AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Miliary tuberculosis (TB) is the widespread dissemination of Mycobacterium tuberculosis from hematogenous spread. Classic miliary TB is defined as milletlike (mean 2 mm, range 1-5 mm) seeding of TB bacilli in the lung, as evidenced on chest radiography. This pattern is seen in 1-3% of all TB cases.

Miliary TB may occur in an individual organ (very rare, <5%), in several organs, or throughout the whole body (>90%), including the brain. The infection is characterized by a large amount of TB bacilli, although it may easily be missed and is fatal if untreated. Up to 25% of patients with miliary TB may have meningeal involvement. In addition, miliary TB may mimic many diseases. In some case series, up to 50% of cases are undiagnosed antemortem. Therefore, a high index of clinical suspicion is important to obtain an early diagnosis and to ensure improved clinical outcomes. Early empirical treatment for possible but not yet definitive miliary TB increases the likelihood of survival and should never be withheld while test results are pending.

On autopsy, multiple TB lesions are detected throughout the body in organs such as the lungs, liver, spleen, brain, and others.

Pathophysiology

Following exposure and inhalation of TB bacilli in the lung, a primary pulmonary complex is established and pulmonary lymphangitis and hilar lymphadenopathy develop. Mycobacteremia and hematogenous seeding occur after the primary infection. After initial inhalation of TB bacilli, miliary TB may occur as primary TB or may develop years after the initial infection. The disseminated nodules consist of central caseating necrosis and peripheral epithelioid and fibrous tissue. Radiographically, they are not calcified (as opposed to the initial Ghon focus, which often is visible on chest radiographs as a small calcified nodule).

Frequency

United States

Data from 1996 indicate that 257 (1.2%) of the 21,337 patients with TB were considered to have miliary TB. The CDC records epidemiologic data for TB.

International

Of all patients with TB, 1.5% are estimated to have miliary TB. The World Health Organization reports that 2-3 million patients die with and/or from all forms of TB each year.¹

Mortality/Morbidity

• Untreated, the mortality rate is assumed to be close to 100%. With early and appropriate treatment, the mortality rate is reduced to less than 10%. The earlier the diagnosis, the better the likelihood of a positive outcome. Early treatment for suspected TB has shown to improve outcome.
• Most deaths occur within the first 2 weeks of admission to the hospital. This may be related to delayed onset of treatment.
• Up to 50% of all cases of disseminated TB detected at autopsy were missed antemortem in reported case series.

Race

• The incidence of miliary TB may be higher in African Americans in the United States because of socioeconomic risk factors. No genetic predisposition has been identified.

Sex

• In the United States, men may have a higher incidence than women because of socioeconomic and medical risk factors.

Age

Miliary disease is more difficult to detect in patients who are very young or very old.

• Children younger than 5 years who acquire miliary TB are more likely to develop life-threatening miliary and/or meningeal TB. The disease usually follows primary infection, with no or only a short latency period.
• Adults older than 65 years have a higher risk of miliary TB. Clinically, it may be subacute or may masquerade as a malignancy. If undiagnosed, the disease is detected at autopsy.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Patients may experience progressive symptoms over days to weeks or occasionally over several months. Symptoms include the following:
• • Weakness, fatigue (90%)
  • Weight loss (80%)
  • Headache (10%)

Physical

• Signs include the following:
• • Subtle signs, such as low-grade fever (20%)
  • Fever (80%)
  • Cough (60%)
  • Generalized lymphadenopathy (40%)
  • Hepatomegaly (40%)
  • Splenomegaly (15%)
  • Pancreatitis (<5%)
  • Multiorgan dysfunction, adrenal insufficiency

Causes

• Risk factors involve immunosuppression and include, but are not limited to, the following:
• • Cancer
  • Transplantation
  • HIV infection
  • Malnutrition
  • Diabetes
  • Silicosis
  • End-stage renal disease
  • Major surgical procedures - Occasionally may trigger dissemination

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Fungal infection
Histiocytosis X (Langerhans cell histiocytosis)
HIV-related pulmonary opportunistic infections
Lymphangitic spread of cancer (eg, thyroid carcinoma, malignant melanoma)
Measles
Pancreatic abscess
Pulmonary alveolar microlithiasis
Talc granulomatosis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Chemistry
• • Hyponatremia: A decrease in sodium levels may correlate with disease severity. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or hypoadrenalism may complicate tuberculosis (TB).
  • Alkaline phosphatase levels are elevated in approximately 30% of cases.
  • Elevated levels of transaminases suggest liver involvement or, if treatment has been initiated, drug toxicity.
• CBC count
• • Leukopenia/leukocytosis may be present.
  • Leukemoid reactions may occur.
  • Patients may have anemia.
  • Thrombocytopenia or, rarely, thrombocytosis may be present.
• The erythrocyte sedimentation rate is elevated in approximately 50% of patients.
• Cultures for mycobacteria (sputum, blood, urine, cerebral spinal fluid [CSF], and other body fluids, as available): Sensitivity testing is essential for all positive isolates. Consider investigation for multidrug-resistant TB (MDR-TB) in all cases.
• Coagulation studies: Measure the prothrombin time/activated partial thromboplastin time (PT/aPTT) prior to biopsy.
• The tuberculin skin test with purified protein derivative (PPD) often yields negative results in patients with miliary TB. This may be explained by the large number of TB antigens throughout the body.
• Nucleic acid probes
• • Specificity for smear-negative and culture-negative specimens is lower than 100% (false-negative results).
  • False-positive TB cultures are of concern, and the rate is estimated to be approximately 5%. This may be due to laboratory contamination.
  • Polymerase chain reaction testing of the blood may yield positive results in most cases of HIV-related disseminated TB; the yield is low in non-HIV miliary TB.
• Mycobacterial blood cultures
• • Findings are positive in approximately 5% of patients who do not have HIV infection.
  • Findings are positive in many patients who have HIV infection. One study yielded an 85% positivity rate.

Imaging Studies

• Chest radiography
• • Findings are typical in 50% of cases.
  • A bright spotlight helps to reveal miliary nodules.
  • Bilateral pleural effusions indicate dissemination versus localized and unilateral pleural TB. This may be a useful clinical clue.
  • Nodules characteristic of miliary TB may be better visualized on lateral chest radiography (especially in the retrocardiac space).
• Chest CT scanning
• • This has higher sensitivity and specificity than chest radiography in displaying well-defined randomly distributed nodules. High-resolution CT scanning with 1-mm cuts may be even better.
  • It is useful in the presence of suggestive and inconclusive chest radiography findings.
• Ultrasonography may reveal diffuse liver disease, hepatomegaly, splenomegaly, or para-aortic lymph nodes.
• Head CT scanning with contrast and/or MRI of the brain
• • Use this to assess for suspected TB lesions.
  • Hydrocephalus or cerebral mass lesion (tuberculoma) may increase the risk of herniation if lumbar puncture is performed.
• Abdomen CT scanning may reveal para-aortic lymph nodes, hepatosplenomegaly, or tuberculous abscess.
• Echocardiography is the most sensitive test for pericardial effusion.

Other Tests

• Funduscopy: This may reveal retinal tubercles.
• Electrocardiography
• • This test helps evaluate for pericardial effusion.
  • Right ventricular hypertrophy may indicate pulmonary hypertension prior to lung biopsy.
• Contact investigation
• • Miliary TB in a child indicates recent transmission. Contact investigation could identify the source case and associated susceptibilities.
  • Contact investigation of child index cases should be conducted quickly.
  • Thoroughly evaluate household contacts by means of tuberculin skin testing and, if the test results are positive, chest radiography.

Procedures

• Sputum induction has low sensitivity. Findings are smear-negative and culture-negative in 80% of patients because of hematogenous spread.
• Fiberoptic bronchoscopy is the most effective procedure for obtaining cultures (bronchoalveolar lavage).
• The culture yield for transbronchial biopsies is 90%.
• Lumbar puncture should be strongly considered, even with normal brain MRI findings.
• • Leukocytes: Approximately 65% of patients have WBC counts with 100-500 mononuclear cells/μL.
  • Lymphocytic predominance (70%)
  • CSF lactic acid levels are mildly elevated.
  • Elevated protein levels (90%)
  • Low glucose levels (90%)
  • RBCs are common
  • Acid-fast bacilli (≥40% with serial spinal taps)
  • Gastric lavage: This requires 3 prebreakfast samples, especially in children, with a yield of approximately 60%.
  • Nucleic acid amplification techniques may aid in the diagnosis, but negative findings do not rule out TB.
• Bone marrow biopsy has no serious adverse effect. The yield is approximately 50%.
• Liver biopsy: Liver bleeding is a serious and potentially life-threatening complication estimated to occur in approximately 10% of cases.
• For abdominal involvement, laparoscopy is useful to obtain tissue and material for culture.

Histologic Findings

Necrotizing granulomas are the hallmark of TB, and staining for acid-fast bacilli reveals rodlike structures in approximately 80% of specimens. The disseminated nodules consist of central caseating necrosis and peripheral epithelioid and fibrous tissue. Radiographically, the nodules are not calcified.

Staging

Miliary TB with meningeal involvement may require prolonged treatment (up to 12 mo).

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Early treatment of patients with suspected miliary tuberculosis (TB) decreases the likelihood of mortality and improves outcome.

Surgical Care

Surgical treatment is rarely necessary. Occasionally, a ventriculoatrial shunt is indicated for hydrocephalus.

Consultations

• Pulmonary and critical care specialists
• Infectious disease specialist
• Neurologist - Steroids for meningitis or paradoxically increasing tuberculomas
• TB expert
• Health department notification
• Appropriate infection control measures

Diet

Adequate attention to nutrition is important. Many patients with miliary TB are debilitated by the disease, and malnutrition can contribute to a weakened immune system.

Activity

Once the patient receives several weeks of effective therapy, experiences significant clinical improvement, and has negative sputum acid-fast bacillus smears, restrictions are minimal. However, one must be certain that the patient truly is no longer contagious. The absence of sputum positivity does not guarantee others protection against exposure. Directly observed therapy is optimal for assuring compliance and preventing relapse.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Early empirical therapy for suspected miliary tuberculosis (TB) is prudent. A delay of even 1-8 days contributes to a high mortality rate.

Steroids are warranted for hypotension due to presumed adrenal insufficiency after an adrenocorticotropic hormone (ACTH) stimulation test.

For susceptible organisms, the treatment period is 6-9 months. For meningitis, it is 9-12 months. For miliary TB with meningeal involvement, daily medications for the entire length of therapy are recommended.

Three basic rules apply in the prevention of entirely "doctor-made" resistant TB, which cost more than $180,000 in the United States in 1991. First, rifampin is the drug of choice for treatment. In most cases, the treatment duration is at least 18 months without rifampin. Second, ethambutol (EMB) is used to prevent rifampin resistance if the organism is resistant to isoniazid (INH). EMB can be discontinued as soon as the organism is found to be susceptible to rifampin and INH. Third, pyrazinamide is used for the first 2 months of treatment to decrease the treatment duration from 9 months to 6 months if the organism is susceptible to rifampin and INH.

For MDR-TB, use a minimum of 1 susceptible injectable and at least 3 additional susceptible drugs to prevent the development of additional resistance. Treat MDR-TB with the consultation of an expert in the care of TB.

Intermittent-type therapies have not been established. If MDR-TB test results are pending, increasing the number of drugs is reasonable. For example, use 6 or 7 initial drugs, including an injectable.

Drug Category: Antitubercular agents

Any regimen must contain multiple drugs to which TB is susceptible. In addition, drug therapy must be taken regularly and continued for a sufficient period.

Miliary TB has a high number (load) of organisms; thus, the initial number of medications should be high.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• If the infected patient lives in a home with immunocompromised persons (eg, with HIV infection) or with children younger than 5 years, or if the patient lives in a communal residence type of facility (eg, homeless shelter, senior citizen facility, jail, prison), keep him or her hospitalized until sputum stain results are negative and significant clinical improvement is shown.
• Evaluate all close contacts who might have been infected prior to initiation of effective therapy for evidence of tuberculosis (TB).
• Contagiousness is low because miliary TB spreads hematogenously, not via the endobronchial system.
• Cavitary lesions are highly unlikely.

Further Outpatient Care

• Patient may start and continue treatment in an outpatient setting if no children or immunocompromised persons are in the home or if the patient is not in a communal residence facility.

In/Out Patient Meds

• Each patient should be offered directly observed therapy in the clinic, home, or workplace.

Transfer

• The patient is usually removed from isolation when 3 consecutive sputum smear results are negative and clinical improvement is shown.
• The patient must not be confined with immunosuppressed patients prior to the establishment of negative sputum cultures.
• Place the patient in a negative pressure room or in adequate respiratory isolation.

Deterrence/Prevention

• Patients who discontinue medication may be subject to public health laws. Patients may be remanded to custody and ordered to continue therapy if judged to be a public health hazard.
• When ordered compliance is not successful, the health department may obtain an order of detention.

Complications

• Paradoxical enlargement of the lymph nodes or intracerebral tuberculomas during adequate treatment may require steroids.
• Hydrocephalus may require neurosurgical decompression.

Prognosis

• The relapse rate is 0-4% with adequate therapy and directly observed therapy, although results from studies vary.
• Most relapses occur during the first 24 months after completion of therapy.

Patient Education

• Educate the patient and contacts about the mode of transmission.
• For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center. Also, see eMedicine's patient education article Tuberculosis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Negative tuberculosis (TB) skin testing results do not exclude the possibility of TB.
• Negative sputum smear results (even 3 negatives) do not exclude the possibility of TB.
• Diagnostic testing for suspected miliary TB should be continued and may include blood cultures, CT scanning, transbronchial biopsies, and bone marrow biopsy.
• Failure to involve a TB specialist may lead to acquired resistant TB.
• The local health department must be involved.

Special Concerns

• Miliary TB during pregnancy can be treated safely with RIE (ie, rifampin, INH, vitamin B-6 [25 mg/d], and EMB [15 mg/kg/d]).
• Miliary TB in a newborn of a mother with TB is difficult to diagnose.
• • Placenta examination by the pathologist is imperative.
  • Three gastric aspirates of the newborn are helpful.
  • Tuberculin skin testing of the newborn during the first 6 months is rarely helpful because of the limited immune response of the newborn.
  • Lumbar puncture is indicated if the newborn does not thrive.
  • Bacille Calmette-Guérin vaccine clouds the interpretation of a positive tuberculin skin test result after age 6 months.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. American Thoracic Society, US Centers for Disease Control and Prevention. Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This stat. Am J Respir Crit Care Med. Apr 2000;161(4 Pt 1):1376-95. [Medline].
2. Alsoub H, Al Alousi FS. Miliary tuberculosis in Qatar: a review of 32 adult cases. Ann Saudi Med. Jan-Mar 2001;21(1-2):16-20. [Medline].
3. Biedrzycki OJ, Baithun SI. TB-related sudden death (TBRSD) due to myocarditis complicating miliary TB: a case report and review of the literature. Am J Forensic Med Pathol. Dec 2006;27(4):335-6. [Medline].
4. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med. Feb 15 2003;167(4):603-62. [Medline].
5. Bourbonnais JM, Sirithanakul K, Guzman JA. Fulminant miliary tuberculosis with adult respiratory distress syndrome undiagnosed until autopsy: a report of 2 cases and review of the literature. J Intensive Care Med. Nov-Dec 2005;20(6):354-9. [Medline].
6. Hussain SF, Irfan M, Abbasi M, Anwer SS, Davidson S, Haqqee R, et al. Clinical characteristics of 110 miliary tuberculosis patients from a low HIV prevalence country. Int J Tuberc Lung Dis. Apr 2004;8(4):493-9. [Medline].
7. Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax. Jul 1998;53(7):536-48. [Medline].
8. Kim JH, Langston AA, Gallis HA. Miliary tuberculosis: epidemiology, clinical manifestations, diagnosis, and outcome. Rev Infect Dis. Jul-Aug 1990;12(4):583-90. [Medline].
9. Lillebaek T, Thomsen VO. A patient with suspected sarcoidosis died from miliary tuberculosis. Scand J Infect Dis. 2000;32(2):218-20. [Medline].
10. Maartens G, Willcox PA, Benatar SR. Miliary tuberculosis: rapid diagnosis, hematologic abnormalities, and outcome in 109 treated adults. Am J Med. Sep 1990;89(3):291-6. [Medline].
11. Mert A, Bilir M, Tabak F. Miliary tuberculosis: clinical manifestations, diagnosis and outcome in 38 adults. Respirology. 2001;6:217-224.
12. Munt PW. Miliary tuberculosis in the chemotherapy era: with a clinical review in 69 American adults. Medicine (Baltimore). Mar 1972;51(2):139-55. [Medline].
13. Shafer RW, Kim DS, Weiss JP, Quale JM. Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. Medicine (Baltimore). Nov 1991;70(6):384-97. [Medline].
14. Sharma SK, Mohan A, Sharma A, Mitra DK. Miliary tuberculosis: new insights into an old disease. Lancet Infect Dis. Jul 2005;5(7):415-30. [Medline].
15. 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 (Baltimore). Sep 1980;59(5):352-66. [Medline].
16. Talavera W, Lessnau KD, Handwerger S. Extrapulmonary tuberculosis. In: Friedman LN, ed. Tuberculosis: Current concepts and treatment. CRC Press: Boca Raton, Fla; 1994.

Article Last Updated: Oct 18, 2007