Community-acquired pneumonia in children Vojko Berce Division of Pediatrics, University Medical Centre and Faculty of Medicine Maribor Slovenia

Pneumonia - definitions Inflammation of lung parenchyma because of air-borne or haematogenous infection WHO: cough and dyspnoea + tachypnea Most of definitions does not require imaging diagnostics Uncomplicated CAP: alveolar infiltrate limited to one lobe, bronchopneumonia, interstitial pneumonia Complicated CAP: pleural effusion, multilobar pneumonia, pulmonary abscess, empyema, pneumothorax Fever signs/symptoms from respiratory tract (cough, respiratory distress, chest pain) Signs of affection of lung parencyhma (imaging method or auscultation)

COMMON BACTERIAL RARE BACTERIAL Cause Characteristic Streptococcus pneumoniae Alveolar consolidation (CXR), effusion, empyema Haemophilus influenzae type B Non-vaccinated Group B beta-haemolytic streptococcus Neonates Staphylococcus aureus After the flu, pneumatocele, empyema, Group A beta-haemolytic streptococcus Empyema Moraxella catarrhalis Mycoplasma pneumoniae Both together represent the most common cause of CAP in school-children Neisseria meningitidis Chlamydophila pneumoniae Chlamydophila psittaci Bird owners Chlamydia trachomatis Infants (1-3 months) Coxiella burnetii Q fever, farmers (sheep) Anaerobes Aspiration pneumonia Legionella species Contaminated water Gram negative bacteria Nosocomial pneumonia Ureaplasma urealyticum Afebrile pneumonia in neonates Haemophilus influenzae – nontypeable

COMMON VIRAL RARE VIRAL Cause Charasteristics Characteristics RSV Bronchiolitis/pneumonia Rhinovirus Symptoms of cold Human metapneumovirus Similar to RSV Enterovirus neonates Parainfluenza type 1-3 Laryngitis Herpes simplex Influenza A, B High fever, winter outbreak Cytomegalovirus Infants (afebrile pneumonia syndrome), immune deficiency Bocavirus Adenovirus Severe pneumonia Measles rash Rhinovirus? Varicella Viruses (RSV) are more common cause of CAP in small children (<3 years) compared to bacteria Moulds (Pneumocystis jiroveci, Aspergillus), Helmints (Ascaris, Toxocara, Strongyloides) Mycobacteriae (TBC in non-tuberculosis)

Clinical and laboratory characteristics Etiology Clinical and laboratory characteristics Bacterial pneumonia (Streptococcus pneumoniae) All ages Sudden onset with high fever, chills (“toxic appearing”), tachypnea, often without respiratory distress Chest (abdomen) pain Localized phenomena on auscultation (crackles, diminished breath sounds, bronchial breathing) Clinical signs often absent in small children (fever without a focus) Leukocytosis (>15.000) CXR: alveolar infiltrate – consolidation (lobar, segmental, round), pleural effusion (50%) Atypical bacteria (Mycoplasma pneumoniae, Chlamydophila pneumoniae) School-children and adolescents Systemic signs (malaise, myalgia, headache, photophobia, sore throat, rash) then gradual appearance of dry cough Low-grade fever Crackles ± wheeze (often unilateral) Extra-pulmonary complications (Stevens-Johnson syndrom, hemolytic anemia, hepatitis, encephalitis) CXR: bronchopneumonia, interstitial infiltrates, pseudoconsolidation, small effusion (20%) Viruses Preschool children Gradual onset with signs of cold and cough (from the beginning) Signs of respiratory distress Bilateral phenomena on auscultation (crackles ± wheeze) Conjunctivitis, rash, diarrhea CXR: bilateral interstitial infiltrates

BPN ALVEOLAR INFILTRATE INTERSTITIAL INFILTRATE

Poor diferentiation between the causes of CAP WBC < 15.000 → good negative predictive value for bacterial CAP Useful for monitoring the effect of therapy ↓CRP at the onset of bacterial CAP, ↑CRP with some viruses and Mycoplasma

Blood culture positive in less than 10% of bacterial CAP Detection of genome (PCR) of respiratory viruses and atypical bacteria from naso-pharynx Culture of sputum (> 5 years) only weakly reflects the infection in lower airways Blood culture positive in less than 10% of bacterial CAP Seroconversion (IgM) to Mycoplasma pneumoniae only after 1 week of illness

Sensitivity of all isolates of Streptoccocus pneumoniae in Slovenia - 2015 National laboratory for health, food and environment

Antibiotic treatment of CAP in children – Slovenian national guidelines/recommendations (Čižman M. Beovič B. Kako predpisujemo antibiotike v bolnišnicah) AGE AND PROBABLE ETIOLOGY ANTIBIOTIC Daily dose (mg/kg/day or IE/kg/day): number of daily doses 4 months to 5 years, probable bacterial – outpatient treatment amoxicillin (drug of choice) 45: 3 peroral penicillin V (alternative) 100.000–200.000 IE: 3 peroral 4 months to 5 years, probable bacterial – severe course (hospital) penicillin G (drug of choice) 150.000–250.000 IE: 4 iv amoxicillin+clavulanic acid (alternative) 100 (amoxicillin): 4 iv 5–18 years, probable atypical bacteria – outpatient treatment azithromycin or  clarithromycin 10: 1 first day, then 5: 1 for 4 day peroral 15: 2 peroral 5–18 years, probable bacterial - outpatient penicillin V or amoxicillin 5–18 years, probable bacterial – severe course (hospitall) penicilin G or amoxiclilin+clavulanic acid 150.000–250.000: 4 iv cefotaxime (CAP with complications – pleural effusion) 150: 3 iv Bacterial pneumonia – allergy to penicillin Cefotaxime?, Clindamycin?, Quinolones?

Antibiotic treatment of CAP in children - Slovenian national guidelines/recommendations Severe course of CAP or CAP after the flu → combination of antistaphylococcal penicillin and third generation of cephalosporin Duration of treatment 7-10 dni in preschool children, 5-7 dni in schoolchildren (at least 3 days without fever) Penicillin can be prescribed in children who received at least 3 dosed of HiB vaccine (otherwise amoxicillin) Hospital treatment: parenteral antibiotic 1-2 days, when 24 hours afebrile → shift to peroral treatment Čižman M. Beovič B. Kako predpisujemo protimikrobna zdravila v bolnišnicah. Ljubljana 2013

STUDY Aims Participants Methods to compare the clinical and laboratory characteristic of different types of CAP (viral, atypical, bacterial), to compare the sensitivity of lung ultrasound (LUS) and chest X-ray (CXR) for detecting CAP to analyze the compliance of antibiotic treatment of CAP with Slovenian national guidelines. Aims 166 children with CAP, hospitalized at Clinic of Pediatrics, Maribor (1.10.2014 – 30.9.2016) Previously healthy, age 3 months – 18 years, no ICU Pneumonia detected with CXR and/or ultrasound Stratification into bacterial, atypical and viral CAP groups (infiltrates, microbiological and laboratory results Participants Chest x-ray and lung ultrasound NF swab - PCR based diagnostics of respiratory viruses and atypical bacteria Blood culture, sputum CRP, WBC Antibiotic treatment on the first and third day Methods

STUDY - RESULTS Mycoplasma pneumonie – 30 subjects 77 (46.4%) 89 (53.6%) Mean age 4.4 years Mycoplasma pneumonie – 30 subjects Chlamydophilia pneumoniae – 2 subjects Probably viral CAP – 54 subjects Probably bacterial CAP – 80 subjects 19 (11.4%) subjects already received antibiotic treatment before the admission. In the first 24 hours of hospitalization antibiotic therapy was administered to 147 (88.6 %) children with CAP.

RESULTS - clinical and laboratory characteristics Characteristic [% (n)] Bacterial Atypical Viral p Chest/abdominal pain 51.2 (41) 18.8 (6) 7.4 (4) < 0.01 Crackles on auscultation 20.0 (16) 84.4 (27) 74.1 (40) Wheezes on auscultation 5.0 (4) 28.1 (9) 48.1 (26) Respiratory distress 15.0 (12) 31.2 (10) 59.3 (32) Diminished breath sounds 27.5 (22) 21.9 (7) 18.5 (10) 0.47 Signs of lung consolidation 21.3 (17) 15.6 (5) <0.01 Need of additional oxygen 6.3 (5) 38.9 (21) Characteristic (mean)   Age (years) 3,5 7.9 3.4 WBC3 (×109/l) 26,6 12.7 15.5 CRP (mg/dl) 169.1 47.7 73.9

RESULTS – lung ultrasound Pneumonic infiltrates were detected with CXR in 137 (82.5 %) of subjects and with LUS in 161 (97.0 %) of subjects (p<0.01).

RESULTS - antibiotic day 1.→ day 3. ANTIBIOTIC THERAPY (Probable) etiology   SUMMARY bacteria atypical (Myc + Chl) viruses amoxicillin+clavulanic acid 27 → 32 4 → 1 22→18 53 → 51 penicillin 26 → 31 5 → 2 7 → 5 38 → 38 azithromycin 6 → 4 13 →26 9 → 6 28 → 36 cefuroxime 4 → 3 1 → 1 6 → 5 ceftriaxone 2 → 5 0 → 0 3 → 6 penicillin and azithromycin 8 → 4 3 → 1 12 → 6 amoxicilin+clavulanic and azithromycin 1 → 1 2 → 1 6 → 3 amoxicillin+clavulanic and gentamycin 1 → 0 no antibiotic therapy 5 → 0 3 → 0 11→21 19 → 21 80 32 54 166

Discussion - limitations Lack of „gold standard“ for determination of etiology of CAP in children Isolation of microbes from upper airways only weakly reflects the cause of inflammation in lower airways (asymptomatic shedding or colonisation of viruses and Mycoplasma in NF) Bacterial CAP as superinfection of viral RTI Insensitive (blood culture) or unfeasible (sputum < 5 years) tests for bacterial CAP Recommendations for antibiotic treatment limited to countries with good susceptibility of pneumococci to penicillin

Discussion – clinical characteristics Chest/abdominal pain Normal auscultation Bacterial CAP Respiratory distress Bilateral phenomena (crackles ± wheeze) on auscultation Viral pneumonia Older children Unilateral crakles Atypical bacterial CAP

Discussion – antibiotic treatment We followed the national guidelines for antibiotic treatment of CAP Results of microbiological investigations did not reduce the proportion of children treated with antibiotic (day 3) Microbiological investigations guided the adjustment of therapy in atypical bacterial pneumonia In most children with proven viral infection we did not abolish the antibiotic therapy

Conclusion Combination of epidemiologic, clinical and laboratory parameters helps to define the etiology of CAP even in the settings with limited diagnostic possibilities Lung ultrasound becomes sensitive, harmless and widely available bed-side tool for the detection of pneumonia in children and can replace the chest x-ray