Treatment Guidelines PPD Interpretation

Tuberculosis (TB) is a pulmonary or systemic disease caused by infection with Mycobacterium tuberculosis (MTB). Transmission occurs via inhalation of droplet nuclei, which are produced by the cough, vocalization, sneezing, or normal breathing of infected persons. Fomites are not a means of infectious transmission. Factors which help determine the probability of infection include (1) the concentration of viable bacilli in the sputum; (2) the degree of aerosolization of droplet nuclei during coughing; (3) the immunization status of exposed persons; and (4) the duration of time of exposure. Studies have shown that within weeks of instituting antituberculous therapy, the infectious potential declines drastically even though smears may remain positive.

In the past, to make a definitive diagnosis of tuberculosis infection, acid fast bascilli (AFB) smears and cultures of sputum or tissue yielding MTB were required. Currently, the diagnosis may be established via a rapid nucleic acid amplification test (MTB/RIF test) which requires less than 2 hours to run at the bedside and can also identify multidrug-resistent strains. The diagnosis may be inferred in patients with a positive purified protein derivative (PPD), positive interferon-gamma-release assay testing, or characteristic chest radiograph abnormalities and characteristic symptoms (cough, sputum production, fever, weight loss, night sweats, and less commonly, hemoptysis). Nucleic acid amplification should be applied to sputum or tissue samples when AFB smears and cultures are negative but the diagnosis is still strongly suspected. QuantiFERON- TB Gold, QuantiFERON-TB Gold In-Tube, or T-SPOT.TB may be performed on peripheral blood sample in lieu of PPD testing. These tests are not affected by prior Bacille-Calmette-Guerin vaccination administration. Other Mycobacterium species are not a consideration with interferon-gamma-release assays. Adenosine deaminase testing may be used on pleural effusions or ascites to determine if tuberculosis is the etiology. Biopsy may be required in cases of TB not associated with obvious pulmonary infection such as osteomyelitis. MTB is an acid-fast rod that is characteristically slow-growing (one replication every 18 hours); therefore, cultures should be followed for a total of 6 to 8 weeks before being declared negative. When a specimen stains positive for acid-fast bacilli by Ziehl-Neelsen staining or other acid-fast techniques, it is not possible to differentiate MTB from other nontuberculous mycobacteria and in some cases from Nocardia or Actinomyces species. Therefore, a definitive diagnosis and treatment plan can not be made until the culture and sensitivity reports are available. Bodily fluids, ascites or pleural effusion, may be tested for tuberculosis by finding an elevated adenosine deaminase level if infection is present.

Once the inhaled bacilli reaches the alveolus, it is ingested by pulmonary macrophages. Since cellular immunity has not yet occurred, the macrophage is inefficient in destroying the bacillus, and proliferation of MTB may occur within the macrophage. During this time, asymptomatic, systemic, hematogenous dissemination of the apical portions of the lung and of other organ systems may occur. Skin test reactivity to PPD occurs 30 to 50 days after infection. The prevalence of clinical symptoms manifesting within 1 year in persons infected with MTB is estimated at 2 to 5%. Of the remaining infected persons, 5% will develop symptomatic disease during their lifetime. Asymptomatic patients with a positive PPD and a normal CXR are said to have latent tuberculosis; whereas, patients with a positive PPD who are symptomatic are said to have active tuberculosis disease. Prior BCG status should not influence diagnosis or PPD interpretation at all.  With regards to PPD  or interferon-gamma-release assays, to test is to treat all positive results.

Symptoms vary depending on the organ system involved. Fever, weight loss, night sweats, and fatigue are common to most cases of infection. Pulmonary TB is further characterized by a productive cough and less commonly hemoptysis. Genitourinary involvement manifests as painless hematuria or sterile pyuria. Symptoms of meningitis (headache, altered mentation, fever, Kernigs or Brudzinskis signs) herald meningeal infection. Pleuritic chest pain indicates pleural involvement, and if there is an associated pleural effusion, shortness of breath will be a prominent symptom. Local pain signifies joint or bone infection. Addisons disease, hepatomegaly, and intestinal perforation with resultant abdominal pain are associated with adrenal, hepatic, and intestinal infection, respectively. Scrofula (cervical lymphadenitis secondary to TB) or diffuse lymphadenopathy are indications of tuberculous infection of the lymphoreticular system. Ascites or pericardial effusions may be associated with peritoneal or pericardial infections, respectively.

Associated lab abnormalities depend on the site of infection. An elevated alkaline phosphatase may be seen with hepatic or bony involvement along with hypercalcemia. A normocytic anemia may be noted. Hyponatremia may be secondary to TB induced SIADH; however, if the abnormality does not correct with fluid restriction, the diagnosis of tuberculous Addisons disease should be considered, especially if there is concomitant hyperkalemia. Hematuria may herald renal involvement.

Radiographic abnormalities consistent with pulmonary tuberculosis infection are of two types. Those consistent with recent primary infection, and those consistent with prior infection. Acute infection usually presents radiographically as a lower lobe infiltrate, which may be associated with hilar adenopathy (a finding more common in pediatric populations); however, in persons with a high index of suspicion for infection, any radiographic abnormalities should be considered consistent with active disease. The radiographic evidence of prior infection is diverse. Upper lobe granulomas or cavitations mostly in the apical or posterior regions, loss of volume (tracheal deviation, elevated hemidiaphragm, or elevated fissures) and hilar adenopathy are all consistent with prior infection.

As stated before, a definitive diagnosis can only be made by culture of infected material. Therefore, in persons with clinical symptoms of TB infection, a positive PPD, positive interferon release assay, or a high index of suspicion for pulmonary infection, sputum samples should be collected, stained with the Ziehl-Neelsen procedure and cultured for MTB. A minimum of 2 and a maximum of 6 sputum samples should be collected to ensure a thorough workup. It is important to note that smears will be nondiagnostic in up to 60% of cases of active pulmonary TB infection. If the sputum samples are negative but the index of suspicion is high, the workup should proceed to include induced nebulized saline induced sputum samples, nucleic acid amplification testing of a sputum sample, bronchoscopy for bronchoalveolar lavage and transbronchial biopsy and, if a pleural effusion is present, thoracentesis (low yield), and a pleural biopsy should be performed. Antituberculous chemotherapy may be instituted during the workup depending on the degree of suspicion and the severity of symptoms. Therapy may then be continued, altered to include different medications or discontinued depending on the culture and sensitivity results. Evaluation of the patients HIV and viral hepatitis status is prudent once the diagnosis of tuberculosis has been considered or established.