Diphtheria

Differential diagnostics of
tonsillitis
Diphtheria — acute anthroponotic infectious
disease with airborne mechanism of
transmission caused by Corynebacterum
diphtheriae and characterized by local
fibrinogenous inflammation (typically of
pharyngeal mucous membrane) and
symptoms of general intoxication mostly with
involvement of cardiovascular and nervous
systems (lat. — diphtheria; eng. —
diphtheria).
 Etiology
Belongs to genus Corynebacteriae, species —
Corynebacterium diphtheriae.
Polymorphous, G-positive, nonmotile, nonspore-
forming, not encapsulated bacterium with no flagella .
Length - 2-8 mcm, the appearance depends on the
cultivation medium.
Typical feature – the presence of club-shaped
thickenings at either end. These thickenings contain
volutine granules.
In thin smears group as the form of a "V" or in pairs, in
thick - as thick felt or pack of pins. Temperature
optimum +37°С, рН — alkalescent; the best growth -
on Loeffler`s medium (coagulated beef serum) and
tellurite medium.
Etiology
 Etiology
 The germs are rather resistant to the action of
different factors: can survive in environment up to
15 days (in autumn — up to 5 months), in water
and milk — 1-3 weeks. Boiling and 1% corrosive
sublimate solution destroy them within 1 minute.
 Corynebacteria diphtheriae have a complex
antigenic structure.
 There are 3 stable types (biovars) of
Corynebacterium diphtheria: gravis, intermedius,
mitis, which have different enzymatic
characteristics, haemolytic activity, appearance of
colonies.
Corynebacteria diphtheriae have 2 main types of
antigens:
 О-antigens (thermostable; can give cross-
reactions with antisera against Mycobacteria and
Nocardia);
 К-antigens (superficial, thermolabile, species-
specific; contain nucleoproteids and proteins with
high immunogenicity). K-antigen features provide
for division of Corynebacterium diphtheriae
biovars to strains.
 Typical feature of these germs is an ability to
produce different factors of pathogenicity; exotoxin
and biologically active substances are the most
important of them.
 Exotoxin (identical in all types) is the third strongest after
botulinum and tetanic; all types (gravis, intermedius, mitis)
include strains with and without toxin (toxigenic and
nontoxigenic).

 Corynebacterium diphtheriae exotoxin — a thermolabile

immunogenic protein, soluble in saline solutions; consists of
two fragments:

 А-thermolabile, determines specificity of action in the

organism. It is responsible for inhibition of cellular protein
biosynthesis which causes death of the cell;

 В-thermostable, acts during contact with a cell. Its main

function – target-cell recognition and binding them
(adhesion).
 Toxin is labile in environment, can be quickly
destroyed by heating (+ 60 °С and above), direct
sun action, oxygen.
 Activity of toxin is measured in units DLM (dosis
letalis minima — minimal lethal dose, 1 DLM
corresponds to toxin which kills a guinea pig with
weight of 250 g on the 4-5 day; this is
approximately 0.0001—0.0002 mg).
 Toxin inhibits synthesis of protein in cells which
causes severe functional and structural changes
in them, sometimes life-threatening (the most
severe in myocardium). Neural tissue affection
causes demyelinization of neural fibers with
following possible development of pareses and
paralyses.
 Besides the toxin, Corynebacterium
diphtheriae produces biologically active
substances (neuraminidase, hyaluronidase,
necrotizing factor and other – more than 20
altogether).
 They can cause incomplete phagocytosis in
macrophages which is important for survival
and multiplication of bacteria in penetration
area. Furthermore, these biologically active
substances favour toxin spread and
absorption.
 It is acknowledged that diphtheria is
caused by germs which can produce toxin
(toxigenic strains). However, nontoxigenic
strains have aggressive factors, except
toxin, which are inherent in toxigenic
strains.
Phage conversion - conversion of a
nontoxigenic strain to a toxigenic is always
possible. Therefore, it cannot be ruled out
that nontoxigenic strains can cause the
same changes in the organism as
toxigenic.
Widely known group of other Corynebacteria is
classified as diphtheroids (C.ulcerans,
C.pseudotuberculoris, C.pyogenes и др.).
They are an integral part of normal microflora of
human and animal mucous membranes or skin
but under certain conditions can cause different
diseases — pharyngitis, lymphadenitis,
abscesses, myocarditis etc.
There is evidence that certain strains of
C.ulcerans and C.pseudotuberculosis can produce
exotoxin similar to C.diphtheriae toxin, therefore,
effects caused by them can be effectively treated
by antidiphtherial serum.
 Epidemiology
Susceptibility to diphtheria is general.
Diphtheria is a manageable infection;
nowadays the majority of the cases are
among unvaccinated or incorrectly
vaccinated persons.
 Source of infection — a sick person or a
carrier of C.diphtheriae. Carriers are
especially dangerous because this
condition is rarely diagnosed.

If a carrier has any ARD with cough,

sneezing the possibility of spread of the
infection among the people around rises
significantly.
 Way of transmission of the germ is mostly
airborne; nasopharyngeal secretion
during the first days of the disease
соntains especially large number of
germs.
 Domestic way is possible (contaminated
toys, kitchen utensils).
 In case of wound diphtheria contact way of
transmission is possible.
 Diphtheroids can enter the organism with
contaminated water, milk.
 Mucous membrane of tonsils, rarer – of
nose, pharynx, larynx, sometimes eyes,
genitalia, skin is the entry of infection.
 Most of the cases are registered in autumn
and winter season when exposure to cold,
respiratory infections reduce local (in
pharynx) resistance and general reactivity
of organism.
 The diseases can be sporadic or present
mass outbreaks which depends on the
level of collective immunity.
 C.diphtheriae biovar gravis — epidemic
biovar, can be isolated mostly in epidemic
period from non-immune persons.
 C.diphtheriae biovar mitis has the lowest
toxigenicity, can be isolated mostly from
immune carriers.
 Decrease of a number of biovar gravis
carriers and increase of a number of
biovar mitis carriers is a sign of epidemic
decline.
 Typical features of epidemic
process nowadays:
 Adults are a primary target;
 Many patients have atypical, mild forms
which are not diagnosed timely;
 Formerly diphtheria mostly was registered in
rural areas where not all people were
immunized and now - in big cities.
 Causes of epidemic in 90s:
 Due to breach of vaccination decrease of
“collective immunity” occurred. For the start of
epidemic 10% of population must be
“unprotected”;
 Migration of population from epidemically
unfavourable countries;
 Changes of C. diphtheriae strain genetic
structure (emergence of G1, G4 ribotypes);
 Ecological and socially-economic factors;
After the disease immunity practically does not
develop!
Susceptibility to diphtheria is determined by
the presence of “protective titers” which
prevent development of:

 Severe forms – 0.03 IU/ml (1:40-80 in

direct hemagglutination test)
 Moderate forms – 0.1 IU/ml (1:160 in
direct hemagglutination test)
 Mild forms - ???
 Antitoxic immunity after the disease is
short-term; one can fall ill again just after
1-1.5 years, often after ARD.
 Vaccination cannot guarantee absolute
protection from the disease: one can fall ill
just in 10-12 months after vaccination but
in vaccinated persons the course of
disease is milder.
 Present classification of diphtheria

 According to localization: pharyngeal, laryngeal,

nasal, tracheal, and bronchial and non-
respiratory (ocular, cutaneous, genital)
 According to spread: local, spread, combined
 According to morphological changes: catarrhal,
membranous, islet-like
 According to severity: mild, moderate, severe,
hypertoxic
 Pathogenesis
Inoculation in Multiplication with
development of Lymphogenous Regional
site of entry lymphade
diphtheritic or Toxin production spread
croupous nitis
inflammation

Local Stimulation of local Hematogenous Affection of

inflammation protective factors spread internals
decline

Toxin production arrest Convalescence Complication

development
Bacteriemic-toxic
shock
Myocarditis
CNS affection
Kidney affection
 Pathogenesis
1. In site of germ localization and multiplication toxin
and other factors of pathogenicity cause local
inflammatory reaction – initially edema and
hyperemia (catarrhal inflammation).
 Subsequently toxin penetrates into mucous
membrane cells and intervene in protein synthesis
processes. Local necrosis nidi are formed. The
necrosis is the most apparent along the periphery of
the germ multiplication focuses. Local inflammatory
reaction intensifies, vascular paralytic dilatation and
hyperpermeability occur, macrophages migrate to
the inflammatory and necrotic areas; large amount
of fibrin is mixed with the exudate, impregnates the
entire mucous membrane and coagulates with
formation of fibrous masses and fibrinogenous
membranes.
 Pathogenesis
 As tonsils and pharynx are covered with
multirowed pavement epithelium, impregnation
of necrotic masses with fibrin is deep; the
membranes are tightly attached to submucous
layer, can be hardly removed and reveal
bleeding surface underneath (diphtheritic
inflammation) – “blood dew” symptom.
 The membranes can have grayish or black color
(due to haemorrhagic impregnation). The
process “crawls” further spreading outside the
tonsils and involving soft and hard palate and
deeper throat.
 Along the lymphatic ways the toxin and
different biologically active substances
move from the site of production deeper
into the tissues which causes regional
lymphatic node enlargement, toxic
lymphadenitis, edema of surrounding
tissues.
 The edema can involve submandibular
area, neck; focal muscular necrosis can
develop.
 Toxin gets directly to the blood. In this case it
is attached to target organs.
 The most vulnerable are cardiac muscle cells,
neural cells, adrenal glands, kidneys.
 The toxin attached to the target cell remains
on its surface. After that, active fragment A
separates and penetrates into the cell where
cell protein synthesis stops which causes
death of the cell.
 Peripheral neuritis can develop in 1 week after
the onset of the disease, myocarditis – on the
5-7th day and even earlier.
 Action of the toxin causes development of typical
changes in different organs:
 In heart (haemorrhages, thrombi, dystrophic
and focal necrotic changes with following
development of acute myocarditis, affection
of extra- and intracardial innervation
apparatus);
 In nervous system (dystrophic and necrotic
changes with myelin degeneration in motor
and sensory branches of peripheral nerves,
their nuclei, structures of vegetative nervous
system);
 In respiratory tract (membraneous
tracheobronchitis, congestive pneumonia);
 In adrenal glands (blood circulation disturbance,
haemorrhages, which causes decrease of steroid
hormone and adrenaline level);
 In kidneys (haemorrhages, degenerative changes
— usually in interstitial tissue, sometimes in
tubules and glomerules);
 In skin and hypodermic tissue of neck and upper
thorax (damage of vascular walls causes increase
of their permeability, surrounding tissue edema
and impregnation of them with fibrin-containing
plasma). Size of edema in the neck is one of the
criteria of process severity.
 Bacteriemia is not typical for diphtheria,
nevertheless, its probability cannot be
excluded against the severe course
background. It does not significantly influence
the course of the disease.
 Convalescence starts after the relief of the
local inflammatory process: gradual activation
of protective factors causes complete
phagocytosis formation; destruction of the
germs leads to termination of toxin
production. After the disease antitoxic
immunity is formed.
 Clinical picture
Clinical picture of diphtheria depends on localization, spread
of pathological process, toxicosis degree and (or) airway
obturation, the presence and character of complications,
concomitant diseases and secondary infection.
Carrier state of С.diphteriae is defined as an isolated type of
infectious process. The following variants of carrier state
are classified:
 convalescent (after having diphtheria);
 carrier state in healthy persons that is those who at the
time of examination or before do not have any signs of
diphtheria.
Carrier state can be:
 Short-term — the germ can be isolated within 2 weeks;
 Middle length — 2 weeks to 1 month;
 Prolonged — more than 1 month;
 chronic — 6 month to several years.
 Clinical picture of typical forms
Incubation period – 2 – 10 days (average 3-5)
 Sore throat (moderate, in severe forms – intense);
 Headache often in frontal area (moderate, in severe forms – intense);
 Nausea, vomiting often in severe forms;
 Short-term fever. Often falls against apparent changes in pharynx;
 Moderate/severe forms are characterized by different extent of hypodermic
tissue edema – from around submandibular lymphatic nodes to trunk
involvement;
 Edema of faryngeal mucous membrane;
 “Congestive” type of mucous membrane hyperaemia;
 Tonsil hypertrophy;
 Fibrinogenous coating (“+ tissue”);
 In moderate and severe forms the membranes spread to arches, soft palate,
larynx;
 Moderate lymphadenitis;
 During the last epidemic adults did not have isolated affection of larynx!
Diphtheria
Diphtheria
Diphtheria
Standard diphtheria case definition
(WHO, 1993)
Suspicious:
 All cases of acute tonsillitis on territories with diphtheria
cases
Possible:
 Acute tonsillitis + contact with patient with diphtheria
 Myocarditis following tonsillitis + cases of diphtheria in
the region
 ARF following tonsillitis
 Sudden death against diphtheria background
Confirmed:
 Isolation of C. diphtheriae from a patient with tonsillitis
 Fourfold rise of titers in direct hemagglutination test
within 2 weeks (in patients who were not treated with
antidiphtheric serum)
Diphtheritic croup includes 3 consecutive stages:
 1st stage — catarrhal; isolated edema and hyperemia of mucous membrane.
General condition is not seriously affected (general weakness, malaise, loss
of appetite), temperature is subfebrile, all the symptoms rise gradually. In a
few hours productive cough, hoarse voice appear; in 1-2 days the cough
becomes barking (in adults not always);

 2nd stage — stenotic; starts in 2—3 days. Laboured breath appears, it

becomes noisy (not always), intercostal retraction appears. Voice is
aphonic, cough is silent. Patients are agitated, rush about the bed.
Acrocyanosis increases. Muffled heart sounds, tendency to tachycardia. BP
can be slightly lowered. Duration of this period — few hours to 2—3 days;

 3rd stage — asphyxial; increasing signs of respiratory failure: tachy-,

hypopnoe, unrhythmical respiration, cyanosis increases. The patients try to
occupy a more comfortable position, but have no strength to do it.
Tachycardia, arrhythmia, low BP. Severe hypoxia causes, first of all, CNS
affection with confusion and then loss of consciousness, cramps followed by
death.
 Combined forms
The most common variants are:
 Diphtheria of tonsils and pharyngeal diphtheria ;
 Diphtheria of tonsils and nasal diphtheria;
 Diphtheria of tonsils and laryngeal diphtheria .

Combined form is characterized by:

 Faster growth of clinical symptoms and their
evolution;
 Major polymorphism of clinical symptoms
reflecting the extent of the process;
 Severe toxicosis.
 Complications
Complication of diphtheria can develop at any
stage of the disease, but each period has its
own typical complications. Terms of their
development have prognostic importance.
 The most severe complication of diphtheria is
bacteriemic-toxic shock, which usually occurs on
the 1—3 day of the disease, sometimes — later,
usually in non-vaccinated untreated patients.
Stages of the shock (I—III) can change each
other so rapidly that it is not always possible to
distinguish them.
 Complications
 Myocarditis — the most common
complication of diphtheria.
 It can occur at early stages of the disease
(the end of 1st week — early myocarditis),
and later (5—6th week — late
myocarditis).
 As a rule, the earlier myocarditis occurs
the more severe its course and the worse
prognosis is.
 Complications
 Nervous system affection can also occur
at early (1-2 weeks) and later (4-6 weeks)
stage of the disease.
 It usually manifests with motor, but not
sensory disorders. Depending on time of
nervous system affection it can be
classified as early or late like myocarditis.
 Development of nephrosonephritis caused by
direct action of diphtherial toxin. The disease
manifests mainly with changes of urine: high (2—
10 g/l) protein level, hyaline and granular
cylinders, high relative density of the urine. Renal
failure is possible but not typical for this
complication. The process is reversible.
 Circulatory disturbance, foci of hemorrhages in
liver contribute to the emergence of diphtheritic
hepatitis. But function of liver is not affected and,
except slight hepatomegaly, there are no other
signs of its affection. Transformation to chronic
hepatitis has not been reported.
 Nonspecific complications caused by
secondary bacterial infection (usually paratonsillar
abscess, otitus, pneumonia) can develop in
different periods of diphtheria, usually in the 2 nd
week.
 Diagnostic methods
 Clinical methods of diagnostics
 General blood test – moderate or evident
neutrophilic leukocytosis with left shift, ESR is
moderately increased.
 Urine protein value is increased, cylinders can
be found (hyaline and granular), single changed
erythrocytes. High relative density and protein
concentration (up to 10g/l) indicate development
of nephrosonephritis.
 Biochemical methods. AST, LDG, acid-base
balance, electrolytes, coagulogram, renal tests
and other parameters.
 Specific diagnostics
 Bacterioscopy of pharyngeal and nasal secretion. Material for
examination should be taken with a dry sterile swab along the
border of affected area. Thin smear is stained by Gram. Provisional
result concerning the presence or absence of the bacteria
morphologically similar to C. diphtheriae can be obtained in 1-2
hours. The method is approximate as it cannot distinguish C.
diphtheriae from other corynebacteria. Negative result cannot be a
ground for cancellation of the diagnosis.

 Bacteriological diagnostics is based on isolation of culture of C.

diphtheriae and investigation of its toxigenic properties. If diphtheria
is suspected the material (nasopharyngeal mucus) should be taken
with a dry swab and immediately inoculated into appropriate elective
medium (Loeffler, Clauberg and other). Examination should be
conducted before the start of antibiotic treatment. After 24 h
bacteriologist can give provisional conclusion. Detection of toxigenic
properties of corynebacteria delays the final result of examination
until 72 or 96 h.
 Serological examination often helps to
confirm the diagnosis retrospectively.
Paired sera are examined in direct
hemagglutination test with 7—10 day
interval. Blood for the first examination is
taken on admission to the hospital before
the start of antibiotic and antidiphtheric
serum treatment.
Differential diagnostics of
tonsillitis
Normal fauces Catarrhal tonsillitis Follicular tonsillitis
Catarrhal tonsillitis

 Bright hyperemia of
mucous membrane
 Moderate edema of
tonsils
 Absence of coating
 Regional
lymphadenitis
Lacunar tonsillitis
 Bright hyperemia of
mucous membrane
 Moderate edema of
tonsils
 Purulent coating in
lacunae
 Apparent regional
lymphadenitis
 Fever
Follicular tonsillitis
 Different intensity of
hyperemia of mucous
membrane
 Edema of tonsils is
not evident
 Suppurated follicles in
tonsils
 Apparent regional
lymphadenitis
 Fever
Paratonsillar abscess

 Apparent painfulness
 Bright hyperemia of
mucous membrane
 Apparent unilateral tissue
edema with the shift of the
uvula to the opposite side
 Trismus
 Apparent regional
lymphadenitis
 Fever
Plaut-Vincent angina
 Unilateral process
 Crateriform ulcers in
tonsils
 Bad breath
 General condition is
not much affected
 Ludwig's angina
(phlegmon of the floor of the mouth)

 Deformity of the floor of the mouth due to severe

tissue edema
 Apparent painfulness
 Edema of anterior surface of the neck
 Pharyngeal candidosis

 Separate islet-like coating covering the entire

pharyngeal mucous membrane
 Erosions of mucous membrane
Herpetic stomatitis

 Bright hyperemia
 Edema and
inflammation of gums
 Vesicles
 Erosions
 Coating on the tongue
 Infectious mononucleosis

 Generalized lymphadenitis
 Fever
 Splenomegaly
 Tonsillitis emerges from the first days, coating on the
tonsils appears after 3rd day of the disease
 Coating can cover the tonsils completely
 Treatment
 All the patients with diphtheria regardless of its severity
and clinical form should be admitted to infectious
hospital as early as possible. Patients with severe
course, signs of bacterial-toxic shock, DIC-syndrome,
diphtheritic croup should be admitted to resuscitation
department.
 Regimen depends on severity of patient condition,
clinical form, stage of the disease. Confinement to bed is
indicated for patient with moderate severity; strict
confinement to bed for at least two weeks (then
depending on patient condition, complications) is
indicated for patients with severe course and all the
more hypertoxic diphtheria. Diet — high-calorie, liquid
food (in case of the slightest signs of deglutitive
problems or in case of need an enteric feeding tube is
introduced).
 Causative treatment
 Antitoxic antidiphtheritic serum is a first priority in
treatment of patients with diphtheria.
 The best results are observed if the patients are
admitted to hospital within 1—2 days of the
disease. Antidiphtheritic serum should be
injected immediately on admission the patient to
the hospital following generally accepted
regulations of heterogenous serum injection.
The dose depends on the severity of patient
condition.
 Dose of antidiphtheritic serum
depending on severity of patient
condition

Severity of condition Dose of serum, IU

Satisfactory 30 000—40 000
Moderate severity 50 000—80 000
Severe 90 000—120 000
Extremely severe 120 000—150 000
(bacterial-toxic shock,
DIC-syndrome)
 Erythromycin (up to 2 g a day) is the most
efficient in treatment of diphtheria,
penicillin (up to 6 000 000 IU) or ampicillin
(3 g a day).
 Chloramphenicol, tetracycline are less
effective towards С.diphteriae. Course of
treatment continues until the elimination of
local process but at least 5—7 days.
 Regulations of discharge
from the hospital
 Convalescents after mild form should be
discharged after 2-3 weeks if no
symptoms and complications are present
and after two negative bacteriological
samples taken in 2 days after termination
of antibacterial treatment. Cardiologist
observation is recommended during 3-4
weeks after discharge from the hospital as
development of late myocarditis is
possible.
 Prophylaxis
 General prophylaxis includes detection and isolation of the
patients and carriers, examination of contact persons.
Disinfection is conducted in the focus, 7-day quarantine is
established.
 Specific prophylaxis. Durable collective immunity is created
by immunization of the whole population starting from 3-
month age with further revaccination.
 In case of epidemics children and persons from group of
risk (medical workers, teachers, salespersons, preschool
institution workers and transport workers) should be
vaccinated annually. During a nonepidemic period children
are vaccinated and revaccinated according to schedule and
children starting from 26 years – every 10 years.
 Direct hemagglutination test is used for the control of the
antitoxic immunity.