MINISTRY OF HEALTH OFTHE REPUBLIC OF UZBEKISTAN
CENTER OF DEVELOPMENT OF MEDICAL EDUCATION
TASHKENT MEDICAL ACADEMY
Department of infectious and pediatric infectious diseases
Subject: Infectious diseases
THEME: Fever
Educational-methodical guideline for teachers and students of Treatment Faculty
TASHKENT
MINISTRY OF HEALTH OFTHE REPUBLIC OF UZBEKISTAN
CENTER OF DEVELOPMENT OF MEDICAL EDUCATION
TASHKENT MEDICAL ACADEMY
"A F F I R M E D"
Pro-rector of educational work
Professor Teshaev O.R.
__________________________
«____»____________2012
Department of infectious and pediatric infectious diseases
Subject: Infectious diseases
THEME: Fever
Educational-methodical guideline for teachers and students of Treatment Faculty
"A F F I R M E D"
at a DNC meeting of Therapeutic Faculty
Protocol № ___from_________2012
Chairman of DNC, Professor
Karimov M.Sh.___________
TASHKENT
THEME: Fever
1. Place of the lessons, equipping
- The auditorium;
- Department of DCI;
- Box Office;
- Outpatient department;
- Diagnostic department;
- The emergency room;
- Laboratories (clinical, biochemical, bacteriological, immunological);
- TCO: Case patients with TPZ, brucellosis, yellow fever, malaria, influenza and acute respiratory
infections, meningococcal disease, toxoplasmosis, infectious mononucleosis; glidescope; TV-video,
teaching, supervising the program, methods of work scenarios in small groups, case
studies. Guidelines for self for practical training in infectious diseases. Guidelines «The laboratory
diagnosis of acute infectious diseases."
2. The duration of the study subjects
Number of hours - 6
3. The purpose of classes
- Develop skills in an integrated approach to clinical diagnosis of infectious diseases with a feverish
syndrome, management of laboratory studies in primary care.
Develop a sense of responsibility for the diagnosis and deontological communication skills with
patients with a diagnosis of "fever of unknown origin" and its relatives. Education of rational
therapy in the home, personal preventive health examinations and rehabilitation of convalescents
febrile patients;
- when parsing the topics at the bedside of an individual patient, in laboratories and in the
classroom, to bring interest to the profession, to stimulate the process of self-education, and develop
a sense of responsibility and compassion to the sick;
- as an example, parsed thematic issues to develop scientific thinking, to stimulate creative approach
to solving non-standard clinical tasks and the ability to make independent decisions. To develop
logical thinking and ability to express their thoughts on professional language.
Objectives
The student should know:
- The differential diagnosis of febrile syndrome in the most common infectious diseases;
- The differential diagnosis of febrile syndrome in the most common infectious diseases with fever
of noninfectious origin;
- Early rational laboratory diagnosis of infectious diseases with fever syndrome;
- Preparation of a diagnostic algorithm for finding the presence of fever in a patient;
- The principles of the treatment and rehabilitation of patients;
- Specific and nonspecific methods of prevention.
The student should be able to:
- To conduct a professional history and examination of the patient;
- Establish a preliminary diagnosis on the basis of early and differential diagnosis;
- Appoint a targeted survey;
- Interpret data from laboratory and instrumental methods of examination;
- Own clinical decision-making logic (to form a definitive diagnosis, to assess the severity of the
patient's condition and prognosis);
- To diagnose the state of emergency and to provide first medical aid in the pre-hospital;
- Decide whether to sending the patient for a consultation or admission to the appropriate hospital;
- To carry out rehabilitation of convalescents febrile patients.
As a result of training the student should learn practical skills:
Skills 1st order
- Examination of the patient;
- To take blood for serology;
- Taking on a thick blood drop, blood cultures;
- To take blood for biochemical research.
Skills of 2nd order
- Interpretation of laboratory data;
- Provide the necessary assistance to the pre-hospital;
- To hold the primary control measures at the source.
4. Motivation
The high incidence of febrile syndrome in various diseases as a therapeutic, and surgical and its
presence in almost all infectious diseases necessitate the skills of differential diagnosis of febrile
syndrome in medical GPs.
5. Interdisciplinary communication
Teaching this topic is based on the knowledge bases of students of biochemistry metabolism,
microbiology, immunology, pathological anatomy, pathological physiology, physiology of the
hypothalamic-pituitary system. The findings of the studies of knowledge will be used during the
passage of medicine, surgery, obstetrics, gynecology, hematology and other clinical disciplines.
6.The content of training
6.1.The theoretical part
Fever (also known as pyrexia) is a common medical sign characterized by an elevation of
temperature above the normal range of 36.5–37.5 °C (98–100 °F) due to an increase in the body
temperature regulatory set-point. This increase in set-point triggers increased muscle tone and
shivering.
As a person's temperature increases, there is, in general, a feeling of cold despite an
increasing body temperature. Once the new temperature is reached, there is a feeling of warmth. A
fever can be caused by many different conditions ranging from benign to potentially serious. There
are arguments for and against the usefulness of fever, and the issue is controversial. With the
exception of very high temperatures, treatment to reduce fever is often not necessary; however,
antipyretic medications can be effective at lowering the temperature, which may improve the
affected person's comfort.
Fever differs from uncontrolled hyperthermia, in that hyperthermia is an increase in body
temperature over the body's thermoregulatory set-point, due to excessive heat production and/or
insufficient thermoregulation.
`Thermoregulation
As in other mammals, thermoregulation is an important aspect of human homeostasis. Most body
heat is generated in the deep organs, especially the liver, brain, and heart, and in contraction of
skeletal muscles. Humans have been able to adapt to a great diversity of climates, including hot
humid and hot arid. High temperatures pose serious stresses for the human body, placing it in great
danger of injury or even death. For humans, adaptation to varying climatic conditions includes both
physiological mechanisms as a byproduct of evolution, and the conscious development of cultural
adaptations.
There are four avenues of heat loss: convection, conduction, radiation, and evaporation. If
skin temperature is greater than that of the surroundings, the body can lose heat by radiation and
conduction. But if the temperature of the surroundings is greater than that of the skin, the body
actually gains heat by radiation and conduction. In such conditions, the only means by which the
body can rid itself of heat is by evaporation. So when the surrounding temperature is higher than the
skin temperature, anything that prevents adequate evaporation will cause the internal body
temperature to rise. During sports activities, evaporation becomes the main avenue of heat loss.
Humidity affects thermoregulation by limiting sweat evaporation and thus heat loss.
The skin assists in homeostasis (keeping different aspects of the body constant e.g. temperature). It
does this by reacting differently to hot and cold conditions so that the inner body temperature
remains more or less constant. Vasodilation and sweating are the primary modes by which humans
attempt to lose excess body heat. The brain creates much heat through the countless reactions which
occur. Even the process of thought creates heat. The head has a complex system of blood vessels,
which keeps the brain from overheating by bringing blood to the thin skin on the head, allowing
heat to escape. The effectiveness of these methods is influenced by the character of the climate and
the degree to which the individual is acclimatized.
In hot conditions Eccrine sweat glands under the skin secrete sweat (a fluid containing mostly
water with some dissolved ions) which travels up the sweat duct, through the sweat pore and onto
the surface of the skin. This causes heat loss via evaporative cooling; however, a lot of essential
water is lost.
The hairs on the skin lie flat, preventing heat from being trapped by the layer of still air
between the hairs. This is caused by tiny muscles under the surface of the skin called Arrector pili
muscles relaxing so that their attached hair follicles are not erect. These flat hairs increase the flow
of air next to the skin increasing heat loss by convection. When environmental temperature is above
core body temperature, sweating is the only physiological way for humans to lose heat.
Arterioles Vasodilation occurs, this is the process of relaxation of smooth muscle in arteriole walls
allowing increased blood flow through the artery. This redirects blood into the superficial capillaries
in the skin increasing heat loss by convection and conduction.
Note: Most animals can't sweat efficiently. Cats and dogs have sweat glands only on the pads of
their feet. Horses and humans are two of the few animals capable of sweating. Many animals pant
rather than sweat because the lungs have a large surface area and are highly vascularised. Air is
inhaled, cooling the surface of the lungs and is then exhaled losing heat and some water vapour.
Thermoregulation in hot and humid conditions
In general, humans appear physiologically well adapted to hot dry conditions. However, effective
thermoregulation is reduced in hot, humid environments such as the Red Sea and Persian Gulf
(where moderately hot summer temperatures are accompanied by unusually high vapor pressures),
tropical environments, and deep mines where the atmosphere can be water-saturated. In hot-humid
conditions, clothing can impede efficient evaporation. In such environments, it helps to wear light
clothing such as cotton, that is pervious to sweat but impervious to radiant heat from the sun. This
minimizes the gaining of radiant heat, while allowing as much evaporation to occur as the
environment will allow. Clothing such as plastic fabrics that are impermeable to sweat and thus do
not facilitate heat loss through evaporation, can actually contribute to heat stress.
In cold conditions
Sweat stops being produced.
The minute muscles under the surface of the skin called arrector pili muscles (attached to an
individual hair follicle) contract (piloerection), lifting the hair follicle upright. This makes the hairs
stand on end which acts as an insulating layer, trapping heat. This is what also causes goose bumps
since humans don't have very much hair and the contracted muscles can easily be seen.
Arterioles carrying blood to superficial capillaries under the surface of the skin can shrink
(constrict), thereby rerouting blood away from the skin and towards the warmer core of the body.
This prevents blood from losing heat to the surroundings and also prevents the core temperature
dropping further. This process is called vasoconstriction. It is impossible to prevent all heat loss
from the blood, only to reduce it. In extremely cold conditions excessive vasoconstriction leads to
numbness and pale skin. Frostbite only occurs when water within the cells begins to freeze, this
destroys the cell causing damage.
Muscles can also receive messages from the thermo-regulatory center of the brain (the
hypothalamus) to cause shivering. This increases heat production as respiration is an exothermic
reaction in muscle cells. Shivering is more effective than exercise at producing heat because the
animal remains still. This means that less heat is lost to the environment via convection. There are
two types of shivering: low intensity and high intensity. During low intensity shivering animals
shiver constantly at a low level for months during cold conditions. During high intensity shivering
animals shiver violently for a relatively short time. Both processes consume energy although high
intensity shivering uses glucose as a fuel source and low intensity tends to use fats. This is a
primary reason why animals store up food in the winter.[citation needed]
Mitochondria can convert fat directly into heat energy, increasing the temperature of all cells in the
body. Brown fat is specialized for this purpose, and is abundant in newborns and animals that
hibernate.
The process explained above, in which the skin regulates body temperature is a part of
thermoregulation. This is one aspect of homeostasis-the process by which the body regulates itself
to keep internal conditions constant.
Pathophysiology
Temperature is ultimately regulated in the hypothalamus. A trigger of the fever, called a pyrogen,
causes a release of prostaglandin E2 (PGE2). PGE2 then in turn acts on the hypothalamus, which
generates a systemic response back to the rest of the body, causing heat-creating effects to match a
new temperature level.
In many respects, the hypothalamus works like a thermostat. When the set point is raised, the body
increases its temperature through both active generation of heat and retaining heat. Vasoconstriction
both reduces heat loss through the skin and causes the person to feel cold. If these measures are
insufficient to make the blood temperature in the brain match the new setting in the hypothalamus,
then shivering begins in order to use muscle movements to produce more heat. When the fever
stops, and the hypothalamic setting is set lower; the reverse of these processes (vasodilation, end of
shivering and nonshivering heat production) and sweating are used to cool the body to the new,
lower setting.
This contrasts with hyperthermia, in which the normal setting remains, and the body
overheats through undesirable retention of excess heat or over-production of heat.[20]
Hyperthermia is usually the result of an excessively hot environment (heat stroke) or an adverse
reaction to drugs. Fever can be differentiated from hyperthermia by the circumstances surrounding
it and its response to anti-pyretic medications.
Pirogues
A pyrogen is a substance that induces fever. These can be either internal (endogenous) or
external (exogenous) to the body. The bacterial substance lipopolysaccharide (LPS), present in the
cell wall of some bacteria, is an example of an exogenous pyrogen. Pyrogenicity can vary: In
extreme examples, some bacterial pyrogens known as superantigens can cause rapid and dangerous
fevers. Depyrogenation may be achieved through filtration, distillation, chromatography, or
inactivation.
Endogenous
In essence, all endogenous pyrogens are cytokines, molecules that are a part of the innate
immune system. They are produced by phagocytic cells and cause the increase in the
thermoregulatory set-point in the hypothalamus. Major endogenous pyrogens are interleukin 1 (α
and β), interleukin 6 (IL-6) and tumor necrosis factor-alpha. Minor endogenous pyrogens include
interleukin-8, tumor necrosis factor-α, tumor necrosis factor-β, macrophage inflammatory protein-α
and macrophage inflammatory protein-β as well as interferon-α, interferon-β, and interferon-γ.
These cytokine factors are released into general circulation, where they migrate to the
circumventricular organs of the brain due to easier absorption caused by the blood-brain barrier's
reduced filtration action there. The cytokine factors then bind with endothelial receptors on vessel
walls, or interact with local microglial cells. When these cytokine factors bind, the arachidonic acid
pathway is then activated.
Exogenous
One model for the mechanism of fever caused by exogenous pyrogens includes LPS, which
is a cell wall component of gram-negative bacteria. An immunological protein called
lipopolysaccharide-binding protein (LBP) binds to LPS. The LBP–LPS complex then binds to the
CD14 receptor of a nearby macrophage. This binding results in the synthesis and release of various
endogenous cytokine factors, such as interleukin 1 (IL-1), interleukin 6 (IL-6), and the tumor
necrosis factor-alpha. In other words, exogenous factors cause release of endogenous factors,
which, in turn, activate the arachidonic acid pathway.
PGE2 release
PGE2 release comes from the arachidonic acid pathway. This pathway (as it relates to
fever), is mediated by the enzymes phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2), and
prostaglandin E2 synthase. These enzymes ultimately mediate the synthesis and release of PGE2.
PGE2 is the ultimate mediator of the febrile response. The set-point temperature of the body will
remain elevated until PGE2 is no longer present. PGE2 acts on neurons in the preoptic area (POA)
through the prostaglandin E receptor 3 (EP3). EP3-expressing neurons in the POA innervate the
dorsomedial hypothalamus (DMH), the rostral raphe pallidus nucleus in the medulla oblongata
(rRPa), and the paraventricular nucleus (PVN) of the hypothalamus . Fever signals sent to the DMH
and rRPa lead to stimulation of the sympathetic output system, which evokes non-shivering
thermogenesis to produce body heat and skin vasoconstriction to decrease heat loss from the body
surface. It is presumed that the innervation from the POA to the PVN mediates the neuroendocrine
effects of fever through the pathway involving pituitary gland and various endocrine organs.
Hypothalamus
The brain ultimately orchestrates heat effector mechanisms via the autonomic nervous
system. These may be:
Increased heat production by increased muscle tone, shivering and hormones like
epinephrine
Prevention of heat loss, such as vasoconstriction.
In infants, the autonomic nervous system may also activate brown adipose tissue to produce
heat (non-exercise-associated thermogenesis, also known as non-shivering thermogenesis).
Increased heart rate and vasoconstriction contribute to increased blood pressure in fever.
Usefulness
There are arguments for and against the usefulness of fever, and the issue is controversial.
There are studies using warm-blooded vertebrates and humans in vivo, with some suggesting that
they recover more rapidly from infections or critical illness due to fever. A Finnish study suggested
reduced mortality in bacterial infections when fever was present.
In theory, fever can aid in host defense. There are certainly some important immunological
reactions that are sped up by temperature, and some pathogens with strict temperature preferences
could be hindered.
Research has demonstrated that fever assists the healing process in several important ways:
Increased mobility of leukocytes
Enhanced leukocytes phagocytosis
Endotoxin effects decreased
Increased proliferation of T cells
The pattern of temperature changes may occasionally hint at the diagnosis:
Continuous fever: Temperature remains above normal throughout the day and does not
fluctuate more than 1 °C in 24 hours, e.g. lobar pneumonia, typhoid, urinary tract infection,
brucellosis, or typhus. Typhoid fever may show a specific fever pattern (Wunderlich curve of
typhoid fever), with a slow stepwise increase and a high plateau. (Drops due to fever-reducing
drugs are excluded.)
Intermittent fever: The temperature elevation is present only for a certain period, later
cycling back to normal, e.g. malaria, kala-azar, pyaemia, or septicemia. Following are its types
Quotidian fever, with a periodicity of 24 hours, typical of Plasmodium falciparum
Tertian fever (48 hour periodicity), typical of Plasmodium vivax and Plasmodium ovale
Quartan fever (72 hour periodicity), typical of Plasmodium malariae.
Remittent fever: Temperature remains above normal throughout the day and fluctuates
more than 1 °C in 24 hours, e.g., infective endocarditis.
Pel-Ebstein fever: A specific kind of fever associated with Hodgkin's lymphoma, being
high for one week and low for the next week and so on. However, there is some debate as to
whether this pattern truly exists.
A neutropenic fever, also called febrile neutropenia, is a fever in the absence of normal
immune system function. Because of the lack of infection-fighting neutrophils, a bacterial infection
can spread rapidly; this fever is, therefore, usually considered to require urgent medical attention.
This kind of fever is more commonly seen in people receiving immune-suppressing chemotherapy
than in apparently healthy people.
Febricula is an old term for a low-grade fever, especially if the cause is unknown, no other
symptoms are present, and the patient recovers fully in less than a week.
Hyperpyrexia is a fever with an extreme elevation of body temperature greater than or
equal to 41.5 °C (106.7 °F). Such a high temperature is considered a medical emergency as it may
indicate a serious underlying condition or lead to significant side effects. The most common cause
is an intracranial hemorrhage. Other possible causes include sepsis, Kawasaki syndrome,
neuroleptic malignant syndrome, drug effects, serotonin syndrome, and thyroid storm. Infections
are the most common cause of fevers, however as the temperature rises other causes become more
common. Infections commonly associated with hyperpyrexia include: roseola, rubeola and
enteroviral infections. Immediate aggressive cooling to less than 38.9 °C (102.0 °F) has been found
to improve survival. Hyperpyrexia differs from hyperthermia in that in hyperpyrexia the body's
temperature regulation mechanism sets the body temperature above the normal temperature, then
generates heat to achieve this temperature, while in hyperthermia the body temperature rises above
its set point.
Hyperthermia is an example of a high temperature that is not a fever. It occurs from a
number of causes including heatstroke, neuroleptic malignant syndrome, malignant hyperthermia,
stimulants such as amphetamines and cocaine, idiosyncratic drug reactions, and serotonin
syndrome.
Fever of unknown origin (FUO), pyrexia of unknown origin (PUO) or febris e causa
ignota (febris E.C.I.) refers to a condition in which the patient has an elevated temperature but
despite investigations by a physician no explanation has been found.
If the cause is found it usually is a diagnosis of exclusion, that is, by eliminating all possibilities
until only one explanation remains, and taking this as the correct one.
Definition
In 1961 Petersdorf and Beeson suggested the following criteria:
Fever higher than 38.3°C (101°F) on several occasions
Persisting without diagnosis for at least 3 weeks
At least 1 week's investigation in hospital
A new definition which includes the outpatient setting (which reflects current medical practice) is
broader, stipulating:
3 outpatient visits or
3 days in the hospital without elucidation of a cause or
1 week of "intelligent and invasive" ambulatory investigation.
Presently FUO cases are codified in four subclasses.
Classic FUO
This refers to the original classification by Petersdorf and Beeson. Studies show there are five
categories of conditions:
infections (e.g. abscesses, endocarditis, tuberculosis, and complicated urinary tract infections),
neoplasms (e.g. lymphomas, leukaemias),
connective tissue diseases (e.g. temporal arteritis and polymyalgia rheumatica, Still's disease,
systemic lupus erythematosus, and rheumatoid arthritis),
miscellaneous disorders (e.g. alcoholic hepatitis, granulomatous conditions), and
undiagnosed conditions.
Nosocomial
Nosocomial FUO refers to pyrexia in patients that have been admitted to hospital for at least
24 hours. This is commonly related to hospital associated factors such as, surgery, use of urinary
catheter, intravascular devices (i.e. "drip", pulmonary artery catheter), drugs (antibiotics induced
Clostridium difficile colitis, and drug fever), immobilization (decubitus ulcers). Sinusitis in the
intensive care unit is associated with nasogastric and orotracheal tubes. Other conditions that should
be considered are deep-vein thrombophlebitis, and pulmonary embolism, transfusion reactions,
acalculous cholecystitis, thyroiditis, alcohol/drug withdrawal, adrenal insufficiency, pancreatitis.
Immune-deficient
Immunodeficiency can be seen in patients receiving chemotherapy or in hematologic
malignancies. Fever is concommittent with neutropenia (neutrophil <500/uL) or impaired cellmediated immunity. The lack of immune response masks a potentially dangerous course. Infection
is the most common cause.
Human immunodeficiency virus (HIV)-associated
HIV-infected patients are a subgroup of the immunodeficient FUO, and frequently have
fever. The primary phase shows fever since it has a mononucleosis-like illness. In advanced stages
of infection fever mostly is the result of a superimposed infections.
Diagnosis
A comprehensive and meticulous history (i.e. illness of family members, recent visit to the
tropics, medication), repeated physical examination (i.e. skin rash, eschar, lymphadenopathy, heart
murmur) and a myriad of laboratory tests (serological, blood culture, immunological) are the
cornerstone of finding the cause.
Other investigations may be needed. Ultrasound may show cholelithiasis, echocardiography
may be needed in suspected endocarditis and a CT-scan may show infection or malignancy of
internal organs. Another technique is Gallium-67 scanning which seems to visualize chronic
infections more effectively. Invasive techniques (biopsy and laparotomy for pathological and
bacteriological examination) may be required before a definite diagnosis is possible.
Positron emission tomography using radioactively labelled fluorodeoxyglucose (FDG) has
been reported to have a sensitivity of 84% and a specificity of 86% for localizing the source of fever
of unknown origin.
Despite all this, diagnosis may only be suggested by the therapy chosen. When a patient
recovers after discontinuing medication it likely was drug fever, when antibiotics or antimycotics
work it probably was infection. Empirical therapeutic trials should be used in those patients in
which other techniques have failed.
Typhoid fever, also known as Typhoid, is a common worldwide bacterial disease,
transmitted by the ingestion of food or water contaminated with the feces of an infected person,
which contain the bacterium Salmonella enterica, serovar Typhi. The bacteria then perforate
through the intestinal wall and are phagocytosed by macrophages. The organism is a Gram-negative
short bacillus that is motile due to its peritrichous flagella. The bacterium grows best at 37°C /
98.6°F – human body temperature.
This fever received various names, such as gastric fever, abdominal typhus, infantile remittant
fever, slow fever, nervous fever, pythogenic fever, etc. The name of "typhoid" comes from the
neuropsychiatric symptoms common to typhoid and typhus.
The impact of this disease fell sharply with the application of modern sanitation techniques.
Classically, the course of untreated typhoid fever is divided into four individual stages, each lasting
approximately one week. In the first week, there is a slowly rising temperature with relative
bradycardia, malaise, headache, and cough. A bloody nose (epistaxis) is seen in a quarter of cases
and abdominal pain is also possible. There is leukopenia, a decrease in the number of circulating
white blood cells, with eosinopenia and relative lymphocytosis, a positive reaction and blood
cultures are positive for Salmonella typhi or paratyphi. The classic Widal test is negative in the first
week.
In the second week of the infection, the patient lies prostrate with high fever in plateau around 40
°C (104 °F) and bradycardia (sphygmothermic dissociation), classically with a dicrotic pulse wave.
Delirium is frequent, frequently calm, but sometimes agitated. This delirium gives to typhoid the
nickname of "nervous fever". Rose spots appear on the lower chest and abdomen in around a third
of patients. There are rhonchi in lung bases. The abdomen is distended and painful in the right
lower quadrant where borborygmi can be heard. Diarrhea can occur in this stage: six to eight stools
in a day, green with a characteristic smell, comparable to pea soup. However, constipation is also
frequent. The spleen and liver are enlarged (hepatosplenomegaly) and tender, and there is elevation
of liver transaminases. The Widal reaction is strongly positive with antiO and antiH antibodies.
Blood cultures are sometimes still positive at this stage. (The major symptom of this fever is that
the fever usually rises in the afternoon up to the first and second week.)
In the third week of typhoid fever, a number of complications can occur:
Intestinal hemorrhage due to bleeding in congested Peyer's patches; this can be very serious but is
usually not fatal.
Intestinal perforation in the distal ileum: this is a very serious complication and is frequently fatal. It
may occur without alarming symptoms until septicaemia or diffuse peritonitis sets in.
Encephalitis
Neuropsychiatric symptoms (described as "muttering delirium" or "coma vigil"), with picking at
bedclothes or imaginary objects.
Metastatic abscesses, cholecystitis, endocarditis and osteitis
The fever is still very high and oscillates very little over 24 hours. Dehydration ensues and the
patient is delirious (typhoid state). By the end of third week the fever has started reducing this
(defervescence). This carries on into the fourth and final week.
The bacteria which causes typhoid fever may be spread through poor hygiene habits and public
sanitation conditions, and sometimes also by flying insects feeding on feces. Public education
campaigns encouraging people to wash their hands after defecating and before handling food are an
important component in controlling spread of the disease. According to statistics from the United
States Centers for Disease Control and Prevention (CDC), the chlorination of drinking water has led
to dramatic decreases in the transmission of typhoid fever in the U.S.A.
A person may become an asymptomatic carrier of typhoid fever, suffering no symptoms, but
capable of infecting others. According to the CDC approximately 5% of people who contract
typhoid continue to carry the disease after they recover. The most famous asymptomatic carrier was
Mary Mallon (commonly known as "Typhoid Mary"), a young cook who was responsible for
infecting at least 53 people with typhoid, three of whom died from the disease. Mallon was the first
apparently perfectly healthy person known to be responsible for an "epidemic".
Many carriers of typhoid were locked into an isolation ward never to be released to prevent further
typhoid cases. These people often deteriorated mentally, driven mad by the conditions they lived in.
Paratyphoid fevers or Enteric fevers are a group of enteric illnesses caused by serotypic
strains of the Salmonella genus of bacteria, S. Paratyphi.
The concept of "serovars" is important to the nomenclature regiment for the Salmonella genus.
Serovar names also follow the genus, but are not to be confused with species. Unlike species names,
serovars are always capitalized and never italicized/underlined.
There are three serovars of the species of S. enterica that cause paratyphoid: S. Paratyphi A, S.
Paratyphi B (S. schottmuelleri and S. pullorum), and S. Paratyphi C (S. hirschfeldii).
They are transmitted by means of contaminated water or food.
The paratyphoid bears similarities with typhoid fever, but its course is more benign.
Paratyphoid A
Distribution
Factors outside the household like unclean food from street vendors and flooding help
distribute the disease from person to person. Because of poverty and poor hygiene and sanitary
conditions the disease is more common in less-industrialized countries, principally owing to the
problem of unsafe drinking-water, inadequate sewage disposal and flooding. Occasionally causing
epidemics, paratyphoid fever is found in large parts of Asia, Africa, Central and South America.
Many of those infected get the disease in Asian countries. There are about 16 million cases a year,
which result in about 25,000 deaths worldwide. Salmonella Typhi can specifically only attack
humans, so the infection nearly always comes from contact another human, either an ill person or a
healthy carrier of the bacterium. The bacterium is passed on with water and foods and can withstand
both drying and refrigeration but by keeping food refrigerated correctly this minimizes the
production of the bacterium significantly.
Causes
Paratyphoid fever is caused by any of three strains of Salmonella paratyphoid: S.
paratyphoid A; S. schottmuelleri (also called S. paratyphoid B); or S. hirschfeldii (also called S.
paratyphoid C). It starts when the bacterium Salmonella typhi is passed from another person due to
bad hygiene such as not washing one's hands after using the restroom. Eventually the bacterium
passes down to the bowel, then penetrates the intestinal mucosa (lining) to the underlying tissue. If
the immune system is unable to stop the infection here, the bacterium will multiply and then spread
to the bloodstream, after which the first signs of disease are observed in the form of fever. The
bacterium penetrates further to the bone marrow, liver and bile ducts, from which bacteria are
excreted into the bowel contents. In the second phase of the disease, the bacterium penetrates the
immune tissue of the small intestine, and the initial symptoms of small-bowel movements begin.
Symptoms
Paratyphoid fever resembles Typhoid Fever but presents with a more abrupt onset, milder
symptoms and a shorter course. Infection is characterized by a sustained fever, headache, abdominal
pain, malaise, anorexia, a non productive cough (in early stage of illness), a relative Bradycardia
(slow heart rate), and Hepatosplenomegaly (an enlargement of the liver or spleen). Approximately
30% of Caucasians will develop rosy spots on the central body. In adults, constipation is more
common than diarrhea. Only 20% to 40% of people will initially have abdominal pain. Nonspecific
symptoms such as chills, diaphoresis (perspiration), headache, anorexia, cough, weakness, sore
throat, dizziness, and muscle pains are frequently present before the onset of fever. Some very rare
symptoms are psychosis (mental disorder), confusion and seizures.
Paratyphoid B
Paratyphoid B is more frequent in Europe. It can present as a typhoid like illness, as a severe
gastroenteritis or with features of both. Herpes labialis, rare in true typhoid fever, is frequently seen
in Para B.
Diagnosis is with isolation of the agent in blood or stool and demonstration of antibodies
anti BH in the Widal test.
The disease responds well to chloramphenicol or co-trimoxazole.
Paratyphoid C
Paratyphoid C is a rare infection, generally seen in the Far East. It presents as a septicaemia with
metastatic abscesses. Cholecystitis is possible in the course of the disease.
Antibodies to para C are not usually tested and the diagnosis is made with blood cultures.
Chloramphenicol therapy is generally effective.
Brill’s Disease is a term to describe a delayed relapse of epidemic typhus, caused by
Rickettsia prowazekii. After a patient contracts epidemic typhus from the bite of an infected louse
(Pediculus humanus), the rickettsia can remain latent and reactivate months or years later, with
symptoms similar to or even identical to the original attack of typhus, including a maculopapular
rash, fever, and transient falling blood pressure. This reactivation event can be transmitted by louse
bites and is usually in times of relative immunosuppression.
Nathan Edwin Brill (1860-1925), an accomplished diagnostician, interned at Bellevue Hospital in
his home city of New York from 1879 to 1881. Subsequently, he began his career at Mount Sinai
Hospital and became professor at Columbia College of Physicians and Surgeons. Besides
describing Brill’s disease (also called Brill-Zinsser Disease) in immigrants from Eastern Europe, he
described a nodular lymphoma, Brill-Symmers disease, and recognized Gaucher’s disease to be a
lipid storage disease. He helped pioneer the use of splenectomy for thrombocytopenic purpura. His
breadth of interests was wide and his attraction to neurology motivated him to write a monograph
on congenital defects of the nervous system.
In 1898 he became aware of what we would eventually call Brill’s disease when he
translated Georg Klemperer’s textbook Clinical Diagnosis. Brill originally noted 17 cases of a
typhoid-like illness during a typhoid fever epidemic in 1896, about which he published in 1898. In
1910 he reported on 221 cases, originally calling the illness “critical fever” because of “the crisistype fall in temperature at the end of the illness.” Hans Zinsser, a pathologist and bacteriologist, in
the 1930s was able to prove Brill’s disease was “an imported form of classical typhus representing
recrudescence of infections initially acquired in Europe.” The causative organism was found to be
Rickettsia prowazekii, discovered by a Brazilian doctor, Henrique da Rocha Lima, in 1916. He and
his colleague Stanislaus von Prowazek were studying typhus in a German prison, when Prowazek
contracted the disease and died in 1915, prompting Lima to name the organism after his fallen
friend. R. prowazekii is of particular interest to evolutionary biologists because its genome is
strikingly similar to that of mitochondria.
Yersinia pseudotuberculosis is a Gram-negative bacterium that causes Pseudotuberculosis
(Yersinia) disease in animals; humans occasionally get infected zoonotically, most often through
the food-borne route. It is urease positve. In animals, Y. pseudotuberculosis can cause tuberculosislike symptoms, including localized tissue necrosis and granulomas in the spleen, liver, and lymph
node. In humans, symptoms of Pseudotuberculosis (Yersinia) are similar to those of infection with
Yersinia enterocolitica (fever and right-sided abdominal pain), except that the diarrheal component
is often absent, which sometimes makes the resulting condition difficult to diagnose. Y.
pseudotuberculosis infections can mimic appendicitis, especially in children and younger adults,
and, in rare cases, the disease may cause skin complaints (erythema nodosum), joint stiffness and
pain (reactive arthritis), or spread of bacteria to the blood (bacteremia).
Pseudotuberculosis (Yersinia) usually becomes apparent 5–10 days after exposure and typically
lasts 1–3 weeks without treatment. In complex cases or those involving immunocompromised
patients, antibiotics may be necessary for resolution; ampicillin, aminoglycosides, tetracycline,
chloramphenicol, or a cephalosporin may all be effective.
The recently described syndrome Izumi-fever has been linked to infection with
Y.pseudotuberculosis.
The symptoms of fever and abdominal pain mimicking appendicitis (actually from mesenteric
lymphadenitis) associated with Y. pseudotuberculosis infection are not typical of the diarrhea and
vomiting from classical food poisoning incidents. Although Y. pseudotuberculosis is usually only
able to colonize hosts by peripheral routes and cause serious disease in immunocompromised
individuals, if this bacterium gains access to the blood stream, it has an LD50 comparable to Y.
pestis at only 10CFU.
Brucellosis, also called Bang's disease, Crimean fever, Gibraltar fever, Malta fever, Maltese
fever, Mediterranean fever, rock fever, or undulant fever, is a highly contagious zoonosis caused by
ingestion of unsterilized milk or meat from infected animals or close contact with their secretions.
Transmission from human to human, through sexual contact or from mother to child, is rare but
possible. Brucella spp. are small, Gram-negative, non-motile, non-spore-forming, rod shaped
(coccobacilli) bacteria. They function as facultative intracellular parasites causing chronic disease,
which usually persists for life. Symptoms include profuse sweating and joint and muscle pain.
Brucellosis has been recognized in animals including humans since the 20th century.
Brucellosis in humans is usually associated with the consumption of unpasteurized milk and soft
cheeses made from the milk of infected animals, primarily goats, infected with Brucella melitensis
and with occupational exposure of laboratory workers, veterinarians and slaughterhouse workers.
Some vaccines used in livestock, most notably B. abortus strain 19, also cause disease in humans if
accidentally injected. Brucellosis induces inconstant fevers, sweating, weakness, anaemia,
headaches, depression and muscular and bodily pain.
The symptoms are like those associated with many other febrile diseases, but with emphasis
on muscular pain and sweating. The duration of the disease can vary from a few weeks to many
months or even years. In the first stage of the disease, septicaemia occurs and leads to the classic
triad of undulant fevers, sweating (often with characteristic smell, likened to wet hay) and migratory
arthralgia and myalgia. Blood tests characteristically reveal leukopenia and anemia, show some
elevation of AST and ALT, and demonstrate positive Bengal Rose and Huddleston reactions. This
complex is, at least in Portugal, known as the Malta fever. During episodes of Malta fever,
melitococcemia (presence of brucellae in blood) can usually be demonstrated by means of blood
culture in tryptose medium or Albini medium. If untreated, the disease can give origin to
focalizations or become chronic. The focalizations of brucellosis occur usually in bones and joints
and spondylodiscitis of lumbar spine accompanied by sacroiliitis is very characteristic of this
disease. Orchitis is also frequent in men.
Diagnosis of brucellosis relies on:
Demonstration of the agent: blood cultures in tryptose broth, bone marrow cultures. The
growth of brucellae is extremely slow (they can take until 2 months to grow) and the culture poses a
risk to laboratory personnel due to high infectivity of brucellae.
Demonstration of antibodies against the agent either with the classic Huddleson, Wright and/or
Bengal Rose reactions, either with ELISA or the 2-mercaptoethanol assay for IgM antibodies
associated with chronic disease
Histologic evidence of granulomatous hepatitis (hepatic biopsy)
Radiologic alterations in infected vertebrae: the Pedro Pons sign (preferential erosion of anterosuperior corner of lumbar vertebrae) and marked osteophytosis are suspicious of brucellic
spondylitis.
The disease's sequelae are highly variable and may include granulomatous hepatitis, arthritis,
spondylitis, anaemia, leukopenia, thrombocytopenia, meningitis, uveitis, optic neuritis, endocarditis
and various neurological disorders collectively known as neurobrucellosis.
Tuberculosis, MTB, or TB (short for tubercle bacillus) is a common, and in many cases
lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium
tuberculosis. Tuberculosis typically attacks the lungs but can also affect other parts of the body. It is
spread through the air when people who have an active TB infection cough, sneeze, or otherwise
transmit their saliva through the air. Most infections are asymptomatic and latent, but about one in
ten latent infections eventually progresses to active disease which, if left untreated, kills more than
50% of those so infected.
The classic symptoms of active TB infection are a chronic cough with blood-tinged sputum, fever,
night sweats, and weight loss (the latter giving rise to the formerly prevalent term "consumption").
Infection of other organs causes a wide range of symptoms. Diagnosis of active TB relies on
radiology (commonly chest X-rays) as well as microscopic examination and microbiological culture
of body fluids. Diagnosis of latent TB relies on the tuberculin skin test (TST) and/or blood tests.
Treatment is difficult and requires administration of multiple antibiotics over a long period of time.
Social contacts are also screened and treated if necessary. Antibiotic resistance is a growing
problem in multiple drug-resistant tuberculosis (MDR-TB) infections. Prevention relies on
screening programs and vaccination with the bacillus Calmette–Guérin vaccine.
One third of the world's population is thought to have been infected with M. tuberculosis, with new
infections occurring at a rate of about one per second. In 2007, there were an estimated 13.7 million
chronic active cases globally, while in 2010 there were an estimated 8.8 million new cases and 1.5
million associated deaths, mostly occurring in developing countries. The absolute number of
tuberculosis cases has been decreasing since 2006, and new cases have decreased since 2002. The
distribution of tuberculosis is not uniform across the globe; about 80% of the population in many
Asian and African countries test positive in tuberculin tests, while only 5–10% of the United States
population tests positive. More people in the developing world contract tuberculosis because of
compromised immunity, largely due to high rates of HIV infection and the corresponding
development of AIDS.
About 5–10% of those without HIV, infected with tuberculosis, develop active disease during their
lifetimes. In contrast, 30% of those co-infected with HIV develop active disease. Tuberculosis may
infect any part of the body, but most commonly occurs in the lungs (known as pulmonary
tuberculosis). Extrapulmonary TB occurs when tuberculosis develops outside of the lungs.
Extrapulmonary TB may co-exist with pulmonary TB as well. General signs and symptoms include
fever, chills, night sweats, loss of appetite, weight loss, and fatigue,[9] and significant finger
clubbing may also occur.
Pulmonary
If a tuberculosis infection does become active, it most commonly involves the lungs (in
about 90% of cases). Symptoms may include chest pain and a prolonged cough producing sputum.
About 25% of people may not have any symptoms (i.e. they remain "asymptomatic"). Occasionally,
people may cough up blood in small amounts and in very rare cases the infection may erode into the
pulmonary artery, resulting in massive bleeding known as Rasmussen's aneurysm. Tuberculosis
may a become chronic illness and cause extensive scarring in the upper lobes of the lungs. The
upper lungs are more frequently affected. The reason is not entirely clear. This may be due either to
better air flow, or to poor lymph drainage within the upper lungs.
Extrapulmonary
In 15–20% of active cases, the infection spreads outside the respiratory organs, causing other kinds
of TB. These are collectively denoted as "extrapulmonary tuberculosis". Extrapulmonary TB occurs
more commonly in immunosuppressed persons and young children. In those with HIV this occurs
in more than 50% of cases. Notable extrapulmonary infection sites include the pleura (in
tuberculous pleurisy), the central nervous system (in tuberculous meningitis), the lymphatic system
(in scrofula of the neck), the genitourinary system (in urogenital tuberculosis), and the bones and
joints (in Pott's disease of the spine), among others. When it spreads to the bones, it is also known
as "osseous tuberculosis". a form of osteomyelitis. A potentially more serious, widespread form of
TB is called "disseminated" TB, commonly known as miliary tuberculosis. Miliary TB makes up
about 10% of extra pulmonary cases.
Meningococcal disease describes infections caused by the bacterium Neisseria meningitidis
(also termed meningococcus). It carries a high mortality rate if untreated. While best known as a
cause of meningitis, widespread blood infection (sepsis) is more damaging and dangerous.
Meningitis and Meningococcemia are major causes of illness, death, and disability in both
developed and under developed countries worldwide.
The disease's host/pathogen interaction is not fully understood. The pathogen originates harmlessly
in a large number of the general population, but thereafter can invade the blood stream and the
brain, causing serious illness. Over the past few years, experts have made an intensive effort to
understand specific aspects of meningococcal biology and host interactions, however the
development of improved treatments and effective vaccines will depend on novel efforts by workers
in many different fields.
The incidence of endemic meningococcal disease during the last 13 years ranges from 1 to 5
per 100,000 in developed countries, and from 10 to 25 per 100,000 in developing countries. During
epidemics the incidence of meningococcal disease approaches 100 per 100,000. There are
approximately 2,600 cases of bacterial meningitis per year in the United States, and on average
333,000 cases in developing countries. The case fatality rate ranges between 10 and 20 per cent.
While Meningococcal disease is not as contagious as the common cold (which is spread through
casual contact), it can be transmitted through saliva and occasionally through close, prolonged
general contact with an infected person.
The patient with meningococcal meningitis typically presents with high fever, meningism (stiff
neck), Kernig's sign, severe headache, vomiting, purpura, photophobia, and sometimes chills,
altered mental status, or seizures. Diarrhea or respiratory symptoms are less common. Petechiae is
often also present, but does not always occur, so its absence should not be used against the
diagnosis of meningococcal disease. Anyone with symptoms of meningococcal meningitis should
receive intravenus antibiotics pending results of lumbar puncture, as delay in treatment worsens the
prognosis.
Symptoms of meningococcemia are, at least initially, similar to those of influenza.
Typically, the first symptoms include fever, nausea, myalgia, headache, arthralgia, chills, diarrhea,
stiff neck, and malaise. Later symptoms include septic shock, purpura, hypotension, cyanosis,
petechiae, seizures, anxiety, and multiple organ dysfunction syndrome. Acute respiratory distress
syndrome and altered mental status may also occur. Meningococcal sepsis has a higher mortality
rate than meningococcal meningitis, but the risk of neurologic sequelae is much lower.
Upper respiratory tract infections (URI or URTI) are the illnesses caused by an acute
infection which involves the upper respiratory tract: nose, sinuses, pharynx or larynx. This
commonly includes: tonsillitis, pharyngitis, laryngitis, sinusitis, otitis media, and the common cold.
Common URI terms are defined as follows:
Rhinitis - Inflammation of the nasal mucosa
Rhinosinusitis or sinusitis - Inflammation of the nares and paranasal sinuses, including frontal,
ethmoid, maxillary, and sphenoid
Nasopharyngitis (rhinopharyngitis or the common cold) - Inflammation of the nares,
pharynx,hypopharynx, uvula, and tonsils
Pharyngitis - Inflammation of the pharynx, hypopharynx, uvula, and tonsils
Epiglottitis (supraglottitis) - Inflammation of the superior portion of the larynx and supraglottic area
Laryngitis - Inflammation of the larynx
Laryngotracheitis - Inflammation of the larynx, trachea, and subglottic area
Tracheitis - Inflammation of the trachea and subglottic area
Acute upper respiratory tract infections include rhinitis, pharyngitis/tonsillitis and laryngitis often
referred to as a common cold, and their complications: sinusitis, ear infection and sometimes
bronchitis (though bronchi are generally classified as part of the lower respiratory tract.) Symptoms
of URI's commonly include cough, sore throat, runny nose, nasal congestion, headache, low grade
fever, facial pressure and sneezing. Onset of symptoms usually begins 1–3 days after exposure. The
illness usually lasts 7–10 days.
Group A beta hemolytic streptococcal pharyngitis/tonsillitis(strep throat) typically presents with a
sudden onset of sore throat, pain with swallowing and fever. Strep throat does not usually cause
runny nose, voice changes or cough.
Pain and pressure of the ear caused by a middle ear infection (Otitis media) and the reddening of the
eye caused by viral Conjunctivitis are often associated with upper respiratory infections.
Infectious mononucleosis (IM; also known as EBV infectious mononucleosis, Pfeifer's
disease, Filatov's disease and sometimes colloquially as the kissing disease from its oral
transmission or simply as mono in North America and as glandular fever in other English-speaking
countries) is an infectious, widespread viral disease caused by the Epstein–Barr virus (EBV), one
type of herpes virus, to which more than 90% of adults have been exposed. Occasionally, the
symptoms can recur at a later period. Most people are exposed to the virus as children, when the
disease produces no noticeable or only flu-like symptoms. In developing countries, people are
exposed to the virus in early childhood more often than in developed countries. As a result, the
disease in its observable form is more common in developed countries. It is most common among
adolescents and young adults.
Especially in adolescents and young adults, the disease is characterized by fever, sore throat
and fatigue, along with several other possible signs and symptoms. It is primarily diagnosed by
observation of symptoms, but suspicion can be confirmed by several diagnostic tests.
Common signs include lymphadenopathy (enlarged lymph nodes), splenomegaly (enlarged spleen),
hepatitis (refers to inflammation of hepatocytes—cells in the liver) and hemolysis (the bursting of
red blood cells). Older adults are less likely to have a sore throat or lymphadenopathy, but are
instead more likely to present with hepatomegaly (enlargement of the liver) and jaundice. Rarer
signs and symptoms include thrombocytopenia (lower levels of platelets), with or without
pancytopenia (lower levels of all types of blood cells), splenic rupture, splenic hemorrhage, upper
airway obstruction, pericarditis and pneumonitis. Another rare manifestation of mononucleosis is
erythema multiforme.
Sepsis is a potentially deadly medical condition that is characterized by a whole-body
inflammatory state (called a systemic inflammatory response syndrome or SIRS) and the presence
of a known or suspected infection. The body may develop this inflammatory response by the
immune system to microbes in the blood, urine, lungs, skin, or other tissues. A lay term for sepsis is
blood poisoning, also used to describe septicaemia. Severe sepsis is the systemic inflammatory
response, infection and the presence of organ dysfunction.
Septicemia is a related medical term referring to the presence of pathogenic organisms in the
bloodstream, leading to sepsis. The term has not been sharply defined. It has been inconsistently
used in the past by medical professionals, for example as a synonym of bacteremia, causing some
confusion.
Severe sepsis is usually treated in the intensive care unit with intravenous fluids and
antibiotics. If fluid replacement isn't sufficient to maintain blood pressure, specific vasopressor
medications can be used. Mechanical ventilation and dialysis may be needed to support the function
of the lungs and kidneys, respectively. To guide therapy, a central venous catheter and an arterial
catheter may be placed; measurement of other hemodynamic variables (such as cardiac output, or
mixed venous oxygen saturation) may also be used. Sepsis patients require preventive measures for
deep vein thrombosis, stress ulcers and pressure ulcers, unless other conditions prevent this. Some
patients might benefit from tight control of blood sugar levels with insulin (targeting stress
hyperglycemia), or low-dose corticosteroids. Activated drotrecogin alfa (recombinant protein C) has
not been found to be helpful, and has recently been withdrawn from sale.
In addition to symptoms related to the provoking infection, sepsis is characterized by presence of
acute inflammation present throughout the entire body, and is, therefore, frequently associated with
fever and elevated white blood cell count (leukocytosis) or low white blood cell count (leukopenia)
and lower-than-average temperature, and vomiting[citation needed]. The modern concept of sepsis
is that the host's immune response to the infection causes most of the symptoms of sepsis, resulting
in hemodynamic consequences and damage to organs. This host response has been termed systemic
inflammatory response syndrome (SIRS) and is characterized by an elevated heart rate (above 90
beats per minute), high respiratory rate (above 20 breaths per minute or a partial pressure of carbon
dioxide in the blood of less than 32), abnormal white blood cell count (above 12,000, lower than
4,000, or greater than 10% band forms) and elevated or lowered body temperature, i.e. under 36 °C
(96.8 °F) or over 38 °C (100.4 °F). Sepsis is differentiated from SIRS by the presence of a known or
suspected pathogen. For example SIRS and a positive blood culture for a pathogen indicates the
presence of sepsis. However, in many cases of sepsis no specific pathogen is identified.
This immunological response causes widespread activation of acute-phase proteins, affecting the
complement system and the coagulation pathways, which then cause damage to the vasculature as
well as to the organs. Various neuroendocrine counter-regulatory systems are then activated as well,
often compounding the problem. Even with immediate and aggressive treatment, this may progress
to multiple organ dysfunction syndrome and eventually death.
8. The recommended literature
1. Zubik TM, Ivanov KS, Kazantsev AP, Foresters, AL Differential diagnosis of infectious
diseases. Leningrad, 1991.
2. VS Vasil'ev, Komar, VI, VM Tsyrkunov The practice of infectious diseases. Minsk, 1994.
3. Kazantsev AP, Zubik TM, KS Ivanov, VA Kazantsev Differential diagnosis of infectious
diseases. Moscow, 1999.
4. Khudayberdiev YK, Mukhamedov KS, BK Saidkoriev Isitmali holatlar tashhisoti.Tashkent, 2006.
5. Emond, R., Rowland H., F. Uelsbi Infectious Diseases. Color Atlas. Moscow, 1998.
6. Zokirhuzhaev AH, Niezmatov B.I, Alimov 1., Matkarimov B. et al. Guidelines "Bird
Flu". Tashkent, 2006.
7. Madzhidov VM Yukumli kasalliklar. Tashkent, 1992.
8. Makhmudov OS Bolalar yukumli kasalliklari. Tashkent, 1995.
9. Uchaikin WR Guidelines for Communicable Diseases in children. Moscow, 1999.
10. Shuvalov, EP Infectious diseases. Moscow, 1999.
11. Musabayev IK "Guide to intestinal infections." Tashkent, 1982.
12. Pokrovsky VI, Pak SG et al, "Infectious disease and epidemiology." Moscow, 2003.
13. Yushchuk ND, Vengerov YY "Lectures on infectious diseases." Moscow, 1999.
14. Uchaikin VF "Guidelines for infectious diseases in children." Moscow, 1998.
15. Online Resources (www.medlinks.ru, www.cdc.gov, ...).