Danylo Halytsky Lviv National Medical University
Department of Clinical Immunology and Allergology
METHODOLOGICAL DEVELOPMENT OF TOPIC №1
practical lesson "Basic immunopathological syndromes" (2 hours) in the
discipline "Clinical Immunology and Allergology" for 6-th year students
of specialty "Medicine"
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1. Theme №1: Basic immunopathological syndromes
2. Relevance of the topic: Modern doctor needs modern, in-depth knowledge of basic
immunopathological syndromes
3. The goals of the class:
- educational: students must study basic immunopathological syndromes;
- professionally oriented: students must know the main stages of clinical and
laboratory immunological diagnostics of basic immunopathological syndromes
- educational: to form a sense of responsibility for the timeliness and
correctness of professional actions.
4. Equipment for conducting classes: Presentation for multimedia demonstration,
schemes, tables, immunograms, tests, situational tasks, histological and cytological
preparations
5. Integrative Relations of the theme:
5.1.Internal Integration: The topic of this practical class is related to the topics
set out in the course of clinical immunology and allergology on the 5th year:
organs of the immune system, immunocompetent cells, structure and functions
of immunoglobulins, types of regulation of the immune response, causes of
violation of immunological regulation, clinical manifestations of
immunopathological syndromes, modern approaches to the use of
immunotherapy
5.2.Interdisciplinary integration:
Disciplines
Anatomy
Histology
Physiology
Knowledges
The skills
Organs of the immune To describe the structure
system
of the immune system
organs
The cells of the immune Microscopically
to
system
distinguish
immunocompetent cells
Estimate
the
basic
functions of the immune
Basic functions of the To estimate the basic
immune system
functions of the immune
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Medical biochemistry
Genetics
Structure and function of
immune proteins
Features of inheritance of
genes associated with
immune response
Pathophysiology
Types of immunological
reactivity
Propedeutic therapy
Features
of
the
examination
of
the
organs of the immune
system in adults and
children
Pharmacology
Basic
groups
of
immunocorrective drugs
Immunotropic
and
neurotropic viruses
Infectious diseases
To interpret levels of
basic immune proteins
To
estimate
the
probabilities
of
genetically deterministic
violations
of
the
functioning
of
the
immune system
To intract changes in
general immunological
parameters
of blood
(leukogram,
proteinogram)
in
conditions
of
immunopathology
Palpation, percussion of
the
immune
system
bodies, evaluation of the
results
of
general
laboratory
and
instrumental methods of
their examination
Approaches to indications
of immunotropic drugs
Diagnostics of chronic
viral infection, antiviral
therapy
6. Contents of the topic of the class:
6.1. Learning questions.
6.1.1. Determination of the concept of long subfebrity / fever unusual genesis.
6.1.2. The main directions of immuniagnostics of long-term subfebrile.
6.1.3. Unbroken fever.
6.1.4. Tactics of patients with long subfebrity.
6.1.5. Etiology and types of immunoproliferative syndromes.
6.1.6. Classification of chronic immunoproliferative syndromes.
6.1.7. Clinical features and modern methods of immunodiagnosis of chronic
immunoproliferative syndromes.
6.1.8. Modern approaches to immunotropic and efferent therapy of patients with
immunoproliferative syndromes.
6.1.9. The main causes of lymphoadenopathy.
6.1.10. Modern classification of lymphoadenopathy.
6.1.11. Differential diagnostics and approaches to the treatment of
lymphoadenopathy.
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A short content of the lesson
Determination of immunopathological syndrome.
Basic immunopathological syndromes: allergic, autoimmune, immunodeficiency
(primary
and
secondary),
immunoconflicting,
cancer
dependent,
immunoendocrine.
Changes in the results of immunological laboratory studies characteristic of these
syndromes.
Subfebrity / fever of the unknown etiology - a state for which for a long time
(more than one month) there is an increase in body temperature to 38-38.3 ° C.
Chronic subfebrile temperature is called an unreasonable body temperature increase
for more than two weeks. In this state, a person can feel unchanged or feel malaise.
Often subfebrility is the only complaint of the patient. Prolonged subfebrile
temperatures and weakness may be the first symptoms of a serious illness.
Possible causes of subfebrile temperature.
Distinguish low subfebrility (up to 37.1 ° C) and high (up to 38.0- 38.3 ° C).
Possible causes of subfebrile temperature in adults: bacterial infections that
cause infection diseases of upper and lower respiratory tract, pneumonia, typhoid
fever and others; viral infections: flu, acute respiratory virus infections, hepatitis,
HIV/AIDS; infections of urinary tract: cystitis, urethritis; allergy - for example, a hay
fever; the reaction to medication therapy (some drugs can cause a temperature
increase, known as a medicinal fever), inflammatory diseases of the pelvic organs;
hyperthyroidism; appendicitis; tuberculosis; hormonal changes (subfebrile
temperatures in women can be observed in the second half of the menstrual cycle,
during pregnancy and climax);
inflammatory diseases of the gauge; lymphoma and other species of malignant
neoplasms; intensive exercise; meal; emotional tension and stress.
The analysis of literature data indicates: most often the cause of the fever of the
unknown etiology is a disease that can be divided into several groups: 1) generalized
or local infectious and inflammatory processes; 2) malignant tumors; 3) noninfectious inflammatory diseases (rheumatic, system, autoimmune); 4) other diseases,
varied by etiology, pathogenesis, course and prognosis.
Chronic immunoproliferative syndromes - among lymphoproliferative diseases, there
is a group of syndromes that have a chronic course and a characteristic clinical
picture of general symptoms called "B-symptoms": lymphadenopathy, hepato- and
splenomegaly, hypergamaglobulinemia, various manifestations of autoimmunopathy.
The etiology of these diseases (syndromes) is unknown, the clinical picture is
similar to malignant lymphoproliferative diseases, systemic diseases of the
connective tissue, "slow" viral diseases, medical hypersensitive syndromes, chronic
parasitic infections (leishmaniosis), etc.
Classification of chronic immunoproliferative syndromes: 1) Chronic polypotent
immunoproliferative syndrome (CPIS); 2) Angioimmunoblasting lymphadenopathy;
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3) Canel-Smith syndrome; 4) Angiopholycular hyperplasia of lymph nodes
(Castleman syndrome); 5) POEMS-syndrome, Takatsuki syndrome; 6) Purtilo
syndrome (Duncan); 7) Chronic polyopotential immunoproliferative syndrome
(HPIS).
Frequency of symptoms in patients with diagnosis of СPIS: reduction of
working capacity - 100%, hepatosplenomegaly - 86%, jaundice - 51%, body weight
loss - 49%, kidney disorders - 26%, system lymphadenopathy - 31%, local
lymphadenopathy - 29%, rash on the skin - 29%, raising body temperature - 29%,
increased sweating, especially at night, - 20%, edema - 9%. According to patients 72% women and 28% of men aged 35-76 years. Immunological laboratory diagnosis
in CPIS showed the presence of hemolytic anemia, the presence of paraproteins,
hypergamaglobulinemia, the presence of anticardiolipin antibodies, cryoglobulins,
cold agglutinins, reducing the content of complement.
А Angioimoblastible lymphadenopathy (AIL). In 1974, FRIZZERA described
a clinical picture with acute manifestations of general clinical symptoms and
lymphadenopathy, hepatosplenomegalia, exanthema, anemia, hypergamlobulinemia.
Causes of development: drugs: diphenylhydantine, penicillin, ampicillin,
sulfanilamides, alopurinol. During biopsy of lymph nodes, the following signs are
found: completely destroyed architectonics, lack of active embryonic centers,
proliferation and proliferation of postpapillary venules, polymorphic infiltration of
lymphocytes, plasma cells and immunoblasts, intercellular layers of amorphous
eosinophilic substances, which is very close to this syndrome to the malignant
process in lymph nodes. This syndrome with immunoblast lymphadenopathy is
considered to be a lymphoma. In the clinical picture of AIL dominates
lymphadenopathy, exanthema, total tensional syndrome, drug allergy. Eczema,
erythroderma, purple - frequent symptoms in AIL and never detect at CPIS, like the
sarcoma of Kaposi, which occurs only in AIL.
Canel-Smith syndrome is characterized by hepatosplenomalia, systemic
lymphadenopathy with a variable histological picture of the lymph nodes (from
hyperplasia to lymphosarcoma), anemia, thrombocytopenia, hypergamaglobulinemia.
The disease begins in children between 1-2 months, manifested hemolytic anemia
and infections. It is believed that Canel-Smith syndrome is "Children's Option" CPIS.
Castleman's syndrome (angiopholyular hyperplasia of LN). Morphologically
distinguish three types of angiopholyular hyperplasia of lymph nodes: hyalinvascularized, mixed, plasmallite. In the case of the first two forms local symptoms
are dominated, with plasmallite - general manifestations of illness. Castleman's
syndrome is associated with an increase in mediastinum lymph nodes, in a third of
patients further develops lymphoma or plasmocytoma. System forms of the course of
Castleman's syndrome are accompanied by such symptoms: fever, loss of body
weight, reducing efficiency ("B-symptomatics"), hepatosplenomegaly, skin
symptoms, anemia, thrombocytopenia, hypergamaglobulinemia. There is a
development of sarcoma kaposhi, peripheral neuropathy, skin papillomas.
POEMS-syndrome. This syndrome is characterized by polyneuropathy,
lymphadenopathy, hepatosplenomegaly, endocrinopathy, "M" -gradient and skin
changes. The clinic dominates polyneuropathy, mostly distal sensory.
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Endocrinopathics changes: diabetes, amenorrhea, gynecomastia, impotence,
hypothyroidism and adrenal insufficiency are often found. Skin changes are
hyperpigmentation, hardening, hirsutism, hyperhidrosis/. Laboratory changes: "M" protein with separate symptoms of myeloma, osteolysis (14%), osteosclerosis (55%)
or mixed osteosclerotic and osteolithic symptoms.
Purtillo syndrome (Duncan). This syndrome covers a number of
immunopathies that arise in response to infection with the Epstein-Barr virus, more
often found in men. The disease is explained by the presence of a patient of the total
variable immunodeficiency with the insufficiency of the B cell level of immunity as a
result of infection of EBV B-lymphocytes in early childhood and prolonged
persistence in cells. Boys are greater risk to become this syndrome if their older
brothers or male relatives on the maternal line had complications after EBV infection:
chronic mononucleosis, neutropenia, aplastic anemia, acquired immunodeficiency,
especially with hyper-IgM, B-cell lymphoma. To confirm the diagnosis it is
necessary to take into account hered anamnesis. From laboratory studies, the absence
of antibodies to an EBV nuclear antigen and an increase in antibodies against the
viral capsid antigen (VCA) and an early antigen virus (EA) in the mother are
informative. In patients, an abnormal ratio of CD4 / CD8 is determined and the defect
of the transition of IgM antibody synthesis to IgA and IgE. The genetic defect in
Purtillo syndrome is localized in X-chromosome (Xg 26-27).
Lymphadenopathy in adults and children: etiology, diagnostics, treatment.
Lymphatic nodes (LN) are palpated in 38-45% of healthy children, increasing in
size under 8-12 years. Normally LN are mobile, not soldered with surrounding tissues
and among themselves, up to 1 sm in diameter (smelter - up to 1.5 cm, axillary - up to
2 cm). Normally can be palpated submandibular, axillary and smelter of LN. LN - an
organ of an immune system formed in places of a merger of several lymphatic
vessels. LN is a barrier for infections, foreign substances, metastases of malignant
neoplasms.
Classification of lymphoadenopathy (LAP): 1) Local - increase of LN in one
anatomical site (for example, neck, axillary region); 2)Regional - an increase in
several LNs in one or two adjacent sites; 3) Generalized - an increase iof LNs in more
than two anatomical sites, with the exception of axillary. The term "persistent
generalized lymphadenopathy" is used to indicate a condition characterized by an
increase of LN > 1 cm in diameter at ≥2 anatomical sites (except for the axillary) for>
3 months
Reasons for increasing LN depending of pathogens: 1) Viruses: EBV, CMV,
HHV-6, Parvovirus B-19, Measles virus, rubella, adenovirus, enterovirus, Hepatitis A
virus, Hepatitis B virus, HIV, Denge fever; 2) Bacterias: Felinosis Scratch Disease
(Felinosis, B. Henselae, B. Clarridgeiae), intestinal pathogens (Salmonella Typhi,
Salmonella Enterica, Yersinia Enterocolitica), respiratory agents (Mycoplasma
Pneumoniae, Legionella Pneumophila), Streptococcus Pyogenes, Spirocheti (Lyme
Disease, primary and secondary syphilis, leptospirosis), brucellosis (Brucella spp.),
Tularemia (Francisella Tularensis); 3) others: Mycobacteria (tuberculosis, atypical
mycobacteriosis),
fungal
infections
(histoplasmosis,
coccidiomycosis,
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paracocycidomicosis), parasitic microorganisms (toxoplasmosis, trypanosomosis,
visceral leishmaniasis, schistosomosis, fillariadosis).
Reasons for increasing LN depending on the child's age: 1) newborns (S.
aureus, S. agalactiae); 2) babies (S. aureus, S. pyogenes, Kawasaki disease); 3) 1-4
years (S. aureus S. pyogenes, non-tuberculous mycobacteria, Kawasaki disease); 4)
5-15 years (anaerobic bacteria, toxoplasmosis, bartonellosis, tuberculosis).
Possible causes of LAP depending on migration anamnesis: 1)
coccidioidomycosis (Arizona, Southern California, New Mexico, West Texas, South
West USA); 2) Bubon Plague, Histoplasmosis (South East and Central Part of the
United States, Southeast Asia, India, North Australia); 3) African trypanosomosis /
sleep disease (Central or West Africa); 4) American Tripanosomosis / Chagas
Disease (Central or South America); 5) Leishmaniosis (East Africa, Mediterranean,
China, Latin America); 6) typhoid fever (Mexico, Peru, Chile, India, Egypt,
Indonesia).
Atypical mycobacteriosis as a cause of LAP. Atypical mycobacterias call all
representatives of the genus Mycobacterium. Unlike M. Leprae and M. Tuberculosis,
the pathogens of atypical mycobacteriosis (Mycobacterium Avium Complex) are
significantly less virulent. Lymphadenitis is most often caused by pathogens that
belong to Mycobacterium avium complex.
Atypical mycobacteria often causes one-sided lymphadenitis. The skin over enlarged
LN can be hyperemic and welded with it. Usually, the front of the upper and
submandibular LN is affected. Atypical mycobacteriosis is most often developed in
children aged 1-5 years. The diagnosis is established on the basis of granulomatous
inflammation, which is detected in a biopsy, analysis of nucleic acids and / or a
biopsy culture study.
Non-infectious causes of LAP in children: 1) systemic diseases: a systematic
variant of juvenile idiopathic arthritis, Still’s disease, sarcoidosis, systemic lupus
erythematia, systemic scleroderma, etc.; 2) tumors: acute leukemia, Non- Hodgkin
lymphoma, lymphogranulomatosis, hystiocytosis, metastases of solid tumors, etc.; 3)
metabolic diseases: Gaucher disease, Niemann-Pick disease, etc.; 4) allergic diseases:
serum sickness; 5) primary immunodeficiencies: chronic granulomatous disease, Xlinked
lymphoproliferative syndrome (Duncan syndrome), etc.; 6) Drugs:
carbamazepine, penicillin, cephalosporins, sulfanilamides, etc.
Tumors as a possible cause of an increase LN in children should be considered
if LAP are combined with fever, anorexia, body weight loss, pain syndrome, severe
fatigue, excessive night sweating.
PFAPA-syndrome as a possible cause of LAP ((Periodic Fevers with
Aphthous stomatitis, Pharyngitis and Adenitis, Marshall’s syndrome) is a chronic
disease of unknown etiology, which is characterized by periodic fever, neck’s LAP,
pharyngitis (often exudative) and Aphthous stomatitis.
Signs of PFAPA syndrome include: 1) periodic fever; 2) manifestation of the
disease mainly at the age of 5 years; 3) neck’s LAP; 4) tonsillitis, pharyngitis; 5)
intervals between attacks are asymptomatic; 6) normal psychomotor development of
the child; 7) excluded cyclic neutropenia. Attacks of Marshall’s syndrome are usually
lasting 4-5 days and repeat every 3-5 weeks. There are no pathological symptoms
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between the attacks, the size of the LN and body temperature are normal. The
diagnosis is established clinically based on symptoms.
Kawasaki disease - acute febrile disease of the child's age of unknown etiology.
Possible triggers of Kawasaki disease: Koxaki virus, adenovirus, etc. Symptoms for
Kawasaki Disease according to the American Heart Association (AHA) 2017 are: 1)
fever duration ≥5 days; 2) conjunctivitis, non-purulent; 3) LAP (an increase of more
than one-sided neck’s LN > 1.5 cm); 4) polymorphic rash; 5) lips are hyperemic and
cracked; diffuse erythema of pharynx; 6) At the beginning of the disease: erythema
and swelling of brushes and feetі; At the recovery stage: peeling of the skin that
begins from fingertips.
Aneurysms of coronary arteries are the most severe complication of Kawasaki
disease, developing about 20% of untreated patients.
Lack of regression LAP for 4-6 weeks can be displayed to biopsy. Impressions
to early excess biopsy include: 1) LN size > 3 cm; 2) "unusual" localization (for
example, a supraclavic LN); 3) the presence of neoplasms in anamnesis; 4)
concomitant symptoms: body weight loss, night sweating, hepatosplenomegaly
It is also important to remember the forms and conditions that "simulate"
LAP: infections of salivary glands, congenital anomalies (carpets, hygra), nodules of
the thyroid gland, hematomas, hemangiomas, lymphangiomas, lipomas, rheumatic
nodules.
Diseases and pathological processes accompanied by increased lymph
nodes: infections, tumor lesions (primary or metastatic), immunoproliferative and
dysmetabolic processes.
I Stage of Diagnostic Search - detection and differentiation. At this stage of
diagnostic search, you should work out skills and skills to detect enlarged LNs.
II Stage of Diagnostic Search - Localization. After verification of enlarged
LV, it is necessary to find out localization and evaluate the prevalence of LAP.
III Stage of Diagnostic Search - Detection of additional features. One of the
guidelines of the direction of diagnostic search may be the age of patients, for
example: mononucleosis is more often found in children's and youth, and chronic
lympholeukemia - in older age. Anamnestic data (limbs injury, surgical intervention,
presence of implant, contact with some patients, etc.) are not only narrow the range of
diagnostic search, and in some cases even acquiring a crucial value. Recommended to
conduct a clinical examination of the patient with LAP for detection of additional
symptoms: skin lesions and mucous membranes (macular-papular rashes,
hemorrhages, scratches, bites, ulcers, etc.); enlargement of liver; splenomegaly;
articular syndrome; fever; respiratory symptoms; urogenital symptoms. An increase
in the spleen in the patient with LAPs may indicate viral infections (infectious
mononucleosis), acute and chronic lympholeukemias, systemic diseases (systemic
lupus erythematics (SLE).
IV Stage of Diagnostic Search – analysis of peripheral blood. Stable absolute
lymphocytosis with the presence of Gumprecht’s cells is a pathognomonic laboratory
feature of chronic lymphoid leukemia, and the presence of blast cells in the blood
may indicates lymphoblastic leukemia or leukemization of lymphoma. Neutrophilic
leukocytosis, leukopenia (neutropenia), thrombocytopenia are not specific, since they
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can occur with a wider circle of diseases accompanied by LAP. Mandatory studies
are also: X-ray examination of the chest, ultrasound of the abdominal cavity,
immuno-serological studies (syphilis, HIV infection, hepatitis B and C). In cases
where an increase in LN is maintained, despite the regression of the local
inflammatory process, especially in the presence of LN dense consistency, a LN
biopsy for histological examination is shown.
6.1. Control questions:
6.2.1. The reasons for prolonged subfebrile.
6.2.2. Main directions of diagnostic clinical and laboratory search.
6.2.3. Management of the patients.
6.2.4. Causes and types of immunoproliferative syndromes.
6.2.5. Classification of chronic immunoproliferative syndromes.
6.2.6. Clinical features and modern methods of immunodiagnostic of chronic
immunoproliferative syndromes.
6.2.7. The main causes of lymphoadenopathy in adults and children
6.2.8. Differential diagnostic and stages of diagnostic search in patients with
lymphoadenopathy
6.2. Practical experience:
6.2.1. -to make a plan for clinical, instrumental and laboratory diagnostics of basic
immunopathological syndromes
6.2.2. - to form the main stages of diagnostics of basic immunopathological
syndromes
6.3.
Plan and organizational structure of class (2 academic hours or 90 min.).
Main stages of classes, their Levels of Methods of
functions and content
knowledge control and
training
1. The first stage
I
Frontal poll
Organization of classes
ExpressEducational goals
poll
Control of the primaryt level of
Test control
knowledge and skills:
-regulation of the immune
response
- the causes of violations of
immune response regulation
Methods
of Time
methodical
in
supporting
min
Tests
10
Schemes
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2. Basic stage
Formation
of
professional II
knowledge and skills:
-Description
of
clinical
manifestations
of
basic II
immunopathological syndromes
-Form algorithm of modern
general-clinical and laboratory
diagnostics
of
basic III, IV
immunopathological syndromes
-Evaluation of recomendations to
immunotropic therapy
Final stage
-Control and correction of
professional
knowledge,
skills
-Diagnostics
of III
immunopathological
syndromes
-Medicamental correction IV
of changes in the immune
response
with
basic
immunopathological
syndromes
Individual
control tests
Professional
training in
typical
tasks ("step2")
Tables
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Schemes
Immunological
observation
cards
Typical
situational
tasks
Histological
and
cytological
preparations,
immunograms
Testing
(Output
Level)
Individual
survey
Solving of
non-typical
situational
tasks
Schemes
Tests
Non-typical
situational
tasks
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Conducting a summary of classes.
Homework for the next topic
6.4. Conclusions:
6.4.1. Mastered knowledge of basic immunopathological syndromes.
6.4.2. Formed understanding of the reasons for the formation of
immunopathological syndromes
6.4.3. Formed knowledge of differences between immune-dependent violation,
immunopathological syndrome and disease of the immune system
6.4.4. Understanding of the methods of correction of the immune system in
various immunopathological syndromes.
6.4. Materials for control
6.5. Tasks for individual work on this topic
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1 /. Make a list of characteristic changes in the basic general-clinical and
immunological laboratory parameters of immunopathological syndromes
2 /. Develop a table (scheme) of the main clinical manifestations of long-term
subfebrillitis, chronic immunoproliferative syndromes, lymphoadenopathy syndrome
3/. To form the main features of differential diagnostics and immunocorrection of
prolonged subfebrillitis, chronic immunoproliferative syndromes, lymphoadenopathy.
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