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281
Chronic Streptococcal and Non-Streptococcal Pharyngitis
R.C. Murray1,2 and S.K. Chennupati2,3,*
1
Department of Otolaryngology, Thomas Jefferson University Hospital, Philadelphia, PA, USA; 2Division of Otolaryngology, Alfred I. duPont Hospital for Children, Wilmington, DE, USA; 3Division of Otolaryngology, Saint Christopher’s
Hospital, Philadelphia, PA, USA
Abstract: Pharyngitis is a common medical problem in the outpatient medical setting, resulting in more than seven million pediatric visits each year. Most types of pharyngitis are caused by infectious etiologies. The most common cause of
pharyngitis is viral infection; however, some of the more serious types of pharyngitis are attributed to bacterial etiologies,
such as group A -hemolytic Streptococcus pyogenes (GAS). Complications from GAS pharyngitis include rheumatic
fever, deep space abscesses, and toxic shock. Although most episodes of pharyngitis are acute in nature, a small percentage becomes recurrent or chronic. With regards to chronic pharyngitis, non-infectious etiologies, such as laryngopharyngeal reflux and periodic fever, aphthous ulcers, pharyngitis, and adenitis syndrome also need to be considered. Both medical and surgical therapies are effective in managing pharyngitis. First-line medical therapy includes antibiotic therapy. For
certain indications, surgical management via adenotonsillectomy is recommended. Adenotonsillectomy has been shown to
be effective in reducing disease burden and improving disease-specific and global quality of life. Several techniques for
adenotonsillectomy exist, including traditional and intracapsular tonsillectomies.
Keywords: Chronic pharyngitis, group A -hemolytic Streptococcus pyogenes (GAS), intracapsular tonsillectomy, quality of
life (QOL), tonsillitis, Waldeyer’s ring.
INTRODUCTION
Sore throat is the third most common chief complaint in
outpatient healthcare appointments [1], accounting for an
estimated 7.3 million pediatric visits each year [2]. In the
pediatric population, most cases of pharyngitis are infectious
in origin. Viruses are responsible for most cases, but bacteria
are blamed for 30-40% of pharyngitis [3]. Group A hemolytic Streptococcus pyogenes (GAS) is of particular
diagnostic importance because of the risk of potentially serious complications. Most pharyngitis occurs as an acute episode that is generally short lived. An estimated 1-2% of
acute pharyngitis progresses to recurrent or chronic disease
[4]. Although an exact definition of chronic or recurrent
pharyngitis escapes consensus, most otolaryngologists consider three or more recurrent infections per year to constitute
a chronic state. Unlike acute pharyngitis, which is almost
universally infectious in etiology, chronic pharyngitis can be
attributed to some important non-infectious causes. Here we
review chronic pharyngitis.
material is presented to the surface reticular cell epithelium
of Waldeyer’s ring and subsequently transported to specialized germinal centers leading to the proliferation of antigen
sensitive B-cells [6]. During the ages of 4 to 10 years, the
tissue of Waldeyer’s ring is at its most immunologically active with a resultant increase in tissue size and recurrent pharyngeal symptoms.
The primary species responsible for colonizing the upper
respiratory tract is group A -hemolytic Streptococcus pyogenes (GAS) but also includes Prevotella, Peptostreptococcus, and Viridians Streptococcus species [7, 8]. These commensal bacterial species act as a barrier to infection by
pathogenic species. Bacterial interference is thought to assist
in infection prevention and is mediated by organisms forming a direct blockade of epithelial binding sites, alteration of
the bacterial microenvironment and competition for nutritional substances [7]. Disruption of these mechanisms to
control the microenvironment allows for localized pharyngitis.
ANATOMY
BACTERIAL PHARYNGITIS
The lymphoid tissue of the pharynx, collectively known
as Waldeyer’s ring, is classically distinguished into three
distinct structures: the palatine tonsils, the pharyngeal tonsils
(or adenoids), and the lingual tonsils. The mucosa of
Waldeyer’s ring contains secondary lymphoid tissue similar
to Peyer’s patches in the bowel and is thought to assist in
regulating secretory immunoglobulin production [5]. Because Waldeyer’s ring is situated at the opening to the
aerodigestive tract, the developing immune system is exposed to both airborne and food-borne antigens. Antigenic
Group A -Hemolytic Streptococcus
*Address correspondence to this author at the Division of Otolaryngology,
St. Christopher’s Hospital for Children, 3601 A St. Suite 2205, Philadelphia,
PA 19134, USA; Tel: 215-427-8915; Fax: 215-427-4603;
E-mail: [email protected]
2212-3989/12 $58.00+.00
Group A -hemolytic Streptococcus pyogenes is a grampositive aerobic organism that is the most frequent bacteria
implicated in infectious pharyngitis. Globally, 616 million
new cases of GAS streptococcus are estimated to occur each
year [9]. In the pediatric population, approximately 15-36%
of acute pharyngitis cases are attributable to GAS [2].
Transmission of disease occurs through droplet spread, with
an incubation period of aproximately1-4 days. Classic symptoms include acute onset of pharyngeal pain, dysphagia, and
fever [1]. Associated symptoms of rhinorrhea, cough,
hoarseness, or conjunctivitis are not typically associated with
GAS and may indicate a viral etiology [10].
© 2012 Bentham Science Publishers
282 Infectious Disorders – Drug Targets, 2012, Vol. 12, No. 4
Individual GAS serotypes are classified based on the
Lancefield classification and also according to differences in
their M protein. Both host factors and bacterial factors appear to play a role in determining the severity of an individual infection [11]. Both group C and G streptococcal spp. are
also associated with pharyngitis and can be distinguished
based on culture. The majority of GAS disease occurs as
self-limiting acute infection that resolves spontaneously
within 3-5 days. Persistent colonization by GAS can also
occur but does not appear to frequently result in recurrent
infection or transmission of disease to contacts [12,13]. A
number of theories have been put forth to explain colonization by GAS resistant to antibiotic treatment. These include
antibiotic resistance [14], biofilm formation [15,16], and
intracellular bacterial reservoirs [17].
Complications of GAS
Treatment of GAS is predicated on the control of serious
complications, notably rheumatic fever and suppurative
complications (i.e., deep neck space infections, peritonsillar
abscess, and cervical adenitis with abscess). Additional
complications, such as post-streptococcal glomerulonephritis
(PSGN), toxic shock, scarlet fever, and autoimmune neuropsychiatric disorder, are also seen [18]. Despite the decreased incidence of some serious complications, the global
burden of these sequellae remains high. Worldwide, an estimated 517,000 deaths are attributed to GAS, primarily as a
result of rheumatic fever and invasive GAS disease [19].
Acute rheumatic fever (RF) is a type II autoimmune hypersensitivity reaction that affects multiple organ systems
and involves the interplay of both host- and pathogen- related factors. Diagnosis is clinical and based on the presence
of two major manifestations, or one major and two minor
manifestations, as defined by the modified Jones criteria
published in 1992 [20]. Morbidity is attributed to carditis
manifesting as aortic or mitral regurgitation with frequently
associated myocarditis or pericarditis [9]. In the modern developed world, most of the serious complications of RF have
largely been minimized due to a combination of effective
antibiotic therapies and improvements in sanitation, nutrition, and access to medical care [21]. Because the mechanism of action of RF is mediated by a type II hypersensitivity reaction, no effective acute treatment exits. Treatment of
GAS has been shown to decrease the incidence of subsequent RF and it is for this reason that early screening and
therapy remain important [9].
While RF is the most morbid complication of GAS, the
most common complication of GAS remains PSGN. Symptoms include edema, hypertension, hematuria, urinary sediment abnormalities, and decreased serum complement levels,
with minimal fever. PSGN can occur after skin infection
caused by GAS but tends to occur more quickly and with
worsening symptomotology in patients with pharyngitis [22].
Unlike the decreased incidence of RF seen following antibiotic therapy, early treatment of GAS has not been shown to
decrease the incidence of PSGN. Instead, treatment is largely
palliative and supportive, with only 1% of children progressing to severe or irreversible renal failure.
Scarlet fever and toxic shock syndrome are also associated with GAS and result from specific exotoxin production.
Murray and Chennupati
Treatment with antibiotics is not always effective, especially
in toxic shock syndrome where mortality can approach 50%
[22]. Suppurative complications of bacterial pharyngitis include the secondary development of deep neck infections
and cervical abscesses. Abscess formation results from tissue
necrosis and super infection. Deep space neck infections
leading to mediastinitis can have significant consequences,
including mortality rates approaching 40% [23]. Pediatric
autoimmune neuropsychiatric disorders associated with
streptococcal infections (PANDAS) is a recently described
entity that links pediatric neuropsychiatric conditions such as
obsessive compulsive disorder and Tourette’s syndrome to
previous GAS infection [24].
Non-Strep Bacterial Pharyngitis
In chronic tonsillitis, tonsillar-core biopsies have shown
that bacterial infection consists of a polymicrobial flora [25].
There is evidence that the types of bacterial infection seen in
children differ from those seen in adults and that they may
be affected by recurrent antibiotic treatment [26]. Non-GAS
organisms associated with pharyngitis include Neisseiria
gonorrhoeae, Corynebacterium diptheriae, Arcanobacterium
haemolyticum, Chlamydia pneumonia Haemophilus influenzae type B (Hib), additional Streptoccal species, Mycoplasma pneumoniae and many viral pathogens [3,27].
C. diptheriae, N. gonorrhoeae, and C. pneumoniae lead
primarily to the self-limited acute infections of diphtheria,
gonnococcal, and chlamydial pharyngitis, respectively, and
rarely become chronic conditions. The introduction of the
conjugate vaccine in the late 1980s has significantly reduced
the incidence of Hib in pharyngitis, although Hib carriage
and acute infection may be on the rise in certain areas [28].
Chronic pharyngitis associated with mycoplasma infection is
typically seen in the context of more systemic illness but has
been described to occur as an isolated phenomenon. Up to a
quarter of non-strep pharyngitis may be attributable to M.
pneumoniae [29]. Treatment for M. pneumoniae pharyngitis
is macrolide-, tetracycline-, or quinolone-class antibiotics,
and failure to recognize M. pneumoniae as a cause of
pharyngitis will necessarily lead to under treatment [30].
VIRAL CAUSES
Viral pharyngitis is thought to be the largest etiology of
acute pharyngitis leading to recurrent symptoms. The most
commonly associated agents implicated include herpes simplex virus (HSV), influenza sp. rubeola, Epstein-Barr virus
(EBV), cytomegalovirus, and human immunodeficiency virus type 1 (HIV). Viral pharyngitis tends to mimic bacterial
infection in clinical presentation. Mucopurulent drainage or
exudates are not typically associated with viral infection, but
EBV may be associated with up to one third of purulent exudates [31]. Concurrent bacterial and viral infection has also
been described and may lead to diagnostic inaccuracies [32].
Herpes simplex virus can cause an acute pharyngitis that
presents with pharyngeal vesicular lesions, tonsilar ulcerations, and gray exudates. While HSV infections typically are
self limiting and resolve within 7–10 days, latent HSV residing in sensory neural ganglion can result in recurrent infection. HSV-2 pharyngitis seen in adolescent or college age
children is associated with oral-genital transmission [31].
Chronic Pharyngitis
Treatment is with viral nucleic acid inhibitors, such as acyclovir. Epstein-Barr virus, which is responsible for the majority of cases of mononucleosis, initially presents with
pharyngitis, lymphadenopathy, and fever. Diagnosis is confirmed with the heterophile antibody test; however, this test
is not sensitive in children under the age of 10 and may need
to be repeated. Patients treated with amoxicillin exhibit a
characteristic pruritic maculopapular rash in 90% of cases
that is considered pathognomonic for EBV [18].
DIAGNOSIS
Because of the associated morbidities, GAS is the only
commonly occurring cause of infectious pharyngitis in
which treatment is necessary. As a result, accurate diagnosis
of pharyngitis focuses on distinguishing GAS from all other
causes [33]. Clinical judgment alone does not appear to be
an effective means of diagnosis, with clinician accuracy
found to be no greater than chance in distinguishing GAS
from other causes [34]. A number of different diagnostic
algorithms have been developed to distinguish GAS from
other causes; however, none have been shown to have a sufficiently reliable specificity to supplant clinical testing with
rapid antigen detection testing or throat culture. Currently,
the American Academy of Pediatrics recommends testing all
patients with suspected pharyngitis with a rapid strep test
and treating those who are found to be positive. Patients who
are found to have a negative rapid strep test should undergo
throat culture, and antibiotic treatment should be withheld
for 48 hours until the results of the culture are finalized [35].
This strategy has been shown to be cost effective with an
acceptably low morbidity when compared to other treatment
approaches [36]. While this approach has led to a decrease in
the overall antibiotic treatment of pharyngitis, it is still underutilized, and empiric treatment is still commonly practiced [2].
BURDEN OF CHRONIC PHARYNGITIS
Societal costs of chronic pharyngitis are significant.
Medical costs likely exceed $539 million per year, and there
are large non-monetary impacts, such as work missed, transportation, and childcare expenditures [37-39]. Children with
chronic pharyngitis have quality of life impairments similar
to other children with diseases thought to be much more debilitating, such as juvenile rheumatoid arthritis and chronic
asthma [39]. Poor quality of life in these children includes
both disease-specific and global health measures [39]. Reduction in episodes of pharyngitis through tonsillectomy or
medical therapy can reverse much of the quality of life disparity seen in these patients [40].
MEDICAL TREATMENT
First-line standard medical therapy of acute GAS is a 10day course of penicillin-class antibiotics with return to
school generally permitted within two days of antibiotic
therapy initiation [8]. Amoxicillin is often used in place of
penicillin due to a chewable formulation and better taste [41].
Penicillin-allergic patients can be treated with macrolide- or
cephalosporin-class antibiotics. Erythromycin along with second-generation azithromycin and clarithromycin all have
demonstrated efficacy in 10-day courses [42]. A single, sec-
Infectious Disorders – Drug Targets, 2012, Vol. 12, No. 4
283
ond recurrent episode of GAS, positive pharyngitis should also
be treated with first-line therapy; however, further recurrent
episodes may require different treatment options.
Failure to complete the full 10-day recommended course
of treatment may lead to treatment failure and should be first
considered in children with recurrent infections [43]. These
patients can be treated with parenteral doses of antibiotics if
difficulty with compliance is suspected. Patients who fail to
respond to repeated first line treatments should be targeted
with antibiotics effective in eradicating the carrier state [33].
The preferred oral agents include a 10-day course of either
clindamycin or amoxicillin-clauvulanic acid, and the preferred intramuscular agents are penicillin G with or without a
four-day course of oral rifampin [33].
The cause of recurrent infectious pharyngitis may be
multifactorial. Although penicillin resistant GAS has not
been identified in the laboratory, clinically, up to one third of
patients fail to respond to penicillin antibiotics [44]. Erythromycin-resistant GAS has also now been isolated in children [45]. Patients who suffer one antibiotic failure for GAS
have a higher likelihood of subsequent treatment failures.
While no clear mechanisms explain penicillin treatment failures, a number of theories have been postulated, including
internalization of GAS into tonsillar tissue, bacterial copathogenicity, GAS biofilm formation, and antibiotic activity
on commensal organisms [44]. An additional consideration
in patients who experience recurrent infections despite appropriate medical management is the possibility of intercurrent viral infections in the context of a GAS-carrier state
[33]. This is difficult to determine clinically, and recommended treatment of these patients is to follow guidelines for
treatment of recurrent GAS.
SURGICAL MANAGEMENT: ADENOTONSILLECTOMY
Tonsillectomy is one of the most common surgical procedures in the United States [46]. Although it is not without
rare but potentially significant risks [47] and occasional difficult post-operative recovery, it is generally well tolerated as
an outpatient procedure in the pediatric population. Current
American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) indications for tonsillectomy and adenoidectomy for recurrent or chronic pharyngitis are the following [48]:
•
Tonsillar hypertrophy resulting in airway obstruction or
orofacial growth restriction
•
Chronic or recurrent tonsillitis in a streptococcal carrier
not responding to beta-lactamase-resistant antibiotics
•
Three or more tonsil infections per year
•
Peritonsillar abscess unresponsive to medical therapy
•
Tonsillitis resulting in febrile convulsions
•
Chronic tonsillitis resulting in halitosis
•
Tonsillar enlargement requiring biopsy to define tissue
pathology
Most otolaryngologists use the number of recurrent infections a child has per year as the guidelines for tonsillectomy.
In this model recurrent or chronic tonsillitis necessitating
284 Infectious Disorders – Drug Targets, 2012, Vol. 12, No. 4
Murray and Chennupati
tonsillectomy is defined as follows: 7 episodes in one year, 5
episodes per year for two consecutive years, or 3 episodes
per year for three consecutive years [18]. Current practice
indicators for tonsillectomy published by the American
Academy of Otolaryngology (AAO), however, require a
minimum of only three infections per year for surgical intervention [48].
aphthous ulcers prior to being diagnosed. Medical therapies,
including corticosteroid administration, are primarily palliative and do not decrease symptom duration. Importantly, oral
antibiotics do not appear to be effective. Adenotonsillectomy
may be an effective management tool; a recent study demonstrated complete resolution of symptoms in up to 96% of
patients [56].
Tonsillectomy performed for recurrent or chronic infection constitutes almost 40% of all tonsillectomy procedures
[49]. Historical prospective studies demonstrating an overall
decrease in the number of recurrent infection in children
undergoing adenotonsillectomy questioned the need in these
cases [50, 51]; however, recent studies looking at additional
outcome measures, including cost of care and both diseasespecific and global quality of life, have further supported
adenotonsillectomy in patients with recurrent or chronic
pharyngitis [40].
Stevens-Johnson syndrome, pemphigus, and epidermolysis bullosa are all diseases that affect epithelial surfaces with
a predilection to the mucous membranes that can present
with pharyngeal symptoms. Epidermolysis bullosa typically
presents in early childhood and can present with almost exclusively oropharyngeal symptoms.
Multiple operative techniques for adenotonsillectomy
have been described [52]. Practically speaking tonsillectomy
can be divided into those performed via an intracapsullar
technique versus those performed using traditional tonsillectomy. Although multiple instruments may be employed in
the removal of the adenoid pad, there is less of an anatomical
distinction to how this is accomplished. Traditional tonsillectomy consists of removal the entire tonsillar tissue including
its surrounding fibrous capsule. Intracapsular tonsillectomy
refers to removing at least 90% of the tonsillar tissue but
sparing the capsule and a small amount of lymphoid tissue
[53]. This latter technique, while initially used for patients
with obstructive sleep apnea, has recently gained wider acceptance for its use in patients with chronic or recurrent infections [47].
NON-INFECTIOUS
PHARYNGITIS
CAUSES
OF
CHRONIC
Laryngopharyngeal Reflux
Laryngopharyngeal reflux (LPR), also referred to as gastroesophageal reflux disease (GERD), is increasingly recognized as a source of chronic irritation and inflammation of
the pharyngeal tissues. In children, LPR has been associated
with rhinosinusitis, chronic laryngitis, recurrent pneumonia,
and asthma [54]. Diagnosis is primarily based on symptomatology and clinical exam. Signs consistent with LPR in children include a chronically inflamed pharynx, with lymphoid
hyperplasia with characteristic cobblestoning, and pharyngeal or lingual tonsillar hyperplasia. Treatment is agedependent and centers initially on dietary and lifestyle modifications. Proton pump inhibitor therapy is instituted in children who fail to respond to behavioral modifications [54].
CONCLUSION
Chronic pharyngitis is a common diagnosis in the pediatric population. While most cases of chronic and recurrent
pharyngitis are related to GAS, it is important to consider
alternative diagnoses. In patients with a classic presentation
for GAS, adenotonsillectomy has been shown to improve
rates of re-infection and to improve quality of life and decrease overall healthcare expenditures.
CONFLICT OF INTEREST
None declared.
ACKNOWLEDGEMENTS
None declared.
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