INFECTIOUS DISEASE CHALLENGES
From the Katz-Wilfert Update in Pediatric Infectious Diseases, presented by Duke University School of Medicine, Durham, NC
Educational Objectives
| The goal of this program is to improve diagnosis and treatment of infectious diseases and to optimize the use of vaccines
to prevent them. After hearing and assimilating this program, the participant will be better able to:
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 | 1. Evaluate the efficacy of cold-inactivated and thermally inactivated influenza vaccines, and identify patients
who should receive the nasal vaccine.
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| 2. Interpret the data on evolution and diversity among isolates of community-acquired methicillin-resistant Staphylococcus
aureus (CA-MRSA), and recognize factors that contribute to its virulence.
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| 3. Analyze reports on the incidence of Streptococcus pneumoniae serotype 19A and the optimal use of vaccination
and antibiotics for diseases caused by this organism.
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| 4. Describe the appropriate use of blood culture for identification of pathogens in febrile children.
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| 5. Diagnose diseases caused by emerging respiratory viruses, and discriminate between new human pathogens
and those recently identified.
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Faculty Disclosure
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, Drs. Jhaveri and Cunningham
and the planning committee reported nothing to disclose.
Acknowledgements
Lectures given by Drs. Jhaveri and Cunningham were recorded at the Katz-Wilfert Update in Pediatric Infectious Diseases,
held April 19, 2008, in Durham, NC, and sponsored by the Duke University School of Medicine. The Audio-
Digest Foundation thanks the speakers and the Duke University School of Medicine for their cooperation in the production
of this program.
| HOT TOPICS IN PEDIATRIC INFECTIOUS DISEASE —Ravi Jhaveri, MD, Assistant Professor, Department of Pediatrics,
Division of Infectious Diseases, Duke University School of Medicine, and Duke Children’s Hospital,
Durham, NC
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| Nasal influenza vaccines: background—cold-adapted inactivated vaccine (CAIV; FluMist) contains attenuated virus
adapted to grow well at lower temperatures in nose; intranasal delivery induces local immunity; approved for
patients ages 2 to 49 yr; patients 2 to 8 yr of age require 2 doses if not previously vaccinated (1 dose if previously
vaccinated), patients >9 yr of age need only 1 dose; indicated for healthy patients only
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| Studies comparing CAIV with thermally inactivated vaccine (TIV): first study—in children aged 6 to 72 mo
(>1000 per group); all children received 2 doses of CAIV or TIV; measured rates of confirmed influenza, influenza-like
illness, and adverse events (including wheezing, which has impeded approval of live vaccine for patients
at high risk, eg, asthmatics); intent-to-treat analysis showed 2.3% of children who received CAIV got
influenza, compared to 4.8% of those who received TIV; analysis of any community-acquired influenza subtypes
shows higher rates of infection but similar relative efficacy; second study—children 6 to 17 yr of age with asthma
received 1 dose of CAIV or TIV (>1000 per group); analyzed for confirmed influenza, influenza-like illness, and
pulmonary function (eg, wheezing); 4.1% of children receiving CAIV got influenza, compared to 6.3% who received
TIV; analysis for any strain gave rates of 4.5% vs 6.6%, respectively; no significant differences in rate of
exacerbations of asthma, hospitalizations, or antibiotic use; other factors—studies performed during year when
vaccines well matched to circulating strains; more recent study showed efficacy of only 44% for current TIV;
CAIV expected to be relatively better when match poor; safety studies of CAIV in infants ≥6 wk of age showed
no adverse events
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| Recommended use: cost and coverage important factors; CAIV approved for children ≥2 yr of age; stored in refrigerator,
use for patients who have recurrent infections (otitis, sinusitis, or pneumonia), who refuse products containing
thimerosal, or who can afford live vaccine; vaccine coverage—recent Centers for Disease Control and
Prevention (CDC) results for coverage showed <20% of children aged 2 to 5 yr received 1 dose (35% in NC); in
United States, on average, 31% of children received 1 dose, 20.6% got 2
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| Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA): causes skin and soft tissue
infections, and necrotizing pneumonia; shorter gene cassette for antibiotic resistance than hospital acquired
MRSA (HA-MRSA) allows easier transmission to other bacteria and propagation of clones
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| Evolution and diversity: study of several isolates—used pulsed-field gel electrophoresis to look at DNA and protein
sequences to determine differences and similarities between isolates; phylogenetic trees (indicating relatedness
of isolates on basis of sequence similarities) showed many isolates highly related, ie, evolved recently, but 2 genetically
distinct; study of virulence in mice — showed reference strain killed 80% by 36 hr, as did most of isolates;
2 isolates that were closely related to others killed only 20%; these 2 isolates produced normal levels of
staphylococcal protein A, but less alpha-hemolysin and Panton-Valentine leukocidin (PVL); other strains that
produced little PVL were very virulent; production of delta toxin also does not explain differences in virulence;
subtle differences that cause large changes in virulence and effects of host susceptibility still poorly understood
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| Streptococcus pneumoniae serotype 19A: high rate of resistance (20%) to antibiotics, susceptible only to fluoroquinolones
and telithromycin; thought to be increasing in prevalence; however, data reported deceptively, eg, multidrug
resistance (MDR) rate of 20% refers to macrolide-resistant strains (20% of total), so MDR rate actually 4%;
study funded by makers of telithromycin (toxic; could cause fulminant liver failure; approval by Food and Drug
Administration withdrawn); serotype 19A frequent cause of invasive disease; vaccine-related strain but not in vaccine;
however, rates of invasive disease stable nationally and down by 70% since introduction of heptavalent conjugate
pneumococcal vaccine (PCV7); keep vaccinating and using antibiotics prudently
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| Febrile children: previously, assumption made that subset of febrile children without localizing signs had bacteremia
that would progress to more severe disseminated infections (eg, meningitis, osteomyelitis); guidelines developed
in 1993 on basis of data from before introduction of Haemophilus influenza vaccine; vaccine now in use for
20 yr, PVC7 approved for 8 yr, and S pneumoniae causes disseminated infection less frequently; speaker recommends
discontinuing practice of performing blood cultures on all febrile children
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| Study data: blood culture data from febrile children aged 3 mo to 36 mo showed that before PCV7 vaccine, 150
children produced 17 positive cultures (7 false-positive); among 10 pathogens isolated, 6 were S pneumoniae; after
introduction of vaccine, 275 febrile children produced 14 positive cultures (11 false-positive); single pathogen
isolated, not S pneumoniae; 7% of children had urinary tract infections (UTIs); UTI now most common bacterial
infection in this patient group (not all children tested for UTI, so actual rate possibly higher)
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| Benefit analysis: since introduction of vaccine, occult bacteremia rate with S pneumoniae down 100% (from 2.8% to
0%); false-positive culture rate 5%, and half of these children receive antibiotics unnecessarily; if occult bacteremia
rate 0.5%, to prevent 1 case of meningitis, blood cultures performed for 20,000 febrile children, 100 of
whom would have bacteremia and one meningitis; 10,000 children would have received empiric antibiotics, and
1000 would have had false-positive cultures; no data to show early treatment of meningitis better than treating at
first symptoms; speaker recommends discontinuing blood cultures and antibiotic treatment for febrile children,
but testing urine on all; follow-up study evaluated recently emerged strain 19A and showed still no cases of occult
pneumococcal bacteremia
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| Viral exacerbations of asthma: study used viral (gene) chip with known viral sequences and tested samples of
nasal washings from patients with exacerbations of asthma; found many isolates of rhinoviruses and coronaviruses;
most rhinovirus isolates (group X) genetically distinct from isolates causing common colds (groups A and B);
speaker predicts use of genetic testing in future for diagnosis of viral infections; second study of class X rhinoviruses
showed they can cause severe respiratory illness in children
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| Transmittal of respiratory infections: study of contamination of masks worn by adults during quiet breathing
for 20 min, reading aloud for 20 min, and coughing 20 times over 3 to 5 min; among patients who had confirmed
viral disease, rhinovirus present in mask after breathing; rhinovirus and parainfluenza virus present after talking
and coughing
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| Microbiology myths: study of “double dip”—found 100,000 bacteria isolated from food dip that had been exposed
to previously bitten cracker; study of “5 second rule”—found Salmonella viable for 4 wk on various surfaces and
transmitted at rate of 99% after 5-sec contact with food
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| Ampicillin resistance: >50% of Escherichia coli isolates resistant; E coli most common cause of UTI, and resistance
rates to trimethoprim sulfamethoxazole have risen over 8 yr from high teens (16%-19%) to 30%; first- and
third-generation cephalosporins may be next step for treatment
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| EMERGENT VIRAL RESPIRATORY INFECTIONS —Coleen K. Cunningham, MD, Associate Professor, Department
of Pediatrics, and Chief, Division of Infectious Diseases, Duke University School of Medicine, and Duke
Children’s Hospital, Durham
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| Background: human metapneumovirus, coronavirus, bocavirus, and polyomavirus cause wide range of respiratory
and gastrointestinal syndromes; some represent new viruses, but most represent long-standing pathogens newly identified
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| Human metapneumovirus: first identified in 2001 report on data from 28 children collected over 20 yr; belongs
to Paramyxoviridae family, which also contains pneumoviruses eg, respiratory syncytial virus (RSV); human
metapneumovirus clinically similar to RSV; can cause pneumonia and severe illness; more often presents as bronchiolitis;
causes severe morbidity and mortality in immunocompromised patients; peak season December through
March (overlaps RSV); appears worse every other year (alternates with RSV severity); causes 10% to 12% of respiratory
tract infections (RTIs); mean age of patients 1 yr (median 7 mo), and 75% of illness occurs in children <1 yr
of age; causes bronchiolitis, croup, and pneumonia
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| Human coronaviruses (HCoV): 2 strains (OC43 and 229E) described in 1960s; severe acute respiratory syndrome
(SARS) identified in 2003, and ≥2 more strains identified since; SARS epidemic—affected >8000 people
in 29 countries, almost 800 died; SARS truly new virus in humans; first case in 2002, last in 2004; symptoms include
high fever, headache, body ache, mild respiratory symptoms at onset, diarrhea in 10% to 20% of patients,
dry cough after 2 to 7 days, then severe pneumonia; high case fatality rate; other strains of HCoV—229E commonly
causes RTI in children and adults; OC43 and HKU-1 rare; NL-63 (similar to 229E) also common cause of
RTI
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| Seroepidemiology: study found 50% of children <2 mo of age have passive maternal antibody to 229E and NL-63;
<10% retain antibody by age 6 mo; by 1 yr of age, 50% have acquired infection (as determined by antibody); infection
may also be asymptomatic; study showed 229E peaks in winter season, as do all respiratory viruses (enterovirus
and parainfluenza peak in different season); HCoV distributed worldwide, generally causes mild upper
RTI with fever, and may cause croup and pneumonia
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| Bocavirus: first human parvovirus identified after parvovirus B-19 (others identified later); related to bovine canine
parvovirus; incidence 3% to 10% in children with lower RTI; high rate (20%-50%) of coinfection with other respiratory
viruses; distributed worldwide; peaks in winter and spring; frequently asymptomatic, so pathogenic role unclear;
primary infection associated with higher viral loads, seroconversion, and viremia; reinfection or colonization
possibly common; symptoms include wheezing (often isolated from asthmatic patients); found in patients with severe
pneumonia; high viral loads correlate with primary infection
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| Other newly identified respiratory viruses: polyomaviruses found in very young and older immunocompromised
patients, and in 1% to 7% of children with RTI; often found in asymptomatic individuals, so association with
disease not conclusive; study—65 children infected with WU polyomavirus had nonspecific symptoms including
cough, diarrhea, tachypnea, and hypoxia
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| Avian influenza: H5N1 common, very contagious, and potentially lethal in poultry; first human cases seen in 2003;
threatening to human health because virus causes serious disease, and no preexisting antibodies present in population,
so no one protected by previous exposure to vaccine or other influenza viruses; influenza does not usually
cross from birds to humans, but H5N1 has; if virus adapts to improve rate of human-to-human transmission, it
could cause pandemic; >300 cases of human infection described so far, with evidence of human-to-human transmission;
many infections have been in younger populations, including young children; preliminary results suggest
infection less often fatal in younger patients
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| Clinical manifestations: incubation period 3 to 8 days; patients have high fever and flu-like symptoms, may have
bloody diarrhea, and often quickly develop lower RTI with high fatality rate; bacterial coinfection common; laboratory
abnormalities include leukopenia, thrombocytopenia, elevated alanine aminotransferase; treatment—use
oseltamivir, not steroids or prophylactic antibiotics (unless pneumonia present)
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Suggested Reading
Allen PJ: The world awaits the next pandemic: will it be H5N1, the ‘bird flu’? J Child Health Care 10:178, 2006;
Antonyrjah B, Mukundan D: Fever without apparent source on clinical examination. Curr Opin Pediatr 20:96,
2008; Bosis S et al: Association between high nasopharyngeal viral load and disease severity in children with human
metapneumovirus infection. J Clin Virol [Epub ahead of print] May 12, 2008; Calvo C et al: Multiple simultaneous
viral infections in infants with acute respiratory infections in Spain. J Clin Virol [Epub ahead of print] May,
2008; Fox JD: Nucleic acid amplification tests for detection of respiratory viruses. J Clin Virol 40(Suppl 1):S15,
2007; Hui DS, Chan PK: Clinical features, pathogenesis and immunobiology of severe acute respiratory syndrome.
Curr Opin Pulm Med 14:241, 2008; Immergluck LC: Community-associated infections in children—update
on community-associated methicillin-resistant Staphylococcus aureus for the practitioner. Ethn Dis 17:S2-46, 2007;
Kahn JS: Newly identified respiratory viruses. Pediatr Infect Dis J 26:745, 2007; Koski Me et al: Community associated
methicillin-resistant staphylococcal infections in a pediatric urology practice. J Urol 179:1098, 2008; Meissner
HV: Influenza vaccines: a pediatric perspective. Curr Opin Pediatr 19:58, 2007; Moore MR et al: Population
snapshot of emergent Streptococcus pneumoniae serotype 19A in the United States, 2005. J Infect Dis 197:1016, 2008;
Paintsil E: Pediatric community-acquired methicillin-resistant Staphylococcus aureus infection and colonization:
trends and management. Curr Opin Pediatr 19:75, 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; Pletz MW et al: Pneumococcal vaccines: mechanism of action,
impact on epidemiology and adaptation of the species. Int J Antimicrob Agents [Epub ahead of print] Mar 29, 2008;
Rihkanen H et al: Respiratory viruses in laryngeal croup of young children. J Pediatr 152:661, 2008; Schildgen
O et al: Human bocavirus: passenger or pathogen in acute respiratory tract infections? Clin Microbiol Rev 21:291,
2008; Sloots TP et al: Emerging respiratory agents: New viruses for old diseases? J Clin Virol [Epub ahead of print]
Apr 10, 2008; Smuts H et al: Role of human metapneumovirus, human coronavirus NL63 and human bocavirus in
infants and young children with acute wheezing. J Med Virol 80:906, 2008; Vesikari T et al: Safety and tolerability
of cold-adapted influenza vaccine, trivalent, in infants younger than 6 months of age. Pediatrics 121:e568, 2008; Walton
RP, Johnston SL: Role of respiratory viral infections in the development of atopic conditions. Curr Opin Allergy
Clin Immunol 8:150, 2008.
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