Teenager with Fever, Petechiae,Confusion, and WeaknessSenthil Velan Bhoopalan, MD, PhD,* Rupesh Kumar Natarajan, MD,†

David Di John, MD†

*Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN†Department of Pediatrics, University of Nevada School of Medicine, Las Vegas, NV

PRESENTATION

A 13-year-old previously healthy girl presents with fever (101.5°F [38.6°C]) for 3

days. It was preceded by generalized headache. The patient reports no history of

vomiting, difficulty breathing, coughing, chest pain, blurry vision, speech dis-

turbance, or trauma. The patient also has diffuse muscle pain, although no

swelling of limbs or limitation of activity is reported. There is no history of any

recent travel, sick contacts, or exposure to animals or insects. She does not

report any intravenous drug abuse. Her dental braces were adjusted 2 weeks

before admission. Our patient has no previous medical or surgical history.

There is no family history of any congenital heart defects, arrhythmia, or

frequent infections. She lives with her parents and has a 31-year-old brother,

who is healthy.

In the emergency department she has a temperature of 102°F (38.9°C), with

associated tachycardia but otherwise normal vital signs. Her physical examination

shows an ill-appearing young febrile girl who is alert and oriented to time, place, and

personbut has trouble recalling events that happened in thepast 5 to 7 days. Strikingly,

there aremultiple nonblanching petechial hemorrhages in the tips of her fingers and

toes (Figs 1–3). In addition, tender nodes are appreciated in both palms and

soles. The patient also has some weakness of all 4 limbs, but no other notable

findings on clinical examination are appreciated. Importantly, auscultation of

the heart reveals normal heart sounds with no murmurs. Initial laboratory data

include a white blood cell count of 12,000/mL (12 � 109/L), a hemoglobin value

of 13 g/dL (130 g/L), and a platelet count of 118 � 103/mL (118 � 109/L). The

comprehensive metabolic panel is normal, but her C-reactive protein level and

erythrocyte sedimentation rate are elevated at 130 mg/L (1,238 nmol/L) and

25 mm/hr, respectively. A blood culture and lumbar puncture are collected.

Cerebrospinal fluid studies do not show any abnormalities. A transthoracic

echocardiogram is performed that confirms the diagnosis.

DIAGNOSIS

The echocardiogram demonstrates mitral valve endocarditis and a mobile veg-

etation measuring 1.5 � 1 cm in the ventricular surface of the anterior leaflet of

the mitral valve (Video 1). Although the patient has normal ventricular function,

the vegetation causes some mitral incompetence (Video 2). The other valves are

AUTHOR DISCLOSURE Drs Bhoopalan andNatarajan have disclosed no financialrelationships relevant to this article. Dr Di Johnhas disclosed that he is principal investigatorfor AstraZeneca and Cempra Pharmaceuticalsclinical trials research on new drugs to treatinfections in children, and he is on thespeaker’s bureau for vaccine-related issues forSanofi Pasteur. This commentary does notcontain a discussion of an unapproved/investigative use of a commercial product/device.

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unaffected. The blood culture is positive for methicillin-

sensitive Staphylococcus aureus. Due to the altered mental

status and weakness of extremities, magnetic resonance

imaging of the brain is performed and shows multiple ische-

mic areas in both cerebral hemispheres as well as a punctate

ischemic stroke in the left cerebellum. No midline shifting,

edema, or mass effect is reported. Our patient is diagnosed as

having bacterial endocarditis caused by methicillin-sensitive S

aureus and is treated with antibiotics.

DISCUSSION

EpidemiologyInfective endocarditis (IE) is less common in the pediatric

population compared with adults. Reported incidence ranges

from 0.3 cases (in older children and teenagers) to 3.3 cases

(in infants) per 100,000 children per year. (1)(2) Although

traditionally reported to be more common in children with

congenital heart disease in developed countries, increased

use of indwelling catheters is believed to contribute to a

rise of IE in children without CHD. Another major pedi-

atric population at risk for IE is newborn infants, even

those with a structurally normal heart. A little more than

7% of pediatric patients with IE are neonates. There seems

to be a bimodal distribution of IE with respect to age in

children, peaking during infancy and again during late

adolescence. (1)

The general clinical presentation is an indolent illness

with nonspecific complaints such as fever, fatigue, weak-

ness, myalgia, and sweating. This, coupled with the rarity of

the condition in children, makes it a challenge to diagnose

IE. (3)(4) Nevertheless, because previously healthy children

without any risk factors can also develop IE (10%–20%),

diagnosis requires a high degree of suspicion and a thor-

ough physical examination. (2)(5)(6)(7)

Causative AgentsThe most common infectious agents implicated in IE are

bacteria, especially gram-positive cocci. Viridans group

streptococci and S aureus are the most common agents.

Other causative agents include coagulase-negative staphy-

lococci, Streptococcus pneumoniae, Enterococcus species, and

HACEK (Haemophilus species, Aggregatibacter species, Car-

diobacterium hominis, Eikenella corrodens, and Kingella spe-

cies) organisms. Less frequently, group B Streptococcus

species and gram-negative rods are also implicated. Fungal

endocarditis, typically caused by Candida albicans and,

rarely, Aspergillus species, is classically reported in children

receiving parenteral nutrition.

Figure 1. Macular lesions in the palm.

Figure 2. Splinter hemorrhage under the nail.

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PathogenesisThe pathogenesis of IE has been well-studied using animal

models and observational studies in humans. The initial

process for developing IE involves turbulent flow-mediated

valvular damage. The turbulent flow may be due to a variety

of reasons, such as intracardiac devices, prosthetic valves,

peripherally inserted central catheters, and congenital heart

disease. This turbulent flow-mediated damage results in

formation of nonbacterial thrombotic endocarditis aided by

a host response involving fibrin deposition and platelet

activation. An initial bacteremia in the presence of a trau-

matized endothelium on the valve surface forms a nidus of

infection. Current research suggests that inherited varia-

tions in genes encoding for inflammatory markers and

cytokines could increase the risk of IE. The initial adhe-

sion of bacteria to the damaged endothelial surface is aided

by a multitude of pathogen-dependent factors, such as ad-

hesions and pili, and by host-derived factors, such as col-

lagen, laminin, fibrinogen, and fibronectin. In addition, as

the bacteria multiply in number they begin forming a

biofilm that creates a barrier for host immune cells and an-

tibiotics to infiltrate the vegetation.

Clinical Presentation and DiagnosisAlthough most patients present with an indolent history

and nonspecific complaints, the occasional child will pre-

sent with fulminant bacteremia and high spiking fevers.

The clinical presentation is related to bacteremia, valvuli-

tis, immune response, and septic emboli. Valvulitis and

vegetations can present as new-onset cardiac murmurs,

but patients usually present without any significant car-

diac findings. Heart murmurs are reported in only 10% to

20% of patients with IE. (5)(6)(7)(8) Immunologic phe-

nomena are primarily due to immune complex deposi-

tion and manifest as glomerulonephritis, Osler nodes

(tender intradermal nodules on digits), and Roth spots

(small retinal hemorrhages). Septic emboli can present as

Figure 3. Purpuric lesions on the plantar aspect of the foot.

Video 1. Parasternal long axis echocardiograph showing vegetation on the ventricular surface of the anterior mitral leaflet. LA¼left atrium, LV¼leftventricle, RV¼right ventricle.

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mycotic aneurysms, septic pulmonary infarcts, conjunc-

tival hemorrhages, and Janeway lesions (painless hem-

orrhage on the palms and soles). Although fever is the

most common presentation, symptoms such as heart

failure and arthralgia, and signs such as splenomegaly,

murmur, petechiae, and embolic phenomena, are noted

in nearly 50% of pediatric patients. Complex and variable

clinical manifestations make IE a diagnostic challenge. The

Duke criteria are a validated tool to diagnose IE. The

modified Duke criteria (Table) use pathological, clinical,

echocardiographic, and laboratory findings to improve sen-

sitivity. (9)

Patients with IE often have nonspecific laboratory find-

ings, such as elevated white blood cell count, C-reactive

protein level, and erythrocyte sedimentation rate and low

complement levels. Blood culture is the most important

investigation because it aids in diagnosis and guides treat-

ment. Multiple blood cultures, with adequate volume for

aerobic and anaerobic culture, are strongly recommended.

In addition, patients should be evaluated with an echocar-

diogram. Although transesophageal echocardiography has

better sensitivity, transthoracic echocardiography is less

invasive and is usually performed first. In patients with

suspicion for septic emboli, it is also ideal to obtain a

magnetic resonance image of the brain.

TreatmentAntibiotics are the mainstay of treatment and should

be started immediately. Broad-spectrum coverage with

vancomycin and gentamicin is recommended until bacte-

rial identification and sensitivity are established. Once

sensitivity is determined, the antibiotic regimen should

be narrowed and treatment continued for 4 to 6 weeks for

uncomplicated infections. For patients with prosthetic

valves, it is recommended to add rifampin for synergy

and to treat for at least 6 weeks. Surgical intervention

should be considered in patients with persistent infec-

tion and positive blood culture for more than 5 to7 days

after starting appropriate intravenous antibiotics. Infec-

tive endocarditis remains a serious condition with sig-

nificant morbidity and mortality, although recent mortality

is improved compared with historical data. High mortal-

ity rates are associated with neonatal IE, IE due to fungus

and S aureus, and poor ventricular function. Patients

with a history of IE are considered to be at high risk

for another IE and require antibiotic prophylaxis for

procedures associated with bacteremia of IE-associated

organisms.

PATIENT COURSE

Our patient continued to have persistent fevers, for which

we added rifampin, as suggested by the infectious disease

consultant. Cardiothoracic surgery was performed to re-

move the vegetation and repair the mitral valve, after which

the patient improved significantly. She received antibiotics

for a total of 8 weeks and has been doing well since

discharge.

Video 2. Flow mapping of regurgitant jet (orange arrow) into the left atrium.

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TABLE. Modified Duke Criteria for IE (Pathological Criteria Not Shown)

MAJOR CRITERIA

1. Blood culture positive for IE

A. Typical microorganisms consistent with IE from 2 separate blood cultures:

i. Viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus; or

ii. Community-acquired enterococci in the absence of a primary focus; or

B. Microorganisms consistent with IE from persistently positive blood cultures defined as follows:

i. At least 2 positive cultures of blood samples drawn >12 h apart; or

ii. All of 3 or a majority of ‡4 separate cultures of blood (with first and last sample drawn ‡1 h apart)

C. Single positive blood culture for Coxiella burnetii or antiphase 1 IgG antibody titer >1:800

2. Evidence of endocardial involvement

3. Echocardiogram positive for IE (TEE recommended in patients with prosthetic valves, rated at least “possible IE” by clinical criteria, orcomplicated IE [paravalvular abscess]; TTE as first test in other patients), defined as follows:

A. Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in theabsence of an alternative anatomical explanation; or

B. Abscess; or

C. New partial dehiscence of prosthetic valve

4. New valvular regurgitation (worsening or changing or preexisting murmur not sufficient)

Minor criteria

1. Predisposition, predisposing heart condition, or injection drug use

2. Fever, temperature >100.4°F (>38°C)

3. Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages,and Janeway lesions

4. Immunologic phenomena: glomerulonephritis, Osler nodes, Roth spots, and rheumatoid factor

5. Microbiologic evidence: positive blood culture, but does not meet a major criterion as noted above,a or serologic evidence of active infectionwith an organism consistent with IE

Definitive IE

1. 2 major criteria; or

2. 1 major criterion and 3 minor criteria; or

3. 5 minor criteria

Possible IE

1. 1 major criterion and 1 minor criterion; or

2. 3 minor criteria

HACEK¼Haemophilus parainfluenzae, Haemophilus aphrophilus, Haemophilus paraphrophilus, Haemophilus influenzae, Aggregatibacter species,Cardiobacterium hominis, Eikenella corrodens, Kingella kingae, and Kingella denitrificans, IE¼infective endocarditis, TEE¼transesophagealechocardiography, TTE¼transthoracic echocardiography.aExcludes single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis.Adapted from Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infectious endocarditis. Clin Infect Dis 2000;30(4):633–638.

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References1. Baltimore RS, Gewitz M, Baddour LM, et al; American HeartAssociation Rheumatic Fever, Endocarditis, and Kawasaki DiseaseCommittee of the Council on Cardiovascular Disease in the Youngand the Council on Cardiovascular and Stroke Nursing. Infective

endocarditis in childhood: 2015 update: a scientific statement fromthe American Heart Association. Circulation. 2015;132(15):1487–1515

2. Johnson JA, Boyce TG, Cetta F, Steckelberg JM, Johnson JN. Infectiveendocarditis in the pediatric patient: a 60-year single-institution review.Mayo Clin Proc. 2012;87(7):629–635.

3. Ferrieri P, Gewitz MH, Gerber MA, et al; Committee on RheumaticFever, Endocarditis, and Kawasaki Disease of the American HeartAssociation Council on Cardiovascular Disease in the Young. Uniquefeatures of infective endocarditis in childhood. Circulation. 2002;105(17):2115–2126

4. Bragg L, Alvarez A. Endocarditis. Pediatr Rev. 2014;35(4):162–167

5. Liew WK, Tan TH, Wong KY. Infective endocarditis in childhood:a seven-year experience. Singapore Med J. 2004:45(11):525–529.

6. Martin JM, Neches WH, Wald ER. Infective endocarditis: 35 yearsof experience at a children’s hospital. Clin Infect Dis. 1997;24(4):669–675

7. Day MD, Gauvreau K, Shulman S, Newburger JW. Characteristicsof children hospitalized with infective endocarditis. Circulation.2009;119(6):865–870

8. Johnson DH, Rosenthal A, Nadas AS. A forty-year review of bacterialendocarditis in infancy and childhood. Circulation. 1975;51(4):581–588

9. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Dukecriteria for the diagnosis of infective endocarditis. Clin Infect Dis.2000;30(4):633–638

Summary• Infective endocarditis is an uncommon but serious pediatriccondition that requires a high degree of suspicion to diagnose.

• Infectious endocarditis has been reported in patients withoutany risk factors and even in the presence of normal cardiacexamination findings. Most pediatric patients present withnonspecific signs and symptoms, which further highlights theimportance of a thorough physical examination in childrenpresenting with unexplained fever.

• Blood culture and echocardiography are the most importantinitial diagnostic tests. Empirical treatment includes vancomycinand gentamicin (with rifampin for patients with prostheticvalves) until culture and sensitivity results are available.

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DOI: 10.1542/pir.2017-01082019;40;e1Pediatrics in Review 

Senthil Velan Bhoopalan, Rupesh Kumar Natarajan and David Di JohnVisual Diagnosis: Teenager with Fever, Petechiae, Confusion, and Weakness

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