (Erythromycin, Clarithromycin, Roxithromycin, Azithromycin) • tetracyclines – over the age of 8 yr • quinolones – over the age of 16 yr

15. Staphylococcal respiratory infections • Upper airway infection due to Staph. aureus: pharyngitis, tonsillitis, otitis media, sinusitis, tracheitis complicating viral croup • Pneumonia may be primary (hematogenous) or secondary after viral infection (influenza) Staphylococci lead to necrotizing pneumonia and common complications are: pyopneumothorax, empyema, bronchopleural fistula, pneumatocele • Therapy: always should be initiated with penicillinase-resistant antibiotic – 90% of staphylococci are resistant to penicillin

16. Staphylococcal respiratory infections Recommended antibiotics: • Methicillin, nafcillin, oxacillin • Clindamycin, lincomycin • Vancomycin and its new generation derivative teikoplanine when bacteria are resistant to semisynthetic penicillins (MRSA) Reports of increasing incidence of Vancomycin-resistant strains (Scandinavia, Japan, USA) • Rifampicin • Imipenem • Ciprofloxacin and other quinolones • Trimethoprime-sulfamethoxazole

17. Pneumococcal pneumonia • Streptococcus pneumoniae is the most common cause of bacterial infections of the lungs although the incidence of pneumococcal pneumonia has declined over the last decades • In older children and adults clinical manifestations are typical: shaking chills, high fever, cough, chest pain, and development of lobar pneumonia Pleural effusion and empyema are typical complications • Therapy: drug of choice is penicillin in the dose 100 000 units/kg/24hr parenterally for 2-3 weeks

18. Aspiration pneumonia • Relationship between gastro-esophageal reflux, dysfunctional swallowing, therapy of respiratory disorders (theophylline, oral beta-agonists) and aspiration pneumonia • Superinfection with mouth flora- predominantly anaerobes occurs in previously healthy non-hospitalized patients Treatment: Clindamycin, penicillins • Chronically ill hospitalized patients may be infected with Gram-negative flora (Pseudomonas, Klebsiella, E.coli); in these patients additional coverage with aminoglycosides, imipenem or both is indicated

19. Pneumocystis carinii pneumonia • Epidemic form in infants between 3 and 6 mo • Sporadic form accounts for majority of cases; occurs in children and adults with primary (SCID, XLA) or secondary (AIDS) immunodeficiencies, malignancies (leukemia), organ transplant receipients • In immunocompromised hosts PCP, if untreated, is fatal within 3-4 weeks • Therapy: Trimethoprim (15-20 mg/kg/24hr) + sulfamethoxazole (75-100 mg/kg/24hr) iv for 2-4 weeks For patients who fail to respond to TP-SMX: Pentamidine isethionate 4 mg/kg/24hr 1x daily

20. Pneumocystis carinii pneumonia • Alternative treatment of PCP: Atovaquone and trimetexate glucuronate Trimethoprime and dapsone Clindamycin and primaquine • Chemoprophylaxis: Trimethoprim 5 mg/kg/24hr + sulfamethoxazole 25 mg/kg/24hr Pentamidine by aerosol Dapsone and pyrimethamine

21. Pulmonary aspergillosis Depending on the type of exposure and condition of the host, different pulmonary manifestation may ensue: • Allergic bronchopulmonary aspergillosis without infection or tissue invasion (the most common aspergillus-related disease), most cases in patients with chronic pulmonary disease (asthma, CF) • Allergic alveolitis in the case of ongoing exposure in allergic patients • Aspergillus pneumonia if the colonisation occurs and infection develops • Invasive disease or necrotizing pneumonia in immunodeficient patients • Aspergillus mycetoma resulting from infection of an extant cavity

22. Pulmonary aspergillosis Treatment: • Aerosolized amphotericin B or direct instillation of the drug into the trachea (Liposomal amphotericin Ambisome) • Systemic amphotericin B iv or 5-fluorocytosine • Itraconazole with systemic steroids

23. Recurrent bacterial pneumonias • Primary or secondary immunodeficiency • Cystic fibrosis • Ciliary dyskinesia • Tracheo-esophageal fistula • Cleft palate • Congenital bronchiectases • Gastro-esophageal reflux and aspiration syndromes • Increased pulmonary blood flow • Foreign body aspiration

24. Microbiologic implications • Streptococcus pneumoniae is the most important bacterial pathogen in all age groups, accounting for 30-70% of CAP • Mycoplasma pneumoniae is the causative agent in 20-30% of adults younger than age 35, but accounts for only 1-9% of CAP in older adults • Legionella pneumophila accounts for only 2-10% of CAP, but is second to pneumococcus as a cause of death from CAP • Chlamydia pneumoniae is implicated in 2-8% of CAP, but severe pneumonias are rare with this pathogen • Haemophilus influenzae accounts for 5-18% of CAP in adults with high rate in smokers with COPD

25. Microbiologic implications • Staphylococcus aureus accounts for 3-8% of CAP in adults, primarily in patients with risk factors and following influenza • Enteric Gram(-) rods, predominantly Enterobacteriaceae account for 3-8% of CAP; only in patients with comorbidities • Moraxella catarrhalis accounts for only 1-2% of CAP; more common in patients with COPD • Viruses are implicated in 5-15% of CAP; most cases occur in winter months

26. Streptococcus pneumoniae • S. pneumoniae accounts for 30-70% of CAP and has been associated with most fatalities • S. pneumoniae can affect previously healthy individuals, but has a predilection for the elderly and for patients with preexisting disease • Outbreaks of severe, invasive infections may occur in nursing homes, chronic care facilities • S. pneumoniae is the leading cause of pneumonia in all age groups; empiric therapy for CAP should always cover S. pneumoniae • Penicillin-resistant and often multiply antibiotic-resistant strains are increasing and threaten the future efficacy of antibiotics

27. S. pneumoniae - antimicrobial resistance • Resistance to penicillins, tetracyclines, macrolides, trimethoprim/sulfamethoxazole, cephalosporins has increased dramatically over the past three decades • Resistance to antibiotics reflects the pattern of antibiotic use • Penicillin resistance is chromosomally mediated and results from alterations in penicillin-binding proteins • In France, Spain and Eastern Europe 15-40% of pneumococci exhibit high-grade resistance to penicillin; in the USA high-grade resistance has only recently emerged and is estimated for 1-7%

28. S. pneumoniae - antimicrobial resistance • Risk factors for penicillin resistance: age under 6 yrs, prior use of beta-lactam antibiotics and nosocomial acquisition • Penicillin resistant strains are often resistant to tetracyclines, erythromycin and TMP/SMX • Resistance to quinolones is unrelated to penicillin susceptibility • Erythromycin resistant strains are resistant to other macrolides and are usually resistant to penicilline and tetracycline • Cephalosporin-resistant strains have also increased • Most penicillin- and erythromycin resistant strains remain susceptible to imipenem, cefotaxime amd ceftriaxone • In the USA 6-30% of pneumococci are resistant to tetracycline • All pneumococci are susceptible to vancomycin, irresspective of susceptibilities to other class of antibiotics

29. S. pneumoniae - preferred therapy • For susceptible strains or in areas where rates of of penicillin-resistance are low: -Penicillin G 4-10 million units iv -Penicillin V 500 mg q.i.d. orally • As empiric therapy when penicillin resistance is suspected: -Cefotaxime 1g q8hr or ceftriaxone 1g q24hr • For strains resistant to penicillin and cephalosporins: -Vancomycin (100% active) -Imipenem/cilastin (active against more than 90% of isolates)

30. S. pneumoniae - preferred therapy • Alternative agents: -macrolide antibiotic (eg. erythomycin, clarithromycin, azithromycin) -beta-lactams and clindamycin are usually active -tetracyclines and TMP/SMX inconsistent (6-30% are resistant) • Penicillin G is less expensive and less toxic than alternative agents and should be used for susceptible strains

31. Haemophilus influenzae • H. influenzae accounts for 5-18% of pneumonias, both community- and hospital-acquired • Both typeable (encapsulated, especially type b) and nontypeable (nonencapsulated) strains can cause the disease • H. influenzae is a common commensal-colonizes the oropharynx in 20-40% of healthy individuals • H. influenzae pneumonia and bronchitis characteristically affect smokers, elderly and debilitated patients, but may also afect previously healthy individuals

32. H. influenzae - antimicrobial susceptibility • Antimicrobial resistance has increased dramatically in the past three decades • By the early 1980s, beta-lactamase-producing ampicillin resistant strains emerged • Ist-generation cephalosporins and erythromycin are nor reliable – only 40-60% of strains are susceptible • The activity of tetracyclines is modest • More than 90% of strains are susceptible to TMP/SMX • Virtually all isolates are susceptible to : ampicillin/sulbactam, cefuroxime, IIIrd-generation cephalosporins, imipenem, fluoroquinolones, new macrolides, extended-spectrum penicillins

33. H. influenzae - preferred therapy • 1st choice agents -ampicillin/sulbactam, cefuroxime or ceftriaxone -oral agents for mild infections or following initial parenteral therapy: amoxicillin/clavulanate, cefuroxime axetil, TMP/SMX • Alternative agents -TMP/SMX, fluoroquinolones -azithromycin or clarithromycin (activity of erythromycin is inconsistent) -ampicillin or amoxicillin (only for beta-lactamase negative strains)

34. Moraxella catarrhalis • M. catarrhalis is part of normal flora of the upper respiratory tract and is an important pathogen in otitis media, sinusitis and acute exacerbations of chronic bronchitis • M. catarrhalis accounts for 1-3% of CAP; most frequently in the winter months • More than 80% of lower respiratory tract infections caused by M. catarrhalis occur in patients with COPD or underlying diseases • Probably not important as a nosocomial pathogen

35. M. catarrhalis - antimicrobial susceptibility • The first beta-lactamase(penicillinase)-producing strains of M. catarrhalis were described in 1977; now 50-85% of isolates are resistant to penicillin • Penicillins with beta-lactamase inhibitors, TMP/SMX, macrolides, 2nd or 3rd generation cephalosporins, tetracycline, fluoroquinolones are active against beta-lactamase positive or negative strains • Beta-lactamase negative strains are susceptible to penicillin, ampicillin and beta-lactams • Beta-lactamase producing M. catarrhalis may confer antimicrobial resistance among coinfecting pathogens (a phenomenon of indirect pathogenicity) resulting in clinical resistance of beta-lactamase negative strains of H. influenzae and Strep. pneumoniae

36. M. catarrhalis - preferred therapy • 1st choice therapy -cefuroxime -ampicillin/sulbactam or amoxicillin/clavulanate • Alternative agents -tetracycline -TMP/SMX -macrolide -fluoroquinolones

37. Atypical pneumonias • Mycoplasma pneumoniae • Chlamydia pneumoniae • Legionella pneumophila • Viruses Other • Pneumocystis carinii • Chlamydia trachomatis • Rickettsiae • Fungi

38. Respiratory manifestations of mycoplasmal infection • Pharyngitis • Sinusitis • Myringitis • Otitis media • Croup • Bronchitis • Bronchiolitis • Bronchopneumonia • Pneumonia with pleural effusion

39. Mycoplasma pneumoniae • M. pneumoniae accounts for 2-14% of CAP • M. pneumoniae has a striking predilection for younger patients; often spares older individuals • M. pneumoniae accounts for 20-30% of CAP in adolescents and adults younger than age 35; 2-9% of CAP among adults age 40-60 and only 1% of pneumonias in adults over age 60 • Epidemics of M. pneumoniae infections may occur in families, schools, institutions; prolonged contact is necessary for transmission of infection • Pneumonia caused by M. pneumoniae occurs in only 3-10% of exposed individuals • M. pneumoniae is rarely implicated as a nosocomial pathogen

40. Characteristic features of Mycoplasma pneumoniae lower airway infection • Infections occur throughout the year • The occurence of mycoplasmal illness is closely related to the patient’s age: -mild or subclinical infections in children younger than 4 yrs -the peak incidence in schoolchildren 5-15 yrs of age • Recurrent infections in adults every 4-7 yrs • Respiratory route of infection • Incubation period 1-3 wk • Gradual onset of the respiratory illness: headache, general malaise, upper airway infection symptoms, dyspnea, dry hacking cough intensifying in the course of the disease, fever • The severity of symptoms usually greater than the condition suggested by the physical signs

41. M. pneumoniae – preferred therapy • Because Mycoplasma spp. lack a cell wall, beta-lactams and other cell-wall active antibiotics have no significant activity • 1st choice therapy -macrolide antibiotic (erythromycin, azithromycin, clarithromycin) -doxycycline 100 mg bid orally or iv • Alternative agents -fluoroquinolones (ciprofloxacin, ofloxacin)

42. Nonrespiratory manifestations of mycoplasmal infection • Skin: -erythema multiforme -maculopapular rush -Stevens-Johnson syndrome • CNS: -meningoencephalitis -aseptic meningitis -transverse myelitis -cerebellar ataxia -Guillain-Barre syndrome • Blood: -hemolytic anaemia -thrombocytopenia -coagulation defects

43. Nonrespiratory manifestations of mycoplasmal infection • Gastrointestinal tract -hepatitis -pancreatitis -protein-losing hypertrophic gastropathy • Cardiovascular system -myocarditis -pericarditis -cardiac dilatation with heart failure • Joints -monoarticular transient arthritis

44. Chlamydia pneumoniae • Within the genus Chlamydia there are three species recognized: Ch.pneumoniae, Ch.psittacci, Ch.trachomatis • Clinical features are similar to M. pneumoniae; fever and cough occur in 50-80% of patients • Infections are often asymptomatic (antichlamydial antibodies present in 26% of schoolchildren) • Associations of Chlamydia infections and coronary artery disease, carotid atherosclerosis, asthma, sarcoidosis have been suggested • Ch. pneumoniae may be an important infection trigger for asthma, CF and COPD

45. Chlamydia pneumoniae – preferred therapy • Beta-lactams and aminoglycosides have no activity • Tetracyclines and macrolids may shorten the duration of illness • Preferred therapy: -doxycycline or tetracycline orally for 14-21 days • Alternative agents: -oral macrolides -fluoroquinolones • Empiric therapy with tetracyclines should be considered for patients with protracted bronchitis or CAP refractory to beta-lactams

46. Legionella pneumophila • Legionella spp. are endemic in the community, accounting for 2-10% of CAP; nosocomial legionellosis is rare in most hospitals • Risk factors for legionellosis and more severe disease include advanced age, renal failure, cigarette smoking, ethanol abuse, organ transplantation, corticosteroids and severe underlying disease • Clinically pneumonia caused by Legionella is indistinguishable from other bacterial pneumonias; common feture of CAP caused by Legionella is progression of pneumonia while taking antimicrobials

47. Legionella pneumophila – preferred therapy • Beta-lactams and aminoglycosides are not active against Legionella • 1st choice antibiotics: -intravenous erythromycin 1g q6hr iv; substitute oral erythromycin 500mg qid following clinical improvement and defervescence for 21 days -rifampin may be synergistic in combination with erythromycin in immunocompromised hosts • Alternative therapy -clarithromycin 500-1000mg bid for 21 days -ciprofloxacin 750mg bid or ofloxacin 400mg bid for 21 days

48. Empiric (initial) therapy for CAP • In most cases of pneumonia therapy is empiric • Initial treatment of CAP should be -sufficiently broad to cover most likely pathogens -avoiding polypharmacy and toxic or excessively expensive antimicrobials • Choice of empiric therapy should be modified based on clinical features as: -age -the presence of underlying disease -radiographic appearance -prior use of antimicrobials -severity of pneumonia

49. Empiric (initial) therapy for CAP • Parenteral antibiotics are preferred as initial therapy in neonates, infants and children with serious associated disease • Other factors warranting parenteral therapy include: respiratory distress, multilobar pneumonia, hypoxemia, hypotension, non-compliance • Oral therapy should be reserved for patients: -presenting no gastrointestinal symptoms that preclude predictable oral absorption -clinically not toxic, hypotensive, severely ill -presenting pneumonia confined to a segment or bronchopneumonia -with no prior underlying disease

50. Empiric (initial) therapy for CAP Empiric strategies for CAP patients with no comorbidities Mild CAP not requiring hospitalization: • Penicillin or ampicillin may be adequate for Strep. pneumoniae in communities where the rate of penicillin resistant pneumococci is low • 2nd generation oral cephalosporin or amoxicillin/ clavulanate • Oral macrolide antibiotic is also recommended: covers atypicals, Strep. pneumoniae and most strains of H. influenzae • Activity of fluoroquinolones against Strep. pneumoniae is modest