Pulmonary Infection or Classic Primary Complex

This presentation is the most common one (90%) and appears in a self-limited form. By having nonspecific respiratory symptoms such as cough and secretions, often it goes unnoticed and is confused with a banal viral infection. Phlyctenular keratoconjunctivitis and nodular erythema are infrequent signs. Small children and adolescents tend to be more symptomatic. Chest X-ray may show the classic radiological image of hilar adenopathy and, less frequently, a figure resembling a loaded barbell, which denotes Ghon’s primary complex. Radiological signs tend to take 6–12 months to disappear, although calcifications may develop in the future.

Patients are diagnosed through a positive PPD test or a boosted PPD test, in the context of a contact study of a bacilliferous case. In these cases, it is important to implement a treatment, because the probability of developing the disease with pulmonary or extrapulmonary presentations increases during the first 2 years after the primary infection.

Pulmonary Disease: Progressive Pulmonary Presentations

Nowadays, this presentation is highly exceptional. The development of this clinical manifestation is basically determined by the immunity of the host, so it increases in children younger than 2 years old, children with a poor nutritional state, those who did not receive the BCG vaccine, or are HIV positive, as well as those who are exposed to close contact with bacilliferous sick patients. The pulmonary manifestation is very similar to the clinical presentation of any pneumonia: coughing, fever, expectoration, and dyspnea, and the differential diagnosis includes the suspicion of this possibility when there is no adequate clinical response. When there is a parenchymal progression to cavitary presentations, caseous pneumonia, or primary phthisis, the following symptoms can also be observed: asthenia, adynamia, night sweats, weight loss, and hemoptysis.

Chest X-ray shows condensations that become cysts from necrosis, which happens in necrotizing pneumonia in connection with the presence of large adenopathies. These adenopathies are rarely symptomatic, except when they compress a main bronchus or erode and drain the brionchus (bronchogenic dissemination). A positive culture result for Koch’s bacillus is observed in more than 80% of the cases (Fig. 35.2). At times, bronchial compromise may progress to a complete expansion of the lung. In such situations, distal lesions disappear with radiological resolution.

Adult-Type Tuberculosis

In high school seniors or adolescents, primary infection progresses to adult-type manifestations. In these patients there is a general health state compromise, fever, coughing, expectoration, hemoptoic or hemoptysis tear, and weight loss. Radiological images show infiltration, predominantly apical, in addition to excavations or caverns. Lesions in these patients are highly bacilliferous and connected to the external environment, so bacteriological tests are usually positive (Fig. 35.3).

Tuberculous Adenitis

Tuberculous adenitis is the most frequent extrapulmonary presentation. It usually presents as a localized adenopathy on a lymph node or lymph pack. It can involve any lymph group, but it usually appears on the head and neck.

Adenopathy can cause a subacute presentation with mild general symptomatology or none. During the examination, the adenopathy is mobile, painless, and without erythema. If it is not treated, it increases in size and a caseous necrosis appears. In this stage, the adenopathy acquires a typical erythema tone, with a fluid texture in the centre. If this adenopathy breaks, it may cause a skin fistula or scrofula, which chronically leaks. Pulmonary compromise must be ruled out for these patients. Differential diagnoses include lymphoma and certain infectious causes, so a biopsy is fundamental for making a definitive diagnosis.

Others

Patients can present with osteoarticular, renal, genitourinary, abdominal, adrenal, parotid, ocular, and skin compromise. However, these extrathoracic presentations of tuberculosis are infrequent.

Miliary Tuberculosis

This presentation is more common in children who are younger than 5 years old, have with a poor nutritional state, and are immunosuppressed. The onset is 2–6 months after the first infection. Clinical manifestations are mixed and may depend on the number of bacilli that enter the bloodstream and the patient’s immune response. Miliary tuberculosis can present itself as an unspecific infection, with an insidious onset, and without apparent seriousness or acute symptoms. As the infection progresses, fever, coughing, weight loss, anorexia, and night sweats start to appear. Three weeks after the onset of the symptoms, chest X-ray shows diffuse micronodular images (<2 mm) in both lung areas. Lesions can be detected early in the retrocardiac space of a lateral radiography. PPD tends to be negative in these patients, and diagnosis is made through physical examination, thoracic radiography, thoracic computed axial tomography scan, and eye examination (choroidal tuberculous can be seen). Confirmation can be obtained through bacteriological tests of expectorations, gastric content, pulmonary puncture, or mieloculture. Given the high meningitis risk, lumbar puncture is always recommended. Early clinical suspicion of meningitis is very important given its high morbidity and mortality rate as well as its neurological sequelae (Fig. 35.4).

Tuberculous Meningitis

This presentation is a meningoencephalitis that mostly compromises the base of the brain and the circle of Willis. Three developmental stages can be identified, which progress during 1 to 2 weeks. In infants and small children, progression can be faster, lasting only a few days. During stage 1, nonspecific signs are predominant, including fever, lack of energy, irritability, vomiting, constipation, and delays in psychomotor development. During stage 2, an intense headache appears, as well as explosive vomiting, disorientation, and seizures. In this stage, physical examination shows meningeal signs, compromise of the cranial pairs, focal neurological signs, or hemiparesis and endocranial hypertension. Stage 3 is the most serious one, as patients display severe consciousness impairment, which ranges from stupor to coma, hemiplegia, or tetraplegia. Severe endocranial hypertension, besides decerebrate or decorticate posture, can also be observed. These patients tend to have a negative PPD test, with thorax chest X-ray revealing parenchymal compromise. Computerized tomography (CT) shows several brain areas affected by strokes and infarctions, although in some cases tuberculomas may also be observed in the cerebral parenchyma. Diagnosis is based on alterations of the cerebrospinal fluid (CSF), which is characteristically clear and low in glucose. Cytochemical analysis also shows a minor presence of chloride, a high protein level, and a slight increase in predominantly mononuclear cells . Koch’s culture, amplification methods, and adenosine deaminase (ADA) in the CSF are useful.

Connatal Tuberculosis

Connatal tuberculosis is fortunately a rare disease. It has a very high mortality rate, even when treated. It is sanguineously transmitted through the umbilical cord or through amniotic fluid aspiration during childbirth. Symptoms include respiratory failure, hepatosplenomegaly, lymphadenopathies, fever, abdominal distension, lethargy, and irritability. Skin lesions, jaundice, seizures, otorrhea, and diarrhea are seen less frequently. Some newborns present with severe septic shock.

PPD Testing

The PPD test (protein purified derivative) is a protein concentrate of Koch’s bacillus, Calmette–Guérin (BCG), and nontuberculous mycobacteria. The PPD test is highly sensitive but nonspecific for Mycobacterium tuberculosis infection. The test consists of 2–10 U of this concentrate delivered intradermally in the external radial side of the left forearm. Subsequently, the cellular immunity response to PPD inoculation is measured. The test uses a hypersensitive delayed response, the value of which peaks at 72 h. At this point, the extent of the transverse induration is measured (pencil test). Internationally, a PPD test is considered positive when it has an induration area equivalent to or greater than 10 mm. In children younger than 4 years old, with malnutrition, immunosuppression (HIV infection), or without BCG vaccine, a test is considered positive if induration reaches or surpasses 5 mm. A tuberculous boost is defined as an induration increase greater or equal to 10 mm with a difference greater than 6 mm, which happens in 3-month intervals (up to 2 years). This reaction is compatible with a recent infection. The PPD test can yield a “false negative” after a viral infection, live virus vaccination, immunosuppression, and in severe tuberculosis presentations, especially for the most widespread forms: 5% to 10% of tuberculous diseases yield a negative PPD test.

PPD test interpretation is difficult and may lead to confusion, particularly in countries with high BCG vaccine coverage. The PPD test is useful for diagnosing double tuberculous infections in countries with a low endemic rate of Mycobacterium tuberculosis, low infection incidence for nontuberculous mycobacteria, and high BCG vaccine coverage.

IGRAS

Bacilloscopy requires at least 5000 BK/ml (two samples) to yield a positive result. A Ziehl–Neelsen stain is used, which requires a microscope with 1000× or greater magnification, and 10–15 min of exposure; alternatively, it is possible to use a fluorophore stain, which requires a 400× reduction in the magnification, and takes 2–3 min of exposure. WHO recommends the latter technique.

Culture requires 10 BK/ml to get a positive result and is the gold standard for diagnosis. In children it is rarely positive, except for the cases in which there are excavated lesions communicating with the central airway. Löwenstein–Jensen culture requires from 3 to 6 weeks, plus 3 additional weeks when resistance is suspected. This is a slow process, but it provides a better identification of Koch’s bacillus and drug resistance. This medium is available in regional laboratories throughout our country. The liquid medium technique takes from 1 to 3 weeks and relies on a continuous automated reading of bacterial growth, which affords greater sensitivity. It has a higher contamination rate, although it is difficult to identify the morphology of the colonies. There are also nonradiometric cultures, such as MGIT (Mycobacteria Growth Indicator Tube), the BACTEC9000MB system, and ESP Culture System II Myco, available in central laboratories.

Samples for bacteriological studies rarely come from the expectorations of sick children. In these cases, it is recommended to obtain samples by sputum induction, using a nebulized hypertonic saline solution, or aspiration of gastric content (three samples). The output of this sample is up to 30% in children, even for immunosuppressed patients with extrapulmonary tuberculosis. If the sample cannot be obtained with the aforementioned techniques, a bronchoalveolar lavage can be performed through bronchoscopy.

Samples from other parts of the body, such as pleural effusion, cerebrospinal fluid, pericardial fluid, peritoneal fluid, synovial fluid, and urine, are useful when extrapulmonary presentations are suspected.

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  Amplification technique for nucleic acids. These techniques can be considered in patients under suspicion of resistance to anti-tuberculosis drugs. They have a high sensitivity (96%) and specificity (85–95%) for positive bacilloscopy samples, so they can rapidly detect a few copies of nucleic acid. They do not need to be performed in a high security laboratory (level 3), and the newest techniques also detect drug resistance and identify specific microbacteria. Nevertheless, they are not too sensitive (66%) for negative bacilloscopy samples, which is the most common situation in children, and they are not available in higher prevalence areas, where they are most needed.

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