FEVER/ASTHMA
| FEVER OF UNKNOWN ORIGIN —Sheldon L. Kaplan, MD, Professor and Vice-Chair for Clinical Affairs, Department
of Pediatrics, Baylor College of Medicine, and Chief, Infectious Disease Service, Texas Children’s Hospital,
Houston, TX
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| Fever of unknown origin (FUO): definition—unexplained fever ≥100.4°F daily for >2 wk; source of fever not
found, despite careful history and physical examination; potential causes—include infectious diseases, rheumatologic
disorders, and malignancies (especially lymphoma and leukemia)
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| Assessment: Steele et al—looked at ≈100 children with fever >38°C that occurred at least twice per week for 2 to 3
wk; initial history and physical examination did not reveal source of fever; initially, children seen in outpatient department;
obtained urinalysis, urine culture, purified protein derivative (PPD) test, routine serologic tests (eg, Epstein-Barr
virus [EBV], antistreptolysin-O [ASO], antinuclear antibody [ANA] titer, and HIV, if risk factors present), blood cultures,
chest radiography, and recorded temperature twice daily at home; child admitted to hospital for further testing if
initial evaluation did not find source of fever; inpatient testing could include lumbar puncture, blood cultures, ophthalmologic
examination (check for iridocyclitis and uveitis), sinus or mastoid radiographs, further serologic tests depending
on history, and liver enzymes; ordered imaging studies, particularly abdominal ultrasonography (US) and
abdominal computed tomography (CT); gallium imaging not particularly useful; indium imaging may be helpful in
older children; consider upper gastrointestinal (GI) series if inflammatory bowel disease (IBD) suspected; consider
bone scan if osteomyelitis or other bone-related abnormality suspected; results showed infectious disease etiology in
22% of patients, autoimmune disease in 6% (all in patients >12 yr of age), malignancy in 2%, other abnormalities in
3%, but no diagnosis found in 67%; infectious disease causes included EBV (most common), urinary tract infection
(UTI), viruses, Lyme disease, bacterial meningitis, and other diseases, including cat-scratch disease (CSD); Jacobs and
Schutze—looked at 150 children with FUO; established diagnosis in 57% of patients; diagnoses included infectious
disease (most common), autoimmune disease, malignancy, and other causes; infectious disease etiologies included
EBV (most common), osteomyelitis, bartonellosis (CSD), UTI, and other illness, including tularemia (specific to Arkansas
and Midwestern states)
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| History in FUO evaluation: look at child’s activity, weight loss or gain, presence of rash (clue to rheumatologic
illness, infective endocarditis, or Salmonella typhi), musculoskeletal complaints (clue to site of infection or rheumatologic
infection), abdominal complaints (suspect IBD, intra-abdominal abscesses [eg, pyogenic liver abscess]), area
of residence, travel history (look for typhoid fever and malaria), drugs (clue to drug-related fevers), contact with infected
individuals (eg, tuberculosis), consumption of unusual foods or unpasteurized milk products (brucellosis), and
ask about pets and other exposure to animals
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| Physical examination: look for skin rash (maculopapular or nondescript rash; consider juvenile rheumatoid arthritis
or other autoimmune illness, drug-related rash, and Kawasaki disease), petechiae (can indicate infective endocarditis
or malignancy), lymphadenopathy (seen in EBV, cytomegalovirus [CMV], CSD, or malignancy), heart
murmur (think about infective endocarditis), hepatosplenomegaly (suspect salmonellosis, tularemia, disseminated
fungal infection, infective endocarditis, CSD, intra-abdominal abscesses, and malignancy), abdominal mass (clue
to malignancy or IBD), joint effusions (juvenile rheumatoid arthritis and other autoimmune diseases), bone pain
(associated with osteomyelitis), ocular examination (consider Kawasaki disease or autoimmune disease if patient
has inflammation of bulbar conjunctiva), and mucous membrane changes (aphthous stomatitis or perianal ulcerations
suggestive of IBD)
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| Evaluation: obtain complete blood count (CBC), erythrocyte sedimentation rate (ESR), and C-reactive protein
(CRP) to look for infectious diseases, IBD, and autoimmune diseases; get urinalysis and urine cultures; obtain PPD
test; obtain serologic tests (eg, EBV, Bartonella henselae, ASO, ANA [consider referral to rheumatologist if patient
has other symptoms suggestive of autoimmune illness]), and HIV if risk factors present; get at least 3 blood
cultures, chest radiography, abdominal US, and record temperatures twice daily
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| Cat-scratch disease: transmission—exposure to cats <1 yr of age (kittens more likely to have high-grade Bartonella
bacteremia); occurs through asymptomatic cat; hepatosplenic CSD—look for history of exposure to kittens,
prolonged fever, and abdominal pain; patient usually well between episodes of fever; check for papule (site of inoculation)
or scratches; liver palpation may reveal tenderness; may observe hepatosplenomegaly; evaluation—obtain
liver US; document infection with evidence of antibodies to B henselae; children with prolonged fevers may respond
to rifampin or rifampin with trimethoprim-sulfamethoxazole (TMP-SMX); study data—looked at 19 patients with
hepatosplenic CSD; mean duration of fever from onset to diagnosis 22 days; several patients had abdominal pain and/
or weight loss; most patients treated with rifampin alone, some with rifampin and TMP-SMX, and some with rifampin
and gentamicin; many children responded within 48 hr
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| Other causes of FUO: typhoid fever—caused by S typhi; documented travel history in 70% of patients with typhoid
fever; look for prolonged fever (average 10 days, with range of 4-35 days); get blood cultures; syndrome of
periodic fever—patients have regular episodes of fever lasting 5 to 6 days, usually once per month; includes familial
Mediterranean fever and hyperimmunoglobulinemia D syndrome (HIDS); most common cause of periodic fever;
patient has onset of periodic fevers at <5 yr of age; strikingly regular pattern of fever; fever ranges from 39° to
40°C; patient may have chills, aphthous stomatitis, pharyngitis, cervical adenitis, or abdominal pain; laboratory
tests show evidence of increased cytokine activity, leukocytosis, and elevation in ESR; fever resolves spontaneously
after 4 to 5 days; not associated with any other physical features (eg, abscesses, pneumonia); relatively common;
hemophagocytic syndrome—fever caused by unusual response to stimulus, usually virus; patient develops
prolonged fevers; laboratory data show decreased hemoglobin, WBC, and platelet counts; may see cytopenia and
elevations in triglycerides and cholesterol; patients have markedly elevated serum ferritin; check for rash and lymphadenopathy
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| TREATING THE DIFFICULT ASTHMATIC —Miles Weinberger, MD, Professor of Pediatrics, and Director, Pediatric
Allergy and Pulmonary Division, University of Iowa College of Medicine, Iowa City, IA
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| Basics of asthma treatment: recognition very important; classification—by clinical pattern; asthma can occur
intermittently from specific environmental exposure, be induced by viral respiratory infection, exist as chronic or
persistent asthma, or occur as seasonal allergic asthma; each pattern associated with different clinical implications;
principles—early and effective intervention for exacerbations with β2 -agonist bronchodilators (albuterol or pirbuterol),
systemic corticosteroids for bronchodilator subresponsiveness; give verbal and written instructions as to
how these agents used; treatment—prescribe maintenance medication for chronic and seasonal asthma; inhaled
corticosteroids most effective at low doses; addition of long-acting β2 -agonists (salmeterol or formoterol) typically
more effective than increased doses of inhaled corticosteroid; consider environmental causes; intervene early with
effective treatment of exacerbations, even in patients with persistent asthma requiring maintenance medication
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| Sudden asphyxic asthma: includes asthma that progresses gradually over time but too little done too late, acute
exacerbation of unstable asthma, and asthma that rapidly decompensates (high incidence of respiratory arrest; patients
often recover rapidly); case—boy, 11 yr of age, with asthma since infancy; initially, viral respiratory
infection-induced asthma, but progressed to chronic asthma with allergic component at 2 to 3 yr of age; asthma
well controlled with maintenance medication and occasional intervention with short course of corticosteroids; patient
began experiencing acute life-threatening events (ALTEs) 1 yr ago after mild exertion (not prevented by albuterol);
patient had consistent rapid response to treatment in emergency department (ED); after precipitation of
ALTEs, physician added fluticasone/salmeterol (Advair) to treatment regimen; severity and poor control of asthma
persisted, despite increasing dose of Advair to 500/50 mcg bid; exercise intolerance persisted, despite multiple
daily uses of albuterol; patient admitted to hospital for further evaluation and management; treadmill exercise test
after albuterol showed 70% decrease in forced expiratory volume (FEV1 ) after 3 min of exercise, with severe dyspnea
and cyanosis; test repeated next day with similar results; patient had downregulation of β2 receptors through
continuous stimulation by β2 -agonist; theophylline substituted for albuterol and resulted in complete block of exercise-induced
bronchospasms; albuterol rarely needed other than before exercise; uncommon phenomenon; genetics
may play role; patients lose bronchoprotective effect of albuterol; disconnect occurs between bronchoprotective
and bronchodilatory effects of albuterol
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| Noncompliance in asthmatic patients: case—girl, 15 yr of age, with long-standing chronic asthma; patient experienced
frequent exacerbations with multiple ED visits and hospitalizations despite optimal management plan; patient
treated with Advair 250/50 mcg and instructed in intervention measures on hand; patient initially acknowledged she
might miss ≈1 dose of Advair per week; however, pharmacy printout showed Advair prescription filled once in previous
year; confronted patient and parent with information and they denied these facts; patient treated with ovalizumab
(Xolair) because of major allergic component to asthma
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| Incorrect diagnosis of asthma: habit cough syndrome—girl, 15 yr of age, with harsh, dry, barking cough of 9-mo
duration; cough incessant during day and occurred multiple times per minute; patient treated with prednisone, theophylline,
and aerosol bronchodilators without response; patient admitted to hospital for intravenous treatment of
cough; cough interfered with school attendance; cough did not occur during sleep (key diagnostic factor); clinical
characteristics include loud, repetitive, dry, barking cough, with duration of weeks or months; cough irritating and
disturbing to others and can prevent school attendance; commonly misdiagnosed as asthma; treatment involves suggestion
therapy; study found 8 of 9 patients treated successfully with 15-min session; minor relapses controlled with
autosuggestion technique; all patients remained asymptomatic for median of 2.2 yr; tracheomalacia—girl, 9 yr of
age, with cough for 2 yr; patient had paroxysmal cough with posttussive emesis and nightly awakening; cough treated
with bronchodilators, theophylline, and prednisone with no response; prednisone caused patient to appear cushingoid
and hirsute; growth suppressed; used bronchoscope to view patient’s airway; lower trachea collapsing, and ulcerations
present where anterior and posterior walls came together; coughing increased intrathoracic airway pressure,
causing trachea to further collapse and creating focus of irritation; self-limiting in some patients if mild; study described
successful treatment of 7 patients with chronic cough because of tracheomalacia with behavioral techniques;
some patients benefit from aortopexy (stenting of trachea using stitch between sternum and aorta to place tension on
connective tissue between aorta and anterior wall of trachea); malformation of uvula—boy, 4 yr of age, with harsh
barking cough present since infancy; diagnosed with asthma; allergy skin testing negative; treated with cromolyn,
montelukast (Singulair), albuterol prn, and steroids with equivocal response; bronchoscopy showed uvula on top of
epiglottis; uvula removed and coughing ceased; corn pollen—girl, 15 yr of age, with 3 wk of wheezing and dyspnea;
first episode occurred while detasseling corn; treated in ED with epinephrine; second episode occurred next day and
same treatment given; daily episodes began occurring without exposure to pollen and without response to epinephrine;
patient treated with bronchodilator, theophylline, prednisone, and hospitalization without response; treadmill exercise
test induced wheezing; spirometry revealed upper airway obstruction indicated by flattening of inspiratory flow
loop; patient had positive skin test to corn pollen; acute laryngeal edema from corn pollen triggered inappropriate response;
treadmill exercise-induced wheezing during inspiration diagnostic of extrathoracic airway obstruction; vocal
cord dysfunction—different patterns of dysfunction; treatment involves speech therapy; anticholinergic inhaler (ipratropium)
can block exercise-induced vocal cord dysfunction; laryngomalacia—flexible laryngoscopy shows exercise-induced
laryngomalacia; exercise-induced dyspnea (EID)—study of 142 patients atypical for asthma; 11 had
exercise-induced bronchospasm, 13 had vocal cord dysfunction, 15 had restrictive abnormalities, 2 had exercise-induced
laryngomalacia, 1 had exercise-induced hyperventilation, 1 had exercise-induced ventricular tachycardia, and
all other patients physiologically normal despite complaints of EID (mistook normal physiologic limitations as something
pathologic); EID not always asthma; does not respond to asthma treatments; identified with appropriate treadmill
exercise testing
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Educational Objectives
| The goal of this program is to educate the listener about fever of unknown origin (FUO) and asthma. After hearing
and assimilating this program, the clinician will be better able to:
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 | 1. Evaluate a patient with FUO.
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| 2. List the most common diagnoses in patients with FUO.
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| 3. Discuss the periodic fever syndrome.
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| 4. Recognize an asthmatic patient who is not complying with medical management.
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| 5. Reassess a patient diagnosed with asthma who is not responding to treatment.
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Discussed on This Program
Albuterol (salbutamol sulphate in United Kingdom) [AccuNeb, Proventil, Proventil HFA, Proventil Repetabs,
Ventolin, Ventolin HFA, Volmax]
Fluticasone propionate/salmeterol [Advair Diskus]
Formoterol fumarate [Foradil Aerolizer]
Gentamicin sulfate [Garamycin, Genoptic, Genoptic S.O.P., Gentacidin, Gentamicin Ophthalmic, Pediatric
Gentamicin Sulfate]
Ipratropium bromide [Atrovent]
Montelukast sodium [Singulair]
Omalizumab [Xolair]
Pirbuterol acetate [Maxair Inhaler, Maxair Autohaler]
Prednisone [Deltasone, Liquid Pred, Meticorten, Orasone, Panasol-S, Prednicen-M, Prednisone Intensol Concentrate,
Strerapred DS]
Rifampin (rifampicin) [Rifadin, Rimactane]
Salmeterol xinafoate [Serevent Diskus]
Theophylline (several trade names)
Trimethoprim-sulfamethoxazole (co-trimoxazole; TMP-SMZ) [Bactrim, Bactrim DS, Bactrim IV, Bactrim Pediatric,
Cotrim, Cotrim D.S., Cotrim Pediatric, Septra, Septra DS, Septra IV, Sulfatrim]
Suggested Reading
Abu-Hasan M et al: Exercise-induced dyspnea in children and adolescents: if not asthma then what? Ann Allergy
Asthma Immunol. 94:366, 2005; Arisoy ES et al: Hepatosplenic cat-scratch disease in children: selected clinical
features and treatment. Clin Infect Dis. 28:778, 1999; Hammo AH et al: Exercise-induced hyperventilation: a
pseudoasthma syndrome. Ann Allergy Asthma Immunol. 82:574, 1999; Kaplan SL: Fever and rash complicating osteomyelitis.
Semin Pediatr Infect Dis. 15:124, 2004; Long SS: Distinguishing among prolonged, recurrent, and periodic
fever syndromes: approach of a pediatric infectious diseases subspecialist. Pediatr Clin North Am. 52:811, 2005;
McCarthy P: Fever without apparent source on clinical examination. Curr Opin Pediatr. 17:93, 2005; Palazzi DL
et al: Hemophagocytic syndrome in children: an important diagnostic consideration in fever of unknown origin. Clin
Infect Dis. 36:306, 2003; Sorensen HT et al: Fever of unknown origin and cancer: a population-based study. Lancet
Oncol. 6:851, 2005; Steele RW: Fever of unknown origin: a time for patience with your patients. Clin Pediatr
(Phila). 39:719, 2000; Weinberger M: Improving care for asthma. J Pediatr. 147:411, 2005; Weinberger M: Innovative
therapies for asthma where we've been and where we're going: innovative approaches of the past, present,
and future. Paediatr Respir Rev. 5 Suppl A:S113, 2004; Weinberger M: Treatment strategies for viral respiratory
infection-induced asthma. J Pediatr. 142:S34, 2003; Weinberger M: Clinical patterns and natural history of
asthma. J Pediatr. 142:S15, 2003; Weinberger M: Corticosteroids for exacerbations of asthma: problems and solutions.
J Pediatr. 136:276, 2000.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
Dr. Kaplan disclosed that he received a research grant from Pfizer Inc.
Dr. Kaplan was recorded June 4-5, 2005, in San Francisco, CA, at the 38th Annual Advances and Controversies in
Clinical Pediatrics, sponsored by the University of California, San Francisco, School of Medicine. Dr. Weinberger
was recorded January 25-30, 2006, in Bal Harbour, FL, at Contemporary and Future Pediatrics, sponsored by the
University of Miami Miller School of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors
for their cooperation in the production of this program.
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