Lecture 2. Infectious diseases with tonsillitis. Diphtheria

Lecture 2. Infectious diseases with tonsillitis. Diphtheria

 

Diphtheria is a vaccine-preventable disease. The incidence of diphtheria has decreased dramatically with immunization programs, and is now rare in developed countries like the United States, but with the influx of emigrants from South East Asia, plus a small incompletely or nonimmunised population, clinical diphtheria may not be so rare in the United States in the future. In addition, the cases may be imported from endemic areas.

 

Diphtheria is an acute toxic infection caused by toxigenic strains of Corynebacterium diphtheria, characterized by a local lesion consisting of a membrane. The constitutional symptoms are due to circulation exotoxin, which has a special affinity for nerve tissue, heart muscle and kidneys. 

 

Etiology:  Corynebacterium diphtheria

·        Corynebacterium species are aerobic, no encapsulated, non-sporeforming, mostly no motile, gram-positive bacilli.

·        Sensitive to high temperature and disinfection

·        Stabile to freezing and dryness

·        Three biotypes –

–mitis

–gravis

–intermedius

 

Epidemiology:

Transmission is from person-to-person (from a patient or carrier)

·        through direct contact

·        or airborne respiratory droplets

These materials include discharge from the nose, throat, and lesions on the skin, eyes and even the vagina.

Contagious index – 10-15%

Seasonality – autumn-winter

Immunity – instable

 

Pathogenesis: 

1.     Entrance for the infection: throat, nose, larynx, sex organs, wound.

2.     Dissemination of the Corynebacterium, production of exotoxin.

3.     Local toxin effects with membranous inflammation.

4.     Toxemia.

5.     Diffuse toxic effects on kidneys, suprarenal glands, cardiovascular system, and peripheral nervous system.

 

Fibrinous inflammation

·        Diphtheritic (on flat multilayer epithelium)

·        Crupous (on cylindrical one layer epithelium)

 

Incubation period is short (from one to seven days)

 

Clinical features: diphtheria may be localized, spread, toxic (with edema of subcutaneous tissue), hypertoxic, hemorrhagic.

 

Classification of Diphtheria

Diphtheria of the tonsils and pharynx

·        localized (catarrhal, islet-like, membranous)  

·        spread form     

·        toxic form:

o   I grade  

o   II grade

o   III grade

o   hypertoxic

·        hemorrhagic   form

·        gangrenous form

 

Diphtheria of the pharynx: The clinical onset is generally insidious with low-grade fever, cough, hoarseness, and mild sore throat. Intensity of the body temperature and intoxication increases proportionally to the square of damages (localized, spread, toxic forms). While examining the throat you could see a gray adherent membranous exudates on the tonsils (localized forms), extending to soft palate, cheeks, even tongue (spread form). The exudates bleed when removed. Hyperemia of throat has cyanotic color with edema of mucous membrane.  Regional lymph nodes are enlarged and tenderness appears. In case of toxic forms you could see “bull neck” due to the neck subcutaneous tissue edema which may extend even to the thorax. Hypertoxic form has sudden onset with hard intoxication (nausea, vomiting, seizures, unconsciousness, body temperature is more than 40^o C) which exceeds local symptoms. Hemorrhagic form is characterized by hemorrhages, bleeding, membranous exudates consists blood.

 

Diphtheria of the respiratory tract (laryngeal form, true croup)

·        Localized croup   

·        Spread croup

o   laryngotracheitis

o   laryngotracheobronchitis

·        Stages of croup

o   Catarrhal croup

o   Stenosis

§  Compensated 

§  Subcompensated

§  Decompensated

o   Asphyxia

 

Diphtheria of the upper respiratory tract demonstrates clinical features of croup. It has slow development, intoxication usually is absent because between membranous exudates and mucous membrane of larynx, trachea and bronchi mucous is present. That’s why toxemia is absent. Croup has catarrhal, stenotic stages and asphyxia.

Catarrhal stage: – duration 2-3 days; intoxication is small or moderate; barking cough, voice becomes hoarse; slow development of signs and symptoms/

Stenotic stage: – duration 2 hours – 2-3 days; moderate intoxication; stenotic breathing appears; signs of hypoxia (peripheral, then general cyanosis, tachycardia, anxiety).

Asphyxia: – pallor or grayness of skin; sleepiness; superficial breathing; arrhythmia, hypotonia, hypothermia, other signs of coma, then – death of the patient.

 

n  Diphtheria of the nasopharynx (adenoiditis)

n  Diphtheria of the nose

o   localized

Ø  catarrhal

Ø   islet-like

Ø   membranous

o   Spread

o   toxic

 

Diphtheria of the nose also may be localized, spread and toxic. Signs of it: slow development; minimal toxic signs; it is hard to breathe by nose; purulent and bleed discharges from the nose; maceration of the perinasal area; rhinoscopy reveals gray adherent membranous exudates on the mucous membranes  or ulcers; in case of spread form they extend to additional cavities; in case of toxic form – perinasal edema appears, intoxication enlarges.

 

Rare forms: diphtheria of the eye, ear, sex organs, umbilical wounds, lip, and cheek.

 

In case of 2 or more localizations combined diphtheria is diagnosed.

 

Diphtheria severity

mild	localized	Tonsils (islet-form), nose eye ear skin genital tract
moderate	localized       spread	Tonsils (membranous-form) Nasopharyngeal Localized croup   Tonsils, nose eye ear skin genital tract
severe	Spread   Toxic, hypertoxic	Spread croup   Tonsils , nose eye ear skin genital tract

 

The course of disease

·        With complication

·        Without complication

 

Complications

·        early:

–        toxic shock syndrome;

–       DIC syndrome

–       suprarenal glands insufficiency;

–       Kidneys insufficiency

–       Respiratory insufficiency

–       Plural organs insufficiency

–        (in the end of 1^st to 2^nd week) nephritis; myocarditis; peripheral cranial nerves palsies;

·        Late (on the 3^rd to 7^th week): myocarditis; peripheral spinal nerves palsies.

 

Laboratory tests. Diphtheria can be confirmed with isolation of C.diphtheriae from the pharyngeal membrane, nose (bacterioscopic or bacteriologic method); serologic reactions, fluorescent antibody techniques are available.

·        Used to confirm infection combine isolation of C diphtheria on cultures with toxigenicity testing.

o   Bacteriologic culturing is essential to confirm the diagnosis of diphtheria.

o   Toxigenicity testing: Perform toxigenicity testing using the Elek test to determine if the C. diphtheriae isolate produces toxin.

·        Polymerase chain reaction

·        Serology: PHAR with erythrocyte diagnostic test before the DAT injection to measure the diphtheria toxin level in the blood; AR, PHAR, CBR with specific diagnostic test systems, growth of antibodies title in the dynamics.

·        Complete blood analysis: leucocytosis, neuthrophylosis with a shift to the left, the increased ESR.

·        Urinalysis: proteinuria, leucocyturia, erythrocyturia, casts, (infectiously-toxic damage of kidneys).

·        Biochemical blood test measure of the rest nitrogen, creatinine, urea

·        ECG in dynamics

·        Otolaryngologist, cardiologist, neurologist examination in dynamics, posterior rhioscopy in case of nasopharyngeal diphtheria, laryngoscopy in case of laryngeal diphtheria.

 

Diagnosis example:

Diphtheria of the pharynx, local membranous form, moderate degree.

Diphtheria, combined form: pharyngeal, toxic 1^st grade and laryngeal, local: severe degree

 

Differential diagnose

Diphtheria of the pharynx must be differentiated from scarlet fever, acute bacterial tonsillitis, infectious mononucleosis; diphtheria of the upper respiratory tract – with viral croup caused by parainfluenza, measles, chickenpox, and influenza viruses.

 

Death may occur from

·        Toxemia toward the end of the firth week

·        Cardiac failure from toxic myocarditis (second week of illness)

·        Respiratory failure due to peripheral neuritis affecting the vagus nerve (third to seventh week)

 

Treatment all the patients are hospitalized into infectious or resuscitative department (for severe forms and in case of laryngeal diphtheria)

·        Absolute bed regime (2-3 wks)

·        Diphtheritic antitoxin therapy (etiological)

·        Antibacterial therapy for 10-14 days in moderate or severe cases

§  BENZYLPENICILLIN  Na 50-100 000 IU/kg/day

§  or cefalosporins 100 mg/кg/day

o   In mild cases:

§  Erythromycin 40–50 mg/кg/day  or

§  Roxitromycinum 5-8 mg/kg or

§  Rifampicin 10-15 mg/кg/day

·        Antiseptic fluids locally (in spray or for gurgling)

·        Desensitization (suprastin 1-3 mg/kg daily in 2 doses)

·        Vitamins B-group, C

·        Disintoxication therapy (50-100 ml/kg/day) with glucose, crystalloid and colloid fluids IV in moderate or severe cases

·        In case of severe form corticosteroids therapy by prednisolone  2-3 mg/kg/day, hydrocortisone 5-10 mg/kg/day in moderate form, prednisolone  10-20 mg/kg/day in severe form

 

Prompt treatment with diphtheria antitoxin (DAT) from horse serum is mandatory following tests for hypersensitivity.

 

Clinical form	First dose Thousand IU	Repeated dose Thousand IU	Total dose Thousand IU
Diphtheria of the pharynx        localized           spread              toxic I grade          toxic II grade             toxic III grade   Diphtheria of the larynx         Localized croup            Spread croup      Diphtheria of the nose, eye, skin         Localized Sex     organs, localized  Toxic	10, 20-30 40-50 60-70 80-100 100-120   30-40 40-50   15-20 20-30 50-80	10 20 40 50 70-80   — 20-30   — 10 40	10, 30-40 60-70 100-120 130-180 200-250   30-40 60-80   15-20 30-40 90-100

 

In the mild case all the dose is given for one time IM.

In case of prolongation of intoxication and exudates or their increasing repeated dose should be given in 24 hours.

In the mild case when diagnosis is disputable serum may be given in 8-24 hours in case of positive bacteriological culture.

In the moderate case the repeated dose in 24 hours is used (as in table).

In the severe case the first dose is 2/3 of the total one. The repeated dose in 12 hours is used, or in 8 hours if all the serum was given IV

In case of toxic and hypertoxic forms I dose of DAT must be put intravenously with physiologic saline.

 

In case of toxic shock syndrome:

– Immediately intravenous infusion of DAT with prednisone intravenously 30-50 mg before DAT;

– Prednisone 10-20 mg/kg/day in equal doses 2-4 times per day;

– Detoxication, correction of acid-base balance and electrolytes;

– Dopamine, trental, corglicon.

 

In case of diphtheria of the larynx (except DAT):

– Inhalation of antiedematous drugs (2% NaHCO₃, hydrocortisone, euphyllin, and mucolithics);

–       suctioning of membranes and mucus;

–       inhalation of oxygen;

–       in the III stage of stenosis – intubation;

–       In case of spread croup, combined with diphtheria of pharynx – tracheotomy.

 

Treatment of complications

Myocarditis: –

·        needs bed regimen on 35-50 days;

·        cardiomonitoring;

·        prednisone 2 mg/kg/ day per os;

·        rhiboxin or ATPh,

·        per oral potassium (panangin);

·        diuretics.

Neuritis:

·        proserin,

·        galanthamin,

·        strychnine nitric;

·        vitamins group B (B₁, B₆, B₁₂), C;

·        diuretics.  

 

Discharge of the patient:

·        Clinically healthy;

o   Mild and moderate in 14-21 days;

o   Severe – in 30-60 days.

·        With two documented negative pharyngeal and nasal cultures taken 24 hrs apart after stopping antibacterial treatment

·        Dispensarization no shorter than 6 months (in uncomplicated cases).

 

Treatment of healthy infected by C.diphtheria persons:

–       Erythromycin 40–50 мg/кg/day 

–       Roxitromycinum 5-8 mg/kg

–       Rifampicin 10-15 мg/кg/day

•      Antiseptic fluids locally

•      Vitamins B-group, C

•      Immune modulators in case of chronic site of infection,

•      Tonsillectomy, adenotomy in case of chronic carrying.

 

Prophylaxis

Specific

·        by DTP vaccine from 3 months age 3 times in 30 days interval (3, 4, 5 months), revaccination in 18 months (DTP), 6, 14, 18 years (DT), later – every 10 years.

Nonspecific

·        Close contacts who were previously immunized longer than 5 years before should receive booster dose of diphtheria toxicoid

o   Antibiotic (erythromycin, rifampin) orally for 7 days

·        Revealing, sanation of healthy infected persons,

·        looking after contacts for 10 days,

·        disinfection of epidemic focus.

 

 

Infectious mononucleosis is an acute infectious disease that is caused by the Epstein-Barr virus is characterized by the fever, tonsillitis, increase of lymphatic nodes, hepato– and splenomegaly, by presence of atypical mononuclear cells in a peripheral blood and heterophyl antibodies.

 

Etiology: an EBV, belong to Herpes viruses, type IV

 

Epidemiology:

·        Source of infection are patients with symptomatic and asymptomatic forms, EBV-carriers

·        Mechanism of transmission is droplet, rarer is contact. The virus is transmitted primarily through saliva during speaking, breathing, coughing, especially during kisses, hand-to-hand contacts.

·        The transmission of EBV through blood product transfusions has been well documented.

·        Susceptibility – any age, disease is low contagious, more frequent up to 15 years, in boys

 

Pathogenesis:

1.     Inoculation of the virus into upper respiratory tract mucous membranes.

2.     Diffusion by lymph to the lymph nodes, spleen, liver.

3.     Lymphoprolipherative syndrome.

4.     Bacterial complications.

5.     Persistence of the virus (even 16 months or more).

 

Clinical criterion

·        Incubation period 10-15 days (may be longer-2 month).

·        Beginning is acute from fever, intoxication (headache, myalgia, arthralgias, malaise).

·        Fever usually febrile from 3 days till 3 weeks

·        Tonsilopharyngitis, which may be exudative (follicular, lacunar) in case of secondary bacterial infection , lymphoid follicles hyperplasia (on the back pharyngeal wall).

·        Adenoiditis, posterior rhinitis (appearance of the patient is typical – breathing with open mouth, absence of nasal discharge, usually snore is present).

·        Generalized lymphadenopathy with previous enlargement of cervical and occipital lymph nodes .

·        Hepatosplenomegaly is the sign of lymphoproliferative syndrome .

·        Maculopapular rashes , wich may confluence with erythema development , sometimes hemorrhagic elements with later skin pigmentation  may occur as a sign of hypersensitivity in case of amoxicillin, ampicillin treatment (in 70-80%).  In the young childhood patient in 25% of cases “spontaneous” rashes can develop.

·        Other signs: hepatitis (jaundice form of infectious mononucleosis);

·        toxic myocarditis

·        diarrhea.

 

Classification     

         Form:         – typical                                           

                            – atypical:   – effaced (mild)              

                                               – asymptomatic (subclinical) mild

                                               – visceral – severe (heart, kidneys, adrenal glands, CNS damage)

         Severity (for typical forms):     – mild

                                               – moderate

                                               – severe

         Duration    –    smooth (uncomplicated)

–         complicated

–         prolonged

 

Infectious mononucleosis Severity Criteria

 

Sign	Mild	Moderate	Severe
Toxic syndrome	absent, mild	Moderate	Expressed
Body t°	Up to 38 °С	38,5-39 °С	More than 40 °С
Lymph nodes damage	mild, cervical predominantly	marked, cervical especially, visible	conglomerates, neck disfiguration, neck subcutaneous tissue swelling
Nasal breathing	Some labored	Labored, “snoring” in sleep	Absent, snoring, opened mouth, puffy face
Throat damage	Catarrhal tonsillitis	tonsils hyperplasia  1st-2nd degree, considerable exudates	tonsils hyperplasia  3rd  degree, large membranous exudates
Hepato–  splenomegaly (outcome from the rib arch)	Up to 2-3 сm	3-4 сm	4-5 сm and more, jaundice
Atypical mononuclear cells number	Up to 30 %	20-50 %	More than 50 %
Cough	Rare	Often	Often
Rashes	Rare	Often	Hemorrhagic in 1/3, nasal bleeding
Dyspepsia	Rare	Present abdominal pain, vomiting	abdominal pain, several vomiting
Heart changes “toxic-infectious heart”	Not typical	Rare	Often

 

Peculiarities of infectious mononucleosis in infants:

·        often catarrhal syndrome is present (cough, sneezing, corryza);

·        expressed polyadenia, snore, edematous face from the first day of the disease;

·        early development of bacterial tonsillitis (on the third day);

·        rashes are more often;

·        dyspepsia;

·        in the peripheral blood – neutrophyllosis with left shift;

·        favorable duration.

 

Complications, which may occur (rare):  

1.     Respiratory tract – pneumonia, airway obstructions.

2.     Neurological – seizures, meningitis, encephalitis, peripheral facial nerve paralysis, Gillian – Barrette syndrome. 

3.     Hematological – thrombocytopenia, hemolytic anemia.

4.     Infectious – recurrent tonsilopharyngitis.

5.     Renal – glomerulonephritis.

6.     Genital – orchitis.

7.     Spleen rupture (is lethal).

 

Laboratory findings

1.     Blood analyses: leucocytosis, even 15-30,000/mm3, lymphocytosis, monocytosis, appearing of atypical mononuclear cells (virocytes) more than 10%, ESR enlarges to 20-30mm/hour.

2.     Heterophil agglutination test (is positive in 25-95% of preschool children, 53-94 young school children, and nearly 100% of older children).

3.     Immune-enzyme method – VCA Ig M, EA Ig M presence in the blood.

4.     PCR (measuring of EBV nucleinic acid in the blood, saliva, lymphatic tissues).

 

Diagnosis example:

Infectious mononucleosis, typical form, moderate severity, complicated by the bilateral  bronchopneumonia  

 

Differential diagnosis should be performed with ‘mononucleosis like’ syndrome caused of AIDS. Another disease, which has similar features: diphtheria, adenoviral infection, acute leukemia, lymphogranulomathosis, viral hepatitis etc.

 

 

Treatment

1.     Reduction of activity and bed rest.

2.     special diet (diet N 5),

·        Exclude heavy fats (like pork), spices, fried foods, “fast food””; avoid stimulators of gastrointestinal secretions, the diet must be rich by metionine, lecithin, and choline to stimulate synthesis of proteins and enzymes in the liver. Diet with normal value of proteins and vitamins, with restriction of fats and carbohydrates is administered, also restrict salt.

·        Foods boiled, steamed and baked are recommended; food taking 5 times daily

3.     Control of fever and myalgia (when the temperature is more than 38.5-39˚C); in children before 2 mo and in case of perinatal CNS damage, seizures in the history, severe heart diseases – when the temperature is up to 38˚C with acetaminophen (paracetamol 10-15 mg/kg not often than every 4 hours (not more than 5 times per day) or ibuprophen 10 mg/kg per dose, not often than every 6 hours. Aspirin is contraindicated for children before 12 years.

4.     Antihistamines (in average doses) – pipolphen, suprastin, claritin, cetirizin.

5.     Corticosteroids – in severe cases 1-2 mg/kg/day prednisone for 3-5 days.

6.     In case of secondary bacterial complications macrolides (erythromycin 30-50 mg/kg/day, azythromycin 10 mg/kg/day, clarythromycin) or cefalosporins (cefalexin 50 mg/kg/day, cefuroxim 50 mg/kg/day, cephasolin 100 mg/kg/day), Ampicillin and other semisynthetic penicillins are contraindicated!

The administration of oral acyclovir does not significantly alter the course of clinical illness from placebo.

 

Prophylaxis: is nonspecific, includes disinfecting;

·        Isolation of the patient, hospitalization of children younger 1 year, in case of severe forms.

·        A quarantine is not imposed

 

 

Literature

1.           Manual of children’s infectious diseases / O. Ye. Fedortsiv, I. L. Horishna, I. M. Horishniy. – TERNOPІL : UKRMEDKNYHA, 2010. – 382 p. – ISBN 978-966-673-145-9

2.           Manual of Childhood Infections: The Blue Book (Oxford Specialist Handbooks in Paediatrics) by Mike Sharland, Andrew Cant and al. Published by  Oxford University Press Inc., New York, 2011 , p. 881  ISBN: 978-019-957-358-5.

3.           Illustrated Textbook of Paediatrics, 4th Edition.  Published by  Lissauer & Clayden, 2012, p. 552 ISBN: 978-072-343-566-2.

4.            Nelson Textbook of Pediatrics, 19th Edition Kliegman, Behrman. Published by Jenson & Stanton, 2011, 2608.  ISBN: 978-080-892-420-3.

5.             Oxford Textbook of Medicine: Infection by David Warrell, Timothy M. Cox, John Firth and Mili Estee Torok , Published by Wiley-Blackwell, 2012

 

Material has been prepared by Associate Professor I. L. Horishna, MD, PhD

Assistant V. B. Furdela, MD, PhD