ANTIVIRAL THERAPY/LABORATORY DATA
| ANTIVIRAL THERAPY UPDATE —Charles G. Prober, MD, Professor of Pediatrics, Medicine, Microbiology and
Immunology, and Senior Associate Dean for Medical Student Education, Stanford University School of Medicine,
Palo Alto, CA
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| Organisms and antiviral agents: herpes simplex virus (HSV; acyclovir effective agent); varicella-zoster virus (VZV;
specific children potentially benefit from acyclovir); cytomegalovirus (CMV); influenza types A and B; respiratory
syncytial virus (RSV; number one cause of hospitalization of healthy children in winter months); hepatitis B and C;
human papillomavirus (HPV; better to prevent with vaccine); Lassa virus (Africa); antiviral agents—many agents
available against HSV and VZV; however, most likely used agents include acyclovir and valacyclovir (others used
in resistant infections); amantadine and rimantadine active against influenza A (activity rapidly fading due to resistance);
oseltamivir and zanamivir (neuraminidase inhibitors) active against influenza types A and B; ribavirin active
against RSV (inhaled; limited efficacy; expensive) and Lassa virus (intravenous [IV])
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| HSV gingivostomatitis: typically occurs in 1- to 3-yr-old children; lesions go through vesicular phase and then develop
into ulcers; lesions potentially extend down chin and neck; drooling common; viral shedding for up to 10
days; duration of illness typically 1 wk (up to 3 wk); acyclovir appears effective for first episodes; data (limited)
show acyclovir (vs placebo) reduces duration of symptoms (drooling, gum swelling, and HSV shedding) and improves
eating difficulty; HSV-1 and HSV-2—HSV-1 primarily occurs above waist and HSV-2 primarily occurs below
waist, but both potentially found in either place; treatment of oral herpes infection—10 mg/kg acyclovir; benefit
more limited in recurrent infections because infection usually resolves in 3 to 4 days
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| Genital HSV: painful genital ulcers; vaginal discharge; systemic symptoms (dysuria; tender inguinal nodes); degree
of illness with HSV-1 same as degree of illness with HSV-2 in genital area; degree of benefit of therapy similar
whether HSV-1 or HSV-2; recurrences less frequent with HSV-1, but primary disease similar; primary genital herpes
typically lasts 3 wk (vesicular and pustular lesions, wet ulcers, and drying and crusting); however, most primary
genital herpes asymptomatic; long duration of viral shedding (2 wk); recurrent infection shows abbreviated
course of 7 to 10 days, with viral shedding lasing 4 days; in patients with first-time infection with genital HSV-2
who had previous infection with HSV-1 (therefore, antibodies to HSV-1), degree of illness lies somewhere between
that associated with primary infection and that associated with recurrent infection; home remedies not scientifically
proven; IV acyclovir more effective in patients with primary symptomatic genital herpes admitted to
hospital (oral acyclovir effective in outpatient setting); acyclovir more effective for primary than recurrent infections;
suppressive therapy effective and reduces attack rate by 70% to 80% in patients with frequently recurrent
disease (ie, 3 episodes in 6 mo or 4 episodes in 1 yr)
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| Neonatal HSV infection: rash, fever, and twitching; cerebrospinal fluid (CSF) findings in neonatal herpes encephalitis
include cell count near 100/µL with prominence of lymphocytes, normal glucose, elevated protein level, and
negative Gram stain; HSV polymerase chain reaction (PCR) on CSF reliable test, with sensitivity of 90%; abnormal
electroencephalography (EEG) with paroxysmal lateralized epileptiform discharges (PLEDs); 3 forms of clinical
manifestations (skin, eye, and mucosal [SEM] disease, disseminated disease, and central nervous system [CNS]
disease); SEM disease—most important one to recognize; occurs in 40% of all cases with onset at 1 to 2 wk of age
(babies may be born with lesions); conjunctivitis common; direct fluorescent antibody (DFA) test on scrape from
lesion; viral cultures; progression to CNS or disseminated disease if not recognized; disseminated disease—often
presents without skin lesions (more difficult to diagnose) and looks like bacterial sepsis; typically presents at 4 to 5
days of age; liver dysfunction hallmark; coagulopathy; respiratory distress; in some institutions, therapy in neonates
with overwhelming disease includes ampicillin, gentamicin, and acyclovir; other institutions add acyclovir
with 2 days of negative cultures; CNS disease—one-third of all cases; onset at 2 to 3 wk of age; lethargy; irritability;
typical EEG (PLEDs); treatment—high-dose acyclovir recommended (vs intermediate or original dose [30 mg/
kg per day]) in disseminated disease and in CNS disease; good outcome (near 100%) in recognized and treated
SEM disease; outcome good in disseminated disease in those who survive, but many die; in CNS disease, whether
low-dose or high-dose acyclovir administered, percentage of normal babies ranges between 25% and 30%
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| Congenital CMV: petechial lesions; hepatosplenomegaly; 1% of all babies in United States have congenital CMV
(defined by positive CMV culture); if symptomatic at birth, high likelihood of bad outcome (eg, hearing loss); if
asymptomatic at birth, substantially less likelihood of bad outcome, but still possible; hearing loss major issue;
study looking at babies with symptomatic CMV at birth who were grouped by whether hearing improved, remained
unchanged at follow-up, or worsened with ganciclovir (vs placebo), showed ganciclovir given by 6 wk of age by
central catheter potentially beneficial; however, treatment does not reverse microcephaly, hepatosplenomegaly,
and other problems
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| Influenza: neuraminidase inhibitors (zanamivir [inhaled] and oseltamivir [oral]); zanamivir—study of children (majority
with proven infection; majority influenza type A) treated with zanamivir vs placebo showed improvement
with zanamivir (reduction in flu symptoms), but improvement not substantial; oseltamivir—study of oseltamivir vs
placebo showed 1.5-day reduction in flu symptoms; otitis media reduced on oseltamivir; details on current status
and recommendations for therapy in Pediatrics 2007
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| INTERPRETING LABORATORY DATA IN CHILDREN —Jon M. Nakamoto, MD, PhD, Associate Clinical Professor
(voluntary) of Pediatrics, University of California, San Diego, School of Medicine, and Managing Director,
Quest Diagnostics Nichols Institute, San Diego, CA
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| Importance of laboratory knowledge: case—woman, 22 yr of age, presents with recurrent vaginal bleeding and abdominal
pain; elevated serum human chorionic gonadotropin (hCG), but not pregnant; possible tumor; treated with
chemotherapy without success; hCG levels confirmed independently by 2 other laboratories; hysterectomy performed
and more aggressive chemotherapy given; computed tomography (CT) scan showed lung nodules; partial
lung resection revealed nodules benign; urine hCG done, with negative result; antibody deemed culprit (interfered
with assay) of elevated serum hCG; antibodies do not cross in urine; take-home point—clinicians expected to know
something about assays and when to question, investigate, and seek further consultation
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| Preanalytic error: case—patient with afebrile seizure; unremarkable work-up (normal magnetic resonance imaging
[MRI] with contrast); admitted overnight for observation; in morning, laboratory results showed low calcium
level with similar repeat results; order for IV calcium cancelled because patient looked well with no
neuromuscular irritability; no laboratory error identified; value attributed to gadolinium-based MRI contrast
(known to potentially cause falsely low calcium levels); pretesting factors (other than disease) potentially alter
laboratory results; patient characteristics—age; sex; puberty stage (hormone levels); time of day; season; geography;
medications; mental state; nutritional status; body mass index; growth rate; ethnicity; collection and handling
of samples—tubes used; serum separator gel (effect often unpredictable); temperature; storage; hemolysis (eg,
degrades insulin); prolonged contact with cells before centrifugation; take-home point—important to know which
factors affect assays in tests and whom to call about tests you send most often; when laboratory result does not
make sense, look for potential interference with results
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| Immunoassays and interferences: case—7-yr-old girl with pubic hair; test ordered for testosterone level, and result
high; by accident, some of same sample sent to different laboratory, with result at high end of normal reference interval;
difficult to distinguish one steroid from another, but extractions and column chromatography helpful in separating,
and can determine whether high or normal value found; potential bias with lower levels of testosterone
(steroid hormone) due to lack of extraction and chromatography; important to ask for certain types of assays at
lower steroid hormone levels; cases—man with gynecomastia; with nonextraction automated radioimmunoassay
(RIA), reported estrogen value 10 times normal; other maneuvers lowered value; with RIA after extraction and
chromatography, reported value in normal range; blood spots—congenital adrenal hyperplasia (CAH); certain
groups (eg, premature infants) get high results, leading to increased false-positive rates; extraction chromatography
would lower rate, but not feasible as part of screening program; take-home message —still in era of measuring with
antibodies; assays not perfectly specific and need “help” to improve on selectivity and specificity
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| Biotransformation: case—patient on low-dose prednisone; physician wanted to measure cortisol and was informed
by laboratory that cortisol has ≤1% cross-reactivity with prednisone; physician overlooked biotransformation (hepatic
metabolism changes medications in body, eg, prednisone to prednisolone) and cross-reactivity consider of
prednisolone on cortisol assay 33%; when concerned about measuring drug levels in body and cross-reactivity,
consider role of biotransformation; take-home point—metabolites and duration of drug in body may play role; important
for physician to understand biologic and pharmacologic mechanisms of actions of medications given to patients
(ensures correct measurements)
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| Analytic sensitivity and specificity: most sensitive test not always best test; case—12-yr-old girl diagnosed with
Turner’s syndrome; physician orders nested PCR that reports positivity for Y-chromosome sequences (confers tumor
risk); literature shows some girls with Turner’s syndrome test as cytogenetically-negative but PCR-positive for
Y-chromosome sequences without increase in incidence of gonadoblastoma; study showed up to 14% of healthy
women (controls) had positivity for Y-chromosome sequences by PCR; utility of PCR information questionable;
sensitivity—PCR very sensitive and potentially oversensitive in certain applications; false background noise problematic;
specificity—if test too specific, potential for too narrow focus, and “big picture” missed
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| Reference intervals: depend on assay platform and analysis approach (parametric vs nonparametric); look at reference
intervals from perspective of methodology used; possible for analyses to differ from one laboratory to another;
screening for CAH—17-hydroxyprogesterone; different commercial laboratories have different upper
thresholds (upper-level threshold values range from 110 to 940 mg/dL); reference intervals not necessary, but
(based on level given) they can help determine probability of disease; data from Europe showed that disease found
in infants (4 days of age) whose levels were >1000 mg/dL (represents clinical threshold); clinical threshold determined
in retrospect (track patients and outcomes, then go back and look at laboratory results to determine cut-off);
speaker considers clinical thresholds more important than reference ranges; take-home point—reference intervals
more subjective than one might think; in pediatrics, rarely enough healthy subjects for reference intervals to be reliable
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Suggested Reading
American Academy of Pediatric Committee on Infectious Diseases: Prevention of influenza: recommendations for
influenza immunization of children 2006-2007. Pediatrics 119:846, 2007; Corey L et al: An update on short-course
episodic and prevention therapies for herpes genitalis. Herpes 14 Supp 1:5A, 2007; Fatahzadeh M, Schwartz RA:
Human Herpes simplex virus infections: epidemiology, pathogenesis, symptomatology, diagnosis, and management.
J Am Acad Dermatol 57:737, 2007; Fiore AE et al: Prevention and control of influenza. Recommendations of the Advisory
Committee on Immunization Practices (ACIP), 2007. MMWR Recomm Rep 56:1, 2007; Friedberg RC et al:
The origin of reference intervals. Arch Pathol Lab Med 131:348, 2007; Hota S, McGeer A: Antivirals and the control
of influenza outbreaks. Clin Infect Dis 45:1362, 2007; Jacquemard F et al: Maternal administration of valacyclovir in
symptomatic cytomegalovirus infection. BJOG 114:1113, 2007; Kimberlin DW: Management of HSV encephalitis in
adults and neonates: diagnosis, prognosis and treatment. Herpes 14:11, 2007; Maruyama Y et al: Fetal manifestations
and poor outcomes of congential cytomegalovirus infections: possible candidates for intrauterine antiviral treatments.
J Obstet Gynaecol Res 33:619, 2007; Michaels MG: Treatment of congenital cytomegalovirus: where are we now? Expert
Rev Anti Infect Ther 5:441, 2007; Ornoy A: Fetal effects of primary and non-primary cytomegalovirus infection in
pregnancy: are we close to prevention? Isr Med Assoc J 9:398, 2007; Antiviral drus for influenza. Med Lett Drugs Ther
49:85, 2007.
Educational Objectives
| The goals of this program are to improve management of viral conditions through greater knowledge of antiviral
agents, and to improve clinicians’ ability to interpret laboratory data regarding children. After hearing and assimilating
this program, the clinician will be better able to:
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 | 1. Describe clinical findings for some current viruses and the use of antiviral agents.
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| 2. Utilize available data on the benefits of antiviral agents.
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| 3. Explain why awareness of preanalytic factors is critical for any clinician who interprets laboratory results.
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| 4. Recognize the importance of biotransformation.
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| 5. Understand the caveats and limitations of using pediatric reference intervals for diagnostic decision-making.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and planning committee
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. Nakamoto is managing director of Quest Diagnostics Nichols Institute. Dr. Prober and the planning committee reported
nothing to disclose.
Acknowledgements
Dr. Prober was recorded at the 29th Annual Las Vegas Seminars, Pediatric Update, held November 15-18, 2007, in
Las Vegas, NV, and sponsored by the AAP California District IX, Chapters 1,2,3,4 and the American Academy of
Pediatrics. Dr. Nakamoto was recorded at the 49th Annual Pediatric Symposium, held October 12-13, 2007 in Anaheim,
CA, and sponsored by Kaiser Permanente. The Audio-Digest Foundation thanks the speakers and the sponsors
for their cooperation in the production of this program.
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