Diphtheria. Differential diagnostics of Acute tonsillitis

DEPARTMENT OF INFECTIOUS DISEASESDEPARTMENT OF INFECTIOUS DISEASES
THEME: Diphtheria.
Differential diagnostic
of acute tonsillitis.
Infectious diseasesInfectious diseases

Diphtheria is an acute infections disease
caused by Corynebacterium diphtheriae (Leffler bacilli),
transmitted mainly in an air-drop way and
characterized by the symptoms of general
intoxication, local inflammation of the mucous
membranes mainly with the formation of
fibrinogenous fur and typical complications on the part
of the nervous system, cardiovascular system and
excretory system.
Klebs discovered the diphtheria pathogen
Corynebacterium diphtheriae in the sections of
diphtheria membranes in 1883. In 1884 Leffler
extracted it in clean culture.
DIPHTHERIADIPHTHERIA

C. diphtheriae is aerobic
and facultatively anaerobic,
growing best on a blood- or
serum-containing medium at
35-37°C. On agar medium
containing tellurite, colonies
of C. diphtheriae are
characteristically black or
gray after 24-48 h.
EtiologyEtiology
Biotypes of C. diphtheriae named gravis,
intermedius or mitis are genomically similar variants
exhibiting distinct biochemical features and cultural
morphology.

The distinctive qualities of the diphtheria
microbes are their polymorphism. Gram-positive
coloring and the typical location of rods in the form of
"bristling fingers" or V-figures. The diphtheria
microbes are immobile, they don't produce spores,
and do not have capsules or flagellums.
EtiologyEtiology
The main biological quality of the
diphtheria microbe is its capacity
to produce toxin (exotoxin) that
causes the pathogenicity of this
microbe.

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Diphtheria has virtually disappeared inDiphtheria has virtually disappeared in
developed countries following mass immunization indeveloped countries following mass immunization in
the 1940s, but is still endemic in many regions of thethe 1940s, but is still endemic in many regions of the
world. About 50000 cases of diphtheria occurred in theworld. About 50000 cases of diphtheria occurred in the
newly independent states of the former Soviet unionnewly independent states of the former Soviet union
during 1990-1996, leading to infection in short-termduring 1990-1996, leading to infection in short-term
visitors from Western Europe. The important feature ofvisitors from Western Europe. The important feature of
epidemic of a diphtheria in 90-th years was prevalenceepidemic of a diphtheria in 90-th years was prevalence
cases among adults.cases among adults.
EpidemiologyEpidemiology

Infection is confined to man and usually involvesInfection is confined to man and usually involves
contact with a diphtheria case or carrier. The mostcontact with a diphtheria case or carrier. The most
important mode of spread is person-to-personimportant mode of spread is person-to-person
transmission by aerosolized droplets when an infectedtransmission by aerosolized droplets when an infected
person coughs, sneezes or talks, or by direct contactperson coughs, sneezes or talks, or by direct contact
with skin lesions. Most clinical infections are probablywith skin lesions. Most clinical infections are probably
contracted from carriers rather than symptomaticcontracted from carriers rather than symptomatic
patients. Prolonged close contact with an infectedpatients. Prolonged close contact with an infected
person and intimate contact increases the likelihood ofperson and intimate contact increases the likelihood of
transmission.transmission.

The most epidemically dangerous are theThe most epidemically dangerous are the
bacteria-carriers who discharge microbes for a longbacteria-carriers who discharge microbes for a long
time (up to 1 month and longer), it is more oftentime (up to 1 month and longer), it is more often
observed in patients with chronic diseases of theobserved in patients with chronic diseases of the
upper respiratory tracts particularly with tonsillitis.upper respiratory tracts particularly with tonsillitis.
The periodicity and seasonal prevalence of theThe periodicity and seasonal prevalence of the
case rate are characteristic of diphtheria as ancase rate are characteristic of diphtheria as an
infection with a dropping mechanism of transmission.infection with a dropping mechanism of transmission.
These epidemiological peculiarities were moreThese epidemiological peculiarities were more
considerably expressed during the prevaccinating timeconsiderably expressed during the prevaccinating time
when the periodic growth of the sickness rate waswhen the periodic growth of the sickness rate was
observed every 10 years.observed every 10 years.

PathogenesisPathogenesis
To cause disease C. diphtheriae must:
• colonize and proliferate in local tissues;
• produce toxin.
In the upper respiratory tract, diphtheria bacilli
elicit an inflammatory exudates and cause necrosis of
the cells of the faucial mucosa. The diphtheria toxin
possibly assists colonization of the throat or skin by
killing epithelian cells or neutrophils.

The organisms do not penetrate deeply into the
mucosal tissue and bacteraemia does not usually
occur. The exotoxin is produced locally and is spread
by the bloodstream to distant organs, with a special
affinity for heart muscle, the peripheral nervous
system and the adrenal glands.
C. diphtheriae can colonize the throats of people
who have been immunized against diphtheria or who
have become immune as a result of natural exposure.

The diphtheria toxin is a heat-stable
polypeptide, composed of two fragments: A (active)
and B (binding). The toxin binds to a specific receptor
on susceptible cells and enters by receptor-mediated
endocytosis. The A subunit is cleaved and released
from the B subunit as it inserts and passes through
the membrane into the cytoplasm. Fragment A
catalyses of ADP-ribose from nicotinamide adenine
dinucleotide to the eukaryotic elongation factor 2,
which inhibits the function of the latter in protein
synthesis. Inhibition of protein synthesis is probably
responsible for both the necrotic and neurotoxic
effects of the toxin.

Implanting in the organism through covering
tissues the diphtheria pathogens form local foci of
histic damage. More often it happens on the mucous
membranes of the stomatopharynx, nasal-courses
where the microbes utilize slime as a medium, less
often the foci develop on the skin and even less often
on the mucous membranes of an eye and other
localizations. Alongside with classic exotoxin; which is
a true lethal factor, the diphtheria microbes in the
zone of inoculation produce numerous solvable local-
acting factors (hyaluronidase and neuraminidase)
damaging the cells and facilitating the diffusion of
bacteria and toxins in the tissues.

Hyperemia, retardation of the blood flowand
sharp rising of the permeability of hystohematic
barriers promote the formation of exudate which is
rich in protein and fibrinous membranes in the
damaged tissue area.
Fibrinous inflammation is the pathomorphologic
manifestation of the macro- and microorganism
interaction in diphtheria. The form of this inflammation
directly relates to the constitution of the affected
mucous membrane.

If the process develops on the mucous
membrane covered with the single-layer cylindrical
epithelium (for example in the respiratory tracts),
croupous inflammation develops; the cover that
develops includes a necrotic epithelial layer. The cover
is not firmly connected with the underlying tissue and
can be easily separated from it. If the process
develops on the mucous membranes covered with a
multilayer flat epithelium (lumen of fauces, pharynx),
it is not only the epithelial layer that necropsies, but
partially the joint tissue basis of the mucous
membrane (tunica propria mucosae). A thick fibrinous
cover develops, it can be hardly removed from the
underlying tissues. It is diphtheria inflammation.

The regional lymph nodes get involved in the
process: they are enlarged owing to the expressed
plethora, edema and the proliferation of the cell-like
predominantly reticuloendothelial elements. Local
necroses develop in them. In the toxic form of
diphtheria develops the edema of the fauces mucous
membrane, pharynx, and also the edema of cervical
fat in the immediate proximity of the affected regional
lymph nodes. In the basis of this edema there is a
serous inflammation in the form of numerous cell-like
infiltrates.

The diphtheria intoxication is characterized by
the affection of the nervous system (mainly the
peripheral nerves of the sympathetic ganglions),
cardio-vascular system, paranephroses and
nephroses.
The changes of the peripheral nerves are
manifested by multiple toxic parenchymatous neuritis.
The cardiovascular system is considerably affected in
the diphtheria intoxication.

Nontoxigenic strains of C. diphtheriae may
cause pharyngitis and cutaneous abscesses. Systemic
disease, including endocarditis, septic arthritis and
ostesmyelitis, has also been reported. The viulence
factors of these strains remain unknown. Conversion
of a nontoxigenic strain to a toxigenic strain by phage
infection can occur in human populations.

In accordance with “International classification”
of WHO diphtheria is divided by the followings
clinical forms
A. After by localization of local process:
diphtheria of tonsil;
diphtheria of nasopharynx;
diphtheria of front department of nose;
diphtheria of larynx and trachea;
diphtheria of other localization (diphtheria of
skin, of wound and other).
Classification.Classification.

B. After by expressed of general toxic, by
character select the followings variants the
terms of appearance and weight of
complications motion of diphtheria:
subclinical;
easy;
middle-severe ;
heavy;
hypertoxic;
bacterium carrier.

C. After by widespread a process:
localized;
widespread;
combined.
D. After by character of local changes:
catarrhal;
islands;
membrano-fibrinous.

Clinical manifestationClinical manifestation
The incubation period of diphtheria is 2-5 days,
with a range of 1-10 days.
At first, patients present with malaise, sore
throat and moderate fever. The tonsils are swollen
either both or mostly, the erythema is strictly
localized. By the end of the first day or by the
beginning of the second day the cover gets a
characteristic diphtheria cover properties: it is dirty-
gray or yellowish, rather thick, rises above the
mucous membrane surface, it cannot be removed
without bleeding; plenty of fibrin and diphtheria bacilli
can be discovered under the microscope in it.

The manifestations of the general intoxication
remain insignificant: a headache, malaise, poor
appetite. In the cases when the disease is not treated
with serum, the cover appears on the uvula, soft
palate, nasopharynx, nasal cavity or the process goes
downwards to the larynx. Laryngeal involvement
leads to obstruction of the larynx and lower airways.

Toxic diphtheria.
The typical form sometimes develops on the 3-
5th day of the disease from the localized form when
the process affects the nasopharynx and oral cavity,
more often it develops as it is from the very
beginning. In this case the disease has an acute
oncoming, which is more rapid than in localized
diphtheria. The temperature immediately rises up to
39-40°C, there is a headache, repeated vomiting. The
pulse is rapid: 140-160 beats per minute, the face is
pale, there is malaise, sleeplessness.

The submandibular glands are enlarged, painful;
it is possible to see a pasty edema of the cellular
under the low jaw angle, usually on one side;
sometimes an edema develops only on the second
day.
At the mouth examination you can see that the
tongue is dry, the fauces are dark-red and hydropic;
there is usually dirty-gray fur on one tonsil, it cannot
be removed by a cotton plug. This cover affects the
entire tonsil, passes to the uvula, sometimes to the
soft palate extremely fast, within several hours. On
the second or third day the disease is in full swing,
and it is not difficult to clinically diagnose toxic
diphtheria.

Cutaneous diphtheria mostly occurs in tropical
countries. The lesion is usually characterized by an
ulcer covered by a necrotic pseudomembrane and
may involve any area of the skin and systemic toxic
manifestation.

Pharyngeal diphtheria with membranes covering
the tonsils and uvula.

“Bull neck” appearance of diphtheritic cervical
lymphadenopathy.

A child with the "bull neck" of diphtheria.

A diphtheria skin lesion on the leg

ComplicationsComplications
The most frequent diphtheria complication for
adults is myocarditis. The affection of the heart is
especially typical for the toxic forms of the disease.
The severe form of myocarditis develops only in the
patients with toxic diphtheria at overdue (after the
5th day of the disease) specific treatment and is often
accompanied by complications on the side of the
kidneys and nervous system. Death is most
commonly due to congestive heart failure and cardiac
arrhythmias.

The complications caused by the affection of
the nervous system are observed less frequently. In
the mild forms of diphtheria develop only the soft
palate paresis — mononeuritis, which has an easy
short-term course (no more than 10-14 days),
characterized by a snuffling voice and chokes while
eating liquid food.
In more than 30 % cases toxic diphtheria is
complicated by polyneuritis in various combinations
and polyradiculoneuritis. Among the cranial nerves
the IX, X, III, VII, XII pairs are affected more often.

The severe forms of polyradiculoneuritis
develop, as a rule, in patients with concomitant
alcoholism, they are characterized by deep wide-
spread paralyses of the extremities, body, neck,
respiratory muscles in combination with the affection
of the cranial nerves, resulting not only in the long-
lived disorders of the working capacity, but also in
lethal outcomes.

Laboratory diagnosticLaboratory diagnostic
The diagnosis is made on clinical grounds,
supported by a history of diphtheria among contacts,
lack of prior immunization or travel in countries
where diphtheria is endemic.
The role of the laboratory is to confirm the
diagnosis by recovery of C. diphtheriae in culture
followed by appropriate tests for detection of toxin
production. The clinician should inform the laboratory
of the presumptive diagnosis of diphtheria because
isolation of C. diphtheriae requires special media. The
modem microbiologic diagnostics of diphtheria is
based on the clean culture isolation and identification
of the pathogen by the cultural-morphological,
biochemical and toxicogenic properties.

Toxigenicity testing is essential. Production of
diphtheria toxin is demonstrated by the agar
immunoprecipitation test. The toxin gene can be
detected by the polymerase chain reaction (PCR). The
detection of the tox gene by PCR directly from clinical
specimens is feasible. All biotypes are potentially
toxigenic.
Measurement of antibodies to diphtheria toxin
in serum collected before administration of antitoxin
may support the diagnosis when cultures are
negative.

TreatmentTreatment
If diphtheria is strongly suspected on clinical
grounds, treatment should not await laboratory
confirmation, which may take several days.
Diphtheria antitoxic serum (hyperimmune horse
serum) is given, since antibiotics have no effect on
preformed toxin which rapidly diffuses from the local
lesions and soon becomes irreversibly bound to tissue
cells. Because antitoxic serum neutralizes only
circulating toxin it should be administered promptly.

Doses of diphtheria antitoxic serum
Patient’s statePatient’s state Doses of serumDoses of serum
EasyEasy 3030000000 -- 4040000000 IUIU
Middle-severeMiddle-severe 5050000000 -- 8080000000 IUIU
HeavyHeavy 9090000000 -- 120120000000 IUIU
HypertoxicHypertoxic 120120000000 –– 150150000000 IUIU

TreatmentTreatment
Treatment with parenteral penicillin or oral
erythromycin eradicates the organism and terminates
toxin production. C. diphtheriae is universally
sensitive to penicillins but some strains are resistant
to erythromycin, tetracyclines and rifampicin.
Erythromycin may be preferred to penicillin for
elimination of the bacilli from the throat, particularly
in treatment of persistent carriers.
Patients should be placed in strict isolation,
nursed by staff whose immunization history is
documented and have daily platelet counts and
electrocardiograms.

ProphylaxisProphylaxis
• The basic method of specific prophylactic of a
diphtheria is vaccination.
• Now is used diphtheria toxoid.
• A level of 0.1 IU/ml (International Units per
milliliter) diphtheria antitoxin in a serum is desirable
for individual protection.

Tonsillopharyngitis (more simply,
pharyngitis) is a common complaint characterized by
inflammation of the mucous membranes of the throat.
Up to 40 million office visits are made annually
by persons of all ages because of this illness, primarily
during colder seasons, and it may account for up to
100 million days lost from work each year.
TONSILLOPHARYNGITISTONSILLOPHARYNGITIS

Pharyngitis caused by a variety of pathogenic
microorganisms, the majority of which are viral. A
minority of pharyngitis episodes are bacterial.
Viral pharyngitis is caused by respiratory viruses
such as rhinoviruses, coronaviruses, adenoviruses,
influenza, and EBV.
Bacteria causing pharyngitis include group A
and non-group A streptococci, Corynebacterium
diphtheria, Corynebacterium pseudodiphtherium,
Neisseria gonorrhoeae, Yersinia enterocolitica,
Arcanobacterium hemolyticum, and anaerobic
bacterial species.

Many patients and clinicians are aware of the
importance of group A β-hemolytic streptococci
(Streptococcus pyogenes) as a cause of pharyngitis,
and concern for this pathogen must be a major focus
in the management of sore throat. It is also felt to be
the only commonly encountered pathogen for which
treatment is clearly indicated. However, numerous
other potentially treatable causes of this illness exist,
and most cases of pharyngitis in adults are not caused
by S. pyogenes.

The severity of the pharyngitis may vary from
mild to life threatening depending on the etiologic
agent. Symptoms of mild pharyngitis are irritation or
sore throat. With increasing severity there may be
severe pain that increases on swallowing or talking,
plus cervical lymphadenopathy with or without fever.
Pharyngitis can be life threatening with inflammatory
edema of pharyngeal walls and extension to the
larynx leading to respiratory distress.

An erythematous pharynx with or without
exudates or cervical lymphadenopathy is the common
finding on examination. Because it impacts therapeutic
decision-making, it is important to attempt clinical
differentiation between viral and bacterial pharyngitis.
However, this may be difficult. Associated clinical signs
and symptoms provide diagnostic clues to formulate a
differential diagnosis. Mild pharyngeal symptoms with
rhinorrhea usually suggest a viral etiology.
Pharyngeal exudates suggest streptococcal pharyngitis
or EBV. Presence of vesicles and ulcers is seen with
herpes simplex and coxsackievirus. Coxsackievirus-
related vesicles often occur on the hard palate.

Adenoviral pharyngitis is associated with
conjunctival congestion. EBV, A hemolyticum, and
streptococcal toxic shock can present with pharyngitis
and a generalized rash. Pharyngitis with elevated
transaminases, splenomegaly, and atypical
lymphocytosis is the typical manifestation of EBV-
induced infectious mononucleosis.
Aseptic meningitis along with pharyngitis should
suggest an acute HIV or enteroviral syndrome.
Systemic viral infections with CMV, measles, and
rubella, among others, can present with acute
pharyngitis.

GAS (Streptococcus pyogenes) pharyngitis
frequently presents with fever of > 38.3 o
C, chills,
sudden-onset sore throat, painful and difficult
swallowing, and tender cervical lymph nodes.
Lymphadenopathy is more likely to be anterior and
tender in GAS pharyngitis, unlike viral pharyngitis,
which is more likely to be generalized and nontender.
Exudate with intense pharyngeal and tonsillar
pillars erythema is seen. Occasionally patients,
especially children, present with systemic symptoms of
nausea, vomiting, and headache.

Streptococcal tonsillitis. Intense erythema of the tonsilsStreptococcal tonsillitis. Intense erythema of the tonsils
and surrounding tissue with a creamy-yellow exudate.and surrounding tissue with a creamy-yellow exudate.

Group A streptococcal pharyngitis with localizedGroup A streptococcal pharyngitis with localized
erythema and edema of the tonsils and soft palate.erythema and edema of the tonsils and soft palate.

Laboratory values may not be of considerable
help. Testing for GAS should be done in all patients in
whom GAS pharyngitis cannot be confidently
excluded on clinical grounds. Diagnosis of GAS
pharyngitis can be made by RADT, which has a
sensitivity of 80-95% and specificity of 95%. Use of
RADT significantly increases the number of patients
receiving appropriate antibiotic treatment. Because of
its relatively lower sensitivity, a negative test should
be confirmed with a throat culture. Throat cultures
taken from the tonsillar fossae and posterior
pharyngeal wall are 90-95% sensitive for the
diagnosis of GAS pharyngitis.

TreatmentTreatment
In patients with a clinical picture consistent with
GAS pharyngitis, empirical therapy should be started to
prevent suppurative and nonsuppurative complications, to
decrease infectivity and transmissibility, and to induce
clinical improvement of symptoms. Patients with a high
index of suspicion for GAS pharyngitis but negative or
pending RADT/culture results can be given empirical
antibiotics until the results are available. An alternative
approach is to withhold antibiotics until the culture is
positive for S. pyogenes. Delaying therapy against GAS
does not increase the incidence of rheumatic heart disease
or recurrences with the same strain of S. pyogenes.
Following the latter course will decrease inappropriate
antibiotic use and control the increase in antibiotic
resistance.

TreatmentTreatment
Antibiotic selection is based on efficacy, ease of
administration, cost, compliance, and spectrum of the
antibiotic. The treatment of choice is penicillin V or
amoxicillin for 10 d to treat and eradicate carriage.
Intramuscular benzathine penicillin G may be given in
patients unlikely to complete a 10-d course. Shorter
courses are not recommended until more definitive
studies are available.
Erythromycin or other macrolides (such as
clarithromycin or azithromycin), or oral
cephalosporins are the recommended alternatives for
bacterial pharyngitis in patients who are allergic to
penicillin.

TreatmentTreatment
Absence of penicillin-resistant GAS and limited
(5%) resistance to erythromycin make it imperative
to choose a cheaper alternative to the newer more
expensive antibiotics. In some patients with recurrent
GAS pharyngitis, penicillin is unable to eradicate
nasopharyngeal carriage. In such patients, rifampin,
clindamycin, or amoxicillin/clavulanate use may
decrease colonization. Patients with negative throat
RADT/cultures should have antibiotics discontinued.
General measures for symptomatic relief
include fluids, warm saline gargles, and nonsteroidal
anti-inflammatory drugs.

Diphtheria. Differential diagnostics of Acute tonsillitis

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Diphtheria. Differential diagnostics of Acute tonsillitis