Infectious mononucleosis
Diphtheria
HIV/AIDS
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. 1).
Fig.1. 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
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. 2).
o
Fig.2. 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.
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.
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
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. 3). 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.3. 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
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.
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
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
The factors leading to the start of diphtheria epidemics are poorly understood. The last major epidemic in
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
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
The incubation period, as in the other forms of diphtheria, lasts from 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. 4), 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.4. 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
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. 5) sometimes an edema develops only on the second day.
Fig.5. 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
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
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
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
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
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.
AQUIRED IMMUNODEFICIENCY SYNDROME
(AIDS/HIV infection)
A secondary immunodeficiency syndrom caused by a virus and characterized by severe immune deficiency resulting in opportunistic infections, malignancies, and neurologic lesion in individuals without prior history of immulogic abnormality.
History
In June 1981 the Morbidity and Mortality Weekly Report carried a report of five deaths due to overwhelming Pneumocystis carini pneumonia in
From early 1982 onwards, efforts to identify the causative agent intensified and in may 1983 group from the institute Pasteur, Paris, reported the isolation and propagation of a T-lymphotropic retrovirus, lymphoadenopathy associated virus, LAV from the lymph node of a patients with persistent lymphoadenopathy, a syndrome know to be assotiated with, and preceding the development of AIDS.
Etiology
Retroviruses are very small viruses composed of a single strong of RNA, the intermediate nucleic acid in the production of proteins (Fig. 6). Normally, the flow genetic information starts with a piece of DNA, which makes a piece of RNA, which in turn codes for, protein. Everything flows in that direction. Retroviruses contain a unique enzyme called reverse transcriptase, which allows this single strand of RNA, that is, the virus, to make itself back into a piece of DNA, going backward against the flow of genetic information. Hence, «retrovirus». This piece of viral DNA than inserts itself into the genetic material of the cell that it is infecting, in this case the helper T-lymphocytes, and it remains intertwined there for the life at the cell.
Fig.6. HIV retrovirus
The emergence of a new infections agent in a human population can have only a limited range of explanation; either the infection was previously in an isolated human population from which it had been exported though some societal change, or else it might have been a zoonosis newly exposed to human transmission. A third line of explanation, that of an extraterrestrial or even a man-made origin, has been popular with conspiracy theorists, but will not be furthers discussed. The natural history of HIV 1 infection is marked by the long period of time between infection and disease.
Epidemiology
The major transmission routes of human immunodifficiency virus are sexual contact, parenteral exposure to blood and blood products and perinatal transmission. early in the AIDS epidemic, epidemiological studies establish that receptive rectal intercourse was the predominant mode of HIV-1 acquisition by homosexual man. Other practices that could traumatize the rectal mucosa appeared to increase further the infection risk for the receptive partner. Insertive rectal sex could also place a men at risk for HIV-1 infection, although the insertive partner would be at lower risk than the receptive partner.
On a world-wide basis sex between man and women apparently is the most common mode of acquiring HIV-1 infection heterosexual transmission accounts for the vast majority of cases. In other country where AIDS cases attributed to heterosexual transmission, although still a small percentage of the total number of reported cases comprise the most rapidly growing category. Therefore an understanding of the rate at which HIV-1 is transmitted between heterosexual couples and of the factors that may impede or enhance heterosexual transmission is important in slowing the worldwide HIV-1 epidemic.
In the country, where HIV-1 infection is more common in men than women, studies of female-to-male transmission of HIV-1 infection are both fewer and smaller than studies of male-to-female transmission. Available date suggest female-to-male transmission may be less efficient than male-to-female transmission.
Overall these American and European studies suggest that heterosuxual transmission from HIV-infected persons to their regular sex partner is relatively inefficient, especially female-to-male transmission. Furthermore, the risk of heterosexual transmission is not related simply to the number of episodes of sex with HIV-infected person because some people have remained uninfected after hundreds of such contacts whereas others have become infected after a single episode of intercourse.
Infectivity may be higher during early infection before the development of antibodies to HIV-1, also genital ulcer diseases and inflammation of the genital tract lead to increased susceptibility to HIV infection.
Mother-to-infant transmission of HIV apparently is relatively efficient; without treatment approximately one in the four infants born to seropositive mothers is infected. With one rapid spread of infection to women of reproductive age perinatal transmission is now a major consequence of HIV epidemic. The precise rate of perinatal transmission in a given setting has been difficult to define because of problems in the infant and the difficulties in maintaining long-term follow-up. Uninfected children born to seropositive mothers may retain passively aquired maternal antibody for 6 to 18 months.
Extensive laboratory research and epidemiological studies indicate that HIV is not transmitted by shaking hands, hugging, kissing, contacting bodily secretion such as sweat, mucus (as in sneezing or coughing) or salive. Nor is HIV transmitted by food, swimming at a pools, drinking at a water fountain and also bloodsucking mosquitoes or other arthropods.
Pathogenesis
Following infection across a genital surface, involving infection of CD-4/CCR 5 bearing cells in the mucosa or submucosa, the virus presumably migrates to a regional lymph node, where viral replications occurs. A number of rounds of viral replication than occur within the bounds of the regional lymph node as no detectable virus or immune respons occurs for up to 42 days post infection. When the quantity of infected cells exceeds a threshold, viremia occurs, and the symptoms of an acute non-specific viral illness with tende adenopathy, sore troath, diffuse macular rush, arthralgia and fever. Following the acute viremia, when up to 107 viral particles /ml plasma can be found, a primary immune response develops with antibodies to viral proteins and a cytotoxic T-cells response, which limit viral replication and clear viral particles from the plasma. The reduction the viral load in plasma is not matched by a clearance of provirus in peripheral blood mononuclear cells, and cellular viremia continues in the face persistent and sustained cellular and humoral immune response for the duration of the infection. Even while plasma viral load is suppressed by the immune response, CD-4 T-lymphocyte number foll in linear manner over time. The most plausible explanation for the pathogenesis of AIDS over time is the sustained less CD-4 cells by ongoing HIV viral replication in nature peripheral blood T-cells and by a slight failure of production of match peripheral destruction of HIV CD-4 cells. However, recent controversy over the pathogenic mechanisms and homestasis of T-cells has revealed that simple viral cytopatphic effect on CD-4 cells may be overly simplistic model.
During the course of HIV infection, CD-4 cells continue to decline in peripheral blood and plasma viral load slowly rises. Over a definite period CD-4 cells number declines from a 800 to 200 ml; at this level, the probability of the cellular immune system containing latent or environmental infections such as P. carinii falls and clinical opportunist infection becomes increasingly possible. As the viral load rises. HIV isolates with altered co-receptor usage appear which can use the CXCR-4 chemocine receptor rather than CCR-5; these isolates are more cytopathic in vitro, and may lead to wider tissue distribution of HIV in later disease, AIDS is therefore, the clinical condition of an immune system which is sufficiently compromised by HIV infection that there is an inability to protect against the growth of low grade pathogenes or viral indeced tumors.
The fact that this virus, after infection of the host, besides destroyed strong immune system also can spread to many body tissues. The ultimate outcode of the infection depends on the host’s immune reaction to the virus either through suppression of HIV replicationor through killing of the infected cell. in some individuals an active immune system has prevented development of the disease for years. The factors important in maintaining this immune response are not yet know and merit close attention. The immune deficiency produced by HIV infection makes patients suseptible to infection by a variety of organisms, including viryses, bacteria, fungi and parasites that are of low pathogenecity in the normal individual and of variable prevalence in different part of the world. In some individuals the immune system appears to make enhancing antibodies to HIV and this phenomenon occurs particularly with progression of disease. It is related to change to antibodies made and in some cases to modifications in the virus so that is more sensitive to enhancing antibodies. Moreover, the immune system can hyperreact, with production of antibodies that might also hasten the development of disease. Clearly changes in the virus and the immune response of the host play important roles in the ultimate steps leading to AIDS.
Clinical manifestations
The time from exposure to HIV until the onset of the acute clinical illness is typically 2 to 4 weeks, although longer incubation period have been reported. The clinical illness is acute in onset and lasts from to 2 weeks. It can be associated with an appreciable degree of morbidity and patient may require hospitalization. The main clinical features of primary HIV infection reflected both the lymphocytopatic and neurologic tropism of HIV. Patients report fever, lethargy, fatigue, headaches, retro-orbital pain, sore throat, muscular pain, occasional diarrhea, maculopustular rash and the onset of swollen lymph nodes (swollen glands). Meningoencephalitis may also occur. Lethargy and malaise are frequent, often severe and may persist for several months after resolution of the other clinical manifestations of primary HIV infection. Lymphoadenopathy develops in approximately 70% of persons, generally in the second week of the illness and usually concomitant with the development of peripheral lymphocytosis, reflects the fact that HIV has activated B-lymphocytes to become plasma cells and secrete HIV antibodies.
Fig.7. AIDS lymphoadenopathy
The lymphoadenopathy may be generalized, but the occipital, axillary and cervical nodes are most commonly involved (Fig. 7). The lymph node enlargement persist after the acute illness bat tend to decrease with time. Splenomegaly has also been reported. The mechanism for this splenomegaly is not apparent; it may be related to increased clearance of virally infected lymphocytes. The most frequently reported dermatologic evidence of primary. HIV infection is an erythematous, nonpruritic maculopapular rash. This rash is generally simmetric, with lesions 5 to 10 mm in diameter, and affects the face or trunk, but it can also affect the extremities including the palms and soles, or can be generalized. Other skin lesions noted during primary HIV infection include a roseola-like rash, diffuse urticaria, vesicular, pustular exanthema and enanthema, desquamation of the palms and soles and alopecia. Mucocutaneous ulceration is a distinctive feature of primary HIV infection. Ulcer have been reported on the buceal mucosa, gingiva, or palate, esophagus, anus, and penis. They are generally round or oval and sharply demarcated, with surrounding mucosa that appears normal. The tongue of patient showing the characteristic symptoms of thrush. Note the milk-white flakes of C. albicans on the tongue surface. An unexplained incident of thrush is often considered an early sign that HIV infection is present. Patients also experience weight loss of as much as 10 % of baseline body weight or more. Constant low-grade fever and diarrhea extending over several weeks. In addition, the fatigue may be so overwhelming that patients cannot lift their heads from the pillow on waking in the morning. One of the most troublesome aspects is the night sweats. Individuals perspire so heavily at night that the bed linens and nightwear become drenched with sweat. Saturation can be extensive enough to require linen changes, and sleep is fitful at best. Few other microbial diseases are accompanied by such heavy sweating.
The isolation of HIV from cerebrospinal fluid (CSF) during primary HIV infection indicates that infection of the central nervous system (CNS) occurs soon after exposure. Elevated neopterin and β2-microglobulin levels have also been found in CSF during primary HIV infection both in individuals with and without clinical meningitis, suggesting that the cellular immune system in the CNS may be activated during this stage even without the development of overt neurologic symptoms or signs. The most commoeurologic symptoms are headaches, retro-orbital pain (particularly during eye movement) and photophobia. Several cases of aseptic meningoencephalitis during primary HIV infection have been reported.
Prolonged infection with HIV is often completely asymptomatic; however, a minority of patients complain of nonspecific constitutional symptoms in the month or years after primary infection. Patients commonly complain of being easily fatigued and report the need to reduce their normal activities somewhat. In patients with more advanced HIV disease and severe de pletion of CD4 cells, constitutional disease may primarily reflect immunosupression or may herald the onset of opportunistic infections or malignancies. Patients with progressive constitutional symptoms should be evaluated carefully for opportunistic pathogens. A history of respiratory, neurologic, gastrointestinal and dermatological symptoms should be elicited and a thorough physical examination completed.
In the late stages of HIV infection when immune defenses have been severely compromised and systemic complications have begun to accumulate, the nervous system becomes highly susceptible to a wide array of disorders involving all levels of the neuraxis, including meninges, brain, spinal cord, peripheral nerve, and muscle.
Systemic lymphoma complicating HIV infection may secondarily to the central nervous system involving the meninges, clinical manifestation may be cryptic but usually include cranial nerve palsies, head aches, or increased intracranial pressure.
From an early stage it become clear that the nervous system was frequently involved in HIV infected patients. Among the severe and life-threatening infections experienced by those with immune deficiency were brain abscesses due to toxoplasmsis. As other neurologic manifestations emerged without signs of recognizable opportunistic infection it became clear that HIV was probably directly neurotropic as well as lymphotropic.
Toxoplasma gondii is an obligate intracellular parasite for which the primary host is the cat. Humans may acquire it from the cat by the fecal-oral route. in man primary infection is usually asymptomatic unless congenitally acquired. The organism forms cysts in all tissues which persist for life and are the source of recrudescent infection in the compromised host. Infection in the brain is usually multifocal as old encysted parasites become actively pathogenic again. The clinical presentation may be focal or diffuse but is a cerebrovascular accident, but is more usually progressive aver a few days or a week or two.
Peripheral neuropathies of several types can complicate the various stages of HIV infection. Early in the course of HIV infection a Guillain-Barre type of neuropathy may be seen. The clinical picture is the same as the familiar acute inflammatory or postinfectious neuropathy, with weakness of limb and facial muscles, minor sensory symptoms and loss of tendon reflexes. The weakness tends to be both proximal and distal. There bay be backache and limb pains. There is evidence that the axonal neuropathy in the late stages of the disease correlated with the presence of dementia. Its ethnology is unknown, but it has been suggested that it may be a direct effect of HIV.
The most prevalent opportunistic disease among persons with HIV in late stage is Pneumocystis carinii pneumonia. Recently, however, studies of ribosomal RNA of P. carinii have shown that phylogenetically the organism is most closely related to the Ascomycetes (yeasts): thus P. carinii should probably be considered a fungus rather than a parasite. This reclassification has little clinical relevance but may suggest new therapeutic approaches and culture techniques. P. carinii is thought to have a life cycle consisting of three stages: cyst, whish are spherical or crescent-shaped form 5 to 8 mm in diameter; sporozoites or intracystic bodies, found only within the cyst; and tropozoites, found outside the cyst and believed intermediate between the sporozoite and the cyst. The Giemsa stain is taken up by both the intracystic sporozoites and extracystic tropozoites; cyst are not pozitively stained and cannot be seen except as negative images within the matrix of a clump of tropozoites. Infection with P. carinii is common early in the life and dose not generally results in symptomatic disease in immunocompetent hosts. Until the occurrence of the epidemic of infection with the HIV P. carinii pneumonia was an uncommon, sporadic disorders that occurred primary in patient with leukemia or other recognized causes of impairment of host defences and in patients who were given immunosuppressive therapy. Several studies in the
Since the beginning of the HIV epidemic an increasing association of Mucobacterium tuberculosis infection with HIV infection has beeoted. Between 1978 and 1985 the yearly rate of tuberculosis more than doubled at one
The association of disseminated Mycobacterium avium complex (MAC) infection with HIV was recognized early in the HIV epidemic. Disseminated MAC infection has been reported only rarely in patients without HIV. Disseminated MAC infection occurs exclusively in patients with very advanced HIV disease essentially only in patients with CD4 lymphocyte counts<100/ml. MAC is a ubiquitous soil and water saprophyte. The source of MAC invasion in HIV patients may be gastrointestinal or respiratory. The presence of large clusters of mycobacterium within macrophagas of the small bowell lamina propria suggests the bowel wight be the portal of entry. However, respiratory isolation of the MAC also frequently precedes disseminated infection, suggesting MAC infection may begin in the lungs as well. Since most HIV patients with disseminated MAC infection have other concomitant infections or neaplasms and since MAC appears to cause little histopathologic evidence of inflammatory response or tissue destruction, the relationship between constitutional symptoms, organ dysfunction, and MAC infection has been uncertain.
Four clinical syndromes often over lapping, have been associated with disseminated MAC infection.
– Systemic symptoms. Fever, malaise, weight loss often associated with anemia, neutropenia.
– Gastrointestinal symptoms.
– Chronic diarrhoea and abdominal pain (MAC infection of colon often observed at autopsy)
– Chronic malabsorbtion (histopatologic changes in small intestine similar to those with Whipple’s disease often observed at autopsy)
– Extrabiliary obstructive jaundice secondary to periportal lymphadenopathy.
Cryptococcus neaformans and tuberculosis are the major opportunistic infection complicating the HIV epidemic world-wide. Although other pathogens may dominate on individual continents or in specific regions, no other major pathogen poses as great a global threat to those immunocompromised by HIV infection. The high mortality and morbidity rates associated with cryptococcal infection and the toxicity of traditional therapy have sparred intense interest iew treatment alternatives. A better understanding of the natural history of HIV-mediated immunodepression has seen the emergence of debate about the use and advisability of fungal prophylactic. This organism a common resident of the lung, is often inhaled from the air. It grows actively in the droppings of pigeons and enters the air in wind borne particles. The fungus is generally noninfectious, but in patients with HIV it multiplies in the lungs, spreads to the blood and localized on the brain and its coverings. The clinical presentation of cryptococcal disease in HIV patient is often subtle and nonspecific. A prolonged febrile prodrome, indistinguishable from that accompanying other opportunistic infections is common. Frequently no localizing signs or symptoms are present to guide the physician toward the diagnosis of cryptococcal disease. Although the portal of entry for C. neoformans is the lung. Pulmonary cryptococcosis is usually clinically. Most cases of pulmonary cryptococcal infection are discovered serendipitously, not because of organ specific signs or symptoms. Occasionally, however, pulmonary symptoms dominate the clinical presentation and progression to respiratory failure and death are not unknown. However, among those HIV-infected patients with cryptococcal disease and without CHS involvement, fully two thirds had cough and shortness of breath. In contrast only 18% of those patients with culture-proven CNS disease had respiratory symptoms. These numbers add weight to the argument that all patients with CNS involvement have or have had antecedent pulmonary infection. Blood-borne spread to any organ, but the organism has a predilection for the CNS. It causes a granulomatous meningitis with or without clinically evident pulmonary or disseminated infection. In addition, there may be small cysts in the cerebral cortex. The clinical presentation is usually with headache, fever, and constitutional upset; neck stiffness, photophobia and focal neurologic signs are present.
Skin disease is an extremely common complication of HIV infection, affecting up to 90% of persons. Some of the skin conditions also are commonly seen in uninfected persons (e.g. seborrheic dermatitis) but are of increased severity in the HIV infected person. Other skin diseases are relatively unique to HIV infection (Kaposi’s sarcoma)(Fig. 8).
Fig.8. Elements of Kaposi’s sarcoma
The average HIV infected patient has at least two and often more different skin conditions simultaneously. It is useful to classify the cutaneous disorder seen with HIV disease as either infectious disorder, hypersensitivity disorders and drug reactions, or neoplasms.
Oral lesions (Fig. 9) have been recognized as prominent features of HIV infection since the beginning of the epidemic. Some of these changes are reflections of reduced immune function manifested as oral opportunistic conditions, which are often the earliest clinical features of HIV infection. Some, in the presence of known HIV infection are highly predictive of the ultimate development of the full syndrome, whereas others represent the oral features of AIDS itself.
Fig.9. Oral lesions in AIDS
They include oral infections in patients with primary immunodeficiency, leukemia, and diabetes, and those resulting from radiation therapy, cancer chemotherapy and bone marrow supression. In the prospective cohorts of HIV infected homosexual and bisexual men hairy leukoplakia pseudomembranous candidiasis are the most common oral lesions.
Fig.10. Oral Kaposi’s sarcoma in AIDS
Kaposi’s sarcoma (KS) in patients with AIDS produces oral lesions in many cases (Fig. 10).
The lesions occur as red or purple macules, papules, or nodules. Occasionally the lesions are the same color as the adjoining normal mucosa. Although frequently asymptomatic, pain may occur because of traumatic ulcerisation with inflammation and infection. Bulky lessions may be visible or may interfere with speech and mastication. Diagnosis involves biopsy. Lesions at the gingival margin frequently become inflamed and painful because of plaque accumulation.
From the outset of the HIV epidemic, clinicians everywhere noted a high prevalence of the gastrointestinal (GI) signs and symptoms. Some of these manifestation such as weight loss, dysphagia, anorexia, and diarrhoea are almost universally among patients with HIV. Early and complete invasive and noninvasive evulation of these patients should be undertaken with particular attention to treatable non-HIV-associated biliary tract disease. Hepatic parenchymal disease likewise is common in patient with HIV infection.
Cramping paraumbilical abdominal pain, weight loss (Fig. 11, 12) and large-volume diarrhea are common in patient with HIV disease.
Fig.11. Loss of weight in AIDS
Fig.12. Loss of weight in AIDS
The majority of HIV patients with these complaints has specific small bowel infection. Certainly routine colonic bacterial pathogens such us Salmonella, Shigella and Campylobacter, which may be persistent and mimic chronic inflammatory bowel disease, should be excluded by the adequate culture techniques. Likewise, routine and atypical parasitic infestation including that caused by Giardia lamblia, E. histolytica, Criptosporidium and
On occasion, patients with HIV may suddenly develop ascites. Since some HIV-infected patient may have underlying cirrhosis (caused by either alcohol consumption or viral hepatitis), a sizeable percentage of them will have transudative ascites related to their chronic liver disease. Careful evaluation of the ascites fluid, including performing cytology, and acid-fast stains should be done early to exclude patients with malignancy and tuberculosis peritonitis.
Malignancies as a complication of immunodeficiency have been well described in the literature, being recognized long before the advent of the HIV epidemic. The incidence of both Kaposi’s sarcoma (KS) and non-Hodgkin’s lymphoma (NHL) are marked by increased in immunosuppressed allograft recipients. It is therefore not suprising that patients with HIV infection, who also have proformed defects in cell-mediated immunity also develop these two malignancies. KS once a rarely reported malignancy is the most commoeoplasm affecting HIV-infected individuals. IT is seen primarily in homosexual men and has only rarely been reported in intravenous drug users or other risk groups. The pathogenesis of KS and HIV-infected patients remain uncertain. The natural history of KS associated with HIV infection more closely resembles that observed in immunosuppressed allograft patients. The disease tends to progress with time and is associated with the appearance of larger and more numerous cutaneous lesions (Fig. 13).
Fig.13. Cutaneous lesions in AIDS
However, the course of the disease is unpredictable. A patient may have relatively few lesions that remain stable over time. New cutaneous lesions may not appear for many months but may be followed by a sudden and rapid increase in disease activity. Visceral involvement with KS is extremely common and can involve almost any visceral site. Careful endoscopic examination will reveal gastrointestinal sites of disease in most patient.
Cutaneous lesions may become painful and if large cutaneous surfaces are involved can restrict movement. Lymphatic obstruction is common and can result in severe edema, most commonly involving the extremities or the face. visceral spread of KS is rarely symptomatic, particularly when it involves the gastrointestinal tract. Careful examination of the skin and oral cavity at each clinic visit is the key to early diagnosis. Once lesions are identified, histologic confirmation should be obtained.
The non Hodgkin’s lymphomas are a heterogenous group of malignancies. Their biologic behavior ranges from indolent requiring no therapy, to aggressive malignancies with few long-term survivors. In the most commonly used classification system for the NHL, these malignancies are divided into three major categories: low grade, intermediate grade, and high grade, according to pathologic characteristics of involved lymph nodes and morphologic criteria of the lymphoma cells.
Infection with the HIV is associated with a wide spectrum of hematologic abnormalities. These abnormalities are found in all stages of HIV disease and involve the bone marrow, cellular elements of the peripheral blood and coagulation pathways. The cause of these abnormalities is multifactorial. A direct suppressive effect of HIV infection, ineffective hematopoiesis, infiltrative disease of the bone marrow, nutritional deficiencies, peripheral consumption secondary to splenomegaly or immune dysregulation, and drug effect all contribute to the variety of hematologic findings in these patients. Many of these abnormalities are clinically significant, whereas others are more of academic interest.
Peripheral cytopenias are common in HIV-infected individuals and are due to either decreased production in the bone marrow or accelerated destruction in the peripheral circulation. In general the cytopenias increase in frequency as HIV-disease progresses. Anemia is the most common hematologic abnormality noted in patients with HIV disease. The largest HIV infection affects the lymphocyte, neutrophil and macrophage monocyte cell lines. Despite the hyperhammahlobulinemia noted in these patient, they suffer complications from both defective cellular immunity and dysregulated humoral immunity. The hallmark of HIV infection is progressive depletion of the CD-4 lymphocytes. This decrement presumably occurs through direct viral invasion of these cells. Early in HIV infection an initial increase in the CD-4 population occurs before a decline in the number of CD-4 cells is noted. Granulocytopenia independent of drug use is noted in approximately 50% of patients with HIV. Drug-induced neuthropenia is in the HIV-infected individual. Medication used to treat infection such as P. carinii pneumonia, toxoplasmosis and cytomegalovirus retinitis or colitis cause neuthropenia. Similarly, ridovudine is implicated as a cause of neuthropenia, ofteecessitating dose reduction or cessation of therapy. As for the complication of neuthropenia, most documented infection involve gram-negative organisms. The most common platelet abnormality found in HIV-infected patients is thrombocytopenia have only minor submucosal bleeding. characterized by petechiae, echymoses and occasional epistaxis. Rare patients have gastrointestinal blood loss. Laboratory findings reveal that patients generally have isolated thrombocytopenia, which usually is not accompanied by anemia and leukopenia. Patients with HIV infection, including those being treated with antibodies for an AIDS-opportunistic infection and those being treated with cytotoxic chemotherapeutic agents for HIV-related malignancies, may also develop thrombocytopenia secondary to a therapeutic intervention. In these patients severe thrombocytopenia should be managed as it is in the non-HIV-infected individual. Medications causing thrombocytopenia should be discontinued and platelet transfusion should be administered when indicated.
Diagnostics
The first test developed to detected HIV infection was isolation of the virus through tissue culture. Unfortunately although sensitive for viral isolation the tissue culture procedure is expensive, time consuming and labor intensive. As a result soon after the initial discovery of HIV several tests were developed using protein products of the newly discovered virus to detect antibodies produced by the infected host. The two antibodi tests used most commonly are the enzyme-linked immunosorbent assay (ELISA) and the western blot. In addition to being less expensive, faster and easier to perform than viral culture, the ELISA and the Western blot test do not require working with like virus and therefore are safer. Over the best some years several novel techniques have been developed. The radioimmunoprecipitation assay (RIPA) is a more time consuming, and labor intensive test the Western blot, yet it provides much finer resolution of the high-molecular-weight envelope proteins than the western blot test. The RIPA is considered more sensitive and specific than the Western blot test, however, the time, expense, and need for active cell lines and radioactive materials make the RIPA a poor choice for routine testing in commercial laboratories. Rather its use is best reserved for difficult-to-diagnose cases. Like the RIPA the indirect immunofluorescence assay (IFA) requires preparation of HIV antigens that are expressed on infected cells and are stained subsequently. Infected cells are placed on the glass slides in a fixed monolayer and are incubated with patient serum. Anti-HIV antibodies present within the serum bind to antigens expressed on the surface of cells, and these bound antibodies are then detected with anti-human antibody that has been labeled with fluorescein isothiocyanate an ultraviolet-activated dye compound. after appropriate processing, the slide is viewed under a fluorescent microscope and the number of cells the intensity of staining and the staining pattern are assessed. Polymerase chain reaction (PCR) technique, introduced in the late 1980s, represent a major advance in the diagnosis of many disorders, including HIV infection. This powerful technique can amplify DNA existing in very small quantities through a series of binary replicative cycles. The PCR procedure can also be applied to RNA.
The pool of human lymphocytes possesses specific glycoproteins of their surface that play an important role in the cells activity and function CD-4 positive lymphocytes are the primary target of HIV infection, and the CD-4 receptor is the primary binding site of HIV. Throughout the course of chronic HIV infection the number of CD-4 lymphocytes is depleted and the loss of these cells is associated with development of the characteristic opportunistic infection and malignancies of AIDS. Thus the measurement of CD-4 positive lymphocytes is one of the most impotent determinates for clinically staging the disease status of HIV infected patients. In uninfected controls normal values for the CD-4/CD-8 ratio are 2.0 to 1.0. Normal values for CD-4 counts are generally 500 to 1000 cells/ml3 in adults.
Treatment
Basic therapy consists of indication of antiviral agents. Use preparations, that inhibit the return transcriptasa of the virus: Azydotymidin (АzТ), Didanosin (ddi), Zalcytobyn (ddc), Stavodin (d4T), Lamivudin , Abacavir (АВС), Nevirapapin (NVP).
Till now monotherapy AZT (Retrovir, Zidovudin) was used. The preparation are prescribed (P.O.) 0,2 gr. 3 times per day constantly or courses, duration is not less than 3 months. Treatment will be carried out under the control of the general analysis of a blood with 2 times per one month during the first 2 months and subsequently once per month. In a stage preAIDS (secondary diseases) AZT is necessary to indicate till disappearance of a clinical symptomatology. If the clinical picture is not better Zidovidin is indicated only for that patient in which blood concentration are less than 500 cells in 1 mkl. With such treatment it is possible to prolong patients life, the number of resistant viruses to a preparation however is marked. So, monotherapy AZT is recommended only for prophylaxis of infection of fetus from mother.
Among new means with other mechanism of action use a specific inhibitor of proteases Krixivan, which is effective concerning resistant to AZT populations of a virus 0,8 g every 8 h. Preparations of a choice may be Rotonavir, Nelfinavir, Sacvinar-SGC, Amprenavir.
Recently it is proved, that efficiency of treatment essentially can be increased using a combination of two or three antiviral preparations. Therefore monotherapy was changed for polytherapy. The most frequently combination of two inhibitors of virus return transcriptasa (stavudin + didanosin, stavudin + lamivudin, zidovudin+didanosin, zidovudin + lamivudin, zidovudin+abacavir) and one inhibitor of a protease is used. At patients with high risk of disease progress (viraemia over 1 000 000 copies / ml.), and also in urgent cases use the two inhibitors of proteases and 1 -2 inhibitors of virus return transcriptasa.
Efficiency of specific treatment is controlled by monitoring with following criteria: 1) level HIV RNA in plasma; 2) quantity of T-lymphocytes CD4; 3) a clinical condition of the patient; 4) morphology and biochemistry of a blood (for detection of undersirable effects of an organism). Level HIV RNA in plasma is researched after 4-8 and 12-16 weeks from the beginning of treatment and subsequently each 3-4 months. The major condition of successful antiretrovirus therapy is its usage during all life of the patient, however it is interfered by a high toxicity of preparations and the complications connected with them. Complete treatment of patients with AIDS remains an unsolved problem. Last combination is considered the most effective, but also it does not cure patients with AIDS.
It is not less important preventive treatment of secondary diseases at AIDS. Against pneumocystic pneumonias the basic agent is Bactrimum. For initial prophylaxis of this disease Bactrimum is indicated 1 tablet duaring 3 days each week. At occurrence of pneumonia daily reception of preparation is prescribed. In case of an intolerance of Bactrim it is possible to indicate Dapsone or Primachin in a combination with Clindamicin. At presence of herpetic infections indicate Acyclovir.
Against criptococus and other funguses use Amphotericinum, against bacteria – the appropriate antibiotic. At sarcoma Kaposhi freezing elements of an eruption by liquid nitrogen, irradiation, chemotherapy are indicated. The immunotherapy of AIDS is at developing stage.