Tuberculosis (pediatrics)

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Tuberculosis (TB; TBC in Czech) is a chronic infectious disease caused by Mycobacterium tuberculosis. It affects mostly the lungs, extrapulmonary forms are less common and can affect any organ. Due to high vaccination rate of the Czech population the overall presence of TB is very low and extrapulmonary forms are rather exceptional. Higher rates of TB infection are notable among the elderly, the homeless, people addicted to alcohol or other addictive substances, the underprivileged and the immigrants. The diagnosis of TB is based on positive epidemiological anamnesis, chest X-ray, tuberculin test, bacteriological proof, biopsy and histological testing, and auxilliary examination methods. A combination of antibiotics is used as a treatment, which lasts at least 9 months. In the Czech republic, a vaccine is available, although it is not a part of the obligatory vaccination program.

A disease caused by related non-tuberculotic bacteria is called mycobacteriosis.

Etiology

• Mycobacterium tuberculosis („Koch's bacillus“) is an acidoresistant rod-shaped bacteria;
• small, immobile, slow growing bacillus;
• very resistant against acidic environment;
• when stained by the Ziehl-Neelsen method the rods are red against a blue background;
• the M. tuberculosis complex includes:
  • M. bovis, M. africanum, M. microti, M. canetti;
  • M. bovis used to be a fairly common cause of infection before the advent of milk pasteurization;
• non-tuberculotic mycobacteria:
  • Mycobacterium avium and M. kansasii – they cause severe illness which includes damage to lymphatic nodes as well as lung tissue (mycobacterioses);
  • M. leprae – the cause of leprosy.

Epidemiology

• risk factors: weakened immunity, malnutrition, HIV positivity (at least ⅓ of people suffering from AIDS has an active tuberculosis), intravenous drug abuse, diabetes mellitus, chronic renal failure, cancer, lung silicosis, biological therapy by TNF-α inhibition;
• transmission: droplet infection – contact with a diseased person that secretes M. tuberculosis into the sputum (active untreated TB);
• the risk increases with the amount of bacteria and the frequency of exposition – the most dangerous are sources within families (a child is in frequent contact with the diseased person);
• the source isn't usually discovered in extrapulmonary TB.

Pathogenesis

• M. tuberculosis usually enters the organism through pulmonary alveoli → absorbed by the macrophages and antigen-presenting cells → contained in the regional lymph nodes (locus of primary infection + infected regional lymph node = primary complex) → if the infection isn't stopped, it progresses to postprimary form;
• often the thoracic lymph nodes are infected primarily;
• TB is a granulomatous inflammation with the participation of macrophages, T-lymphocytes, B-lymphocytes and fibroblasts → it creates a granuloma around the infectious agent, the granuloma is surrounded by lymphocytes → the granuloma prevents the infection from spreading and allows the cells of the immune system the elimination of bacteria controlled by interferon γ (activator of acrophages) → granulomas undergo a typical necrosis (caseous necrosis) → if any mycobacteria survive, it turns to a latent state with the risk of reactivation

The infection can be divided into primary and postprimary.

1. Primary tuberculosis
   • happens after the first contact of the organism with the bacteria
   • its sign is the enlargement of lymph nodes (in both pulmonary and extrapulmonary forms)
   • it is the most common form of this disease in young age
   • a so-called primary complex appears – primary locus + lymphangoitis + lymphadenitis in the pulmonary hilum
   • during the creation of the primary complex the hematogenous spread is happening
   • it can remain latent or turn into postprimary forms
   • the primary pulmonary tuberculosis can be accompanied by – atelectasis (caused by the pressure of a swollen node against the bronchus – clean atelectasis; or by the prolapse of the node into the bronchus and the subsequent aspiration – unclean atelectasis)
2. Postprimary tuberculosis
   • in persons who underwent primary tuberculosis
   • it is caused either by transition from primary form during unfortunate circumstances (puberty, weakened organism), or by endogenous reactivation of an older, untreated primary complex, rarely by exogenous superinfection
   • early forms – a few weeks or months after the first infection
     • hematogenous spread – acute miliary tuberculosis, tuberculotic meningitis, tuberculotic exsudative pleuritis
   • latent forms
     • after a period of one or more years after the first infection
     • bone and joint tuberculosis, urogenital tuberculosis, tuberculosis of the kidney

Clinical manifestation

Primary form

• it is the most common form of tuberculosis in children
• usually completely asymptomatic (both clinically and in the laboratory)
• infected children do not cough, lose weight or have fever, they are not tired and their appetite is normal
• the disease is revealed only through an appearance on X-ray

Postprimary form

• usually during the initial period of puberty;
• it affects the respiratory system in about 85% of cases → coughing, subfebrilia, tiredness, night sweats, anorexia, loss of weight → fevers with shivers, chest pain, hemoptysis;
• complications: chest empyema, pneumothorax, pyopneumothorax;
• physical manifestation on the lungs is usually negative in pulmonary forms.

Extrapulmonary tuberculosis

Aside from lungs any organ can be affected by tuberculosis. The manifestation of tuberculosis is non-specific (increased temperature or fever, night sweats, weight loss, etc.), often combined with local manifestation of organ damage (e.g. ostalgia, hematuria, diarrhea) that can imitate other diseases. The diagnosis is therefore difficult.

Most common forms of extrapulmonary tuberculosis in the Czech republic.

• peripheral lymphadenopathy
  • most often neck, supraclavicular and submandibular lymph nodes;
  • often accompanies the primary pulmonary TB;
  • neck lymphadenitis – unilateral painless swelling of the node packet; no signs of pharyngitis or tonsilitis, no fever
• Bone and joint TB
  • most often affects the spine – Pott's disease, then hips and fingers of upper and lower limbs;
  • by hematogenous spread or by direct expansion from a caseous lymph node;
  • cortical destruction on an X-ray; proof by biopsy and cultivation;
• urogenital TB
  • caused by late reactivation of the disease; always secondarily from pulmonary or bone loci, most often by hematogenous spread, rarely even through the lymph;
  • it affects the renal parenchyma, epidydimis, sometimes even prostate tissue, from there it spreads further;
  • eventually specific changes develop in the affected organs, caseous granulomas are created;
  • long-term urological problems which do not recede and do not respond to usual treatment are characteristic of the disease – dysuria, hematuria and "sterile" pyuria;
  • very common form of extrapulmonary TB in adults; rare in children;
• Skin TB
• tuberculous meningitis – most severe extrapulmonary form;
  • it most often affects children up to 5 years old;
  • it usually develops within 6 months from primary infection, during which M. tuberculosis colonizes the meninges → they replicate and trigger the inflammatory response;
  • initially inconspicuous manifestation: increased temperature, headache, subtle changes of personality → basilary meningitis with damage to head nerves – symptoms of meningeal irritation, intracranial hypertension and the development of altered consciousness → coma, death;
  • risk of severe consequences even after early treatment (hydrocephalus, head and motor nerve paralysis, blindness);
• abdominal tuberculosis
  • caused by the ingestion of milk contaminated by bovine TB; rare in developed countries.

Miliary tubreculosis

• hematogenous spread of the infection with diffuse damage in the form of tiny 2mm loci (bacteria with local inflammatory response);
• clinical manifestation with various severity (mild manifestation of respiratory infection → severe septic state).

Diagnosis of tuberculosis

Mycobacterium tuberculosis can be proved:

• directly (microscopically, through classic cultivation – long generation period (6 weeks), but allows the assessment of sensitivity; or by accelerated cultivation in the MGIT system – Mycobacterium Growth Indicator Tube – 2 weeks) or by molecular genetic methods (PCR – Polymerase Chain Reaction – risk of false positivity/negativity, AMTD – Amplified Mycobacterium Tuberculosis Direct test);
• indirectly by serological proof of IgG class antibodies against the Mycobacteruim tuberculosis complex through the ELISa method.

Widespread caseifying granulomas with necroses and the presence of giant polynuclear Langhans cells is typical of the histological image of TB. In the case that extrapulmonary form is to be proven it is necessary to rule out a concurrent active pulmonary form.

The bacteriological proof of mycobacteria is decisive (but it is successful in only about 10% in the most common pulmonary form). This is why we have the following three criteria:

1. epidemiological connection – the child is examined in relation to an adult with TB
2. chest X-ray: primary TB – the infection of intrathoracic nodes; postprimary TB – loci of infiltration (especially in upper lobes) or even a striped shadow, loci of decay and the increase in size of hilum nodes; miliary pulmonary TB – homogenous spread of tiny, 2mm large round shadows;
3. tuberculin test (Mantoux II):
   • strictly intradermal injection of 2 tuberculin units into the forearm
   • reaction is judged after 48-72 hours, only palpable induration is being classified = local cellular response; it is measured at a right angle to the axis of the forearm;
   • within 5 mm – negative; 6–10 mm – post-vaccination reaction; over 10 mm post-infection reaction; over 15 mm – suspected active TB;
   • in extrapulmonart forms the test is often weak or negative;
   • the tuberculin test should not be used in persons treated with corticosteroids and radiation, during acute febrile disease, during florid skin diseases;

M. tuberculosis can be proved in the sputum, gastric lavage, pleural effusion, bronchial aspirate or lavage, in urine, lymph node punction sample, etc.

Diagnosis of extrapulmonary TB

• positive epidemiological anamnesis (contact with a diseased human or animal);
• biopsy from the affected organ (bacteriology + histological examination) – decisive for diagnostics;
• image of the chest – often negative;
• tuberculin test – often slightly positive or negative;
• Quantiferon TB-Gold test (proof of specific interferon gamma in blood during active form of the disease) – unreliable in children.

Therapy

Tuberculosis is subject to reporting and mandatory treatment. The treatment is strictly in the hands of a specialist. Combinations of antituberculotics are used to prevent reoccurrence and the creation of resistant strains. Following drugs are considered basic antituberculotics – isoniazid (INH), rifampicine (RMP), ethambutol (EMB), pyrazinamide (PZA), streptomycin. Basic treatment takes 9 months.

• intensive treatment during initiation phase (2 months): INH + RMP + EMB + PZA
• sustained treatment during continuation phase (7 months or longer): INH + RMP
• during the administration of INH, it is necessary to administer pyridoxine at the same time to prevent the development of neuropathy;
• complementary drug (effusion, miliary TB, TB of the CNS): glucocorticoids.

Prevention

1. "Calmetisation" (inoculation)
   • in the Czech republic, widespread inoculation was cancelled in 2010
   • only newborns from groups at risk are being vaccinated, for example when the family of the child travels to the Czech republic from an area where the spread of the disease is higher than in the CR
2. Isolation of sources
   • mandatory treatment, hospitalisation during infectious stages
3. Chemoprophylaxis
   • non-vaccinated children with change of the result of the tuberculin test to positive are to be treated prophylactically with isoniazid for 3 months, children in contact with a diseased person sometimes as well

Notes

Mycobacterium tuberculosis was first described by Robert Koch in 1882 ("Koch's bacillus"). Between 1986 and 1993, when the inoculation of non-risk groups of children was suspended in some regions of the Czech republic, the incidence of TB in children rose sixfold and many cases of neck lymphadenitis with a histological proof of specific granulation tissue caused by M. avium appeared. This pathogen doesn't infect calmetized (i.e. BCG-vaccinated) patients. Between 1980 and 2008, when all newborns used to be calmetized before being discharged, 59 cases of bone damage of various localisation appeared as a complication of BCG vaccination. No bone complications appear after inoculation at higher age. One of the reasons for the cancellation of widespread vaccination of newborns was the risk of fatal generalization of the live BCG vaccine in newborns with unrecognized severe combined immunodeficiency (SCID).

„BCG“ is short for the Bacillus Calmette-Guérin vaccination strain introduced into practice by Albert Calmette and Camile Guérin. It is a live reduced strain of M. bovis, which has been used to vaccinate people since as early as 1921 (cross-immunogenicity with M. tuberculosis is utilized). The vaccine doesn't fully prevent the disease, but protects from the development of severe forms. It also reduces the risk of infection by atypical mycobacteria (aviary mycobacteriosis). The Danish strain SSI Copenhagen 1331 is currently being used in the Czech republic.