Tonsillitis is a common disease of childhood and adolescence. The diagnosis of tonsillitis generally requires the consideration of Group A beta-hemolytic Streptococcus (GABHS) infection. However, numerous other bacteria alone or in combinations, viruses and other infections and non-infectious causes should be considered. Recognition of the cause and choice of appropriate therapy are of utmost importance in assuring rapid recovery and preventing complications.

Penicillin is currently the first-choice treatment for GABHS pharyngotonsillitis. However, the growing failure of penicillin to eradicate GABHS is of concern. This website discusses the potential causes of penicillin failure ( i.e. the presence of beta-lactamse producing bacteria that can “protect” GABHS from penicillins) and methods to overcome them. It also discusses the role of anaerobic bacteria in tonsillitis and its complications.


Microbiological Causes of Pharyngo-Tonsilitis

Pharyngo-tonsillitis (PT) is characterized by the presence of increased redness and finding of an exudate, ulceration or a membrane covering the tonsils.  Because the pharynx is served by lymphoid tissues of the Waldeyer ring, an infection can spread to include various parts of the ring such as the nasopharynx, uvula, soft palate, tonsils, adenoids and the cervical lymph glands.  Based upon the extent of the infection, the infection can be described as pharyngitis, tonsillitis, tonsillopharyngitis and nasopharyngitis.  The duration of any of these illnesses can be acute, subacute, chronic or recurrent.
The diagnosis of PT generally requires the consideration of  Group A beta-hemolytic streptococci (GABHS) infection.  However, numerous other bacteria, viruses and other infections and non-infectious causes should be considered.  Recognition of the cause and choice of appropriate therapy are of utmost importance in assuring rapid recovery and preventing complications.




                The tonsillar crypts where GABHS interacts with other bacteria 



Table 1 lists the different causative agents and their characteristic clinical features.  The occurrence of a certain etiological agent depends on numerous variables that include environmental conditions (season, geographical location, exposure) and individual variables (age, host resistance and immunity).  The most prevalent agents accounting for PT are GABHS, adenovirus, influenza virus, parainfluenza virus, Epstein‑Barr virus and enterovirus.  However, the exact etiology is generally not determined and the role of some potential pathogens is not certain.
Recent studies suggested that interactions between various organisms, including GABHS, other aerobic and anaerobic bacteria and viruses may occur during PT. Some of these interactions may be synergistic (i.e., between EBV and anaerobic bacteria), thus enhancing the virulence of some pathogens, while others may be antagonistic (i.e., between GABHS and certain "interfering" alpha hemolytic streptococci).  Furthermore, beta‑lactamase producing bacteria can protect themselves as well as other bacteria from beta‑lactam antibiotics. 
A concomitant GABHS and influenza A virus pharyngo-tonsillitis can occur, as was evident in a recent study when an increased in the ASO and anti-DNase B titers was found in a third of the patients who had both of these organisms isolated. 

Aerobic Bacteria
Because of the potential of serious suppurative and non-suppurative sequellae, GABHS are the best known cause of sore throat.  Occasionally Groups B, C and G beta-hemolytic streptococci are responsible.  The clinical presentation of PT due to all types of streptococci is generally identical, and is characterized by exudation, palatal petechiae, follicles, tender cervical adenitis, and scarlet fever rash . What are generally absent are the classical signs of viral infections such as  cough, rhinitis, conjunctivitis and diarrhea.
GABHS PT should be suspected in the presence of abrupt onset of fever  in a child older than 2 years ( with or without “sore throat”), higher temperature, ill appearance, headache, neck muscle pain, tenderness, abdominal pain, nausea, or vomiting, flushed cheeks & circumoral pallor, palatal “petechiae”&circular and semicircular red marks, early strawberry tongue or scarlatinaform rash, a history of exposure to the organism, winter season, and the presence of a peculiar, sour-sweet, yeasty breath odor.
The isolation rate of GABHS varies with patient age, with the highest prevalence in school years. The isolation rate of non-GABHS is higher in adults than children.
There was a marked decrease in the incidence of acute rheumatic fever in the United States over the past 4 decades that is correlated with the replacement of rheumatogenic types by nonrheumatogenic types. However, streptococcal tonsillitis is still a potential serious illness because rheumatic fever still occurs, and GABHS is manifesting increased virulence.  More cases of sepsis, pneumonia and toxic shock syndrome due to streptococci have been observed in the past decade. Streptococci can be involved in suppurative complications of tonsillitis such as peritonsillar, and retropharyngeal abscesses.

                          Gram stain of Group A beta-hemolytic streptococci





Streptococcus pneumoniae can also be involved in PT that can either subside or spread to other sites. Corynebacterium diphtheria can cause a bull neck, and as can Corynebacterium hemolyticum both can cause an early exudative PT with grayish-green thick membrane that may be difficult to dislodge, and often leaves a bleeding surface when torn off.  The infection can spread to the throat, palate and larynx.  C. hemolyticum  produces a lethal systemic exotoxin.   Arcanobacterium hemolyticum incidence of causing PT is 2.5-10%, and occurs mostly in 15-18 year old individuals, and about half of the patients have a scarlatiniform rash.
                                          Gram stain of Streptococcus pneumoniae


Neisseria gonorrheae is common in homosexual males and can be detected in adolescents with pharyngitis.  The infection is often asymptomatic but can exhibit ulcerative or exudative pharyngitis, may result in bacteremia, and can persist after treatment.  Neisseria meningitidis can cause symptomatic or asymptomatic PT which can be a prodrom for septicemia or meningitis. 

                                       Neisseria gonorrheae (intracellular on left)




 Neisseria meningitidis


Non-typable Haemophilus influenzae and Haemophilus parainfluenzae can be recovered from inflamed tonsils.  These organisms can cause invasive disease in infants and elderly, as well as acute epiglotitis, otitis media and sinusitis.

                                                      Haemophilus influenzae




Staphylococcus aureus  in PT is often recovered from chronically inflamed tonsils and peritonsillar abscesses.  It can produce the enzyme beta-lactamase, that may interfere with the eradication of GABHS. High tissue concentration of Haemophilus influenzae, Staphylococcus aureus and Streptococcus pyogenes correlates with clinical parameters of recurrent infection and hyperplasia of the tonsils. A recent increase in the recovery of methicillin (MRSA)  resistant S. aureus was reported, where MRSA was isolated from 16% of the cores of surgically excised tonsils.
                                                         Staphylococcus aureus 




Rare causes of PT are Francisella tularemia, Treponema pallidum, Mycobacterium sppand Toxoplasma gondii.

Anaerobic bacteria
The anaerobic species that have been implicated in PT are Actinomyces spp., Fusobacterium spp. and pigmented Prevotella and Porphyromonas spp.


                                                         Fusobacterium spp.




Anaerobes role is supported by their predominance in tonsillar or retropharyngeal abscesses,  Vincent's angina (Fusobacterium spp. and spirochetes), and Lemierre's syndrome (Fusobacterium necrophorum). Furthermore, patients with non‑GABHS tonsillitis as well as infectious mononucleosis response to antibiotics directed only against anaerobes ( Metronidazole ); and elevated serum levels of antibodies to Prevotella intermedia and Fusobacterium nucleatum were found in patients with recurrent non‑GABHS tonsillitis and peritonsillar cellulitus and abscess. 

More about the role of anaerobic bacteria can be found in the website devopted to these bacteria.

Mycoplasma
Mycoplasma pneumoniae and Mycoplasma hominis can cause PT usually as a manifestation of a generalized infection.  The prevalence of Mycoplasma infection increases with age.


Viruses and Chlamydia

Viral PT is generally characterized by the absence of an exudate, the presence of ulcerative lesions, minor non-tender adenopathy, enanthems, cough, rhinitis, hoarseness, conjunctivitis, or diarrhea.
The viruses known to cause PT are:  Adenovirus (Concomitant conjunctivitis), Coxsackie A virus, Parainfluenza virus, Enteroviruses (Pharyngeal vesicles or ulcers, vesicles on palms and soles in summer), Epstein-Barr virus (Exudative pharyngitis, liver & spleen enlargement, cervical adenopathy), Herpes simplex (Anterior oral and lip lesions, fever), Respiratory syncytial virus, rubella virus (Oral erythema and Koplik spots, prior to exanthema) and CytomegalovirusChlamydia pneumoniae may cause PT , often accompanying pneumonia or bronchitis.                             




                         Transmission electron microscopic picture of adenovirus






      Table 1: Infectious Agents of Pharyngo-Tonsillitis

I.
Bacteria
Clinical Lesions
Clinical Frequency

      Aerobic



      Groups A,B,C and G streptococci
F, Er, Ex, P
A

      Streptococcus pneumoniae
E
C

      Staphylococcus aureus
F, ER, Ex
C

      Neisseria gonorrhoeae
Er, Ex
C

      Neisseria meningitidis
Er, Ex
C

      Corynebacerium diphtheriae   
Er, Ex

C

      Cornebacterium hemolyticum  
      Arcanobacterium hemolyticum
Er, Ex
Er, Ex
C
C

      Bordetella pertussis
Er,Er
C

      Haemophilus influenzae
Er, Ex
C

      Haemophilus parainfluenzae
Er, Ex
C

      Salmonella typhi
Er
C

      Francisella tularensis
Er, Ex
C

      Yersinia pseudotuberculosis
Er
C

      Treponema pallidum
F, Er
C

      Mycobacterium spp.
Er
C





      Anaerobic



      Peptostreptococcus spp.
Er, E
C

      Actinomyces spp.
Er, U
C

      Pigmented Prevotella and Porphyromonas
Er, Ex, U
B

      Bacteroides spp.
Er, Ex, U
C




II.
Mycoplasma



      Mycoplasma pneumoniae
F, Er, Ex
B

      Mycoplasma hominis
Er, ex
C




III.
Viruses and Chlamydia



      Adenovirus
F, Er, Ex
A

      Enteroviruses (Polio, Echo, Coxsackie)
Er, Ex, U
A

      Parainfluenzae 1-4
Er
A

      Epstein‑Barr
F, Er, Ex
B

      Herpes hominis
Er, Ex, U
C

      Respiratory syncytial
Er
C

      Influenzae A and B
Er
A

      Cytomegalovirus
Er
C

      Reovirus
Er
C

      Measles
Er, P
C

      Rubella
P
C

      Rhinovirus
Er
C

      Chalmydia trachomitis






IV.
Fungi



      Candida spp.
Er, Ex
B




V.
Parasites



      Toxoplasma gondi
Er
C




VI.
Rickettsia



      Coxiella burnetii
Er
C




Clinical lesions:
            F =       Follicular
            Er =     Erythematous
            Ex =     Exudative
            U =      Ulcerative
            P =      Petechial
Frequency:
            A =       most frequent (more than 66% of cases)
            B =      frequent (between 66% to 33% of cases)
            C =      uncommon (less than 33% of cases)