INFECTIOUS DISEASE UPDATE
| BUGGED BONES AND HOT JOINTS —Joel D. Klein, MD, Clinical Professor of Pediatrics, Jefferson Medical College,
Thomas Jefferson University, Philadelphia, PA, and Chief, Division of Pediatric Infectious Diseases, Alfred I. duPont Hospital
for Children, Wilmington, DE
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Osteomyelitis
| Epidemiology: osteomyelitis—occurs in 2 in 10,000 children; more common in boys than girls; ≥50% of affected patients
<5 yr of age; septic arthritis (SA)—with development of Haemophilus influenzae vaccine, much less common;
seen in younger children; more common in boys than girls
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| Pathophysiology of osteomyelitis: different in children than in adults; adults get osteomyelitis through direct inoculation;
in children, virtually all cases hematogenous
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| Acute hematogenous osteomyelitis (AHO)
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 | Pathophysiology: tiny venules near metaphysis (in young infants, venules near epiphysis) thrombosed due to bacteremia,
which causes sludging; small abscess forms in bone marrow; abscess enlarges, periosteum becomes involved as bone
begins to stretch (painful); possible soft tissue or joint involvement; symptoms can take 1 or 2 wk to develop
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| Presentation: children febrile and unhappy; acute signs of infection—unlike children with SA, most children with osteomyelitis
do not have external signs of infection; some warmth and swelling possible; point tenderness most important diagnostic
clue; if arm hurts or patient cannot move arm, gently “walk” down bone (patient will react if involved site
palpated); limitation of motion in nearby joint (possibly due to sympathetic effusion in joint) can mimic arthritis; point
tenderness merits further evaluation
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| Acute osteomyelitis investigations
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| Laboratory data: complete blood cell count (CBC) mandatory for hospitalized patients; white blood cell count (WBC) elevated;
some children slightly anemic; C-reactive protein (CRP) test sensitive marker for inflammation (elevated within 1 day of infection;
erythrocyte sedimentation rate [ESR] takes 2 or 3 days); blood cultures (bacteria detected <50% of time)
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| Imaging studies: x-ray of extremity involved; ultrasonography (US) useful, but view similar to x-ray if osteomyelitis has
progressed; plain x-ray—may detect periosteal reaction (line of periosteum over side of bone); may see soft tissue
swelling (may not be evident on examination); bony changes take ≥2 wk; bone scan—can make diagnosis early; sensitive
test (in rabbit model, bone scan positive in 24 hr); in children, test not specific; useful if multifocal osteomyelitis
suspected; if site difficult to examine, bone scans helpful; magnetic resonance imaging (MRI)—best imaging study for
osteomyelitis; can detect fluid in adjacent joint, and marrow edema secondary to abscess; marrow edema present early
in osteomyelitis; MRI shows soft-tissue edema and abscess (if present); young children need sedation (MRI takes
time), and sedation has risk; if case not clear from plain x-ray or bone scan, MRI necessary; US—can see same signs
(subperiosteal abscesses, adjacent SA or fluid in joint) as on plain x-ray; real-time imaging
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| Surgery: aspiration for culture in osteomyelitis; drainage of subperiosteal abscess; drainage of adjacent joint sepsis; debridement
of dead tissue; biopsy (in equivocal cases)
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| Initial treatment of AHO: initially, empiric intravenous (IV) bactericidal antibiotics to kill organism (as opposed to
bacteriostatic agents, which stop organism from growing [if discontinued too soon, organism grows again]); when culture
results obtained, select antibiotic based on susceptibility; investigate if no improvement
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| Pathogens in children: >50% of cases of AHO due to Staphylococcus aureus infection; rarely, Streptococcus pyogenes
(more rarely, Streptococcus pneumoniae); occasionally—H influenzae (children not fully immunized); Kingella kingae;
Bartonella henselae
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| Empiric antibiotics for AHO in children: directed against S aureus and group A streptococci; cephalosporin (eg,
cefazolin [eg, Ancef]) or β-lactam antibiotic (oxacillin or nafcillin) anti-staphylococcal agents; community-acquired methicillin-resistant
S aureus (MRSA)—50% of staphylococcal infections; consider empiric administration of clindamycin
or vancomycin; if young child not fully immunized with H influenzae type b conjugate vaccine (Hib), consider H influenzae
coverage
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| Duration of therapy for children: 4 to 6 wk; treatment failure in staphylococcal osteomyelitis (study)—if treatment
<3 wk, failure rate almost 20% (rate lower at >3 or 4 wk); findings supported by other studies; duration of IV therapy—trend
1 to 2 wk; if patient doing well, send home on oral antibiotics that target pathogen involved; may reduce morbidity and duration
of hospitalization; uncertain compliance (young child may not tolerate medication); may need high doses to achieve adequate
levels in blood (eg, 2-3 times normal dose of cephalexin [eg, Keflex])
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| Subacute osteomyelitis: weeks or months of intermittent symptoms; slow onset; if pain intermittent, patients may not
seek prompt treatment; patients generally well; ESR and CRP less elevated than in acute osteomyelitis; usually metaphyseal,
but can be epiphyseal; differential diagnosis of positive MRI—Brodie’s abscess (typically involves long-standing
staphylococcal infection); Staphylococcus and bone form symbiotic relationship, causing intermittent pain; localized
eosinophilic granuloma (low-grade malignancy) may mimic subacute osteomyelitis; treatment—antibiotics; Brodie’s
abscess may require surgical excision
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| Predicting organism by age
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| Neonates: S aureus predominant; also, group A streptococci and gonococcal infection (particularly in intensive care
unit); gram-negative rods (some very resistant to treatment)
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| Infants and children: S aureus; H influenzae; S pneumoniae; K kingae
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| Children >5 yr of age: S aureus; in some children, hemoglobinopathy; Salmonella; in some injuries, Pseudomonas; group
A streptococci and S pneumoniae
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| Young adolescents: S aureus predominates; occasionally, gonococcal infection (usually in small fingers of hand)
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| Sequelae: bone destruction; occasionally, growth plate destruction in young children, with loss of function
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Septic Arthritis
| Pathogenesis: routes—1) hematogenous via synovium or 2) direct (from metaphyseal osteomyelitis or by inoculation
[trauma]); sites of underlying metaphyseal osteomyelitis—if in eproximal femur, humerus, radius, or distal tibiofibular
complex, risk of infection entering nearby joint; if in shoulder or hip, infection in joint; bacteria leaking from site of osteomyelitis
can infect synovial fluid; if synovial fluid causes increased pressure in joint space, head of bone can die; distribution
of SA—knee and hip common sites (particularly in young children)
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| Differential diagnosis of SA: patient presents with limp and knee pain (transient synovitis of hip or knee); reactive arthritis;
in most cases, severity of symptoms makes diagnosis obvious (patients with SA have severe pain); eg, if young
patient able to climb onto examination table unassisted, problem probably not SA
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| Clinical evaluation: signs of septic hip—flexed, abducted, and externally rotated; patients irritable and sick; if distal,
joint hot and swollen; in infants, jiggling table elicits pain; laboratory data—WBC, ESR, and CRP elevated; 30% to
50% of blood cultures positive; x-ray can detect increase in joint space suggestive of septic joint (US shows same); order
analysis of synovial fluid if WBC negative; Gram stain and appropriate cultures; imaging—good x-ray able to detect
problem immediately; bone scan helpful; if adjacent bones infected, more likely joint infected also; clinical variables—
fever; ability to bear weight; ESR, CRP, and WBC; examination of joint space
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| Acute SA organisms: S aureus; H influenzae; group A streptococci; S pneumoniae; gram-negative rods; gonoccus;
Kingella
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| Treatment: SA of hip surgical emergency; if head of femur lost, hip replacement needed; debridement of joints; antibiotics
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| Complications: joint destruction and loss of function; beware of aseptic necrosis of femoral or humeral head
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AHO and SA in Neonates
| Introduction: immune system immature; osteoarthritis or SA may present with few signs; most common site of osteomyelitis
right proximal humerus (during delivery, right shoulder hits pubis of mother); signs—pseudoparalysis of arm; infants
and neonates may have normal laboratory parameters; frequently, multifocal osteomyelitis (bone scan important);
infection not localized to metaphysis (can enter epiphysis across growth plate)
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| Features: >75% of affected patients have associated osteomyelitis; infection crosses into joint across growth plate; intra-
articular destruction of joints; local destruction of cartilage
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| Pathogens: S aureus; group B streptococci; Escherichia coli; occasionally—coagulase-negative Staphylococcus; Candida
; Neisseria gonorrhoeae
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| Acute presentation (picture of septicemia): lethargy; infant not feeding well; irritability; resistance to movement
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| Neonatal osteomyelitis/SA: most common in premature infants; watch for silent bones and joints (eg, osteomyelitis of
mandible or calcaneus [secondary to heel stick]); diagnosis—bone scan “not great test” but necessary because of risk of
multifocality and silent bones; MRI and CT difficult to perform on premature infants; prognosis—not good (most children,
in contrast, do well); appropriate cultures necessary; beware of osteomyelitis and SA in same patient; antibiotic
therapy—directed against S aureus, group B streptococci, and gram-negative rods, according to resistance pattern in particular
nursery
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| HPV AND ADOLESCENTS: PREVENTION OF CERVICAL CANCER —Maria Trent, MD, MPH, Assistant Professor of
Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
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| Epidemiology: human papillomavirus (HPV) common; >125 types (>40 types affect genital region)
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| Association with cervical cancer: low-risk types—HPV type 6 (HPV-6) and HPV type 11 (HPV-11); external genital
warts; low-grade squamous lesions of cervix; high-risk types—eg, HPV types 16 (HPV-16), 18 (HPV-18), 31 (HPV-
31), and 33 (HPV-33); associated with low- and high-grade lesions; squamous cell cancer
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| Incidence in United States (data from Centers for Disease Control and Prevention [CDC]): 6.2 million
sexually transmitted HPV infections annually; $1.6 billion in direct medical costs; currently, 20 million people have detectable
HPV infection; prevalence—≥50% of sexually active men and women acquire HPV at some point in their lives; 80% of
women have acquired genital HPV infection by 50 yr of age; genital warts—incidence as high as 1 in 1000; perform genital
examination on boys
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| Epidemiology of cervical cancer: worldwide, 500,000 cases annually; developing world—most common malignancy
in women (24% of cancers); United States—sixth most frequent malignancy in women ( ≈7% of cancers)
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| Transmission of genital HPV: predominantly associated with sexual activity; transmissible from patients with asymptomatic
and subclinical disease; risk factors for women—young age; sexual behavior (risk increases with number of
male sexual partners and early age of first sexual intercourse); sexual behavior of male sexual partners (ie, risk increases
if male partner has history of multiple sex partners); immune status (HPV more likely in immunocompromised women)
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| Risk factors for cervical lesions and cancer: initiation of sexual intercourse at <17 yr of age; risks for cervical intraepithelial
neoplasia (CIN) and invasive carcinoma increase with decreasing age of first sexual intercourse
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| Youth Risk Behavior Survey: by time of graduation from high school, majority had already initiated sexual intercourse;
of ninth graders, ≈30% initiated intercourse; ≈7% of adolescents report sexual debut at <13 yr of age
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| Natural history: most HPV infections transient, asymptomatic, or subclinical; in most immunocompetent individuals,
no clinical consequences; duration of new cervical infections variable (mean, 8 mo); clearance likely due to development
of effective immune response; persistent infection more likely to progress to cervical cancer
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| Clinical manifestations and sequelae: most commonly, genital warts and cervical cell abnormalities; anogenital
squamous cell lesions; recurrent respiratory papillomatosis; in most cases, genital HPV infection transient (no clinical
manifestations or sequelae); cervical cell abnormalities—usually subclinical; detected by Papanicolaou (Pap) test, colposcopy,
or biopsy; usually caused by high-risk HPV types; often regress spontaneously without treatment
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| Pap test: 55 million tests performed annually in United States (incidence of cervical cancer decreased 75%); histologic
classification—CIN 1 (mild dysplasia) to CIN 3 (severe dysplasia; invasive cancer); liquid-based technologies—eg,
ThinPrep, AutoCyte; improved preparations (fixed immediately, dispersed, and filtered); computer-assisted screening;
oncogenic testing to support histologic findings
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| Atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial
lesions (LSIL): ≈3 million cases/yr; management options—immediate colposcopy safe and sensitive but costly
and invasive; repeat Pap test in 4 to 6 mo (less sensitive and less safe, but less costly and less invasive); HPV triage may increase
sensitivity and safety; may decrease invasiveness; regression in young women (Moscicki et al, 2004)—91% of
LSIL regressed within 36 mo (only 3% progressed to high-grade lesions)
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| Recommendations for adolescents: cervical cytology within 3 yr of initiation of vaginal intercourse or 21st birthday;
annual Pap test thereafter; reflex HPV testing cost-effective; little role for general HPV screening in women <30 yr
of age, unless patient exceeds risk of typical patient
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Prevention
| American Academy of Pediatrics (AAP): in 2006, HPV vaccine added to routine adolescent visit
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| Efficacy of bivalent virus-like particle (VLP) vaccine for prevention of HPV-16 and HPV-18 (Harper
et al, 2004): >1000 women in North America and Brazil; bivalent vaccine highly effective against persistent infection;
vaccine safe, well tolerated, and highly immunogenic
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| Efficacy of quadrivalent HPV (HPV-6, -11, -16, -18) vaccine (Villa et al, 2005): incidence of combined infection
decreased 90% for those in vaccine group
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| Food and Drug Administration (FDA)-approved prescribing information: indications—vaccine FDA-approved
for female patients 9 to 26 yr of age; recommended by CDC’s Advisory Committee on Immunization Practices
(ACIP) in 2006 for prevention of cervical cancer, genital warts, and precancerous or dysplastic lesions; administration—
series of 3 vaccinations (0.5 mL intramuscularly at months 0, 2, and 6); pregnancy category B (not indicated for pregnant
women; if woman becomes pregnant during series, stop and restart after delivery); no data about breast milk, but safe for
women who are nursing; no indication to restart series if dose missed (resume schedule)
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| Key issues: age at immunization—recommended for preteen age group (especially patients 11-12 yr of age); delivery system
and expense—Vaccine For Children program includes HPV vaccine; behavior change—no evidence that vaccine increases
sexual behavior or that vaccine alone changes behavioral risk for other sexually transmitted diseases (STDs);
waning immunity—issue with varicella vaccine; CDC surveillance ongoing; continue routine gynecologic care (eg, pelvic
examinations, STD screening)—patients may have been exposed to >1 HPV type (continue to screen for sequelae associated
with earlier exposure); risk for other STDs (discuss prevention with patients); pregnancy can continue if no contraception
used
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Suggested Reading
Bachur R, Pagon Z: Success of short-course parenteral antibiotic therapy for acute osteomyelitis of childhood. Clin Pediatr
(Phila) 46:30, 2007; Caird MS et al: Factors distinguishing septic arthritis from transient synovitis of the hip in
children. A prospective study. J Bone Surg Am 88:1251, 2006; Goergens ED et al: Acute osteomyelitis and septic arthritis
in children. J Paediatr Child Health 41:59, 2005; Harper DM et al: Efficacy of a bivalent L1 virus-like particle
vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomized controlled
trial. Lancet 364:1757, 2004; Kocher MS et al: Validation of a clinical prediction rule for the differentiation between
septic arthritis and transient synovitis of the hip in children. J Bone Joint Surg Am 86:1629, 2004; Kufeji O et al:
Chronic recurrent multifocal osteomyelitis is a differential of childhood limp. Arch Dis Child 91:30, 2006; Moscicki AB
et al: Regression of low-grade squamous intra-epithelial lesions in young women. Lancet 364:1678, 2004; Nelson JD:
Skeletal infections in children. Adv Pediatr Infect Dis 6:59, 1991; Pichichero ME: Who should get the HPV vaccine? J
Fam Pract 56:197, 2007; Shah SS: Abnormal gait in a child with fever: diagnosing septic arthritis of the hip. Pediatr
Emerg Care 21:336, 2005; Stanitski CL: Changes in pediatric acute hematogenous osteomyelitis and septic arthritis.
Clin Orthop Relat Res 409:186, 2003; Tissot AM et al: Effective strategies for HPV vaccine delivery: the views of pediatricians.
J Adolesc Health 41:119, 2007; Villa LL et al: Prophylactic quadrivalent human papillomavirus (types 6, 11,
16, and 18) L1 virus-like particle vaccine in young women: a randomized double-blind placebo-controlled multicentre
phase II efficacy trial. Lancet Oncol 6:271, 2005; Zimmerman RK: HPV vaccine and its recommendations, 2007. J
Fam Pract 56:S1-5, 2007.
www.audiodigest.org
To locate lectures of related interest, or to see a complete listing of Audio-Digest CME Programs, including written summaries.
Educational Objectives
| The goal of this program is to improve primary care management of bone infections in children and human papillomavirus
(HPV) infection in adolescents. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Diagnose and manage osteomyelitis in children.
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| 2. Choose appropriate therapy for managing septic arthritis.
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| 3. Address special issues in septic arthritis and osteomyelitis in neonates.
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| 4. Discuss the epidemiology of HPV infection.
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| 5. Describe current recommendations for the HPV vaccine.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members 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. Trent has participated in the Speakers’ Bureau
of Merck Medical Forums.
Acknowledgements
Dr. Klein was recorded at Pediatric Infections and Pulmonary Diseases, presented September 8-10, 2006, in Rehoboth, DE,
by Nemours; Dr. Trent was recorded at the 35th annual Pediatric Trends, presented April 16-20, 2007, in Baltimore, MD,
by Johns Hopkins University Children’s Center.
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