Applied Radiology

Dr. Chow is with the Department of Radiology, Stanford University School of Medicine, Stanford, CA and Dr. Stark is with the Department of Radiology at the VA San Diego Healthcare System and the University of California, San Diego, CA.

Tuberculosis (Tb) has been the scourge of civilization since before recorded history, afflicting humans and domestic animals alike in all parts of the world. The multitude of names including "the white plague," "consumption," and "phtisis" that has been applied to Tb attests to its protean manifestations.

While the earliest classical descriptions of Tb can be found in the writings of Hippocrates, it was the experiments of P.F.H. Klencke in 1843 and of Jean Antoine Villemin in 1865 that elucidated the contagious nature of the disease. The identification of the tubercle bacillus by Koch in 1882 allowed for the understanding of the pathogenesis of Tb. ¹ Subsequent developments in public health measures, diagnosis, and chemotherapeutic regimens led to a decline in the incidence and prevalence of the disease in the United States from 1930 to 1984 that led many to envision a complete eradication of the disease, much like smallpox. By 1985, however, approximately 4 years after the outbreak of the AIDS epidemic, the secular decline of Tb reverted for the first time in half a century. ²

With the resurgence of Tb since the advent of the AIDS epidemic, a miliary pattern of pulmonary involvement is seen on chest radiographs with increasing frequency in both immunocompromised as well as immunocompetent patients. As miliary tuberculosis represents a potentially lethal entity that generally demonstrates favorable response to therapy, the radiologist must recognize this pattern and suggest its possible presence in the appropriate clinical setting. This article will address the pathogenesis of miliary Tb, its classical roentgenographic appearance, and its changing epidemiology among adults, children, and immunocompromised patients.

Pathogenesis

Miliary tuberculosis develops as a sequela of the obligatory hematogenous dissemination in primary infection or as a complication of reactivation when tubercle bacilli are discharged from a focal infection into the lymphatics or blood. Viable bacilli disseminate to the capillary beds of multiple organs where they may lodge and proliferate. This is most frequently a complication of primary disease and generally occurs within 6 months of initial infection. ³ While pulmonary involvement is most conspicuous, other organs including the liver, spleen, and bone marrow may be affected. Likewise, the origin of
dissemination may be pulmonary or extrapulmonary. Within the lungs, the earliest changes detectable histologically include foci of polymorphonuclear exudation within two to five alveoli. ⁴ This stage is undetectable radiographically. With time, however, these foci develop into small nodules which may necrose. These nodules are generally discrete and randomly distributed throughout the lung parenchyma and along the pleura. They are generally first detectable when they reach 1 mm in size but may enlarge with time. ⁴ It is the 2 to 3 mm stage that is most commonly seen radiographically and for which the process is named: miliary from the Latin miliarus--of the size of a millet seed. They are generally uniform in size and of the same histologic age indicating a single, common episode of dissemination. ⁵ Without treatment, these nodules may enlarge further, eventually coalescing and giving rise to confluent opacities on the chest radiograph as a result of diffuse alveolar damage--an appearance often accompanied by adult respiratory distress syndrome (ARDS) clinically.

Epidemiology

While miliary Tb has been classically associated with progression of primary disease in childhood, the advent of effective chemotherapy has resulted in a shift of disease prevalence to the elderly. As a result of decreased exposure of the population to Tb during childhood, an increased proportion of the adult population is now at risk for primary Tb, which accounts for approximately 24% of adult cases. ⁶ Radiographically detectable miliary pulmonary Tb affects somewhere between 1% to 7% of all patients with Tb. ⁷ The elderly, children younger than 5 years, and immunocompromised hosts remain at greatest risk. ⁸

Before the AIDS epidemic, nearly 90% of patients with miliary Tb were younger than 1 year or older than 60 years. In patients with AIDS-induced immunocompromise, however, this rule no longer holds true. Both progressive primary infection, as well as reactivation of prior disease, may result in miliary disease. Patients with AIDS have a diminished T-cell response to infection and are more likely to continue on to progressive primary Tb and/or disseminated Tb infection in its miliary form when compared with non-HIV-infected patients. In one study, 60% of patients with AIDS and Tb presented with diffuse or miliary interstitial patterns on chest films. ⁹ Other predisposing factors for miliary disease include immunocompromise owing to hematopoietic disease, corticosteroid therapy, other immunosupressive medication, and renal failure. ^4,10

Clinical manifestations

The clinical presentation of patients with miliary Tb is often insidious in nature with non-specific constitutional symptoms and signs including fever, weakness, anorexia, fatigue, weight loss, cough, tachycardia, tachypnea, and inanition. Less commonly, hepatosplenomegaly, enlarged lymph nodes, and adventitious pulmonary sounds may be detected. Choroidal tubercles, bilateral poorly marginated white-gray patches on the order of ¾ 1 mm seen on ophthalmoscopic examination, are infrequently detected but represent perhaps one of the more specific signs suggesting hematogenous dissemination of Tb. ¹¹

Although insidious in onset, the development of miliary Tb is a life-threatening event which may ultimately lead to death if not treated in a timely fashion. Respiratory failure and/or disseminated intravascular coagulation are usually the immediate causes of patient death.

Radiology

The classic description of millary Tb on chest radiographs is of uniform 2 to 3 mm discrete nodules evenly distributed throughout the lung parenchyma (figures 1 and 2). Sometimes, a slight basal predominance may be detected, most likely reflecting a combination of factors including a summation effect of the x-ray beam traversing more lung tissue at the bases than apices as well as gravity-induced increased blood flow at the bases resulting in deposition of more Tb foci (figure 3). In 15% of cases, an assymetric pattern may be seen.

However, the presence of 2- to 3-mm nodules represents a point along a continuum of features. Initially after lymphohematogenous dissemination, the chest radiograph may be normal for approximately 2 to 6 weeks before the nodules attain a detectable size. ³ This is an important concept and dictates that a normal chest radiograph in the setting of suspected disease must be closely followed up with an HRCT (figure 4). Empiric treatment and isolation should not be delayed if active tuberculosis is clinically suspected. Berger and Samortin ¹² reported that the initial chest radiograph was normal in 12 of 14 cases of miliary Tb. Up to 10% of patients who succumb to miliary Tb have no abnormal findings on chest radiographs. When they first become detectable, nodules may measure only 1 mm and may best be seen through the intercostal spaces and superimposed on the cardiac silhouette in the lateral projection. With time, they may reach sizes of >= 5 mm or form areas of confluent opacity (figure 5).

The differential diagnosis of a disseminated miliary pattern on chest radiograph is extensive. According to Felson, ¹³ more than 80 conditions can incite such a pattern. The more common of these include other infections such as the disseminated mycoses, viral pneumonias, inhalational diseases such as silicosis and extrinsic allergic alveolitis, metastatic disease (particularly thyroid carcinoma), and bronchioloalveolar carcinoma.

The presence of lymph-node enlargement is commonly associated with miliary pulmonary Tb in children (95% incidence) but less so in adults (12%) ¹⁴ (figure 3). Similarly, other evidence of primary Tb, including focal parenchymal consolidation that may represent the source of dissemination, has been shown to be a more frequent finding in children (42%) than in adults (12%) (figure 6). ¹⁴

Reed and coworkers ¹⁴ have also shown that, in adults, evidence consistent with prior tuberculous infection (such as areas of cavitation, a calcified parenchymal granuloma, and/or calcified hilar and mediastinal lymph nodes [Ghon-Ranke complex]) are relatively frequent findings (31%). However, such findings are rarely seen in young children. Other findings, such as pleural effusion, were uncommonly associated with miliary Tb in both adults (19%) and children (11%). Concomitant pneumothorax or pneumomediastinum are rarer still. Miliary calcifications are virtually never seen, instead indicating infection with Histoplasma capsulatum. ⁷

HIV-infected patients present yet a different scenario. As in children, lymph-node enlargement is more common (43%) than in non-HIV infected individuals (13%). ¹⁵ If a patient was infected with Tb before acquiring the HIV virus or while their CD4 count was >200, findings resembling typical post-primary infection may be seen. In HIV-infected patients, a major differential consideration for a reticulonodular pattern on chest radiograph is Pneumocystis carinii infection which may mimic early miliary Tb. Similarly, cytomegalovirus pneumonitis, Mycobacterium avium complex, and lymphocytic interstitial pneumonitis can also produce a miliary pattern.

With proper treatment of miliary Tb, radiographic clearing over 4 to 6 weeks is the norm. While the time to normalization of the chest radiograph is highly variable and depends on many factors, including the age of the patient and the severity of disease at time of initiation of treatment, complete clearing is generally seen by 16 weeks and often after just 4 to 6 weeks. ¹⁶ Younger patients usually recover more rapidly than older patients. ¹⁴

Conclusion

Just as Tb has been assigned many names throughout time, its radiologic manifestations are legion. Miliary Tb is one subset of all forms of tuberculous infection which is often readily identifiable on plain chest radiograph. In consideration of its potential for morbidity and mortality and its equally favorable response to proper timely therapy, it is essential that the radiologist is familiar with the appearance of miliary Tb and suggests the possibility in the proper clinical setting. AR

References

1. Rubin SA: Tuberculosis--Captain of all these men of death. Radiol Clin North Am 33:619-639, 1995.

2. Centers for Disease Control: Cases of specified notifiable diseases-United States. MMWR 1992;39:944

3. Sahn SA, Neff TA: Miliary tuberculosis. Am J Med 109:554-560, 1974.

4. Fraser RG, Pare JAP, Pare PD, et al: Diagnosis of Diseases of the Chest, ed 3, pp 885-933. WB Saunders, Philadelphia, 1988.

5. Slavin RE, Walsh TJ, Pollack AD: Late generalized tuberculosis: A clinical pathologic analysis and comparison of 100 cases in the preantibiotic and antibiotic eras. Medicine 59:352-358, 1980.

6. Woodring JH, MacVandiviere H, Fried AM, et al: Update: The radiographic features of pulmonary tuberculosis. AJR 146:497-506, 1986.

7. McAdams BP, Erasmus J, Winter JA: Radiologic manifestations of pulmonary tuberculosis. Radiol Clin North Am 33:655-678, 1995.

8. Goodman PC: Tuberculosis and AIDS. Radiol Clin North Am 33: 707-717, 1995.

9. Chaisson RE, Schecter GF, Theuer CP, et al: Tuberculosis in patients with the acquired immunodeficiency syndrome. Am Rev Respir Dis 136:570-574, 1987.

10. Buckner CB, Walker CW: Radiologic manifestations of adult tuberculosis. J Thorac Imag 5(2):28-37, 1990.

11. Olazabal F, Jr: Choroidal tubercles--A neglected sign. JAMA 200:374-377, 1967.

12. Berger HW, Samortin TG: Miliary tuberculosis: Diagnostic methods with emphasis on the chest reoentgenogram. Chest 58:586-589, 1970.

13. Felson B : Acute miliary diseases of the lung. Radiology 59:32-47, 1952.

14. Reed MH, Pagtakhan RD, Zylak CJ, et al: Radiologic features of
miliary tuberculosis in children and adults. J Can Assoc Radiol 28:175-181, 1977.

15. Kwong JS, Carignan S, Kang EY, et al: Miliary tuberculosis--Diagnostic accuracy of chest radiography. Chest 110:339-342, 1996.

16. Biehl JP: Miliary tuberculosis: A review of sixty-eight adult patients admitted to a municipal general hospital. Am Rev Tuberc 77:605-622, 1958.