Infectious mononucleosis

Herpetic infections. Infectious mononucleosis (Epstein-Barr infection). Diphtheria.

http://www.who.int/bulletin/volumes/86/10/07-046128/en/

Herpes simplex virus (HSV) infections are among the most common maladies affecting humans. Often they are annoying and troublesome; occasionally they are life-threatening.

The term herpes is derived from the Greek word meaning to creep, and clinical descriptions of herpes labialis go back to the time of Hippocrates. Astruc, physician to the king of France, is credited with the first description of genital herpes in 1736. Between 1910 and 1920, the infectious nature of herpes lesions was demonstrated by producing corneal lesions in rabbits with material derived from herpes keratitis and labialis. As techniques for isolating and characterizing the virus became more simplified and serologic procedures were developed, our understanding of the HSV clinical spectrum has greatly expanded. Studies during the past two decades have brought insights into the molecular biology of HSV. the mechanisms of HSV latency and recurrence, and the first successful approaches to therapy for certain types of HSV infections.

Etiology

Herpes simplex virus (herpesvirus hominis) shares many properties with other members of the herpesvirus groups, which in humans includes varicella-zoster, cytomegalovirus, Epstein-Barr virus, and human herpesviruses type 6 and 7. The members of this group have an internal core containing double-stranded DNA, an icosahedral capsid with 162 hollow capsomeres, and a lipid-containing laminated membrane or envelope (Fig.1).

http://www.cdc.gov/std/Herpes/default.htm

http://www.bioscience.org/u37153137/gaDTRQo7632rgysaGWQYT64356/2002/v7/d/taylor/taylor.pdf

The overall diameters of enveloped herpesviruses are 150-200 nm. Replication occurs primarily within the cell nucleus and is completed by the addition of protein envelopes as the virus passes through the nuclear membrane. Complete virus replication is associated with lysis of the productive cell. All members of the human herpesvirus group can also establish latent states within certain types of cells they infect, although the physical nature of the viruses during periods of latency is unclear.

Fig.1. Herpes simplex virus

 

The development of monoclonal antibody and restriction enzyme technologies have permitted an even finer definition of variations among individual HSV isolates. It is now clear that HSV-1 and HSV-2 share certain glycoprotein antigens and differ with respect to others. Serologic differentiation between HSV-1 and HSV-2 infections can be readily made by detection of type-specific gG antibodies.

 

Epidemiology

Herpes simplex viruses have a worldwide distribution. There are no known animal vectors for HSV, and although experimental animals can easily be infected, humans appear to be the only natural reservoir. Direct contact, with transmission through infected secretions, is the principal mode of spread. HSV-1 is transmitted primarily by contact with oral secretions and HSV-2 by contact with genital secretions. Transmission can occur both from overtly infected persons and from asymptomatic excretors, although virus titers are higher in persons with active lesions and thus transmissability may be greater. Approximately 15 % of the adults may be excreting HSV-1 or HSV-2 at any given time depending on the population studied. For example, because shedding of HSV-2 is related to sexual activity, prostitutes may have unusually high rates of excretion.

The risk of heterosexual acquisition of HSV is greater in women than men, and previous HSV-1 infection reduces the risk of subsequent HSV-2 infection.

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Pathogenesis

On entry into skin sites HSV replicates locally in parabasal and intermediate epithelial cells, which results in the lysis of infected cells and the instigation of a local inflammatory response. This feries of events results in the characteristic lesion of superficial HSV infection, that is, a thin-walled vesicle on an inflammatory base. Multinucleated cells are formed with ballooning degeneration, marked edema. Such lesions are indistinguishable from those caused by varicella-zoster virus. Lymphatics and regional lymph nodes draining the site of primary infection become involved. Further virus replication may result in viremia and visceral dissemination, depending on the immune competence of the host.

In murine models the maturity of macrophages at the site of local infection helps determine whether virus remains localized or disseminates. Subsequently, other host defense mechanisms, for example, the production of interferons, natural killer cells, protective antibodies, and sensitized killer lymphocytes, are elicited to prevent the spread of infection.

http://emedicine.medscape.com/article/964866-clinical#showall

Clinical manifestations

Primary HSV-1 infection is frequently asymptomatic but may present as gingivostomatitis and pharyngitis most commonly in children under the age of 5 years but occasionally in older persons. Incubation periods range from 2 to 12 days and are followed by fever and sore throat with pharyngeal edema and erythema. Shortly after its onset, small vesicles develop (Fig.2) on the pharyngeal and oral mucosa: these rapidly ulcerate and increase iumber, often involving the soft palate, buccal mucosa, tongue, and floor of the mouth. Gums are tender and bleed easily, and lesions may extend to the lips and cheeks (Fig.3).

Fig.2. Vesicles in case of herpetic infection

Fig.3. Herpetic infection of gums

Fever and toxicity may persist for many days, and the patient complains of severe mouth pain. Breath is fetid, and cervical adenopathy is present. In children, dehydration may result from poor intake, drooling, and fever. In college-aged persons, primary HSV infection often presents as a posterior pharyngitis or tonsilitis. Included in the age-related differential diagnosis are streptococcal or diphtheritic pharyngitis, herpangina. aphthous stomatitis. Stevens-Johnson syndrome, Vincent’s infection, and infectious mononucleosis.

Herpes simplex virus infections of the eye are usually caused by HSV-1 (Fig. 4).

Fig.4. Herpetic infection of eye

Primary infections may be manifested by a unilateral follicular conjunctivitis with regional adenopathy and/or a blepharitis with vesicles on the lid margin. Photophobia, chemosis, excessive tearing, and edema of the eyelids may be present. Some patients develop dendritic figures or coarse, punctate, epithelial opacities. If disease is limited to the conjunctiva, healing takes place within 2-3 weeks. However, if systemic symptoms and signs of stromal involvement are present, the healing phase may be delayed. Spontaneous healing of the conjunctiva and cornea is usually complete.

Primary genital infection is most common in adolescents and in young adults and is usually (in 70-95 % of the cases) caused by HSV-2 (Fig.5).

Fig.5. Herpes genital infection

The duration of incubation periods 2-7 days. In men, vesicular lesions on an erythematous base usually appear on the glans penis or the penile shaft. In the female, lesions may involve the vulva, perineum, buttocks, cervix, and vagina and are frequently accompanied by a vaginal discharge). Extra-genital lesions occur during the course of primary infection in 10-20 % of patients. Primary infection in both sexes may be associated with fever, malaise, anorexia, and tender bilateral inguinal adenopathy. Although vesicular lesions may persist for several days in men, in women they rapidly ulcerate and become covered by a grayish-white exudate. Such lesions may be exquisitely tender, and urethral involvement may result in dysuria or urinary retention. Herpetic sacral radiculomyelitis accompanying genital infection may also lead to urinary retention, neuralgias, and obstipation; in such patients a loss of anal tone, diminished bulbocavernosus reflex, and cystometrographic evidence of lower motor neuron dysfunction can sometimes be demonstrated. Lesions of primary genital herpes may persist for several weeks before healing is complete. Previous HSV-1 infection may reduce the severity and duration of a first episode of genital herpes caused by HSV-2. In the diagnosis of genital herpes other sexually transmitted infections such as chancroid or syphilis, erosions secondary to excoriation, genital manifestations of Behcet syndrome or erythema multiforme, and local candidiasis must all be distinguished.

Although primary infections are usually in perioral, ocular. or genital areas, any skin site may be initially involved. Primary HSV skin infections may be extensive and mimic herpes zoster. Although a dermatomal distribution is not usually maintained and the pain is less severe.

Primary perianal and anal HSV-2 infection is becoming increasingly well recognized, both in women and in male homosexuals. Pain is the primary symptom, with itching, tenesmus, and discharge also noted. Systemic complaints of fever, chills, malaise, headache, difficulty in urinating, and sacral paresthesias may be present. On examination, vesicles and ulcerations may be seen in perianal and sometimes in anal areas. They may become confluent and result in a grayish ulcerating cryptitis surrounded by a red edematous mucosa. Bilateral inguinal adenopathy is common. The course is generally self-limited unless bacterial infection supervenes, with healing occurring in 1-3 weeks. However, in the setting of the acquired immunodeficiency syndrome (AIDS), herpes proctitis as well as other cutaneous manifestations of HSV infection may be prolonged and progressive.

Recurrent infections

Recurrent herpes labialis is frequently heralded by prodromal symptoms (pain, burning, tingling, or itching) generally lasting for less than 6 hours but occasionally as long as 24-48 hours. Vesicles appear most commonly at the vermillion border of the outer lip and are associated with considerable pain. The lower lip is more frequently involved, although individual patients may have stereotyped lesions at similar sites during each recurrence. The lesion area is usually less than 100 mm, and lesions progress from the vesicle to the ulcer/crust stage within 48 hours. Pain is most severe within the first 24 hours after the appearance of lesions. Healing is generally complete within 8-10 days. Rarely, recurrences may occur in the mouth or on the nose, chin, or cheek. Systemic complaints do not usually accompany recurrent herpes labialis, although local adenopathy may occur.

Ocular infection may recur as keratitis, blepharitis, or kerato-conjunctivitis. Recurrent keratitis is usually unilateral but is rarely (in 2-6 % of the cases) bilateral. Two main types of keratitis may develop: dendritic ulceration or stromal involvement. Branching dendritic ulcers that strain with fluorescein are virtually diagnostic and are often accompanied by a loss in corneal sensation. Visual acuity may be decreased because the ulcers frequently involve the pupillary portion of the cornea. They may be accompanied by minimal anterior opacification or deep stroma involvement. Occasionally, extensive ameboid corneal ulcers may evolve, particularly if topical steroids have been applied. Superficial keratitis usually heals, but recurrent infection may lead to deep stromal involvement and uveitis, which may in part be mediated by hypersensitivity reactions to viral or altered cellular antigens. A gradual diminution in visual acuity takes place, and individual attacks may last for several months with the formation of dense scars, corneal thinning, and neovascularization. Permanent visual loss may result, and rarely, rupture of the globe develops.

Recurrent genital lesions in both sexes are generally associated with less severe systemic symptoms and less extensive local involvement than are primary attacks. A prodrome of tenderness, itching, burning or tingling is ofteoted for several hours before a recurrence. Lesions in women are most ofteoted on the labia minora, labia majora, and perineum and less commonly on the mons pubis or buttocks. Lesions in men are most often found on the glans or penile shaft. In women recurrences tend to be more severe. Healing generally occurs in 6-10 days. Virus shedding diminishes more slowly in women and can occur between recurrences in both sexes. Occasionally, genital recurrences are associated with headache and even with aseptic meningitis. Urethral stricture and labial fusion have also been reported after recurrent genital infections.

Recurrent HSV-1 or HSV-2 infections may develop on extremities; occasionally such lesions are associated with severe local neuralgia. Local edema and lymphangitis may also occur during recurrences on extremities.

Varicella-zoster virus (VZV) is the agent causing varicella, otherwise known as chickenpox, the common childhood infection. Following resolution of chickenpox, VZV lies dormant in the spinal dorsal root ganglia until a decrease in cellular immunity triggers the reactivation of the virus, resulting in herpes zoster, otherwise known as shingles.

Shingles is a syndrome characterized by a painful, vesicular rash that is usually restricted to a unilateral dermatomal distribution. At times, especially in the immunosuppressed patient, the infection may spread and produce severe systemic illness, with involvement of multiple visceral organs and multiple dermatomes (disseminated zoster). The shingles-associated rash is seen in the images below. (See Etiology and Pathophysiology.)

Herpes zoster on the neck.

 Herpes zoster on the lateral part of the abdomen.

Shingles usually has a benign course, but complications may occur, ranging from mild to life threatening. In properly selected patients, early treatment with antivirals and corticosteroids has been shown to decrease the duration of symptoms and to possibly prevent or ameliorate some complications. (See Pathophysiology and Treatment and Management.)

The clinical manifestations of herpes zoster can be divided into the preeruptive phase (preherpetic neuralgia), acute eruptive phase, and chronic phase (postherpetic neuralgia).

Preeruptive phase

This phase is characterized by unusual skin sensations or pain within the affected dermatome that heralds the onset of lesions by 48-72 hours.

During this time, patients may also experience other symptoms, such as malaise, myalgia, headache, photophobia, and, uncommonly, fever.

Acute eruptive phase

This phase is marked by the emergence of vesicular eruptions. As in the preeruptive phase, patients may also experience such symptoms as malaise, myalgia, headache, and fever. Lesions begin as erythematous macules and papules (seen in the image below) that quickly develop into vesicles. New lesions tend to form over a period of 3-5 days, sometimes coalescing to form bullae.

Maculopapular rash due to herpes zoster in a child with a history of leukemia. Courtesy of the CDC.

After they form vesicles, lesions progress through stages in which they rupture, release their contents, ulcerate, and finally crust over and become dry.

Almost all adult patients experience pain (ie, acute neuritis) during the eruptive phase. A few experience severe pain without any evidence of a vesicular eruption (ie, zoster sine herpete), and a small number of patients have a characteristic eruption but do not experience pain.

Symptoms and lesions in the eruptive phase tend to resolve over 10-15 days. However, lesions may require up to a month to completely heal, and the associated pain may become chronic.

Patients are infectious until the lesions have dried. Anyone who has not previously had varicella is at risk of acquiring this readily transmitted virus. Pregnant women and immunosuppressed patients have the highest risk of serious sequelae.

Chronic phase (postherpetic neuralgia)

Postherpetic neuralgia is persistent or recurring pain lasting 30 or more days after the acute infection or after all lesions have crusted. It is the most frequent complication of herpes zoster, observed in 9-45% of all cases of zoster.

Most people report a deep burning or aching pain, paresthesia, dysesthesia, hyperesthesia, or electric shock–like pains. The pain can be severe and incapacitating.

Resolution of the pain may require an extended period of time. Pain lasting longer than 12 months has been described iearly 50% of patients older than 70 years.

The prevalence of postherpetic neuralgia in herpes zoster cases increases with age, with a 14.7-fold higher prevalence in patients older than 50 years compared with their younger counterparts.

Complications

Herpes simplex encephalitis is a rare complication of herpetic infection and yet is one of the most common acute sporadic viral diseases of the brain. Although little is known about the pathogenesis of HSV-1 encephalitis in humans, the virus is believed to spread by neural routes into the brain during either primary or recurrent infection. Temporal lobes are the principal target areas of the virus, and a necrotizing hemorrhagic encephalitis results.

Herpes simplex encephalitis occurs at all ages in both sexes, and in all seasons. The clinical course may begin suddenly or after a brief influenzalike prodrome. Headache, fever, behavioral disorders, speech difficulties, and focal seizures are prominent features; olfactory hallucinations may be present. Cerebro-spinal fluid examination is variable but frequently shows a moderate pleocytosis with mononuclear and polymorphonu-clear leukocytes: protein levels are slightly elevated, and glucose is generally normal. Infectious virus is rarely present in cerebrospinal fluid during encephalitis, and brain biopsy with appropriate histologic and cultural techniques is currently the most reliable way to make the diagnosis. Although various antibody and antigen assays may provide adjunctive information. they are not sensitive enough to provide a sufficiently early diagnosis. Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid has been reported by certain research laboratories. Herpes simplex virus encephalitis must be distinguished from other forms of viral encephalitis, tuberculous and fungal meningitis, brain abscesses, cerebrovascular accidents, and brain tumors.

The course in untreated patients is usually one of rapid deterioration over several days that progresses to coma and death. Mortality in untreated biopsy-proven cases is 60-80 %, and fewer than 10 % of the patients are left without significant neurologic sequelae.

 

Relationship to Other Diseases

Erythema Multiforme. Allergic cutaneous and mucous membrane disorders may accompany or follow acute HSV infections. Up to 75 % of all cases of erythema multiforme are regularly preceded by an attack of herpes simplex. Both HSV-1 and HSV-2 may be involved, and the cutaneous manifestations range from mild to severe (Stevens-Johnson syndrome) and may be recurrent. Inactivated HSV antigens injected intra-dermally into persons subject to erythema multiforme have induced such attacks, and HSV antigen has been identified in skin biopsy specimens from affected lesions.

Cancer. Although HSV has been suspected as a cause of cervical and other cancers on the basis of both epidemiologic and laboratory studies, many recent studies do not support its etiologic role in human cancers.

Idiopathic Neurologic Syndromes. Herpes simplex virus infections have been implicated as possible factors involved in the pathogenesis of various neurologic disorders of unknown etiology, including idiopathic facial paralysis (Bell’s palsy), multiple sclerosis, atypical pain syndromes, ascending myelitis, trigeminal neuralgia, Mollaret’s meningitis, and temporal lobe epilepsy. The associations are based on the known predilection of HSV for nerve tissue, on serologic or nucleic acid studies, and on the occasional observations of temporal relationships between attacks of herpes labialis or genitalis and attacks of the neurologic syndrome.

http://emedicine.medscape.com/article/218683-differential

Diagnosis

Although experimental animals and embryonated eggs are susceptible to infection with HSV strains, tissue cultures have largely replaced these hosts for diagnostic purposes. Primary human embryonic kidney, rabbit kidney, and human amnion cells readily support the replication of HSV. Continuous cell strains or cell lines of human diploid origin and certain continuous monkey kidney cell lines also support HSV replication, but to a lesser extent. Cytopathic effects usually appear rapidly, within 24-48 hours if the virus inoculum is high. Cells become rounded and clump, with rapid progression of cytopathic effects throughout the cell monolayer. Ballooning degeneration and the formation of multinucleated syncytial giant cells may be observed, particularly with HSV-2 isolates. Vesicles contain their highest tilers of virus within the first 24-48 hours, and specimens should be collected early and promptly inoculated into tissue cultures. If a delay is unavoidable, specimens can be stored in appropriate carrying medium at 4-9°C for a few hours. but for longer periods they should be stored at -70°C. Typing of isolates can be accomplished by using a variety of serologic techniques including immunohistochemistry or microneutralization. When tissue specimens such as neural ganglia are being studied for the presence of virus, tissue explanation or cell cocultivation techniques have proved useful in facilitating virus isolation.

The recent development of monoclonal antibodies to individual herpes virus antigens should allow for the more precise identification and typing of HSV isolates. HSV-1 and HSV-2 have both type-specific and cross-reactive antigens that are useful for both grouping and type discrimination. Moreover the cloning of herpes DNA fragments in recombinant bacteria may permit the production of probes to identify herpes genomes in the absence of infectious virus.

For a rapid diagnosis of skin or mucous membrane lesions, scrapings from suspect lesions may be smeared, fixed with ethanol or methanol and stained with Giemsa or Wright preparation. The presence of multinucleated giant cells indicates infection with HSV or varicella-zoster virus. When using cytologic techniques, the Papanicolaou cervicovaginal stain or the Paragon multiple stain, intranuclear inclusions may also be seen. Alternatively, such material can be examined for herpes antigens by immunohistochemical techniques or by in situ DNA hybridization.

Serologic techniques may be helpful in diagnosing primary HSV infections but are rarely of value in recurrent infections. A variety of assays have been used including neutralization, complement fixation, passive hemagglutination, indirect immunofluorescence, radioimmunoassay, enzyme immunoassays, complement-mediated cytolysis, and antibody-dependent cellular cytolysis. During primary infections, a fourfold or greater rise in titer is observed between acute and convalescent sera. In recurrent infections such rises may or may not be observed. Many licensed enzyme immunoassays appear to give inaccurate information concerning HSV-infecting subtypes.

Measurement of IgM HSV antibodies in infants may be helpful in the diagnosis of neonatal infection. Such antibodies usually appear within the first 4 weeks of life in infected infants and persist for many months. Measurement of IgM antibodies in older persons has not proved useful in separating primary from recurrent infections.

Approaches to detect specific HSV antigens, antibodies, or DNA in cerebrospinal fluid are under development. Such techniques may circumvent the need for invasive procedures such as brain biopsy to make the diagnosis of herpes encephalitis.

Treatment

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A number of nucleoside derivatives interfere with the synthesis of HSV DNA. Some of these (trifluorothymidine, vidarabine) are useful in and licensed for the topical treatment of herpes keratitis. Vidarabine and acyclovir are also useful for systemic HSV infections. None of these agents affects latent virus.

In the immunocompromised host, acyclovir is useful as both treatment and suppression of recurrent mucocutaneous HSV lesions. For the treatment of acute episodes, virus shedding, local symptoms, and time to healing can be reduced by intravenous or oral regimens (400 mg five times per day). Acyclovir is also useful in the prevention of herpetic recurrences in immunocompromised hosts including transplant recipients, leukemics undergoing induction chemotherapy, and patients with AIDS. Regimens of 200-400 mg two to five times per day have been satisfactory in preventing recurrences among seropositive patients.

Parenteral acyclovir is indicated for disseminated or central nervous system HSV infections. In patients with biopsy-proven HSV encephalitis, acyclovir was compared with vidarabine and found to be superior in reducing mortality. Doses of 10 mg/kg every 8 hours for 14-21 daysare recommended. In newborns with disseminated HSV infections, acyclovir and vidarabine appear equivalent but because of ease of administration, acyclovir is recommended.

Acyclovir has little acute toxicity. Drug-related neurotoxicity (disorientation, hallucinations, tremors, ataxia, and seizures) has been described rarely, and reversible renal dysfunction may occur, particularly following a rapid bolus infusion.

http://emedicine.medscape.com/article/218683-treatment#aw2aab6b6c10

Prophylaxis

Experimental vaccines against HSV have shown promise in animal models, and some are undergoing human trials. Limited trials in humans, however, have been unsuccessful, and it is unlikely that a human HSV vaccine will be generally available in the near future.

The prevention of neonatal disease in the offspring of mothers with genital infection presents special problems.

 

Infectious mononucleosis

 

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http://www.cdc.gov/ncidod/diseases/ebv.htm

Infectious mononucleosis (also known in North America as mono, the kissing disease, or Pfeiffer’s disease, and more commonly known as glandular fever in other English-speaking countries) is a disease seen most commonly in adolescents and young adults, characterized by fever, sore throat, leg and muscle soreness and fatigue (symptoms of a common cold or allergies). White patches on the tonsils or in the back of the throat may also be seen (resembling strep throat). Mononucleosis is caused by the Epstein-Barr virus (EBV), which infects B-cells (B-lymphocytes), producing a reactive lymphocytosis and atypical T-cells (T-lymphocytes) known as Downey bodies (Fig. 6).

Fig.6. Atypical mononuclears

The disease is so-named because the count of mononuclear leukocytes (white blood cells with a one-lobed nucleus) rises significantly. There are two main types of mononuclear leukocytes: monocytes and lymphocytes. They normally account for about 35% of all white blood cells. With infectious mononucleosis, it can become 50-70%. Also, the total white blood count may increase to 10000-20000 per cubic millimeter.

Epidemiology

The sources of infection are sick individuals and virus carriers. Morbidity has sporadic nature. Contagiousness is not high.

The virus is typically transmitted from asymptomatic individuals through blood or saliva (hence “the kissing disease”), or by sharing a drink, sharing eating utensils, or being in proximity of an infected person who is coughing or sneezing. The disease is far less contagious than is commonly thought. However, in rare cases a person may have a high tolerance to infection.

Pathogenesis

EBV has tropism to lymphoid and reticular tissues. That is why lymph nodes, liver, spleen, kidneys, bone marrow are affected. Infectious mononucleosis also is considered to be a disease of immune system. The virus can persist  in B-cells. It does not destroy them, but it stimulates their proliferation. Fixation of the virus on the B-cell membranes causes activation of circulating antibodies to a superficial antigen. The main way of destoing the EBV infected cells is producing specific cytotoxic T-killer cells.

Stages

·          Penetration (hyperemia and edema of mucous membranes)

·          Lymphogenous drift in regional lymph nodes

·         Virusemia with dispersion of the originator and systemic reacting of lymph tissue

·         Infectious-allergic

·         Convalescence with development of immunodefence

 

Clinical manifestations

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A person can be infected with the virus for weeks or months before any symptoms appear. Symptoms usually appear 4-7 weeks after infection, and may resemble strep throat or other bacterial or viral respiratory infections. These first signs of the disease are commonly confused with cold and flu symptoms. The typical symptoms and signs of mononucleosis are:

·         Fever – this varies from mild to severe, but is seen iearly all cases.

·         Enlarged and tender lymph nodes – particularly the posterior cervical lymph nodes, on both sides of the neck.

·         Sore throat – seen iearly all patients with EBV-mononucleosis.

·         Fatigue (sometimes extreme fatigue).

o        White patches on the tonsils/back of the neck are often seen (indicating infection) (Fig. 7).

o       

Fig.7. Mononucleosis tonsillitis

 

Some patients also display:

• Enlarged spleen (splenomegaly, which may lead to rupture) or liver (hepatomegaly)
• Abdominal pain
• Aching muscles
• Headache
• Loss of appetite
• Jaundice
• Depression
• Weakness
• Skin rash
• Dizziness or disorientation
• Supra-orbital edema (the eyes become puffy and swollen) may occur in the early stages of infection

After an initial prodrome of 1-2 weeks, the fatigue of infectious mononucleosis often lasts from 1-2 months. The virus can remain dormant in the B cells indefinitely after symptoms have disappeared, and resurface at a later date. Many people exposed to the Epstein-Barr virus do not show symptoms of the disease, but carry the virus and can transmit it to others. This is especially true in children, in whom infection seldom causes more than a very mild illness which often goes undiagnosed. This feature, along with mono’s long (4 to 6 week) incubation period, makes epidemiological control of the disease impractical. About 6 % of people who have had infectious mononucleosis will relapse.

Mononucleosis can cause the spleen to swell, which in rare cases may lead to a ruptured spleen. Rupture may occur without trauma, but impact to the spleen is usually a factor. Other complications include hepatitis (inflammation of the liver) causing elevation of serum bilirubin (in approximately 40% of patients), jaundice (approximately 5% of cases), and anemia (a deficiency of red blood cells). In rare cases, death may result from severe hepatitis or splenic rupture.

Reports of splenomegaly in infectious mononucleosis suggest variable prevalence rates of 25 % to 75 %. Among pediatric patients, a splenomegaly rate of 50 % is expected, with a rate of 60 % reported in one case series. Although splenic rupture is a rare complication of infectious mononucleosis, it is the basis of advice to avoid contact sports for 4-6 weeks after diagnosis.

Usually, the longer the infected person experiences the symptoms the more the infection weakens the person’s immune system and the longer he/she will need to recover. Cyclical reactivation of the virus, although rare in healthy people, is often a sign of immunological abnormalities in the small subset of organic disease patients in which the virus is active or reactivated.

Although the great majority of cases of mononucleosis are caused by the E.B. virus, cytomegalovirus can produce a similar illness, usually with less throat pain. Due to the presence of the atypical lymphocytes on the blood smear in both conditions, most clinicians include both infections under the diagnosis of “mononucleosis”. Symptoms similar to those of mononucleosis can be caused by adenovirus and the protozoan Toxoplasma gondii.

 

Atypical presentations of mononucleosis/EBV infection

In small children, the course of the disease is frequently asymptomatic. The course of the disease can also be chronic. Some patients suffer fever, tiredness, lassitude (abnormal fatigue), depression, lethargy, and chronic lymph node swelling, for months or years. This variant of mononucleosis has been referred to as chronic EBV syndrome or chronic fatigue syndrome, although the most recent medical studies have discounted the link between chronic EBV infection and chronic fatigue syndrome (CFS). In case of a weakening of the immune system, a reactivation of the Epstein-Barr Virus is possible, though the course of the resultant disease is usually milder.

Although studies conducted by the CDC and others have discounted a link between EBV and CFS, this flies in the face of decades of anecdotal reports given to physicians by patients complaining of fatigue years after a bout of mono. This confusion seems to lie in the nature of the link. Current studies have verified and confirmed that in fact there is a link between infectious mononucleosis and CFS. Chronic fatigue states appear to occur in 10 % of those who contract mononucleosis. This would make chronic fatigue a rather common side effect of infectious mononucleosis.

A chronic post infectious fatigue state appears not be caused by a chronic viral infection, but be triggered by the acute infection. Mononucleosis appears to cause a hit and run “injury” to the brain in the early stages of of the acute phase, thereby causing the chronic fatigue state. This also explains why in mononucleosis, fatigue very often lingers for months after the Epstein-Barr Virus has been controlled by the immune system. Just how infectious mononucleosis changes the brain and causes fatigue in certain individuals remains to be elucidated.

Laboratory tests

The laboratory hallmark of the disease is the presence of so-called atypical lymphocytes (a type of mononuclear cell, see image) on the peripheral blood smear. In addition, the overall white blood cell count is almost invariably increased, particularly the number of lymphocytes.

Mononucleosis causes so-called heterophile antibodies, which cause agglutination (sticking together) of non-human red blood cells, to appear in the patient’s blood. The monospot is a non-specific test that screens for mono by looking for these antibodies. Confirmation of the exact etiology can be obtained through tests to detect specific antibodies to the causative viruses. The spot test may be negative in the first week, so negative tests are often repeated at a later date. Since the spot test is usually negative in children less than 6-8 years old, an EBV serology test should be done on them if mononucleosis is suspected. An older test for heterophile antibodies is the Paul Bunnell test, in which the patient’s serum is mixed with sheep red blood cells and checked for agglutination of these cells.

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Treatment

Infectious mononucleosis is generally self-limiting and only symptomatic and/or supportive treatments are used. Rest is recommended during the acute phase of the infection, but activity should be resumed once acute symptoms have resolved. Nevertheless heavy physical activity and contact sports should be avoided to avoid the risk of splenic rupture, for at least one month following initial infection and until splenomegaly has resolved, as determined by ultrasound scan.

In terms of pharmacotherapies, tylenol/paracetamol (acetaminophen) or non-steroidal anti-inflammatory drugs (NSAIDs) may be used to reduce fever and pain – aspirin is not used due to the risk of Reye’s syndrome in children and young adults. Intravenous corticosteroids, usually hydrocortisone or dexamethasone, are not recommended for routine use but may be useful if there is a risk of airway obstruction, severe thrombocytopenia, or hemolytic anemia.

There is little evidence to support the use of acyclovir, although it may reduce initial viral shedding.^[ Antibiotics are not used, being ineffective against viral infections, with amoxicillin and ampicillin contraindicated (for other infections) during mononucleosis as their use can frequently precipitate a non-allergic rash. In a small percentage of cases, mono infection is complicated by co-infection with streptococcal infection in the throat and tonsils (strep throat). Penicillin or other antibiotics should be administered to treat the strep throat, but are not effective against EBV. Opioid analgesics are also contraindicated due to risk of respiratory depression.

Dietary supplements are given to foster the immune system. As especially helpful are recommended proteolytic enzymes, spirulina, ester-c-vitamine with bioflavonoides, free-form-amino acid complex, acidophilus; further more Royal jelly, lecithin, green kamut, L-tryptophan, inositol.

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Mortality/morbidity

Fatalities from mononucleosis are very rare in developed nations. Potential mortal complications include splenic rupture, bacterial superinfections, hepatic failure and the development of viral myocarditis.

Uncommon, nonfatal complications are rarely seen, but include various forms of CNS and hematological affection.

• CNS: Meningitis, encephalitis, hemiplegia, Guillain-Barré syndrome and transverse myelitis. EBV infection has also been proposed as a risk factor for the development of multiple sclerosis (MS), but this has not been affirmed.

Hematologic: EBV can cause autoimmune hemolytic anemia (direct Coombs test is positive) and various cytopenias.

Complications

• Secondary bacterial throat infection
• Rupture of spleen (this is rare; avoid pressure on the spleen)
• Neurological complications (these are rare, but include meningitis, seizures, ataxia, Guillain-Barre syndrome, and Bell’s palsy)
• Hepatitis with jaundice (more common in patients older than 35)
• Hemolytic anemia
• Orchitis
• Death in immunocompromised individuals

• Severe sore throat or swollen tonsils
• Difficulty breathing
• Abdominal pain
• Severe headache
• Persistent high fevers
• Yellow discoloration of your eyes or skin
• Weakness in the arm or legs

 

DIPHTHERIA

http://www.cdc.gov/ncidod/dbmd/diseaseinfo/diptheria_t.htm

http://emedicine.medscape.com/article/782051-overview#showall

Diphtheria is an acute infectious disease caused by 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.

Historic reference

Diphtheria belongs to the most ancient epidemic diseases of mankind. Homer and Hippocrates mentioned this disease. Artemey Kapadokes gives the extremely detailed descriptions of diphtheria under the title of the Egyptian Syrian ulcer about 19 centuries ago. The records of diphtheria were found in the Middle Ages.

The first writer who gave the classic description of diphtheria and mainly its pathologic anatomy basics was Bretonno; he also proposed the term “diphterit” from the Greek word “diphtera” (membrane). Bretonno’s student Truss elaborated the doctrine about the specific nature of diphtheria as an  infectious disease, he was the first who proposed the word “diphtheria” for the title of the disease, instead of Bretonno’s anatomical term “diphterit”. Klebs and Leffler, who received clean diphtheria bacilli on blood serum, discovered diphtheria pathogen in 1883-1884. Ru and Yersen received diphtheria toxin and studied its qualities in 1888-1900; Bering and Ru made the discovery of antitoxin in the form of antidiphtheria serum in 1894. The idea of active immunization against diphtheria belongs to Bering.

Klebs discovered the diphtheria pathogen Corynebacterium diphtherias in the sections of diphtheria membranes in 1883. In 1884 Leffler extracted it in clean culture and infected a number of animals, among which Guinea pigs turned out to be responsive to the infection.

 

Etiology

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 (Fig. 8). The diphtheria microbes are immobile, they don’t produce spores, and do not have capsules or flagellums. They are usually situated one by one, however, in the diphtheric membranes and clean cultures they are often found in the form of assemblage resembling a constitution of felt.

Fig.8. Diphteria microbs

On the Lefler medium the diphtheria microbes yield the best growth (colonies) during 16-20 hours; the growth can be observed even in 6-8-10 hours after sowing.

All aniline paints can tincture diphtheria microbes. They are well tinctured by Neisser’s method. The diphtheria pathogens located in membranes do not die at a temperature of 98 °C within one hour. The clean culture can survive at a temperature of 60 °C only within several minutes. However, at low temperatures, absence of light and moisture the diphtheria microbe is not destroyed for a long time (even below 0 °C); it can tolerate even freezing and thawing. At the same time straight sunlight kills it comparatively fast.

The main biological quality of the diphtheria microbe is its capacity to produce toxin (exotoxin) that causes the pathogenicity of this microbe.

C diphtheria is responsible for both endemic and epidemic diseases, and it was first described in the 5th century BC by Hippocrates. Diphtheria manifests as either an upper respiratory tract or cutaneous infection and is caused by the aerobic gram-positive bacteria, Corynebacterium diphtheria. The infection usually occurs in the spring or winter months. It is communicable for 2-6 weeks without antibiotic treatment. People who are most susceptible to infection are those who are not completely immunized or have low antitoxin antibody levels and have been exposed to a carrier or diseased individual. A carrier is someone whose cultures are positive for the diphtheria species but does not exhibit signs and symptoms. Studies show that as the number of asymptomatic carriers decrease, the number of diphtheria cases consequently decline.

C diphtheria is a nonencapsulated, nonmotile, gram-positive bacillus; this is shown in the image below. Pathogenic strains can result in severe localized upper respiratory infection, localized cutaneous infections, and rarely systemic infection.

Photomicrograph depicts a number of gram-positive Corynebacterium diphtheriae bacteria, which had been stained using the methylene blue technique. The specimen was taken from a Pai’s slant culture.

Exotoxins are associated with both invasive localized and systemic forms of this disease; however, case reports of invasive disease in absence of the exotoxin release have been documented. Exotoxins are encoded in viral bacteriophages, which are transmitted from bacteria to bacteria. The 3 isolated strains of C diphtheria include gravis, intermedius, and mitis. Intermedius is thought to be responsible for systemic elaboration of the disease, as it is most often associated with the exotoxin. However, all 3 strains are capable of producing toxins.

Corynebacterium ulcerans is a relatively rare species, which more frequently causes cutaneous diphtheria; however, this species may rarely cause respiratory symptoms. Severity of disease is dependent on exotoxin production. C ulcerans has also been linked to zoonotic transmission to humans and has been most frequently seen in agricultural communities associated with livestock

Epidemiology

The source of diphtheria is a person in whom it is manifested in various clinical forms – from serious toxic forms up to the deleted ones and healthy bacteria-carrying. There are infrequent reports on people being infected with diphtheria from animals.

The duration of the microbe vegetation in the organism and the terms of purification mostly stipulate the epidemic danger of the bacteria-carrier as a source of infection. In practice it is difficult to determine the true duration of bacteria discharge because of the absence of precise information about its beginning.

The most epidemically dangerous are the bacteria-carriers who discharge microbes for a long time (up to 1 month and longer), it is more often observed in patients with chronic diseases of the upper respiratory tracts particularly with tonsillitis.

It is known that the diphtheria infection is transmitted in an airdrop way, which is inherent for the majority of respiratory infections. Nevertheless it is necessary to briefly mention some aspects of the transmission mechanism, particularly the pathogen survival rate in the environment. Various enviromental factors can influence the transmission of the diphtheria infection, however, they play a small role and more often have casuistic nature. The leading role in the epidemiology of diphtheria belongs to the drop mechanism of the transmission.

The periodicity and seasonal prevalence of the case rate are characteristic of diphtheria as an infection with a dropping mechanism of transmission. These epidemiological peculiarities were more considerably expressed during the pre-vaccinating time when the periodic growth of the sickness rate was observed every 10 years.

The autumn-winter seasonably is characteristic of diphtheria. In the 20s – 50s the specific prophylactic agents of diphtheria were introduced into the practice of public health services of many countries, it resulted in the considerable decrease of the sickness rate. The diphtheria sickness rate decreased considerably fast in the USA, Canada and most countries of Europe.

Diphtheria used to be one of the major causes of children’s mortality a century ago. Even in the 1920s the incidence in the USA and Canada was approximately 150 cases per 100,000 people, but decreased to 10/100,000 in the 1940s.The introduction of immunization resulted in the decrease of the yearly number of notified cases to single figures in most Western countries, in the USA a total of 1.288 cases were reported during 1971-1981, compared to, only 40 cases in 1980-1993. In England and Wales, there were 800.000 notifications of diphtheria during 1920-1934 with 50,000 deaths. The number of cases decreased from over 40,000 in 1940 to 37 in 1957, and during the  period of 1970-1994 only 124 cases were identified. In some countries, including Finland and Sweden, decades passed without any cases after the implementation of diphtheria vaccinations in the 1950s. Reduction in the number of diphtheria cases has also taken place m the developing world, but the cutaneous forms of the C. diphtheriae infection especially still remain endemic in several tropical countries.

The factors leading to the start of diphtheria epidemics are poorly understood. The last major epidemic in Europe, before the current one, occurred in the 1940s. In 1943 the annual incidences per 100,000 population were as high as 212 in Germany, 760 in Norway and 622 in the Netherlands. It has been estimated that in 1943 there were 1 million cases and 50.000 deaths due to diphtheria in Europe. Limited epidemics have thereafter been reported both in developing (including China, Tajikistan, Ecuador, Jordan, Lesotho, Sudan, Yemen and Algeria) and industrialized (USA, Sweden, Germany) countries. These epidemics have all been local and relatively small; numbers of cases have varied from a few to a few hundred. The carriage rate of C. diphtheria even, in the proximity of the patients, has been low, and no significant spread of the infection has occurred in the general population. Since 1990, a massive epidemic has prevailed in Eastern Europe, mostly in the Russian Federation, Ukraine and their neighboring countries. A smaller epidemic occurred previously in 1983-1985, when the annual number of cases in the Soviet Union exceeded 1.400 – being less than 200 in preceding years. After a few-years of low incidence, rates per 100,000 population started to increase from 0.5 in 1990 to 10.2 in 1993, 26.9 in 1994 and 24.2 in 1995.  Especially in large cities, the rates were high (St. Petersburg, 52.5/100,000 and Moscow, 47.1/100.000). In some areas the incidence rate even exceeded 100/100.000. Over 63,000 cases were reported from Russia in 1990-1994. Thereafter, the epidemic started to decline and, in 1996, the incidence was only 9.2/100.000.

Another country suffering badly from the epidemic is Ukraine. The annual number of diphtheria cases remained below 100 until the end of 1980s, but increased rapidly thereafter. The incidence rates increased from 0.1/100,000 in-1989 to 5.7 both in 1993 and in 1994. The total number of cases in Ukraine between 1990 and 1994 was estimated at nearly 9,000. Reflections of the epidemic can also be seen in other countries close to Russia and Ukraine, although the numbers are smaller. In 1994, Belarus reported 230 cases (incidence 2.5/100,000), Estonia 7 (0.4), Latvia 250 (9.6), Lithuania 31 (0.3), and Moldova 372 cases (8.6/100,000). Case fatality rates in this epidemic ranged from 3 % to 21 % in different countries.

Features that might be important in understanding the dynamics of the epidemic and its prevention have been studied. The most important is the high percentage of adults, 60-77 % of cases. This is, in contrast with the experience from the prevaccination period, when the corresponding figure used to be below 30 %. Certain groups at increased risk were suggested: medical staff, teachers, vendors, transport employees, food handlers, and military personnel.

No significant spread occurred outside the countries of the former Soviet Union. The European Union countries reported only a few cases of diphtheria during the period of this epidemic. In 1990-1996, there were 27 cases in  Germany, 33 in the UK, 3 in Belgium, 10 in Finland, 3 in Greece, 4 in Italy, 2 in the Netherlands and 3 in Portugal. 23 of the 85 cases in EU countries could be linked epidemiologically to Eastern Europe. None of the other EU countries reported cases in this period.

Pathogenesis

The diphtheria infection develops only in case of the parenteral entering of poison into the organism.

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 vulva-vaginal area. 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.

That is why the damage of almost all tissues is observed in the inoculation zone including the mucous membranes, skin, muscles, and nervous fulcrums. Hyperemia, retardation of the blood flowand sharp rising of the permeability of hysto-hematic barriers promote the formation of exudate which is rich in protein and fibrinous membranes in the damaged tissue area.

At the intranevral injection the diphtheria toxin causes the primary lesion of oligodendrocytes (Shvann cells) and myelin with the subsequent development of the sectional demyelination in area of inoculation. As a result the speed of PA decreases, the retractor periods are  prolonged, but the full passing block does not appear.

The local cytopathogenic effect of the toxin is determined by the rate of the poison entering the tissues, by the toxin-aggregating capacity of the cells and the availability of the microbial spreading factors (neuraminidase, hyaluronidase). If poison enters slowly, there appear conditions for the manifestation of its local cytotoxic action in the area of inoculation, but if the toxin concentration in this area increases rapidly, then in a short time the “threshold” dose is accumulated, and in case of its exceeding the poison is reabsorbed in the circulation system and already has a predominantly systemic pathogenic effect.

In the blood the toxin contacts with globulins, and at a greater saturation with albumines. The poison forms complexes with hemolysins and hemagglutinins.

The process of the poison fixation in tissues is not accompanied by any disorders of proteins, carbohydrates and fat metabolism. After the completion of the latent stage and the development of the characteristic symptoms of toxic diphtheria the patients have only a mild increase of the sugar content in the  blood without changing the tolerance to galactose and levulose.

There is noticeable weakening of phosphorylation processes in toxic diphtheria. The changes of oxidative phosphorylation in mitochondrions are not the result of the toxin direct pathogenic action, but the indirect one through the neurohumoral part including the sympaticoadrenal system.

Pathologic anatomy

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, in diphtheric polyneuritis the process can spread on the intraganglion fibers of intervertebral nodes and their cranial homologues.

The cardiovascular system is considerably affected in the diphtheria intoxication. The vessels affection is mainly manifested in their paretic dilatation with the symptoms of stagnation which can transform into stasis. The deep degenerative changes are observed on the part of myocardium. The changes of myocardium in the hearts of children who died on the 3-5-th day  of the third degree toxic diphtheria or hemorrhagic diphtheria were manifested only in expressed plethora, an edema of the intermuscular tissue with frequent hemorrhages: the fibrinous degeneration of the vessels walls was constantly observed.

The typical picture of diphtheria myocarditis (hyperemia, hemorrhage, the cell-like infiltration) was observed in children who died during the 2-3-rd week of the disease. As a rule, the conductive system of the heart is also affected. The simultaneous affection of the cardiac muscle, nervous system (sympathetic system), which enervates the vessels and stipulates their tone, the violation of the paranephros function results in cardiovascular weakness, which is so characteristic of the serious forms of diphtheria. Depending on these lesion combinations, the phenomena of either cardiac or vascular weakness can dominate. The degenerative processes in epithelia of canaliculi develop in the kidneys, it looks like nephrosis.

Clinical manifestations

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The incubation period, as in the other forms of diphtheria, lasts from 3 to 10 days. The disease has either an acute, sudden, or step-by-step oncoming with hardly noticeable symptoms, in the first case the temperature immediately rises up to 38-39 °C, there is a headache, malaise. In the second case a child develops poor appetite, flaccidity, slight temperature rise (37.5-38 °C) during several days. Quite often even senior children do not complain of a sore throat or the pain is insignificant, and if the doctor is not in the habit of examining a throat in each patient with a fever, diphtheria in such cases is not revealed by the parents and the doctor as well. If the patient is examined during the first day of the disease it is possible to notice a slight pulse acceleration, which correlates with the temperature; the cervical glands are usually slightly enlarged on one side, painful at pressing. The tongue is furred, the tonsils are swollen either both or mostly, one of them, turn red, but the erythema is strictly localized and does not spread on the uvula and soft palate as in scarlet fever. It is possible to discover fur on the reddened tonsil, during the first hours of the disease it looks like a mild combustion of the mucous membrane or a heavy-bodied web grid; it is possible even to remove it by a cotton plug but a new one appears on its place extremely fast, and it cannot be removed any more. By the end of the first day or by the beginning of the second day the fur 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. The borders of the heart are normal and the tones are clean. The pulse is accelerated; the blood pressure is in  the normal range or slightly heightened. The liver and spleen are not changed; the urine does not contain protein. There is moderate leukocytosis (10.000-12.000) and neuthrophylia in the blood. The following course of the disease can be diverse. Nowadays, when the serum treatment is widely applied, the natural course of diphtheria can be observed very seldom. Therefore, it is necessary to distinguish the diphtheria course during serum treatment and without it.

If serum is injected, sometimes within the first day there is no essential change in the patient’s condition: the temperature remains elevated, the general condition is also abnormal, fur can even increase. But as a rule, there is a sharp improvement in 24 hours: the temperature critically drops, sometimes down to normal, the child becomes vigorous and cheerful, the appetite improves, the cervical glands-get smaller, the fur changes its appearance: it becomes more porous, it looks as if it is uplifted above the mucous membrane, there is a girdle of sharply expressed erythema on the edges, the diffusion of the fur, is intercepted. Within the following day and night the considerable part of the fur disappears, in 2-3 days the fauces completely refine, and the child recovers. If serum is injected in time, the consequences of the intoxication (paralyses, heart weakness) don’t usually develop.

There are also cases when the temperature drops on the 3-5-th day and the fur also disappears rather fast without any serum treatment. But such cases are an exception. In most cases the disease progresses, the fur covers both tonsils, it can spread to the uvula and aerofoil; the cervical glands are enlarged, painful, but there is no edema of the cervical cellular tissue and fauces. There are sometimes traces of protein in urine. The temperature is of the remittent (febris remittens) or improper type and lasts during 7-12 days. The fur disappears slowly without any ulcerations or detects of the mucous membrane. The disease ends on the 7-15th day; the isolated paralyses (paralysis of the soft palate) and unexpressed cardiac disorders are sometimes observed.

In the cases when the disease is not treated with serum, it is impossible to be sure in the complete recovery of the patient even if the process stops and the fur disappears. The fur sometimes appears again and can spread to the nasopharynx and nasal cavity or the process goes downwards to the larynx.

Diphtheria of the fauces and diphtheria of the nose

The transfer of the process from the tonsils to the nasal cavity is implemented either directly or skipping the soft palate and pharynx, the process affects the nasopharynx  and rear parts of the nose. Such transfer is usually observed not earlier than on the 3-5-th day of the disease and is accompanied by a new temperature rise and deterioration of the general condition, and there are characteristic symptoms indicating the affection of the nasopharynxes and nasal cavity. The voice becomes nasal, the mouth is open, the tongue is dry and coated with peels, a slimy at first and then sanious discharge comes out of the nose, and frets the skin ‘around the nostrils and on the lips. An abundant purulent discharge can also be seen on the rear wall of the pharynx. Not only the submandibular lymphatic glands, but also the lymphatic glands situated around m. sterno-cleido-mastoideus swell up a little on-the neck. If the process has gone far and has affected the forefronts of the nose, it is possible to see the covers without any instruments having cleared the nose entrance from purulent discharge and peels. The spreading of diphtheria on the nose worsens the prediction, as sometimes an edema of the cervical cellular and the symptoms of general intoxication accompany it, i.e. the widespread diphtheria changes into toxic one. In other cases the process can proceed to the nasal sinuses and middle ear. Clinically this transfer can remain unnoticed or corresponding symptoms may appear (edema of blepharous and the back of the nose, discharge form the ears). Whether this transfer is caused by the diphtheria infection itself or a mixed infection plays some role (streptococcus, pneumococcus), — it is not always possible to find out (the information on primary diphtheria of the nose can be found below).

 

Diphtheria of the fauces and  the mouth

If the process spreads to the oral cavity, dirty-gray densely sitting covers develop on the palate (Fig. 9), on the mucous membrane of the lips and cheeks, and also on the tongue. The bacteriological research discovers Leffler’s bacilli in the covers.

The clinical symptoms: abundant salivation, smell from the mouth, painful mastication and swallowing, large swelling of submandibular glands. The covers disappear slowly leaving the ulcers that do not heal for a long time.

 

Fig.9. Diphtheria of the oral cavity

 

The diphtheric affection of the larynx and respiratory tracts is known under the name of a croup.

Croup (true, diphtheric) can be secondary, if it develops after the affection of the fauces or the nose, and primary – at the primary localization of the diphtheria process in the larynx.

 

The course of croup can be divided into three stages.

1. A croup cough stage. The first symptom indicating the starting affection of the larynxes is sharp loud cough, which becomes rasping, barking very soon. Senior children complain of the sense of smart and pressure in the larynx; the palpation of the larynx appears to be painful. At the same time the voice becomes hoarse, unclean, and then completely silent (aphonia). At the examination with a laryngeal mirror it is often possible to see an edema and hyperemia of the epiglottis, and often there are no covers at this stage. This period lasts 1-2-3 days and develops into a second stage.

2. A stenosis stage. The respiration becomes labored, unclean; at each inspiration the sawing or whistling sound is audible. This sound is weak at the beginning and audible only during exaltation and the child’s cry, then it becomes sharp, constant and is audible from the distance. Another symptom is the larynx narrowing — retraction of compliant, weaker places of the thoraces. As the insufficient amount of air enters the lungs through the narrowed glottis, the intrapulmonic pressure becomes lower than the atmospheric one and under its influence- the compliant places of the thoraces — the supraclavicular and bulbar-fossas; intercostal spaces, anticardium – are more or less sharply retracted at each inhalation. At first a child is quiet, satisfactorily manages the air deficiency. Then the oxygen deficiency develops – the child becomes restless, rushes in bed, jumps up, grasps the handles of the bed, wants to be held in his mother’s arms, showers his head to the back. The auxiliary muscles start to work – intercostal, mm. sterno-cleido-mastoidei, mm. scaleni. The sterno-clavicular muscle appears to be noticeably tight at the palpation during an inhalation. When the child is in such a condition, injecting the serum and  providing the adequate treatment (an operation and other treatment measures; (see Treatment of croup below) can save him. If the disease has its natural course, the condition improves and the stenosis easies in the extremely infrequent cases when the cover disappears; in most cases the disease reaches its last stage.

3. An asphyxia stage. In the struggle with stenosis the child exhausts, the respiratory muscles get tired. The child becomes calm, sleepy, he inditfferently lies in bed. The respiration is accelerated, but it is superficial, the retractions are already not so visible. The lips, tip of the nose and nails become blue, the face turns pale, sweat quite often appears on the forehead. The extremities are cold, the pulse is very rapid, thready, sometimes paradoxical (abasement of the pulse wave during the inhalation). From time to time there are attacks of acute dyspnea – the child jumps up, rushes because of air-deficiency, the eyes express fright, the face becomes cyanotic; sometimes such attacks result in the immediate death; in other cases the child dies after a more or less continuous agony with the symptoms of exhaustion of respiratory and circulation centers.

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, sometimes abdominal pains. Senior children complain of a pain at swallowing. The pulse is rapid: 140-160 beats per minute, the face is pale, there is malaise, sleeplessness, sometimes exaltation. The submandibular glands are enlarged, painful; it is possible to see a quaggy pasty edema of the cellular under the low jaw angle, usually on one side (Fig. 10) sometimes an edema develops only on the second day.

 

 

Fig.10. Toxic diphtheria

At the mouth examination you can see that the tongue is dry and furry, 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 fur 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. The temperature remains high: 39-40 °C. The face is pale, pathy. There is sanious fluid discharge from the nose, it frets the skin. The mouth is open, the lips are dry and cracked; the smell can sometimes be sensed even from the distance. The respiration is hoarse, the voice is muffled, with a strong nasal tone. The glands are enlarged even more, but it is more difficult to palpate them because the edema of the fat cellular takes a considerable part of the neck. The glands are not so tight because of the edema of the cellular, as compared with scarlatina. Thick, dirty-gray covers are not only on the tonsils and uvula, but also on the mild and firm palate; the edema of the whole fauces is considerably expressed; the uvula is especially edemic and enlarged; it is squeezed and strangulated by the enlarged tonsils, sometimes it is twisted backwards, so that the back wall of the pharynx is not visible. As a result of such swelling of the fauces the respiration becomes labored, stenotic (stenosis of the pharynx). The swallowing is extremely painful, and the feeding of the patient becomes difficult. Simultaneously with worsening of the local process the phenomena of the general intoxication also increase: the pulse is rapid and weak, the heart sounds are dummy, the blood pressure is low; there is protein in urine, sometimes cylinders; general malaise is considerably expressed. There is considerable leukocytosis in the blood (up to-15-20 thousand) and neutrophilia.

 

Complications

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 (except subtoxic) at overdue (after the 5th day of the disease) specific treatment and is always accompanied by complications on the side of the kidneys and nervous system.

The complications caused by the affection of the nervous system are observed less frequently. In the mild forms of diphtheria (localized, wide-spread) the adults 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 1/3 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, it results in paresis or paralyses of the soft palate, pharynx, tongue, accommodation paresis and mimicry affection.

 The severe forms of polyradiculoneuritis develop only 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, even in subtoxic diphtheria.

One or two-sided focal pneumonia quite often develops at the early stage of the disease in toxic diphtheria.

 

Diagnosis

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The modern microbiologic diagnosis of diphtheria is based on the clean culture isolation and identification of the pathogen by the cultural-morphological, biochemical and toxicogenic properties. Thus, it is necessary to strictly observe a number of conditions. The slime from the stomatopharynx and nose as well as the secret from other areas of the pathological process localization are collected by separate wads before eating or after it but not earlier than in 2 hours, and also before gargling and other kinds of treatment (drops, ointments, wads).

Taking the material for research correctly is of great importance. In the stomatopharynx slime is taken from the tonsils, palatal aerofoils, uvula and trailing wall of the pharynx by rotary movements of a wad obligatory with the help of a glass spreading rod, not touching the mucous membrane of the cheeks and tongue. If there is fur of fibrinous nature, the material should be taken both from the affected tissues and the healthy tissues adjacent to them. A small part of the removed coat, which is carefully ground between glasses, or a smear taken by a separate wad are sent to the laboratory for the direct bacterioscopic investigation. The scooping of the material from the nose should be done after the careful preliminary purification of it from the slime by a dry cotton plug or after blowing the nose.

Though the streamlining of some stages of the bacteriological research accelerates the terms of carrying out an analysis to some extent, they all remain rather prolonged and do not guarantee the early diagnostics of diphtheria.

Serological, immune-chemical and the immunological methods play a more and more relevant role in the diagnostics and epidemiological evaluation of the disease. On their basis are designed the accelerated methods of discovering diphtheria toxin in clean and blended cultures in case of growing them in liquid mediums and other substrates.

The serological tests are applied to study collective immunodeficiency. RDGA is the most accessible, simple and quite informative.

 

Differential diagnosis

http://emedicine.medscape.com/article/782051-differential

The diagnosis of diphtheria of any localization is quite difficult, as it is similar to many diseases of the infectious and non-infectious origin. The number of diagnostic mistakes increased in the period of diphtheria elimination, at a sporadic case rate, as the vigilance towards this infection vanished. The mistakes are the most frequent in diagnosing diphtheria of the stomatopharynx — the most widely spread form of the disease.

The localized form of diphtheria of the stomatopharynx is the most difficult for the clinical diagnostics. The disease should be suspected if there is dense and nitidous fur situated on the domed surface of the tonsils, their swelling, which corresponds to the area of the fur, limited hyperemia of the mucous membrane in the form of a thin rim with a cyanotic shade. The diffuse bright hyperemia, which affects all the departments of the stomatopharynx, is not characteristic of localized diphtheria. While observing the patients it is possible to notice other symptoms, which help to diagnose the case. So, such symptoms as a short-living (1-3 days) fever, the absence of pain at swallowing in 2-3 days with the remaining fur are characteristic of localized diphtheria of the stomatopharynx.

It is necessary to remember that in the patients suffering from chronic tonsillitis the symptoms of diphtheria may be distorted. In such patients the fever remains long, the fur is situated in the hypertrophied tonsils lacunas, and the hyperemia of the mucous membrane is of a diffuse nature. If there are no convincing symptoms of angina in the patient who is in the diphtheria focus, it is necessary to diagnose diphtheria even if there is no bacteriological confirmation of the diagnosis.

In comparison with other diseases, localized diphtheria of the stomatopharynxes should be differentiated from follicular and lacunar angina of the streptococcal and staphylococcal etiology more, frequently. The considerable intoxication (malaise, weakness, joint aches, headache) is characteristic of these diseases even if there is slight fur on the tonsils. The fur that is located on the lacunas and has a quaggy, viscid consistence, yellow or virescent color is different too. The fur is localized or solid, usually dull and can be easily removed by a glass spreading rod. The hyperemia of the mucous membrane is more often bright and diffuse. The appearance of the patient is also different: palenesses characteristic of diphtheria, but feverish blush, shine in the eyes, brightness and dryness of the lips are characteristic of angina.

Ulcerus-necrotic angina of Simanovsky-Vincent’s is quite often taken for diphtheria, and vice versa. The peculiarity of this angina is the absence or minor expressiveness of intoxication. The temperature is subfebrile or normal, the pain at swallowing is slight. As a rule, the process is one-sided. On the tonsil develops the ulceration in the shape of a crater, coated by clotted fur of the dirty white color. The areas of necrosis can also be found on the palatal airfoil, uvula or soft palate.

The anginous form of tularemia looks like diphtheria by the form of the fur on the tonsils, but it differs by a rather late development (on the 3-5th day), absence of an edema of the tonsil, the ulcer-necrotic-nature of a lesion (the fur not only rises above the level of the healthy tissue, but is also located below it), a considerable increase of the regional lymph nodes that continue enlarging after the disappearance of tonsillitis.

Necrotic angina in scarlet fever can be considered to be diphtheria owing to the vastness of the lesion areas and dense fur cohesion with die tonsils surface. However, in this case the affected areas of the tonsils do not rise above the level of the healthy tissue, the edema of the mucous membrane is insignificant, the hyperemia is extremely bright and at the same time has a distinct border. It is also necessary to take into consideration the patient’s appearance: bright hyperemia of the cheeks and paleness of the nosolabial triangle. The development of the small-dot rash in the typical places for scarlatina solves the problem of the diagnosis.

Widespread diphtheria of the stomatopharynx is diagnosed easier than localized one: the spreading of the fur from the tonsils on the adjacent parts of the stomatopharynx — palatal aerofoils, uvula — indicates that the process is not ordinary. The edema of the mucous membrane testifies in favor of diphtheria. While diagnosing widespread diphtheria, it is necessary to be convinced of the absence of the hypodermic cellular edema of the neck not to fail to diagnose toxic diphtheria.

Toxic diphtheria of the stomatopharynx is characterized by in especially bright clinical picture, nevertheless, the greatest number of mistakes is made in both children and adults in this case. Apparently, the main cause of  it lies in the fact that toxic diphtheria is a comparatively rare disease and the doctor lacks personal observations, which could help him to diagnose the disease. The main symptoms of the early period of toxic diphtheria are an edema of the neck-hypodermic, cellular, an edema of the stomatopharynx mucous membrane and widespread fur on it.

Contagious mononucleosis should sometimes be differentiated from toxic diphtheria. The resemblance is explained by the fur on the tonsils that has irregular depth irregular consistence of the neck hypodermic cellular above the enlarged lymph nodes. In contrast to toxic diphtheria contagious mononucleosis develops step-by-step, the quaggy fur on the tonsils occurs not earlier than on the 3-4-th day, it can be rather easily removed by a glass spreading rod and is triturated. A long-lived fever, polyadenitis with primary enlargement of the posterior neck lymph nodes, hepatolienal set of symptoms and characteristic pattern of the peripheral blood, in which one the uninuclear cells dominates, — testify in favor of contagious mononucleosis.

Treatment

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http://emedicine.medscape.com/article/782051-medication#showall

 

 Hospitalization of patients is obligatory. In case of a  toxic diphtheria  patients transport only laying. The severe confinement bed regime is necessary during 20-25 days, then at absence of complications the patient allow to sit and gradually dilate impellent regime. At mild forms (localized diphtheria of pharynx,  diphtheria of nose) duration of confinement bed regime is reduced up to 5-7 days. In the acute period of disease fluid and semifluid nutrition is necessary. Treatment may be specific and pathogenic.

Specific treatment will carry out by high purified horse hyper immune serum. For prevention of anaphylactic reactions infuse serum behind by Bezredko method. First of all 0,1 mL diluted 1 : 100 of serum infuse intracutaneous of forearm. If after 20-30 min. on a place of injection there are not changes or the papule in diameter is not more than 0,9 sm, – reaction is negative, and infuse 1 mL undiluted Serum sub dermal, and at absence of reaction – after 30 min all prescript dose in muscle.

At toxic diphtheria II-III stage and the hyper toxic form a serotherapy is carried out necessarily, under protection of hormonal preparations, and sometimes – narcosis. In case of positive intradermal assay or at presence of anaphylactic reactions further subdermal infusion of serum only behind unconditional indications. Serum in dilution 1: 100 is infused in a sub dermal fat of brachium in doses 0,5; 2; 5 mL consecutive with intervals 20 min. At absence of reaction to previous dose infuse 0,1 mL undiluted serum subcutaneously. If reaction is not present, through 30 min infuse all prescribed dose subcutaneously. In unusual cases serum is infused under narcosis.

Antitoxic serum neutralizes only a toxin, which circulates in a blood, and does not influence on fixed in tissues. Therefore specific treatment may be carried out as soon as possible (optimum in 1 – 3 rd day of disease).

The form of diphtheria determines doses of serum for the first introduction and course of treatment.

At late (after 2 nd day of disease) beginning of treatment of patients with the widespread or toxic form the first dose of serum should be increased. The form of disease also determines frequency rate of infusion of serum. In case of localized diphtheria of a throat, nose, rare localization of process and early serotherapy is possible to be limited by disposable infusion of serum. If diphtheria of throat is widespread, infuse Serum during 2-3 days (at the toxic form – through every 12 hours). The first dose makes 1/3 – 1/2 course; in first two days patient may receive ¾ of course doses.

In case of diphtheritic croup the initial dose of Serum is determined by it’s stages – 15-20 thousand AUN, II stage – 30-40 thousand AUN ,  at III stage- 40 thousand AUN, through 24 hours this dose repeat, and the following one of these days if it is necessary, infuse half dose of Serum.

Usually the course of serotherapy lasts no more than 3-4 days. Indications for stopping of serotherapy are disappearance or decreasing of spot, edema of pharynx and hypodermic fat of the neck, at croup – complete disappearance or decrease of stenotic respiration. At suspicion on toxic diphtheria serum should be infused immediately; at localized form – it’s possible waiting the reception of results of bacterioscopy, otolaryngology’s-review etc., but under condition of constant surveillance in hospital; on diphtheritic croup – infusion of serum is obligatory if this diagnosis is not refused after carrying out of intensive cure during 1-1,5 hours.

For intensifying action of Serum intramuscularly recommended infusion once a day 25 % of a solution of magnesium sulfates right after beginning of serotherapy.

Pathogenetic treatment is directed on desintoxication, restoration of hemodynamic and elimination of adrenal gland insufficiency. Desintoxication therapy provides intravenous infusion of 10 % solution of glucose with insulin, albuminous preparations and colloid solutions in the ratio 1:1. A liquid is infused at the rate of 20-30 mL/kg of mass. Diuretic agents, are indicated under the control of arterial pressure and diuresis.

For improvement of tissue metabolisms cocarboxylase, acidum ascorbinicum, a nicotinic acid, ATP are indicated. The nicotinic acid decreases also an influence of diphtheritic toxin, and ascorbic – stimulates imunogenesis and function of cortex of the adrenal glands.

Prednisolonum (2-3 mg/kg) or Hidrocortizonum (5-10 mg/kg per day) are prescribed to the patient with widespread and toxic forms of diphtheria with the purpose of replaceable, anti-inflammatory and hyposensibilisative treatment for 5-6 days. In the first 2-3 days Glucocorticoides are infused in vein, then per os. In case of hypertoxic and hemoragic forms the daily dose of Prednisolonum is enlarged up to 5-20 mg/kg according to stage of shock.

At toxic form of diphteria, since the first day there is indicated 0,1 % solution of Strychninum of Sodium nitritum (0,5-1,5 mL subcutaneously) during 2-3 weeks and more. Strychninum stimulates tone of the central nervous system, stimulates respiratory and vasomotor centers, tones up sceletal muscles and a myocardium, stimulates oxidant-recreated processes in myocardium. Use of Cordiaminum, Corazolum raise a tone of organs of circulation. At cases of DIC for desagrigation, except Reopolyglucini, indicate antihistamines, vasodilators, Trentalum, Ksantinoli. For reception of anticoagulative effect infuse Heparini (150-400 UN/kg  per day). Inhibitors of proteases are recommended.

Antibacterial therapy is prescribed with the purpose to impact on Corynebacterias diphtherias and secondary flora. It is expedient to apply Benzylpenicilini, Tetracyclinums, Cefalosporines, Erythromicini.

Treatment of patients with diphtheria of larynx. Patogenic treatment is indicated: Sibazonum (Seduxenum) and etc. Oxygen therapy is provided. In case of a stenosis of larynx without respiratory failure the good effect gives a warm soda drink, Sinapismuses and etc. hyposensibilisative preparations (Dimedrolum, Pipolfeni, Tavegili etc.) are used to decrease the edema of mucous, locally antiedema and anti-inflammative therapy in aerosols (inhalations) is prescribed.

Complex treatment provides also indication of Glucocorticosteroides, in particular Prednisolonum (2-3 mg/kg per day), which, except for anti-inflammatory action, assist decrease of edema of larynx, reduce a permeability of wall of capillaries and exudation. Half of daily dose is infused intravenous or in muscle, the rest is given per os. After prescriptions desintoxicative therapy will carry out. Antibiotics of wide spectrum action are prescribed. If conservative treatment is not effective, operative measures are used.

Triad of signs to be the indications to initial intubations (tracheostoma):

а) Paradoxical pulse (inspiratory asystolia of Raufus); b) sign of Baie: continuous contraction sternocleidomastoideus muscles during  inspiration; c) proof cianosis of labiums and face. In case of a localized croup – long nasotracheal intubation, at a wide-spread descending croup tracheostomy with the following drainage of trachea and bronchuses are indicated.

Treatment of complications. At myocarditis optimum duration of the bed period regime is near 3-4 weeks. There are indicated Strychninum (a long course); solution of glucose with cocarboxylase, Acidum ascorbinicum, ATP, calcium pangamatis, agents which influence on tissue metabolism (a methandrostenolone, a potassium Orotatis). At serious and medium myocarditis Prednisolonum per os and parenteraly (in a daily dose 40-60 mg) is recommended. Introduction of cardiac glicosodes is supposed only at manifests of heart insufficiency without disorders of contraction. Anticoagulants of indirect action are prescribed for prophylaxis of tromboembolitic complications (Dicumarinum, Neodicoumarin, Pelentanum).

The patient with diphtheric polyneuritis should be indicated Strychninum, vitamins of group B, glucocorticosteroides. In the recreating period an Oxazili inside during 15-20 days, massage, medical gymnastics (cautiously), diathermy, galvanization, quartz are applied.

At attributes of defeat of respiratory muscles indicate antibiotics of wide spectrum of action in the maximal doses for prophylaxis of pneumonia. Patient can be transfer on apparatus respiration in conditions of departament of reanimation after indications. Proceeding from action of diphtheritic toxin as inhibitor of acetylcholinesterase, Proserini at neurologic complications is indicated after fading acute displays of disease.

Treatment of toxygenic corinebacterias diphtherias carriers. At repeated allocation of bacteria – antibiotics of tetracycline lines, Rifampicini are recommended. After a seven-days course usually there comes sanitation. The basic attention should be payed to chronic disease of nasopharynx. Treatment begins with fortifying (Methyluracilum, Pentoxylum, Aloe, vitamins) and hyposensibilisative agents with physiotherapy (UHF, UF-radiation, ultrasound).

Duration of hospitalisation is determined by gravity of diphtheria and character of complications. If complications are not present, patients with the localized form may discharge from the hospital at 12 – 14-th day of disease, with spread form at – 20 – 25-th (bed regime – 14 days). Patients with subtoxic and toxic forms should be on bed regime 25-30 days; they may discharge at 30 – 40-th day of disease. In case of a toxic diphtheria II – III degree and serious current of disease the regime lasts 4-6 weeks and more. The obligatory condition for leaving the hospital of the patient with any form of a diphtheria is negative result of two control inoculations received with an interval of 2 days.

 

Prophylaxis

http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/diphtheria.htm

http://emedicine.medscape.com/article/782051-followup#showall

The major manifestations of diphtheria can be prevented in individual patients by immunization with formalin-inactivated toxin. Therefore, documentation of inadequate levels of antitoxin in large proportion of the adult population in North America and Western Europe has caused great concern that a toxigenic strain introduced into these populations could cause a major outbreak of disease. Serum antitoxin levels can be measured by toxieutralization tests in rabbit skin, in Vero cell culture, or by hemagglutination, with roughly equivalent results. Concentrations of 0.1 –  0.01 (international units) generally are thought to confer protection. For example, data from a recent outbreak showed that 90 % of clinical cases had antitoxin levels below 0.01 IU/mL, whereas 92 % of asymptomatic carriers had liters above 0.1 IU/mL. Following immunization, antitoxin levels decline slowly over time so that as many as 50 % of individuals over age 60 have serum liters below 0.01 IU/mL. For this reason, booster doses of toxoid should be administered at 10-year intervals, to maintain antitoxin levels in the protective range.

Recommendations from the Immunization Practices Advisory Committee, published by CDC in 1991 are as follows.

For children from 6 weeks to 7 years of age: three 0.5-mL intramuscular injections of (DPT) vaccine should be given at 4-8-week intervals, beginning at 6-8 weeks of age, followed by a fourth dose 6-12 months after the third.

For persons 7 years or more of age: 0.5 mL Td (toxoid—adult) is given twice at a 4-8-week interval, with a third dose 6-12 months later. Because the pertussis component of DPT is re­sponsible for most of its side effects, and the risk of pertussis is much less after age 6, that component of the vaccine is omitted. Moreover, because subjects over age 7 have a higher incidence of local and systemic reactions to the concentration of diphthe­ria toxoid in pediatric DPT vaccine (7-25 limit flocculation [Lf] units) and because a lower dose of toxoid has been shown to induce protective levels of antitoxin, the Td formulation of vaccine contains a maximum concentration of 2 Lf units of diph­theria toxoid. If the recommended sequence of primary immuni­zations is interrupted, normal levels of immunity can be achieved simply by administering the remaining doses without need to restart the series.

Booster immunizations: children who have completed their primary immunization before age 4 should receive a booster dose of DPT at the time of school entry. Persons above 7 years of age should receive booster immunization with Td at 10-year intervals. As a help to memory, this should be done at decade or mid-decade intervals (e.g., ages 15, 25, 35, etc., or 20, 3О, 40, etc.). Travelers to areas where diphtheria is still endemic should be particularly careful to be sure their immunization is current. Although the recommended booster dose of 1.5-2.0 Lf units will increase antitoxin levels to above 0.01 IU in 90-100 % of previously immunized individuals, some authori­ties have recommended using 5 Lf units, because antitoxin lev­els remain above 0.01 IU/mL for a longer period than with 2 Lf units.

Patients should receive toxoid immunization in the convales­cent stage of their disease because clinical infection does not always induce adequate levels of antitoxin. Close contacts whose immunization status is incomplete or unclear should promptly receive a dose of toxoid appropriate for their age, and complete the proper series of immunizations. In addition, they should receive prophylactic treatment with erythromycin or penicillin, pending the results of pretreatment cultures. Given these preventive measures, the prophylactic use of antitoxin is considered unwarranted.

http://intranet.tdmu.edu.ua/data/books/And-INF.pdf