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Natural history and clinical spectrum
It has been traditionally useful to distinguish between “infection” and “disease” in the natural history of tuberculosis. Following initial exposure to a case of transmissible tuberculosis, the hallmark of tuberculosis infection is conversion of the tuberculosis skin test (TST). Subsequent tuberculosis disease is characterized by the development of signs and symptoms and/or radiographical changes. Without chemoprophylaxis, 40-50% of infants and 15% of older children with infection will develop disease in 1-2 years.

Infection
Initial infection in the lung (98%) is characterized by the constellation of a Ghon lesion and regional lemphadenitis, together called the primary complex, which may not be obvious radiographically. In most children this resolves spontaneously with residual calcification or scarring.

The distinction between infection and disease is an important one for many reasons, including the different treatment regimen and the fact that children are more likely than adults to develop disease after primary infection with M.Tuberculosis.

Tuberculosis in children,
as different from tuberculosis in adults

1. Children of different ages vary in terms of the risk of developing active tuberculosis and in the likelihood of transmission of infection.
2. Children rarely develop cavitary lesions.
3. Children more commonly have extrapulmonary disease.
4. Children usually have a smaller number of M. tuberculosis organisms: therefore, fewer children are culture-positive and they have less secondary drug resistance.
5. Children respond to antituberculous medications differently: they tolerate higher relative doses per kilogram of body weight with fewer side effects.

The diagnosis of tuberculous infection in children is established by a positive TST for which 5 TU/ 0.1ml of purified protein derivative are used. The child has no signs and symptoms of tuberculosis and the chest radiograph either is normal or reveals only granuloma or calcifications or scars in the lung parenchyma and/or regional lymph nodes. In children the tuberculous infection is a preclinical stage of tuberculosis and not a simple infection.

Tuberculosis progresses to clinical disease when the primary infection is not contained by the host response, or when the latent infection reactivates and clinical signs and symptoms are apparent. Estimates suggest that 5-10% of adults with M.tuberculosis infection progress to active disease at some time during their life. Most children diagnosed with TB infection without disease are identified during contact investigations or skin test screening. Preventive treatment should be given in a timely fashion at this stage to prevent progression to active disease of any form.


Active tuberculosis disease
The diagnosis of tuberculosis in children is based mainly on a combination of positive history of contact with an adult infectious case, clinical signs and symptoms, investigations such us tuberculin skin test, chest radiograph and mycobacterial culture from three early-morning gastric aspirates or from other sites (cerebrospinal fluid, bones, joints, etc.)

If the source-case culture results are known for a child with probable tuberculosis, attempting to culture the child’s strain is usually not necessary – negative culture results do not rule out disease and the susceptibility of the strain isolated from the source case can be used to direct therapy.

Approximately 80% of infants aged less than 1-2 years are symptomatic at the time of diagnosis. Cough, fever and moderate (but sometimes frank) respiratory distress are the major presenting features. Localized or diffuse wheezing and/or rales are common. Any delay in diagnosis, and therefore treatment, may lead to severe and even life-threatening complications.

Chest radiographs are analyzed in the section on diagnosis.

Non-reactivity to tuberculin does not exclude the diagnosis of tuberculosis. Besides that, interpretation of skin tests may be confounded by previous BCG vaccination. BCG does not afford full but partial protection for infants against massive household contamination. Therefore, it is imperative to locate the adult source-case.

Because the incubation period of tuberculosis in young children can be very short (6-8 weeks for meningitis and disseminated disease), children exposed to adults with pulmonary tuberculosis should be investigated without delay.

Timetable for development of tuberculosis
Form of tuberulosisTime from infection to onset
Immune conversion4-8 weeks
Primary complex1-3 months
Local lung complications3-9 months
Pleural effusion (usually teenagers)3-12 months
Miliary/ meningeal3 months onwards
Bone10-36 months
Skin5 years onwards
Renal10 years onwards
Secondary breakdown5 years onwards
Hoskyns W. Postgrad med. J. 2003; 79: 272-278

Lymph Node disease

Enlarged regional lymph nodes on chest radiograph rarely cause symptoms, except when they are associated with bronchial disease, or when excessive nodal caseation cause persistent fever and weight loss. The subcarinal nodes were most commonly involved and rarely pericardial effusion developed following nodal erosion with caseous discharge into the pericardial space. Lymph node enlargement can impinge on proximal anatomical sites and result in various clinical manifestations, such as bronchial obstruction, odynophagia with esophageal compression, and vocal cord or hemidiaphragmatic paralysis caused by local nerve compression.

Bronchial obstruction can lead to a “collapse-consolidation” picture on chest radiogram, usually with minimal symptoms or signs.

Pulmonary tuberculosis

Depending on its progression, active pulmonary tuberculosis in children manifests in a variety of forms, including endobronchial disease with regional lymphadenopathy, progressive pulmonary disease, pleural involvement and reactivated pulmonary disease. Many radiographic findings arise from a combination of lung disease and the mechanical changes (partial or complete airway obstruction) caused by enlarging intrathoracic lymph nodes, especially in infants.

In conclusion, the most common manifestations in children are hilar or paratracheal lymphadenopathy and/or obstruction of a segmental bronchus.

Extrapulmonary tuberculosis

Extrapulmonary tuberculosis includes peripheral lymphadenopathy in approximately 60% of patients, tuberculous meningitis in 10-15%, infection of bones or joints in 5%, and miliary tuberculosis (infection at several distant sites) in 5% of patients.

Peripheral tuberculous lymphadenitis

Is the result of local spread from the primary site of infection especially to supraclavicular or cervical nodes. Lymphohematogenous dissemination can spread infection to distant lymph nodes from the primary infection. Rarely, peripheral adenitis is the result of a primary extrapulmonary site of infection (nose, tonsils, external ear etc.)

Tuberculous lymphadenitis usually presents as enlarged, firm, non-tender, painless lymph nodes with little erythema or fluctuance. The adenitis can progress to caseation and necrosis and cause erythema, fluctuance, and occasionally spontaneous drainage. Most commonly involved are the anterior or posterior cervical and supraclavicular lymph nodes: less commonly, the submandibular, submental, axillary and inguinal nodes are involved.

Tuberculous meningitis (TBM)

Is the most serious complication of childhood tuberculosis and has its highest incidence between the ages of 1 and 3 years. At this age it is often associated with miliary tuberculosis and if untreated a majority of children with miliary tuberculosis will die of TBM.

In both developed and developing countries the diagnosis of TBM is frequently delayed with disastrous consequences for the patient as the prognosis is closely linked to the stage of the disease at the time of diagnosis. Initially (stage 1), non-specific signs and symptoms predominate. This includes mild fever, decreased appetite, vomiting and behavioral changes. Patients diagnosed at this point, should recover fully. When focal neurological signs appear or the patient is mentally confused, the disease is considered to be at stage II. Although the majority of patients presenting at stage II will survive, they are likely to do so with a physical or intellectual deficit. By stage III, the patient is comatose, with convultions, unable to localize pain and may develop hemiplegia or rarely quadriplegia. A third of these patient may die and the great majority of survivors will have severe physical and mental handicaps.

Miliary tuberculosis

Acute miliary disseminated tuberculosis is a part of a broad spectrum of hematogenous spread of M.T. with various and variable degrees of clinical manifestation and severity. It may occur during primary disease or within 6-8 months of primary disease. In endemic areas, hematogenous spread may occur in neonates and infants, leading to primary miliary or disseminated tuberculosis.

Miliary tuberculosis is caused by the rupture of caseous material into a blood vessel, resulting in hematogenous spread to numerous sites throughout the body. Approximately one third of children with miliary tuberculosis presents with meningitis as one of the many involved sites.

The presentation of miliary tuberculosis depends on the specific sites involved. It can either occur subacutely with weigh loss, fatigue, malaise and low-grade fever or acutely with high fever and rapid onset of associated symptoms. The child usually has lymphadenopathy, hepatosplenomegaly and a paucity of respiratory signs. Respiratory manifestations often evolve and include cough, tachypnea, cyanosis and respiratory distress. Subtle findings such as papular, necrotic or purpuric lesions on the skin or choroidal tubercles on the retina should be carefully sought in the physical examination.

Skeletal tuberculosis

Is a late complication of lymphohematogenous spread of bacilli, usually presenting years after the primary infection. Infants and young children are at great risk of tuberculosis of the bone or joints because of the increased vascularity of the growing bones. Focal infection often begins in the metaphysis from bacilli seeding the endarteries. Endarteritis leads to local bone destruction and subsequent drainage into the adjacent joint capsule or through a sinus tract to the skin. The most common sites involved are the large weight-bearing bones or joints such as the vertebrae (30-40%), hip (7%), knee(7%) and elbow (5%). Tuberculosis of the bone or joint presents either acutely or subacutely, as do the other common pyogenic bacterial skeletal infections. Vertebral tuberculosis may be very insidious, preseding with signs of referred pain, abnormal posturing or even a paravertebral abscess. Bone destruction with bone deformity is a late sign of skeletal tuberculosis.

Congenital tuberculosis

Occurs rarely. There are several hundred cases reported in the literature. Infection of the fetus can occur through transplacental spread or bacilli through the umbilical vein, bacilli reaching the amniotic fluid from tuberculous endometritis, placentitis or both, or from ingestion of infected amniotic fluid at the time of derivery. The clinical presentation of congenital tuberculosis commonly begins in the second or third week of life and is similar to that of bacterial sepsis or other congenital infections. Signs and symptoms often include poor feeding and poor weight gain, jaundice, hepatosplenomegaly, abdominal distension, cough, tachypnea, irritability, lethargy and lymphadenopathy. TST is usually negative in infants especially in the first 6-8 weeks of life. Most infants have an abnormal chest radiography and almost half demonstrate a miliary pattern.

Perinatal tuberculosis

Is more common than congenital tuberculosis, but has a lower mortality rate. The route of infection is most commonly inhalation of tuberculous bacilli from the mother or any caregiver with active pulmonary tuberculosis. Clinical presentation is usually delayed until the patient is 1 to 3 months of age and varies according to the infecting dose of bacilli and the sites involved. The clinical presentation may suggest congenital TB, tuberculous meningitis, miliary tuberculosis or primary pulmonary tuberculosis.


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