Cases & Commentaries

Rapid Mis-St(r)ep

Commentary By Edward L. Kaplan, MD

The Case

A 5-year-old girl was brought to an urgent care
center by her father with a 2-day history of fever to 103°F,
sore throat, and diffuse abdominal pain. There was no history of
cough or runny nose. On examination, she appeared ill and had a
temperature of 101°F. Her posterior oropharynx was erythematous
without exudates, and the tonsils were not enlarged. She had tender
anterior cervical lymphadenopathy. The remainder of the
examination, including the abdominal examination, was
unremarkable.

With concern for strep throat, the urgent care
physician swabbed the child's throat and performed a rapid antigen
detection test (RADT) in the clinic. The "rapid strep test" was
interpreted as negative. A culture of the posterior oropharynx was
not performed. Urinalysis revealed 3+ ketones and a specific
gravity (SG) >1.030. The child was given a diagnosis of viral
syndrome and dehydration, and the father was reassured. He was
advised to give her antipyretics and extra water and juice and to
observe her closely for adequate urine output or worsening of
symptoms.

Four hours later, the child appeared more ill to
the father and developed a fever of 104°F. Concerned, the
father took the child to the nearest emergency department (ED). In
the ED, she had a fever of 103.5°F and an erythematous
posterior oropharynx and tender lymphadenopathy on examination. The
ED physician repeated the RADT. The result was strongly positive
for group A streptococcal infection. The child was treated with
oral amoxicillin and was afebrile with minimal sore throat 2 days
later.

The Commentary

This 5-year-old with a sore throat illustrates an
issue faced millions of times in the United States each year.
Streptococcal pharyngitis/tonsillitis is among the most common
illnesses seen by primary care physicians. The importance of this
infection is evidenced by the many guidelines published by
professional societies not only in the United States, but around
the world.(1-3)
Despite this attention and a far greater understanding of the
microbiology and epidemiology of group A streptococci
(Streptococcus pyogenes), there has been essentially no
"translation" (to use the current buzzword) of the results of
laboratory research to everyday clinical management of
streptococcal pharyngitis during the past half-century. Parents
still bring their children with a sore throat to the clinician for
a throat swab and are often given an antibiotic indiscriminately
(most often a penicillin). Essentially no change in management has
occurred!

The clinical diagnosis of streptococcal
pharyngitis is frequently difficult, in part because patients don't
always present with classic signs and symptoms.(4,5) Moreover, presenting symptoms vary with the age of
the patient.(4) For
example, this 5-year-old had the classic clinical presentation for
school-age children, who tend to present with anterior cervical
lymphadenitis (tender lymph nodes) and abdominal
pain. Further adding to the management challenge, many patients
with a viral upper respiratory tract infection will also be
concomitant carriers of group A streptococci.(5) Given these factors, published clinical algorithms are
often imperfect in making the diagnosis and guiding appropriate
therapy.

As patients usually improve symptomatically even
without antibiotic therapy, the goal of antibiotic therapy for
streptococcal pharyngitis is eradication of the organism
from the throat. Eradication is necessary to prevent nonsuppurative
sequelae such as rheumatic fever in infected individuals.

Although the amoxicillin given to this child is
identical or similar to that recommended by most clinical
guidelines, therapy can be problematic. While there has never been
a group A streptococcal clinical isolate that has shown resistance
to penicillin(s) (7),
penicillin's bitter taste is such that children do not like to
ingest it, leading many clinicians to prefer the more palatable
amoxicillin suspension. Recent support by some for short-course
antibiotic therapy (fewer than 10 full days of a penicillin or
cephalosporin, macrolide, or azalide) remains controversial and has
not been included in most current guidelines in the United States.
At the present time, a full 10-day course of most antibiotics is
recommended in most authoritative guidelines.(1-3)

Perhaps a practical, clinically adaptable advance
in management of group A streptococcal infection of the throat is
RADTs for group A streptococci. One problem with RADTs is
illustrated by the patient presented here. Studies during the past
20 years indicate that the specificity (i.e., the ability of a
positive test to detect the presence of group A streptococci) of
these tests is much better than the sensitivity (the ability of a
negative test to exclude the presence of group A streptococci).
That is, if the rapid strep test is positive, the patient likely
has a group A streptococcal infection, but a negative test does not
rule out the infection. Since essentially all rapid streptococcal
tests are based upon an antigen-antibody reaction involving the
group-specific carbohydrate of the cell wall, a sufficient number
of organisms must be present on the swab in order to result in a
"positive" test. This means that insufficiently thorough swabbing
of the pharynx/tonsils and/or a relatively low organism load in the
throat can result in falsely negative results. Sampling error
(Figure) is one key reason why authoritative sources
and major guidelines recommend that if a rapid test is negative, a
concomitant culture should be carried out.

False-positive throat RADTs also occur, but these
are much less common. One documented cause for a falsely positive
rapid test is related to the fact that some strains of
Streptococcus milleri, a common part of the oral flora,
carry the group A carbohydrate antigen on their surface and thus
react positively with the usual commercially available RADT for
Streptococcus pyogenes.(8)
These false positives are rare and should not affect clinical
management. A positive RADT should result in antibiotic therapy for
patients with consistent signs and symptoms. Some clinical
microbiology laboratories may overlook or incorrectly identify the
presence of group A streptococci on agar plates; this possibility
is recognized.(9)

In this case, the physician was concerned about
the possibility of streptococcal pharyngitis. There are only two
aspects of the medical care that one might question. The presence
of tender anterior cervical lymph nodes is a very important
clinical finding and has been correlated with true streptococcal
infection.(5)
This should have emphasized the need for a back-up agar plate
culture. When one suspects streptococcal infection, a strep culture
should be sent even when the RADT is negative. In retrospect, the
initial rapid test may have been negative due to a sampling issue.
The sample obtained on the swab may not have been sufficiently
representative to trap an adequate number of streptococci to allow
the rapid test to disclose their presence. When swabbing the
tonsils and posterior pharynx, care should be taken to avoid the
tongue. The swab is then moved back and forth across the posterior
pharynx, tonsils, or tonsillar fossae. The physician appropriately
advised the parent to return if the child's symptoms worsened.

The presented case illustrates several clinical
and laboratory issues that remain controversial and result in
variation in the medical management of streptococcal tonsillitis
and pharyngitis. In the future, a cost-effective streptococcal
vaccine may become available to assist in the control of this
infection and its sequelae. Until then, more "translational"
research is needed to improve both the medical care of patients
with streptococcal tonsillitis/pharyngitis and the public health
approaches to this common infection and its sequelae.

Take-Home Points

  • Because of variable symptoms and
    microbiologic factors, the diagnosis and appropriate therapy of
    group A streptococcal pharyngitis remain challenging.
  • While frequently used, it must be
    remembered that the specificity of rapid antigen detection tests is
    much better than the sensitivity. Most guidelines recommend that if
    the rapid test is normal in a patient with a compatible illness, a
    back-up throat culture be done.
  • Inadequate sampling of the posterior
    oropharynx can lead to false-negative results on rapid strep tests
    or streptococcal cultures.

Edward L. Kaplan, MD
Professor of Pediatrics
Department of Pediatrics
University of Minnesota Medical School

References

1. Bisno AL, Gerber MA, Gwaltney JM Jr, Kaplan
EL, Schwartz RH, for the Infectious Diseases Society of America.
Practice guidelines for the diagnosis and management of group A
streptococcal pharyngitis. Clin Infect Dis. 2002;35:113-125.

[go to PubMed]

2. Pickering LK, Baker CJ, Long SS, McMillan JA,
eds. Red Book: 2006 Report of the Committee on Infectious Diseases.
27th ed. Elk Grove Village, IL: American Academy of Pediatrics;
2006.

3. Dajani A, Taubert K, Ferrieri P, Peter G,
Shulman S. Treatment of acute streptococcal pharyngitis and
prevention of rheumatic fever: a statement for health
professionals. Committee on Rheumatic Fever, Endocarditis, and
Kawasaki Disease of the Council on Cardiovascular Disease in the
Young, the American Heart Association. Pediatrics. 1995;96:758-764.

[go to PubMed]

4. Wannamaker LW. Perplexity and precision in the
diagnosis of streptococcal pharyngitis. Am J Dis Child.
1972;124:352-358.
[go to PubMed]

5. Kaplan EL, Top FH Jr, Dudding BA, Wannamaker
LW. Diagnosis of streptococcal pharyngitis: differentiation of
active infection from the carrier state in the symptomatic child. J
Infect Dis. 1971;123:490-501.
[go to PubMed]

6. Kaplan EL, Johnson DR. Unexplained reduced
microbiological efficacy of intramuscular benzathine penicillin G
and of oral penicillin V in eradication of group a streptococci
from children with acute pharyngitis. Pediatrics.
2001;108:1180-1186.
[go to PubMed]

7. Macris MH, Hartman N, Murray B, et al. Studies
of the continuing susceptibility of group A streptococcal strains
to penicillin during eight decades. Pediatr Infect Dis J.
1998;17:377-381.
[go to PubMed]

8. Johnson DR, Kaplan EL. False-positive rapid
antigen detection test results: reduced specificity in the absence
of group A streptococci in the upper respiratory tract. J Infect
Dis. 2001;183:1135-1137.
[go to PubMed]

9. Johnson DR, Kaplan EL, Sramek J, et al.
Laboratory Diagnosis of Group A Streptococcal Infections: A
Laboratory Manual. Geneva, Switzerland: World Health Organization;
1996.

Figure


Figure. Example of Sampling Error in Throat
Cultures. Two swabs were taken from the same child within 20
seconds and immediately plated onto appropriate agar. One swab
(right) resulted in a strongly positive plate, while the other
(left) led to only three colonies on the plate [in the photo, only
one can be seen clearly (arrow)]. This weakly positive culture
almost certainly would have resulted in a negative rapid antigen
detection test, yet the organisms can be detected on the culture
plate. (Slide by Edward L. Kaplan, MD; 2003.)