Lecture 6: Etiology and pathogenesis of primary

forms of pulmonary tuberculosis in children

Primary tuberculosis develops in people with a weakened protective reaction of the body as
a result of the first, usually massive infection with virulent MBT. In a tense epidemiological
situation, primary infection with MTB often occurs in childhood, therefore primary forms of
tuberculosis are more often detected in children and adolescents. In children, tuberculosis has its
own characteristics of clinical manifestations, which differ from tuberculosis in adults, and
proceeds according to the primary type. For children, the source of infection is usually an adult
patient who is in close contact with the child (most often living in the same family). The immune
response (delayed hypersensitivity and cellular response) develops 4–6 weeks after primary
infection with Mycobacterium tuberculosis. Most often, the immune response suppresses the
growth of MTB, and the presence of infection in the body can only be indicated by a positive
result of the tuberculin skin test (TST).
Primary tuberculosis develops as a result of recent infection of the macroorganism with
Mycobacterium tuberculosis (primary infection) . When air particles containing mycobacteria
enter the peripheral parts of the lungs during inhalation, they remain there and slowly multiply,
forming a primary pulmonary affect (focus). In this case, some of the mycobacteria enter the
lymph, from which they are transported to a nearby lymph node. According to its anatomical
structure, the lymphoglandular system of the lung serves as a regional lympho-vascular system
of the lung, and the lymph nodes of the lung root serve as a collector in which lymph is
collected. With the development of tuberculosis in the lung, the lymph nodes of the root react to
it with an inflammatory process. However, in the lymph nodes of the mediastinum and the root
of the lung, pathological processes can occur regardless of the disease in the lungs.

Patients with primary tuberculosis make up about 0.8-1% of newly diagnosed tuberculosis
patients. In some cases, the immune response is not strong enough to contain the development of
the infectious process, and then after a few months tuberculosis develops. The risk of developing
the disease increases if infection occurs during pre-adolescence (before 10 years) and, in
particular, in young children (0-4 years), as well as in children with weakened immune systems.
The development of the disease can occur in several ways:

а) progression of the primary lesion in the lung with and without the formation of
cavities;
b)progression of the pathological process in the lymph nodes;
c)spread of the process by hematogenous and/or lymphogenous routes.
d) а small number of children (usually older age groups) develop post-primary
(secondary) tuberculosis, which is the result of reactivation of latent tuberculosis
infection or reinfection.
Risk factors for primary infection and tuberculosis in children:

 presence of contact with patients with active forms of tuberculosis;

 age <5 years;
 HIV-infected and AIDS patients;
  lack of weight (hypotrophy);
 children with chronic diseases, such as diabetes mellitus, chronic renal failure, chronic
or acquired immunological deficiency.
The outcome of primary infection is determined by the number and virulence of MBT, the
duration of their arrival and, to a large extent, by the immunobiological state of the body.
Primary infection in most children is not accompanied by symptoms of intoxication; within 6–8
weeks a trained clone of T-lymphocytes is formed; the disease does not occur as a result of
developed non-sterile cellular immunity.

Pathogenesis and pathological anatomy . After primary infection with MTB, typical
morphological changes usually form in the intrathoracic lymph nodes, lung or pleura. These
changes are rare in other organs.

Specific features of primary period of tuberculosis аre:

1) Paraspecific reactions in different organs and tissues;
2) Reaction of lymphatic system;
3) Involvement in process of wall of bronchi;
4) Reaction of serous layers;
5) Hypersensibilization of body which promotes generalization of process
hematogenous, lymphogenous and bronchogenic pathways;
6) tendency to spontaneous healing.

Purposeful survey for primаry tuberculosis includes:

1) Сollection of аnаmnesis (include contаct of child with tuberculous patient);

2) Clinico-lаborаtory study;
3) Tuberculin skin test (Mantoux test with 2 ТU PPD-L);
4) Bacteriological survey;
5) X-rаy of organs of chest .

The main clinical forms of primary tuberculosis:

 tuberculosis intoxication,
 tuberculosis of intrathoracic lymph nodes,
 primary tuberculosis complex.
Tuberculosis intoxication is the earliest clinical form of primary tuberculosis without clear
localization of specific changes. It usually develops after episodic contact with a source of
infection with a relatively small decrease in the body's resistance.
MBT that has penetrated into the alveoli with the lymph flow enters the intrathoracic lymph
nodes, lingers in them and causes the development of a specific inflammatory reaction. The area
of pathological changes is small, and symptoms of local damage practically do not appear. Due
to its small size, visualization of the affected area in a clinical setting is often impossible.
The progression of tuberculosis infection is accompanied by the entry into the intercellular
space, and then into the lymph and blood, of lysosomal enzymes of destroyed macrophages and
MBT waste products. These biologically active substances are carried through the bloodstream
into various organs and cause a variety of functional and metabolic disorders. Toxic products of
impaired metabolism enter the blood. This is how intoxication syndrome develops . Its
individual signs can be observed already at the stage of symbiosis between the human body and
the office, but the full picture of the disease develops later with the appearance of delayed-type
hypersensitivity and the formation of tuberculous granulomas. Cell hypersensitivity to the office
and toxemia can lead to the development of toxic-allergic reactions. Morphological signs of
toxic-allergic thrombovasculitis, perivascular nodular or diffuse infiltrates of lymphocytes,
mononuclear and plasma cells appear in various organs and tissues (Fig. 8.1). These changes are
called paraspecific. At the initial stages of the disease, hyperplasia of the lymphoid tissue is
noted, which leads to an increase in peripheral nodes. Over time, sclerotic processes develop in
them. The size of the nodes decreases, the density increases, and sometimes inclusions of
calcium salts appear. All these changes are called micropolyadenopathy.
The duration of tuberculosis intoxication as a form of primary tuberculosis rarely exceeds 8
months. It usually proceeds favorably. The specific inflammatory reaction gradually subsides,
single tuberculous granulomas undergo connective tissue transformation. Calcium salts are
deposited in the area of tuberculous necrosis. Sometimes tuberculosis intoxication becomes
chronic or progresses with the formation of other forms of primary tuberculosis.
The most common form of local primary tuberculosis in children is tuberculosis of the
intrathoracic lymph nodes; primary tuberculosis complex is less commonly diagnosed. Processes
such as disseminated tuberculosis, pleurisy, meningitis, and other extrapulmonary processes are
significantly rarely diagnosed. In addition, with a complicated course of primary tuberculosis,
the following may develop: damage to the bronchi, impaired bronchial obstruction with
bronchopulmonary lesions, collapse of the lung tissue, and caseous pneumonia. The classic form
of morphological manifestation of primary tuberculosis is the primary tuberculosis complex.

ТB of intrathoracic lymph nodes is form of primary TB when dаmаge lymph nodes

develops without inflammation in lung tissue.

Tubercu
losis of
the
intratho
racic
lymph nodes (TILN) is the most common form of primary tuberculosis. It develops with the
deepening of immune disorders and an increase in the MBT population. Under these conditions,
specific inflammation in the intrathoracic lymph nodes progresses. The volume of the lesion
increases. Gradually, the tissue of the lymph node is almost completely replaced by tuberculous
granulations. Many mediastinal lymph nodes and adjacent tissues are involved in the
pathological process. The total volume of the lesion can be quite large, but specific changes
usually do not occur in the lung tissue (Fig. 102). However, a complicated course can lead to
lymphohematogenous and bronchogenic generalization of the process.

Lymph nodes, depending on their relationship to the trachea and bronchi, are divided into:
paratracheal, tracheobronchial, bronchopulmonary (right and left), bifurcation (classification by
V. A. Sukennikov, 1903 , see the chapter “Anatomical and physiological structure of the
respiratory organs”).

In modern conditions, three clinical forms of tuberculosis of the intrathoracic lymph nodes
are distinguished:

• “small”;
• infiltrative;
• tumor-like (tumorous).
Small forms of tuberculous bronchoadenitis in the infiltration phase are characterized by mild
hyperplasia of 1–2 groups of lymph nodes (size from 0.5 to 1.5 cm).

The infiltrative form of TILN is most often manifested by unilateral damage to one or
several groups of lymph nodes with predominant infiltration around them.

With tumor-like bronchoadenitis, several groups of lymph nodes are affected, often with
bilateral localization, which increase to a significant size, followed by caseous degeneration,
while the inflammatory process does not extend beyond the capsule of the lymph nodes.
However, the division of bronchoadenitis into infiltrative and tumorous forms is arbitrary, since
they can transform into one another. With TILN, large bronchi, vessels, mediastinal tissue, nerve
ganglia and trunks, and pleura may be involved in a specific process.

Clinic. The clinical picture of bronchoadenitis is determined, first of all, by the symptoms of
intoxication, as well as the degree of involvement of the intrathoracic lymph nodes and
surrounding organs in the process. The minor form of bronchoadenitis is, as a rule,
asymptomatic; patients do not complain; they are detected during preventive examinations by
performing the Mantoux test. Children may experience decreased appetite, fatigue, and
irritability. Micropolyadenia can be detected. Percussion and auscultation data are usually not
informative. MBT is found in bronchial washings in 8–10% of cases. In the diagnosis of small
forms, the X-ray method plays a decisive role.

The infiltrative form of tuberculosis of the intrathoracic lymph nodes is asymptomatic. The
onset of the disease may be gradual. The child develops increased fatigue, decreased appetite,
sleep disturbances, periodic headaches, irritability, and elevated temperature to subfebrile levels.
Pale skin, slight weight loss, blue under the eyes. Micropolyadenia is detected - an increase in
peripheral lymph nodes in 4 or more groups to the size of a pea; they are of a soft-elastic
consistency, mobile, not fused to the surrounding tissue, and painless.

Paraspecific reactions are less common in modern conditions, but can still be observed:
conjunctivitis, phlyctena, erythema nodosum, otitis, pleurisy. Percussion and auscultation
symptoms are usually absent. There may be changes in the hemogram: moderate leukocytosis
(15x109/l), eosinophilia, lymphopenia, monocytosis, accelerated ESR.

The tumor-like form of TILN is characterized by a more pronounced clinical picture of the
disease, as it is accompanied by damage to several groups of lymph nodes followed by their
complete caseification. The onset of the disease can be gradual or acute. The child develops
gradually increasing symptoms of intoxication. Some patients have a dry cough, which takes on
a “ whooping cough-like ” quality (in older children), less often a “ bitonal character ” (a high
overtone is heard at the same time as a low fundamental tone). In young children, in addition to
bitonic cough, there may be expiratory stridor - a noisy prolonged exhalation during normal
inhalation. On the anterior chest wall you can see the expansion of the peripheral venous
network in the first - second intercostal space on one or both sides due to compression of the
azygos vein ( Widerhofer's symptom ). Some children experience dilation of the venous
capillaries in the area of the lower cervical and upper thoracic vertebrae ( Frank's sign ).

X-ray picture of TILN:

 change in the shape of the root of the lung (normally it is in the form of a comma), its
alignment or it becomes convex;
 asymmetry of the roots of the lungs or unilateral expansion of the upper mediastinum;
 the root of the lung is increased in width or length, the outer contours of the root are
blurred;
 the root structure is disrupted due to a general inflammatory perifocal reaction;
 the projection of the stem bronchus (with right-sided localization) is veiled or not defined
at all;
 the pulmonary pattern is enhanced in the hilar zone due to enlarged lymph nodes.
The complication most often occurs in infants and preschool children. Impaired bronchial
obstruction can be detected by the Holtzknecht-Jacobson test (with a quick inhalation after a
slow deep exhalation, a short-term shift of the mediastinum occurs to the affected side).

Differential diagnosis of TILN. Differentiation should begin with determining the

localization of the process . It is advisable to use a diagram according to which the
mediastinum is divided into three sections by frontal lines drawn along the anterior and
posterior walls of the trachea - anterior, posterior and middle.

In pediatric practice, enlargement of the intrathoracic lymph nodes most often occurs in a
number of nonspecific inflammatory diseases (measles, whooping cough, acute and prolonged
pneumonia). In such cases, during differential diagnosis, it is necessary to take into account
medical history (contact with a TB patient, past infections), the dynamics of tuberculin tests,
hemogram indicators, X-ray patterns, and the effect of nonspecific therapy.

Localization of diseases in the mediastinum

Anterior mediastinum Central mediastinum Posterior mediastinum

Thymic hyperplasia TILN Neurogenic formations
Nonspecific adenopathy Severe abscess
(measles, whooping cough, viral
infections, pneumonia)
Sarcoidosis
Lymphogranulomatosis

With nonspecific adenopathy, the X-ray picture is bilateral, the structure of the root changes,
but less than with tuberculosis, the contours are blurred. The process is characterized by rapid
dynamics (within 2–3 weeks) in the form of a decrease in the size of the lung root, restoration of
the structure, and disappearance of infiltration.

Localization of pathology in
mediastinum:

1 – lymphogranulomaatosis;

2 – tymomа;

3 – terаtomа;

4 – celomic cyst;

5 – neurogen tumors;

6 – sarcoidosis

7 – enterogenic cyst.

Differential diagnosis is carried out with variants of the development of the thymus gland,
which is not a pathology. In the first three years, the thymus gland grows, then its growth slows
down and atrophies during puberty. The thymus gland is located retrosternally and has right and
left lobes. The shape of the gland is varied: triangle, convex shadow, trapezoid, etc. Children are
usually healthy and have no complaints. X-ray diagnostics:

 On a direct x-ray of the chest, the mediastinum is expanded more often on the right, the
lower pole at the level of the 1st rib is determined by a thin tendril as a result of contact
of the base with the additional interlobar groove,
on the left in the form of a triangle - with the
pleura;
 An additional shadow appears behind the
sternum on the lateral radiograph.
 РX-{X-ray of enlarged thymus
(thymoma)

Systemic hyperplasia of adenoid tissue

Sarcoidosis (Besnier-Beck-Schaumann disease) is a systemic disease of unknown etiology,

characterized by damage to the lymphatic system, internal organs and skin with the formation of
specific granulomas. Stage I of sarcoidosis is characterized by a significant increase in the lymph
nodes of the roots of the lungs and mediastinum. In childhood, it occurs more often in boys. The
disease is asymptomatic. Physical changes can be in the form of a slight shortening of percussion
sound in the interscapular space and parasternally. In some patients, an acute and subacute onset
is possible, accompanied by Löfgren's syndrome : an increase in temperature to 38-39 o ,
erythema nodosum on the skin, pain in the joints, and peripheral lymph nodes are palpated. An
important differential feature is a negative tuberculin reaction, which is observed in 85–90% of
cases. The blood count is usually not changed, but there may be leukemia and lymphopenia,
monocytosis, eosinophilia with normal or slightly accelerated ESR. A positive Kveim-Nickerson
test helps in diagnosis . X-ray picture of sarcoidosis: bilateral, symmetrical enlargement of the
intrathoracic lymph nodes with sharp delimitation, the lumens of the large bronchi are preserved.
Intrathoracic lymph nodes with sarcoidosis in 29–30% of cases may have inclusions of calcium
salts. A reliable method for diagnosing sarcoidosis is a peripheral lymph node biopsy.

Often we encounter another more serious systemic disease – lymphogranulomatosis (LGM).

LGM is characterized by a higher temperature of a wave-like nature. Lymphogranulomatosis is
accompanied by skin lesions in the form of urticaria, focal pigmentation, papules, nodes or
various other rashes; patients are bothered by generalized skin itching, pain in the chest and
limbs. Peripheral lymph nodes in LGM are affected in 90–95% and predominantly in the
cervical and supraclavicular groups; they can reach significant sizes, have a woody density, are
mobile, are not fused with the surrounding tissue (the “potato in a sack” symptom), and are not
subject to purulent melting. With tuberculosis, the lymph nodes increase in size, gradually fuse
with each other, forming conglomerates, are accompanied by periadenitis, and are prone to the
formation of fistulas with caseous discharge. In patients with LGM, tuberculin sensitivity is
anergic. When examining blood in patients with lymphogranulomatosis, anemia, leukocytosis,
neutrophilia, lymphopenia, eosinophilia and high ESR are more often observed. In case of
lymphogranulomatosis, the intrathoracic lymph nodes are affected on both sides, most often the
paratracheal and tracheobronchial groups; in tuberculous bronchoadenitis, the process is more
often localized in one of the bronchopulmonary groups. The X-ray picture of LGM is
characterized by a significant increase in intrathoracic lymph nodes of a tumor-like type, which
have a symmetrical distribution, the structure of these lymph nodes is homogeneous. The upper
mediastinum is expanded, with clear polycyclic contours, the lumens of the bronchi remain free.
The diagnosis of lymphogranulomatosis is made on the basis of puncture biopsy of a peripheral
node. The detection of Berezovsky-Sternberg cells, the presence of plasma cells, lymphocytes,
and eosinophils indicates lymphogranulomatosis.

Primary tuberculosis complex

Pathogenesis. There are two possible ways of development of the primary tuberculosis
complex (orthograde and retrograde). Air particles containing MBT, when inhaled, enter the
peripheral parts of the lungs, form a primary pulmonary effect (focus), while part of the MBT
enters the lymph (an outflow lymphangitic path appears to the root of the lung) and affects
nearby lymph nodes. With the retrograde route, the lymph nodes of the root are primarily
affected, and the process proceeds to the lungs sequentially. Thus, the primary tuberculosis
complex consists of three components: pulmonary, glandular, vascular.

Formаtion of primаry, stages: а — I (pneumonic): 1 — lymph nodes of the root, 2 — lymphangitis, 3 —pulmonary affect (focus); б
(— II (resorption): 1 — regional lymph nodes, 2 — bronchopulmonary vessels, 3 — perifocal inflammation; в — III (compaction); г
— IV ( formation of Gohns focus)

With specific inflammation, epithelioid cells, Pirogov-Langhans giant cells, and lymphoid
elements appear. Caseosis (cheesy necrosis) forms in the center.

Clinic

According to the course, they distinguish between smooth and complicated course of primary
tuberculosis. Multiple lesions or an extensive inflammatory reaction are characteristic of a
complicated primary complex. An uncomplicated course is characterized by limited lesions
(focus 2-3 cm in diameter) in the lungs, a slight increase in intrathoracic lymph nodes and mild
lymphangitis. Occasionally, a progressive course is observed, which is manifested by the
formation of a cavity in the lungs, the development of caseous - necrotic reactions in the lung and
intrathoracic lymph nodes, and in some cases the development of generalized miliary
tuberculosis and meningoencephalitis is observed. Clinical manifestations of the primary
tuberculosis complex are varied and depend on the size of perifocal inflammation in the lungs
and intrathoracic lymph nodes.

Fig. Primary tuberculous complex. A –macrospacement, B- TBC in left lung , Pneumonic stage.X-
ray of lungs on frontal projection

In infants and young children, the disease is characterized by striking clinical manifestations.
At older ages, their symptoms are often quite sparse. The onset of the disease is asymptomatic.
However, the appearance of previous signs of general tuberculosis intoxication in the form of
changes in the child’s behavior (increased fatigue, lethargy or irritability) is mandatory. There is
a low-grade fever, loss of appetite, weight loss, and the child becomes lethargic. During the
period of fever, a sick child remains in relatively satisfactory health, which is characteristic of a
specific process. Complaints of cough are rare, although in young children a bitonic, dry
paroxysmal cough is possible.

paraspecific reactions (toxic-allergic nonspecific) occur : phlyctena, keratoconjunctivitis,

blepharitis, erythema nodosum (Fig). Ponce pseudorheumatism, eosinophilic pneumonia,
polyserositis (pleuritis), bronchitis.

Fig. Pаrаspecific reactions in primary tuberculosis:

А – сonjuctivitis; Б –flictenа; В – erythema nodosа.

Percussion changes during PTC prevail over auscultation: a shortening of the percussion
sound is determined at the location of the pulmonary component and enlarged lymph nodes.
After coughing, at the height of inspiration, unstable, fine, moist rales are sometimes heard.
Tuberculin sensitivity is usually positive. In young children, a hyperergic reaction may be
observed. In the initial period of the disease, changes in the general blood test are detected:
moderate leukocytosis (up to 15x10 9 /l.), eosinophilia, lymphopenia, monocytosis, increased
ESR (20–30 mm/hour). In a general urine analysis, a small amount of protein, single leukocytes
and red blood cells can be determined. Children rarely produce sputum, therefore, to identify
Mycobacterium tuberculosis, it is necessary to examine bronchial or gastric lavages, smears from
the larynx, “enrich” the test material by flotation, and then carry out the study.

X-ray examination is one of the important diagnostic methods. 3 stages are conventionally
distinguished : pneumonic, resorption and compaction, petrification. These stages correspond to
the clinical and morphological patterns of the course of primary tuberculosis.

IIP tuberculous complex: I stage – pneumonic (А); II stage – resorption (Б); III stage – compaction (В);
IV stage – calci ation (Г).

infiltration
phase, an area of shading is determined in the lung tissue (reminiscent of pneumonia),
inhomogeneous in nature, with blurred contours, which can close the path and overlap the
enlarged root of the lung (Fig) .

During treatment, after 2-4 months, the next phase begins - the resorption of inflammatory
phenomena (bipolarity - resembles a dumbbell). The X-ray image shows all three components of
the primary complex separately. The third stage, which occurs after another 3–5 months of
treatment, is the compaction phase - the pulmonary component and the root of the lung decrease
in size, its contours become clearer. The fourth stage is characterized by further compaction and
calcification within 12 months of pulmonary and glandular components and ends with the
formation of a Gohn lesion, usually up to 1 cm in size; its shadow is intense, homogeneous, with
clear contours. Complications of the primary tuberculosis complex arise with the deepening of
disorders in the immune system and are associated with lymphohematogenous and bronchogenic
spread of infection, as well as with the formation of a cavity in the affected area and
generalization of the pathological process. Complications: pleurisy, lymphohematogenous
dissemination, atelectasis, bronchial tuberculosis, primary cavity in the lung and lymph nodes,
caseous pneumonia and tuberculous meningitis.

Differential diagnosis of primary tuberculosis complex

The primary tuberculosis complex in the infiltration phase often has to be differentiated from
nonspecific inflammatory lung diseases. In modern conditions, protracted segmental pneumonia
has become quite common. The reverse development of such processes may be delayed up to 3–
8 months from the onset of the disease. In the etiology of segmental pneumonia, the leading role
is played by viral infections, adenoviruses; less often they complicate measles, whooping cough,
sepsis and other diseases. A child with prolonged pneumonia, as a rule, has a history of frequent
colds.

Nonspecific acute lobar and segmental pneumonia is characterized by an acute onset of the
disease with chills, a serious condition, catarrhal symptoms, severe symptoms of intoxication,
and intermittent chest pain. With pneumonia, a dry paroxysmal cough is observed in the first
days, which in subsequent days becomes wet with the release of mucous sputum. On
examination, symptoms of respiratory failure are revealed: cyanotic-labial triangle, flaring of the
wings of the nose, participation of auxiliary muscles in breathing, retraction of the intercostal
spaces.

In the primary complex, percussion changes prevail over auscultatory ones, and in
pneumonia, auscultatory data are more informative: moist rales of various sizes against the
background of weakened, sometimes bronchial breathing. With pneumonia: more pronounced
leukocytosis with neutrophilia, band shift to the left, accelerated ESR. X-ray picture: acute
pneumonia is more dynamic, characterized by lower lobe localization in the lung, polysegmental
and bilateral lesions, the shadow is often irregular in shape, less intense, but more homogeneous.

Streptococcal and staphylococcal pneumonia are characterized by multifocality, bilateral

spread, and variability of the X-ray picture in a short time. A triad of characteristic symptoms is
known: foci of infiltration, rounded cavities of decay, pleural exudate.

Pneumonia of rheumatic etiology is characterized by rapid dynamics of radiological changes

in the lungs, most often affecting the lower lobe of the lung in the presence of other symptoms:
joint pain, frequent sore throats, shortness of breath, the presence of heart disease.

Friedlander's pneumonia, despite its long course, unlike tuberculosis, is characterized by a

dynamic process with the manifestation of unfavorable local shifts. Rapid formation of cavities,
drainage with elimination of contents and their transformation into thin-walled ones are
observed.