Infectious Disease Consult

Educational Objectives

The goal of this program is to improve the diagnosis and treatment of pediatric community-acquired pneumonia (CAP) and to briefly review some key issues of interest in the field of pediatric infectious diseases. After hearing and assimilating this program, the clinician will be better able to:

1.   List the most common causes of CAP in children.

2.   Describe factors that vary with the etiology of CAP and that may provide clues when diagnosing a child’s CAP.

3.   Utilize the patient’s age, clinical presentation, physical examination, and laboratory tests to focus anti-infective therapy against the most likely disease-causing pathogens.

4.   Discuss recent studies documenting the impact of PCV7 on pneumococcal pneumonia and meningitis. 

5.   Recognize indicators for switching from intravenous to oral antibiotics in the treatment of osteomyelitis.

Acknowledgements

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Bradley’s institution (Children’s Specialists of San Diego) receives consulting fees from Johnson & Johnson, Bayer HealthCare Pharmaceuticals, and Cubist Pharmaceuticals. Dr. Bradley is a clinical investigator for Johnson & Johnson, Cubist Pharmaceuticals, Pfizer, and the National Institutes of Health. Drs. Bradley and Jhaveri present information in their lectures that is related to off-label use of a therapy, product, or device. Dr. Jhaveri and the planning committee reported nothing to disclose.

Faculty Disclosure

Dr. Bradley spoke at Advances in Pediatrics: the 20th Annual Las Vegas Postgraduate Pediatric Conference, held April 16-19, 2009, in Las Vegas, NV, and sponsored by the American Academy of Pediatrics, California Chapter 2. Dr. Jhaveri was recorded at the Katz-Wilfert Update in Pediatric Infectious Diseases, held April 25, 2009, in Durham, NC, and sponsored by the Duke University School of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Pediatric Community-acquired Pneumonia

John S. Bradley, MD, Director, Division of Infectious Diseases, Rady Children’s Hospital, San Diego, CA

Introductory remarks: we are all experts in pediatric pneumonia (“you know it when you see it”); issue of how much of pneumonia viral and how much due to agents that require antibiotic treatment (eg, bacterial, atypical); questions include when does physician need to treat and how to distinguish between pneumonias with different eti­ologies

Clinical characteristics of pediatric community-acquired pneumonia (CAP): vary with age; characteristics of vi­ral and bacterial disease fairly distinct, eg, fever of 40ºC, extreme toxicity, and trouble breathing clearly indicate pneumococcal pneumonia; afebrile child who has bronchiolitis, looks fine, but just cannot catch breath probably has respiratory syncytial virus RSV; viruses seasonal and tend to come in waves;

Etiology: exposures to illness, eg, via travel; geographic location; underlying disease state; immense diversity of pathogens that can infect lungs; pneumonia accounts for »19% of childhood mortality worldwide; common causes of CAP in children include viruses, Mycoplasma pneumoniae, Chlamydia pneumoniae, and certain bacte­ria (eg, Mycobacterium tuberculosis); take-home message  —  physicians currently able to identify more underly­ing organisms that cause pediatric pneumonia than in past (polymerase chain reaction [PCR] excellent detection tool; however, unclear how many children who test positively actually have disease attributable to virus; further­more, mixed infections common [eg, bacterial/viral; viral/Mycoplasma]; in these cases, can determine that child has virus, but may be unclear what role virus playing); often unclear which positive blood tests indicate coloniza­tion and which indicate infection

Haemophilus influenzae type B (Hib) conjugate vaccines have eliminated H influenzae pneumonia; Streptococcus pneumoniae conjugate vaccine (Prevnar) has efficacy of 30% to 50% for pneumonia (including disease caused by vaccine serotypes); vaccinated children can have lobar pneumonia diagnosed by x-ray and clinical signs and symptoms without positive blood culture; pneumonia is disease of preschool children (majority of cases occur in children 0-4 yr of age)

Clues to pathogen identification: epidemiology; characteristics of disease progression, eg, pneumococcal pneumo­nia severe early on, while RSV pneumonia starts in upper airway and moves down slowly; physical examination (PE); laboratory tests; antimicrobial therapy based on suspicion of treatable pathogens

Season: many viruses manifest in community during winter; RSV and parainfluenza virus type 1 occur in some seasons and not in others, while Mycoplasma and parainfluenza virus type 3 tend to occur year round

Clinical clues: acute vs slowly progressive illness; presence of clinical toxicity; upper respiratory tract symptoms (eg, coryza); bilateral vs unilateral disease (pneumococcal disease almost always unilateral); whether immuniza­tions for Hib and S pneumoniae complete

Common pathogens: in study by Michelow et al, »44% of cases caused by S pneumoniae; 3% by other bacterial in­fections; »58% by viral infections; and »28% by atypical agents (M pneumoniae; C pneumoniae); same study one of first to document frequency of coinfection with viral and bacterial pathogens (percentage varies with age); mixed viral infections  —study by Bonzel et al; PCR used to identify viral pathogens in children hospitalized with acute re­spiratory tract infections (ARI); viral coinfection found in »35% of cases where RSV  identified, »87% where hu­man bocavirus (HBoV) identified, and  »33% where rhinovirus identified

Signs and symptoms: efficacy of fever and cough in diagnosing pneumonia  —  study by Juven et al (Finland) com­pared pneumococcal vs RSV vs mixed infections ; authors determined that fever and cough not very good for dif­ferentiating between pneumococcal and RSV disease; »50% of children with sole pneumococcal disease and »54% of those with sole RSV pneumonia had ill appearance; »45% of children with sole pneumococcal pneumonia had rhinorrhea (unexpected finding; suggests viral, rather than pneumococcal disease)

Laboratory diagnosis: high white blood cell (WBC) count and C-reactive protein (CRP) helpful but not sensitive enough for diagnosis; negative tests may be more helpful in detecting virus (Juven et al found »85% of children di­agnosed with pneumococcal pneumonia had WBC count >15,000/mL and »67% had CRP >40 mg/L, while only »4% of patients with RSV disease had WBC count >15,000/mL and »6% had CRP >40 mg/L; speaker has also looked at patients with influenza, in which only »6% have WBC count >15,000/mL and »13% have CRP >40 mg/L)

Specific tests: diagnosis of infection promotes specific and appropriate therapy; blood culture still gold standard for bacteria; viral tests (antigen; blood culture; PCR; good tests for influenza A or B virus, cytomegalovirus [CMV], adenovirus, RSV and human metapneumovirus [HMPV]); pertussis tests (good PCR test for pertussis, but not widely available); bacterial, Mycoplasma, and fungal serologies available; purified protein derivative (PPD) skin test still gold standard for diagnosing tuberculosis (TB) (QuantiFERON blood test approved by FDA for screening for latent TB in adults)

Efficacy of chest auscultation: in Juven et al study, »32% of patients with sole pneumococcal pneumonia sounded normal on chest auscultation; however, only »4% of children with RSV pneumonia sounded normal (suggests aus­cultation not very good for diagnosing pneumococcal disease, but could be helpful for identifying RSV); »24% of patients with pneumococcal and »39% with RSV disease had crackles (suggesting auscultation not good way to distinguish between two); if findings detected during auscultation unilateral, strong indication that infection bacte­rial and not viral; lobar infiltrates tend to be much more common in bacterial disease

Chest x-ray in diagnosing pneumonia: in study by Davies et al, only »72% of children with laboratory-documented bacterial pneumonia had airspace disease that radiologist called bacterial pneumonia; and of these, only »71% ac­tually had laboratory-documented bacterial pneumonia

Challenging understanding of host-pathogen interaction: in speaker’s study, children with CAP randomized to re­ceive levofloxacin or comparator antimicrobial therapy (amoxicillin/potassium clavulanate [Augmentin] or ceftri­axone alone in age group 6 mo-5 yr; clarithromycin or ceftriaxone plus clarithromycin in children ³5 yr of age); »66% of children in younger age group who received levofloxacin diagnosed with Mycoplasma pneumonia (twice as many as those treated with Augmentin); 89% of children with Mycoplasma pneumonia treated with levofloxacin cured (result expected); however, 83% of those treated with Augmentin (which has no documented activity against Mycoplasma), also cured; speaker offers possible reasons for this; his group still trying to explain results

Concluding comments: majority of strains of influenza A virus subtype H1N1 circulating in United States now re­sistant to oseltamivir (Tamiflu), but susceptible to amantadine and rimantadine; resistance seems unrelated to use of Tamiflu; infant or child who presents with coryza and fever, no toxicity and bilateral rales most likely has viral dis­ease and does not need treatment; based on age, clinical presentation, PE, season, and  laboratory tests, can focus anti-infective therapy against most likely pathogens; always watch for expected response; more tests and broader therapy may be needed

Hot Topics in Pediatric Infectious Diseases

Ravi Jhaveri, MD, Assistant Professor of Pediatrics and Assistant Professor in Molecular Genetics and Micro­biology, Division of Pediatric Infectious Diseases, Duke University Medical Center, Durham, NC

Impact of 7-valent pneumococcal conjugate vaccine (PCV7): vaccine contains polysaccharide capsules of 7 sero­types that cause »85% of pneumococcal disease, attached to diphtheria toxin; approved in February 2000 for use in children; early studies demonstrated major impact on prevention of pneumococcal bacteremia, meningitis, and pneumonia; other benefits  —  evidence that PCV7 provides herd immunity

Two recent studies on benefits of PCV7: in Morbidity and Mortality Weekly Report (MMWR), Centers for Disease Control and Prevention (CDC) data on pneumonia hospitalizations before and after introduction of PCV7  —  compared hospitalizations from 1997 to 1999 to those in 2005 and 2006; examined all children <2 yr of age and those 2 to 4 yr of age; annual rates of all-cause pneumonia in children <2 yr of age in 2005 and 2006 were »25% lower than those seen in prevaccine period; also saw a modest benefit in nonpneumonia acute respiratory infec­tion (ARI); caveats; study by Hsu et al on effect of PCV7 on pneumococcal meningitis  —compared cases of men­ingitis from 1998 to 2005 (adults and children); results showed reduction in cases of meningitis, particularly in children likely to get vaccine; bulk of benefit seen in disease caused by PCV7 serotypes; also saw drop in rates of PCV7-related serotype disease; some increase in non-PCV7 serotype disease; however, total disease burden still much lower than that in prevaccine period

Reason for recent increase in nonvaccine serotypes, eg, 19A: may be more issues at play than use of PCV7 (eg, natural shifts in circulating serotypes; changes in use of certain antibiotics [eg, azithromycin] can cause shift in cir­culating serotypes); take home point  —  that increase not due to direct cause and effect between vaccine and shifting serotypes

Changes in acute otitis media (AOM): AOM one of  top reasons for child medical visits and number one reason for antibiotic use; study by Sox et al looked at trends in treatment failure and relapse of AOM in community over 9 yr  (1996-2004); did separate assessment of effect of high-dose amoxicillin; findings  —incidence of AOM dropped from »400 cases/1000 person years to <200 cases at end of study period; rates of treatment failure and relapse also declined over time; authors concluded that declines unrelated to use of high-dose amoxicillin or use of pneumococ­cal vaccine; physicians’ altered criteria and threshold for treatment most likely reason

Human bocavirus not just “viral syndrome”: HBoV recently discovered parvovirus; early studies showed high de­tection rate, but also high rates of coinfection and inadequate studies of asymptomatic patients (unclear whether HBoV pathogen or passenger); study by Brieu et al (2008) examined children hospitalized with lower respiratory tract infection (LRTI) vs asymptomatic controls; used direct fluorescent antibody, enzyme-linked immunosorbent assay, and reverse transcription PCR tests to detect battery of viruses that cause LRTI; found 33 children with HBoV monoinfection (no significant difference in symptoms between high and low viral load; could detect virus for several months after acquisition); did comparison of features associated with HBoV vs HMPV and RSV  —  age (9 mo with HboV vs 6 mo with HMPV and 4 mo with RSV); duration of hospitalization (3 days) shorter for HboV); duration of oxygen requirement also shorter; seasonal variation also involved; study suggests that HBoV real pathogen, but may be weaker than influenza orRSV, and it requires susceptible host;  HBoV may also infect gastrointestinal (GI) tract

Treatment of osteomyelitis: some practitioners wedded to notion of exclusive intravenous (IV) therapy to avoid re­lapses and treatment failures; speaker and others disagree; recent study by Zaoutis et al looked at all children 2 mo to 17 yr of age diagnosed with osteomyelitis from 2000 to 2005 at 29 children’s hospitals; compared patients who received IV for full course of therapy to those switched to oral antibiotics; looking at primary outcomes (treatment failure within »6 mo of diagnosis; chronic osteomyelitis; need for surgery; complications of osteomyelitis) and sec­ondary outcomes (hospitalization within »6 mo of diagnosis; catheter-associated complications; adverse effects of antimicrobial agents), children treated with oral therapy did better in all categories; bottom line  —  switch to oral an­tibiotics just as efficacious for osteomyelitis and avoids complications of prolonged IV therapy; indicators used to make switch include child becoming afebrile; normal or close to normal CRP; decreasing erythrocyte sedimenta­tion rate [ESR]; child running down hall

Hepatitis B vaccine nonresponders (NRs): »10% of individuals do not respond to conventional 3-dose series of hepatitis B vaccine; conventional wisdom suggests repeat of 3-dose series (some respond; hope that others have enough cell-mediated immunity (CMI) to protect them); study by Cardell et al  —authors used 3 doses of combina­tion hepatitis A and B vaccine given at 0, 1, and 6 mo; study compared »48 NRs to conventional hepatitis B vaccine to 20 vaccine-naive subjects; all adults 20 to 69 yr of age; authors measured those that achieved >10 IUs of anti­body (Ab) and absolute levels of hepatitis B surface antibody (HBsAb); results  —  all patients in either group re­sponded completely to anti-hepatitis A vaccination and  all but 2 achieved protective levels of HBsAb; levels of HBsAb significantly lower in NRs than in vaccine-naive group; »60% of NRs had brisk response after just 1 dose of combined vaccine, suggesting they had memory response; possible explanations  —  higher antigen load in com­bination vaccine; possibility that hepatitis A antigen stimulated positive response to hepatitis B vaccine; combined vaccine approved only for patients ³18 yr of age, but many studies have looked at use in younger children

Treatment of Helicobacter pylori: Marshall and Warren won Nobel Prize in Medicine in 2005 for work linking H Pylori with peptic ulcer disease (PUD) and gastric cancer; before and since that time, practitioners have treated many people for H pylori and have decreased infection and colonization dramatically; what consequences associ­ated with this aggressive treatment? 2008 paper by Chen and Blaser looked at link between H pylori eradication and asthma prevalence in children; used data from National Health and Nutrition Examination Survey (NHANES) from 1999 and 2000 on children 3 to 19 yr of age; looked at prevalence of asthma, wheezing, dermatitis, and aller­gic rhinitis in children H pylori-negative or positive (all lower in H pylori-positive group); looking at age break­down, difference greatest in children 3 to 13 yr of age; inverse correlation of H pylori positivity and asthma held up when controls for socioeconomic status and herpes simplex virus type 1 and Toxoplasma status included; message of study  —   physicians should strongly consider how much effort should be expended to treat patients for H pylori and what other consequences treatment may have for patients and for society in general

Suggested Reading

Bonzel L et al: Frequent detection of viral coinfection in children hospitalized with acute respiratory tract infection using a real-time polymerase chain reaction. Pediatr Infect Dis J 27:589, 2008; Bradley JS et al: Comparative study of levofloxacin in the treatment of children with community-acquired pneumonia. Pediatr Infect Dis J 26:868, 2007; Bradley JS et al: Unique consid­erations in the evaluation of antibacterials in clinical trials for pediatric community-acquired pneumonia. Clin Infect Dis 47 Suppl 3:S241, 2008; Brieu N et al: Human bocavirus infection in children with respiratory tract disease. Pediatr Infect Dis J 27:969, 2008; Cardell K et al: Excellent response rate to a double dose of the combined hepatitis A and B vaccine in previous nonre­sponders to hepatitis B vaccine. J Infect Dis 198:299, 2008; Centers for Disease Control and Prevention (CDC): Pneumonia hospitalizations among young children before and after introduction of pneumococcal conjugate vaccine--United States, 1997-2006. MMWR Morb Mortal Wkly Rep 58:1, 2009; Chen Y, Blaser MJ: Helicobacter pylori colonization is inversely associated with childhood asthma. J Infect Dis 198:553, 2008; Davies HD et al: Prospective comparative study of viral, bacterial and atypi­cal organisms identified in pneumonia and bronchiolitis in hospitalized Canadian infants. Pediatr Infect Dis J 15:371, 1996; Da­vies HD et al: Reliability of the chest radiograph in the diagnosis of lower respiratory infections in young children. Pediatr Infect Dis J 15:600, 1996; Harper SA et al: Seasonal influenza in adults and children--diagnosis, treatment, chemoprophylaxis, and in­stitutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 48:1003, 2009; Hsu HE et al: Effect of pneumococcal conjugate vaccine on pneumococcal meningitis. N Engl J Med 360:244, 2009; Juvén T et al: Clinical profile of serologically diagnosed pneumococcal pneumonia. Pediatr Infect Dis J 20:1028, 2001; Mahon B et al: Effectiveness of seven-valent pneumococcal conjugate vaccine. Lancet 369:459, 2007; McIntosh K:  Commu­nity-acquired pneumonia in children. N Engl J Med 346:429, 2002; Pelton SI: Prospects for prevention of otitis media. Pediatr In­fect Dis J 26(10 Suppl):S20, 2007; Pelton SI et al: Emergence of 19A as virulent and multidrug resistant Pneumococcus in Massachusetts following universal immunization of infants with pneumococcal conjugate vaccine. Pediatr Infect Dis J 26:468, 2007; Sox CM et al: Trends in otitis media treatment failure and relapse. Pediatrics 121:674, 2008; Zaoutis T et al: Prolonged in­travenous therapy versus early transition to oral antimicrobial therapy for acute osteomyelitis in children. Pediatrics 123:636, 2009.