ABSTRACT
Miliary tuberculosis (TB) results from a massive lymphohematogenous dissemination of Mycobacterium tuberculosis bacilli and is characterized by tiny tubercles evident on gross pathology resembling millet seeds in size and appearance. The global HIV/AIDS pandemic and widespread use of immunosuppressive drugs and biologicals have altered the epidemiology of miliary TB. Considered to be predominantly a disease of infants and children in the pre-antibiotic era, miliary TB is increasingly being encountered in adults as well. The clinical manifestations of miliary TB are protean and nonspecific. Atypical clinical presentation often delays the diagnosis. Clinicians, therefore, should have a low threshold for suspecting miliary TB. Focused, systematic physical examination helps in identifying the organ system(s) involved, particularly early in TB meningitis, as this has therapeutic significance. Fundus examination for detecting choroid tubercles offers a valuable clinical clue for early diagnosis, as their presence is pathognomonic of miliary TB. Imaging modalities help in recognizing the miliary pattern, defining the extent of organ system involvement. Examination of sputum, body fluids, image-guided fine-needle aspiration cytology or biopsy from various organ sites, needle biopsy of the liver, bone marrow aspiration, and biopsy should be done to confirm the diagnosis. Cytopathological, histopathological, and molecular testing (e.g., Xpert MTB/RIF and line probe assay), mycobacterial culture, and drug susceptibility testing must be carried out as appropriate and feasible. Miliary TB is uniformly fatal if untreated; therefore, early initiation of specific anti-TB treatment can be lifesaving. Monitoring for complications, such as acute kidney injury, air leak syndromes, acute respiratory distress syndrome, adverse drug reactions such as drug-induced liver injury, and drug-drug interactions (especially in patients coinfected with HIV/AIDS), is warranted.
INTRODUCTION
Miliary tuberculosis (TB) is a lethal form of disseminated TB that results from a massive lymphohematogenous dissemination from a Mycobacterium tuberculosis-laden focus (1–5). The term “miliary TB” (derived from the Latin word miliarius, meaning related to millet seed) was coined by John Jacob Manget (6) in republishing the work of Bonetus (7) in 1700 to describe the resemblance of gross pathological findings to that of innumerable millet seeds in size and appearance (Fig. 1). Traditionally, the miliary pattern on a chest radiograph has been defined as “a collection of tiny discrete pulmonary opacities that are generally uniform in size and widespread in distribution, each of which measures two mm or less in diameter” (8). In 10% of the cases, the nodules may be greater than 3 mm in diameter (9).
FIGURE 1
Previously, miliary TB was considered to be a disease of infants and children; however, during the last three decades, it has become increasingly recognized in adults as well. Several factors, such as the emergence of human immunodeficiency virus (HIV) infection, the AIDS pandemic, increasing use of immunosuppressive drugs, the effect of bacillus Calmette-Guérin (BCG) vaccination (resulting a substantial reduction in miliary TB among young vaccines), increased awareness and use of computed tomography (CT), and wider application of invasive diagnostic methods, have been responsible for this change in the epidemiology of miliary TB (2–5).
Diagnosis of miliary TB requires the presence of a diffuse miliary infiltrate on a chest radiograph or high-resolution CT (HRCT) or histopathological evidence of miliary tubercles in tissue specimens obtained from multiple organs. The myriad clinical manifestations and atypical radiographic findings often delay the diagnosis of miliary TB. Not surprisingly, mortality from miliary TB has remained high despite effective therapy being available.
EPIDEMIOLOGY
Community-based data on the prevalence of miliary TB are lacking. Data derived from clinical series are hampered by factors such as lack of a gold standard for the diagnosis and variation in the nature of invasive methods used for securing tissue to confirm the diagnosis. Autopsy studies contain few data regarding miliary TB in children and frequently include patients with advanced disease or a missed diagnosis. These issues make meaningful comparison of data difficult and should be kept in mind while interpreting epidemiological data. Among immunocompetent adults, miliary TB accounts for less than 2% of all cases of TB and up to 20% of all extrapulmonary TB cases in various clinical studies (10–17). Among HIV-seropositive and immunosuppressed persons, extrapulmonary TB becomes increasingly common as immunosuppression progresses, and in late HIV infection, extrapulmonary TB accounts for more than 50% of all cases of TB (Fig. 2) (18, 19). Autopsy studies reveal a higher proportion of miliary TB among adult TB cases (20–26) (Table 1). Per the U.S. Centers for Disease Control and Prevention (CDC) data (27), during the period from 2012 to 2014, the prevalence of miliary TB was 349 to 357 cases/year among all reported cases of TB; miliary TB accounted for 3.5% to 3.8% of all reported cases of TB and 11.2% to 12.2% of all reported cases of extrapulmonary TB (Table 2) (27).
FIGURE 2
TABLE 1
TABLE 2
| Yr | No. of cases of miliary TB/no. of all TB cases (%) | No. of cases of miliary TB/no. of all extrapulmonary TB cases (%) |
|---|---|---|
| 2012 | 349/9,945 (3.5) | 349/3,116 (11.2) |
| 2013 | 353/9,582 (3.7) | 353/2,889 (12.2) |
| 2014 | 357/9,421 (3.8) | 357/2,916 (12.2) |
a
Data are from reference 27.
Age
Gender
Ethnicity
In the United States, a higher incidence of miliary TB has been described for black Americans in some of the earlier publications, though such a trend is not evident from recent data (2–5, 30, 38). Whether this is due to ethnic variation alone or is the consequence of host genetic factors or because of other factors, such as socioeconomic and nutritional status and comorbid illnesses, needs further study.
PATHOGENESIS
Miliary TB can develop either at the time of primary infection or later, during reactivation of a dormant focus. In areas where TB is endemic, with increased transmission of Mycobacterium tuberculosis, reinfection also has an important role in the development of miliary TB. A massive lymphohematogenous dissemination of Mycobacterium tuberculosis from a pulmonary or extrapulmonary focus and embolization to the vascular beds of various organ systems result in miliary TB. Rarely, simultaneous reactivation of multiple foci in various organs can also result in miliary TB (Fig. 3) (2–5). When miliary TB develops during the course of primary disease (early generalization), the disease has an acute onset and is rapidly progressive. During post-primary TB, late generalization can be rapidly progressive (acute miliary TB), episodic, or protracted (chronic miliary TB).
FIGURE 3
Occasionally, discharge of caseous material from an extrapulmonary site can result in miliary TB. If the caseous material is discharged into the portal circulation, hepatic involvement occurs initially, with the classical pulmonary involvement becoming evident late (2–5). In neonates, hematogenous spread from infected placenta through the umbilical vein or aspiration of amniotic fluid in utero can cause congenital TB; miliary TB is a common manifestation of congenital TB. Miliary TB may also develop in neonates as a result of acquisition of infection during the perinatal period through aspiration and ingestion of infected maternal genital tissues and fluid and subsequent hematogenous dissemination.
Predisposing Conditions
Several predisposing or associated conditions that have been described for patients with miliary TB are detailed in Table 3 (2–5).
TABLE 3
| Childhood infections |
| Malnutrition |
| HIV/AIDS |
| Alcoholism |
| Tobacco smoking |
| Diabetes mellitus |
| Chronic kidney disease, dialysis |
| Postsurgery (e.g., gastrectomya) |
| Organ transplantation |
| Connective tissue disorders |
| Pregnancy, postpartum |
| Underlying malignancy |
| Silicosis |
a
Predisposes to TB in general.
Iatrogenic Dissemination
Use of certain drugs (45–48) and several procedures and interventions (49–53) have been implicated in facilitating hematogenous dissemination and the causation of iatrogenic miliary TB (Table 4). Corticosteroids and immunosuppressive and cytotoxic drugs are increasingly being used for the treatment of connective tissue disorders and in organ transplant recipients. Miliary TB can develop as a consequence of their use (2–5). Fatal TB, including miliary TB, has been described for patients with rheumatoid arthritis who were treated with immunomodulator drugs, such as the anti-tumor necrosis factor agents infliximab (48, 54), etanercept (47), and adalimumab (46). A report from the British Society for Rheumatology Biologics Register national prospective observational study (45) among rheumatoid arthritis patients indicates a higher rate of development of TB with adalimumab (144 events/100,000 person years) and infliximab (136/100,000 person years) than etanercept (39/100,000 person years). The median time to development of TB was lower for infliximab (5.5 months) than for etanercept (13.4 months) and adalimumab (18.5 months). Extrapulmonary TB constituted 25 of the 40 (62%) cases; 11 cases (27.5% of all TB cases and 44% of extrapulmonary TB cases) were disseminated and miliary TB (45).
TABLE 4
| Drugs |
| Corticosteroids |
| Immunosuppressive and cytotoxic drugs |
| Immunomodulator drugs (e.g., infliximab, etanercept, and adalimumab) |
| Procedures and interventions |
| Ureteral catheterizationb |
| Extracorporeal shockwave lithotripsyc |
| Laser lithotripsyc |
| Cardiac valve homograft replacementd |
| Intravesical BCG therapy for urinary bladder carcinoma |
Immunopathogenesis
The inadequacy of effector T-cell (Teff cell) response in containment of Mycobacterium tuberculosis is thought to be responsible for the development of miliary TB (55–58). Although both Th1 and Th2 responses are inflammatory reactions, Th1 reactions characterize protective immunity and Th2 reactions seem to have a counterregulatory effect. Miliary TB probably represents the Th2 end of the spectrum. The abundance of Th1 and Th2 polarized Teff cells in the peripheral blood and local disease site(s) among patients with miliary TB has been described (57, 58). Interleukin-4, with its ability to downregulate inducible nitric oxide synthase, Toll-like receptor 2, and macrophage activation, may play an important role in the events that determine whether the infection becomes latent or progressive (2, 55, 56). Inadequate T-cell response, particularly at the pathologic site(s), is believed to depend on the host immunoregulatory mechanisms. Thus, Mycobacterium tuberculosis can either fail to evoke the protective response or drive the protective mechanisms and then deliberately “sabotage” them, leading to progressive disease (2, 55–58).
Regulatory T cells (Treg cells) are thought to play a critical role in the immunopathogenesis of miliary TB by suppression of the effector immune response against Mycobacterium tuberculosis at the pathologic site(s). Increases in the frequency of Treg cells (CD4+ CD25+ FoxP3+) and FoxP3 mRNA levels at the local disease site in miliary TB have been described (58). Furthermore, FoxP3+ Treg cells in bronchoalveolar lavage (BAL) fluid from patients with miliary TB predominantly produced interleukin-10 and suppressed the autologous T-cell proliferation in response to Mycobacterium tuberculosis antigen (57).
In miliary TB, the attempt by the host to selectively recruit the Teff cells at the pathologic site fails to provide an adequate level of effector immunity at the disease site due to efficient and comparable homing of Treg cells (FoxP3+), which inhibit the function of the Teff cells that have infiltrated at the pathologic disease site. This probably leads to a state of local immunosuppression and dissemination of disease (2, 57, 58).
Molecular Basis of Dissemination
Several molecular mechanisms have been implicated in the development of miliary TB. These include impaired expansion of γ/δ T cells (59); failure to generate adequate cell-mediated immunity (60); the presence of HLA-Bw15 (61), HLA-DRB1*15/16, DRB1*13, and DQB1*0602 (62); the absence of HLA-Cw6, HLA-DRB1*10, and DQB1*0501 (62); impaired major histocompatibility complex class II-restricted target cell lysis; and overexuberant lysis of target cell macrophages (63) and LTA+368 G/A polymorphisms (64).
PATHOLOGY
The frequency of organ involvement at autopsy is shown in Table 5 (21, 25, 28, 31–33, 40). Organs with a high blood flow, such as the spleen, liver, lungs, bone marrow, kidneys, and adrenals, are frequently affected. On gross examination, small, punctate, gray to reddish brown, rounded lesions of more or less uniform size may be seen in the lungs and various other organs. The “tubercle” constitutes the histopathological hallmark of miliary TB. When miliary TB is the result of acute massive hematogenous dissemination, the lesions in all viscera appear similar (“soft” or “exudative” tubercles) (2–5, 65, 66); an obvious caseous focus invading the blood vessel is usually demonstrable, and the lesions often reveal acid-fast bacilli (AFB). When the dissemination is due to the discharge of bacilli into microscopic blood vessels within the caseous lesions, which, in turn, seed large vessels, the acute soft lesions are found to be admixed with “hard” tubercles. The AFB are seldom demonstrable in these hard lesions (1–5). When acute respiratory distress syndrome (ARDS) develops due to miliary TB, hyaline membranes are present in addition to the cellular infiltrate. Occasionally, vasculitic lesions can be discerned in miliary TB patients with TB meningitis. Choroidal tubercles, when present, are pathognomonic of miliary TB (see below). They are multiple in number and are usually evident in both eyes, mostly in the posterior pole. As the acute infection resolves, the center of the choroidal tubercles may become white or yellow, with a surrounding peripheral rim of pigmentation; the margins become sharply delineated and distinct. Subsequently, an atrophic scar may develop. Rarely, infective endocarditis, pericarditis, intracardiac mass, or mycotic aneurysm may also be evident at autopsy.
TABLE 5
| Variable | Chapman and Whorton (21)b | Gelb et al. (32)b,c | Campbell (31)b,c | Grieco and Chmel (33)b,c | Aderele (28)b,c | Prout and Benatar (40)b,c | Slavin (25)b |
|---|---|---|---|---|---|---|---|
| Yr of publication | 1946 | 1973 | 1973 | 1974 | 1978 | 1980 | 1980 |
| No. of autopsies | 63 | 21d | 23e | 10f | 11g | 34h | 100 |
| Organ system involvement (%) | |||||||
| Spleen | 100 | 86 | 70 | 80 | 82 | 79 | 100 |
| Liver | 100 | 91 | 61 | 60 | 55 | 85 | 97 |
| Lungs | 63 | 100 | 100 | 100 | 100 | 77 | 86 |
| Lymph nodes | 33 | 38i | 39 | 80 | 73 | 79 | ND |
| Bone marrow | 84 | 24 | ND | ND | ND | 47 | 77 |
| Kidneys | 53 | 62 | 43 | 30 | 55 | 56 | 64 |
| Adrenals | 42 | 14 | 22 | 30 | ND | 29 | 53 |
| Ocular choroid | ND | ND | ND | ND | ND | ND | 50j |
| Thyroid | ND | 19 | ND | ND | ND | 06 | 14 |
| Breast | ND | ND | ND | ND | ND | ND | 13 |
| Pancreas | 20 | 14 | ND | ND | ND | ND | 12 |
| Heart | 10 | ND | ND | ND | 36 | 06 | 10 |
| Prostate | ND | ND | ND | ND | ND | ND | 07 |
| Testis | 41 | ND | ND | ND | ND | ND | 05 |
| Pituitary | ND | ND | ND | ND | ND | ND | 04 |
| Central nervous system | 41 | ND | 22 | ND | 36 | 26 | ND |
a
All values are expressed as a percentage corrected to the nearest round figure. ND, not described.
b
Autopsy data.
c
Clinical data.
d
Autopsy was performed in 21 of the 30 patients who died.
e
Autopsy was performed in 23 of the 25 patients who died.
f
Autopsy was performed in 10 patients who died.
g
Pediatric series. Autopsy was performed in 11 of the 44 children.
h
Autopsy was performed in 34 of the 40 patients who died.
i
Mediastinal lymph nodes.
j
Fourteen eyes were available for histological examination.
When patients with advanced HIV infection develop miliary TB, the salient pathological features include poor granuloma formation with minimal cellular reaction, severe necrosis, and presence of abundant AFB. Foci of acute TB pneumonia involving airspaces rather than the interstitium are also common in HIV-coinfected patients with miliary TB (18, 19).
CLINICAL MANIFESTATIONS
Adults
The clinical manifestations of miliary TB in adults are protean and nonspecific and can be obscured until late in the disease (Table 6).
TABLE 6
| Variable | Adult series (%)b | Pediatric series (%)c |
|---|---|---|
| Symptoms | ||
| Fever | 35–100 | 61–98 |
| Chills | 15–28 | ND |
| Anorexia | 24–100 | 4–81 |
| Weight loss | 20–100 | 4–60 |
| Night sweats | 8–100 | 8–75 |
| Weakness/fatigue | 25–100 | 14–54 |
| Cough/sputum | 27–82 | 17–90 |
| Chest pain | 3–49 | 1–3 |
| Dyspnea | 8–100 | 7–25 |
| Hemoptysis | 3–15 | 1 |
| Headache | 2–18 | 2–8 |
| Altered sensorium | 5–26 | 2–8 |
| Seizures | ND | 7–30 |
| Nausea | 1–19 | ND |
| Abdominal pain | 5–19 | 3–15 |
| Diarrhea | 2–3 | ND |
| Urinary symptoms | 2–6 | ND |
| Signs | ||
| Fever | 35–100 | 39–75 |
| Pallor | 36–59 | 31 |
| Cyanosis | 1–2 | ND |
| Icterus | 5–9 | 3 |
| Lymphadenopathy | 2–30 | 5 |
| Chest signs | 29–84 | 34–72 |
| Hepatomegaly | 14–62 | 39–82 |
| Splenomegaly | 2–32 | 24–54 |
| Ascites | 4–38 | 6–9 |
| Choroidal tubercles | 2–12 | 2–5 |
| Neurological signs | 3–26 | 19–35 |
Constitutional symptoms
Patients with miliary TB classically present with fever of several weeks’ duration, anorexia, weight loss, weakness, and cough (1–5). Recently, the occurrence of daily morning temperature spikes (67) was reported to be characteristic of miliary TB. Occasionally, fever may be absent and the patients may present with progressive wasting strongly mimicking a metastatic carcinoma. Proudfoot et al. (68) suggested “cryptic miliary TB” for this presentation in the pre-CT era. Since its initial description, cryptic miliary TB is increasingly being reported for the elderly (69, 70). Previously, cryptic miliary TB could be diagnosed only at autopsy. However, with the availability of HRCT, affected patients can now be diagnosed during their lifetime (2–5, 42).
Chills and rigors, usually seen in patients with malaria or sepsis and bacteremia, have often been described for adult patients with miliary TB (1–5). The utility of a damp shadow sign (where sweat engraves the patient’s silhouette on the bed, closely resembling a body’s shadow) in raising the suspicion of miliary TB has been noted (71).
Systemic involvement
Since miliary TB can involve many organs, patients present with symptoms and signs referable to various organ systems (Table 6). Dry cough and dyspnea are often present. Sometimes, cutaneous lesions are the only discernible clues to miliary TB (Fig. 4). These include erythematous macules and papules (tuberculosis miliaria cutis) (1–5). Choroidal tubercles, when present, offer a valuable clue to miliary TB as the diagnosis (1–5, 42). TB meningitis (TBM) has been described for 10% to 30% adult patients with miliary TB (14, 25, 28–44); about one-third of patients presenting with TBM have underlying miliary TB (72). In a study published from India (73), the spectrum of neurological involvement in adult patients with miliary TB (n = 60) included TBM with (45%) and without (35%) tuberculoma and included thoracic transverse myelopathy (15%). These observations warrant a careful clinical examination and appropriate investigations to ascertain neurological involvement.
FIGURE 4
Children
Comparatively fewer published series on miliary TB in children (11–13, 28, 41) than in adults (14, 25, 28–44) are available. Clinical presentation of miliary TB in children (Table 6) is similar to that observed in adults, with some important differences. Miliary TB develops less often in children who have received the BCG vaccination (2–5). Chills and night sweats, hemoptysis, and productive cough are less common than in adults; peripheral lymphadenopathy and hepatosplenomegaly are more frequent in children with miliary TB (Table 6). A larger proportion of children with miliary TB (20% to 40%) (11–13, 28, 41) than adults (15% to 30%) (14, 25, 28–44) suffer from TBM.
Immunosuppressed Individuals
The prevalence of miliary TB in persons with early HIV infection (CD4+ cell counts of >200/mm3) is similar to that observed in immunocompetent individuals. With progression of immunosuppression, in late, advanced stages of HIV infection (CD4+ cell counts of <200/mm3), miliary TB is seen more often (2–5, 18, 19). Cutaneous involvement, a rare clinical manifestation in HIV-seronegative patients with miliary TB, is more commonly seen in HIV-infected patients with CD4+ cell counts below 100/mm3 (2–5, 18, 19, 76–78), in whom these lesions (1–5) appear as tiny papules or vesiculopapules, described as tuberculosis cutis miliaris disseminata, tuberculosis cutis acuta generalisita, and disseminated tuberculosis of the skin (Fig. 4). Sometimes, macular, pustular, or purpuric lesions, indurated ulcerating plaques, and subcutaneous abscesses have been reported (79). In miliary TB patients coinfected with HIV, especially in those with profound immunosuppression, intrathoracic lymphadenopathy and tuberculin anergy are more common; sputum smears are seldom positive, and blood culture may grow Mycobacterium tuberculosis (2–5, 18, 19, 76–78). These observations seem to be applicable to other causes of immunosuppression as well. In a study from China (80), miliary TB was present in 31% of immunocompromised patients (n = 39), compared to 2.6% of immunocompetent persons (n = 79).
ATYPICAL CLINICAL MANIFESTATIONS
Several atypical clinical manifestations have been observed in adult and pediatric patients with miliary TB (Table 7) (2, 4, 5). Atypical clinical presentations often result in a delay in the diagnosis, and miliary TB is often a “missed diagnosis.”
TABLE 7
| Cryptic miliary TB |
| Presentation as pyrexia of unknown origin |
| Incidental diagnosis |
| ARDS |
| Air leak syndrome (pneumothorax, pneumomediastinum) |
| Myelophthisic anemia, myelofibrosis, pancytopenia, immune hemolytic anemia |
| Acute empyema |
| Septic shock, MODS |
| Thyrotoxicosis |
| Renal failure |
| Immune complex glomerulonephritis |
| Sudden cardiac death |
| Mycotic aneurysm of aorta |
| Native valve and prosthetic valve endocarditis |
| Myocarditis, congestive heart failure, intracardiac masses |
| Cholestatic jaundice |
| Presentation as focal extrapulmonary TB (e.g., hepatic miliary TB) |
| Syndrome of inappropriate antidiuretic hormone secretion |
| Deep vein thrombosis |
Acute Respiratory Distress Syndrome
Miliary TB is a rare but an important treatable cause of ARDS. Although ARDS may develop anytime during the course of miliary TB, it is usually seen at the time of initial presentation (81–85). Sometimes, ARDS may develop as a component of the multiorgan dysfunction syndrome (MODS) due to TB or as a manifestation of immune reconstitution inflammatory syndrome (IRIS) (81–85). In a study from two large teaching hospitals at New Delhi and Tirupati in India (85), among patients with TB, prolonged illness, miliary TB, absolute lymphocytopenia, and elevated alanine aminotransferase were found to be independently associated with the development of ARDS. In another study (86) from Korea, higher C-reactive protein levels and an increasing nutritional risk score were found to be independent risk factors for the development of ARDS in patients with miliary TB.
Air Leak Syndromes
Pneumothorax, which may sometimes be bilateral, may be the presenting feature or may sometimes develop while the patient is receiving treatment (1–5, 87, 88). Typical miliary shadows may not be evident initially and may become apparent once the lung expands. Intrapulmonary rupture of alveoli and consequent air leak that traverses into the mediastinum after spreading along the vascular sheath can result in pneumomediastinum with subcutaneous emphysema, which may be fatal (89).
Renal Failure
In patients with miliary TB, apart from being a part of MODS, acute kidney injury (AKI) may occur due to direct renal parenchymal involvement (2–5, 90). AKI can also develop as a manifestation of IRIS in HIV-infected patients (91). Rarely, renal failure can develop as a consequence of obstructive uropathy caused by the disease process (18).
Hepatic and Gastrointestinal Complications
Asymptomatic rise in hepatic transaminases is common in patients with miliary TB, and anti-TB treatment should not be withheld on this evidence alone. In this scenario, liver functions should be periodically monitored. Fulminant hepatic failure due to widespread liver cell necrosis may rarely be the presenting manifestation in miliary TB (92, 93). In some of these patients the characteristic pulmonary lesions that constitute the hallmark of miliary TB are absent, resulting in a delay in diagnosis (92, 93). This could probably be the result of an extrapulmonary focus discharging the tubercle bacilli into the portal circulation, resulting in hepatic miliary TB. Anti-TB drug-induced hepatotoxicity is also common; standard guidelines (94) should be followed in its management. Small intestinal perforations at the site of granulomatous involvement have been described for some patients on treatment (95).
Cardiovascular Complications
Immune Reconstitution Inflammatory Syndrome
IRIS, occasionally described to occur in HIV-negative individuals with TB, has been reported to occur in 32% to 36% of patients coinfected with HIV and TB within days to weeks of the initiation of antiretroviral therapy (96). Manifestations range from isolated instances of fever to increased or initial appearance of lymphadenopathy, new or worsening pulmonary infiltrates, serositis, cutaneous lesions, and new or expanding central nervous system mass lesions (19, 96). IRIS can be brief or prolonged with multiple recurrences. AKI (91, 97) or ARDS (81) can develop during the course of IRIS.
APPROACH TO DIAGNOSIS
Even in an area where TB is endemic, the diagnosis of miliary TB can be difficult, as the clinical symptoms can be nonspecific, the chest radiographs do not always reveal the classical miliary changes and atypical presentations such as ARDS, and shadows larger than miliary on chest radiograph commonly occur. Therefore, a high index of clinical suspicion and a focused diagnostic testing to establish the diagnosis of miliary TB can facilitate early institution of anti-TB treatment that can be lifesaving.
The following criteria have been suggested for the diagnosis of miliary TB: (i) clinical presentation consistent with a diagnosis of TB, such as pyrexia with evening rise of temperature, weight loss, anorexia, tachycardia, and night sweats of greater than 6 weeks’ duration responding to anti-TB treatment; (ii) classical miliary pattern on chest radiograph; (iii) bilateral diffuse reticulonodular lung lesions on a background of miliary shadows demonstrable either on plain chest radiograph or HRCT; and (iv) microbiological, cytopathological, histopathological, or molecular evidence of TB (2–5, 42).
Fundus Examination
Choroidal tubercles are bilateral, pale, grayish white, and oblong patches that are pathognomonic of miliary TB. Though rare (Table 6), their presence is diagnostic of miliary TB (1–5, 42). Thus, systematic ophthalmoscopic examination after mydriatic administration must be done in every suspected patient with miliary TB to look for this valuable clue to the diagnosis (1–5, 42).
Sputum, Body Fluid, and Tissue Examination
For patients with suspected miliary TB, attempts must be made to confirm histopathological microbiological diagnosis. Sputum, other body fluids (such as pleural fluid, pericardial fluid, ascitic fluid, cerebrospinal fluid, joint fluid, pus from cold abscess, and endometrial aspirate), urine, bronchoscopic secretions, blood, and tissue biopsy specimens have all been employed to confirm the diagnosis of disseminated and miliary TB, with various results. For patients with miliary TB, relative diagnostic yield with the conventional microbiological methods from various body fluids and tissues that are commonly tested are listed in Table 8 (14, 16, 17, 28–44, 54, 98).
TABLE 8
| Variable | Cumulative yield (%) |
|---|---|
| Sputumb | 41.4 |
| Bronchoscopyb,c | 46.8 |
| Gastric lavageb | 61.1 |
| CSFb,e | 21.2 |
| Urine | 32.7 |
| Bone marrowb,d | 66.7 |
| Liver biopsy | 88.9 |
| Lymph node biopsy | 90.9 |
a
Data are from references 14, 16, 17, 28 to 44, 54, and 98. Criteria for subjecting the patients to these tests were not clearly defined in any of the studies. Often, more than one test was performed for confirming the diagnosis. For histopathological diagnosis, the presence of granulomas and caseation and demonstration of AFB have been variously used to define a positive test.
b
Yield from smear and culture.
c
Includes yield from bronchoscopic aspiration, washings, brushings, BAL, and transbronchial lung biopsy.
d
Yield from aspiration and/or trephine biopsy.
e
CSF, cerebrospinal fluid.
Laboratory Abnormalities
A number of hematological and biochemical abnormalities are known to occur in miliary TB (Table 9) (14, 16, 17, 28–44, 98), but their significance is controversial. Disseminated intravascular coagulation (83, 85) has been described for patients with miliary TB in the setting of ARDS and MODS and is associated with a high mortality rate. Miliary TB has also been implicated as a cause of pancytopenia and hypoplastic anemia (99). Immune mechanisms have been implicated in causing bone marrow suppression in patients with miliary TB (2–5). Hypercalcemia has been documented in miliary TB but is uncommon (100).
TABLE 9
| Hematological | Biochemical |
|---|---|
| Anemia | Hyponatremia |
| Leukocytosis | Hypoalbuminemia |
| Neutrophilia | Hyperbilirubinemia |
| Lymphocytosis | Elevated transaminases |
| Monocytosis | Elevated serum alkaline phosphatase |
| Thrombocytosis | Hypercalcemia |
| Leukopenia | Hypophosphatemia |
| Lymphopenia | Elevated serum ferritin levels |
| Thrombocytopenia | |
| Leukemoid reaction | |
| Hemophagocytosis | |
| Elevated ESRa and CRPb levels |
a
ESR, erythrocyte sedimentation rate.
b
CRP, C-reactive protein.
Hyponatremia in patients with miliary TB may indicate the presence of TBM (38) and may also be a predictor of mortality (42). Hyponatremia in miliary TB has been thought to be due to an acquired disturbance of neurohypophyseal function resulting in unregulated antidiuretic hormone release due to an antidiuretic principle in the lung tissue affected by TB that may either produce antidiuretic hormone or absorb an inappropriately released hormone from the posterior pituitary (101–103). Rifampin-induced adrenal crisis in a patient with miliary TB and Addison’s disease who developed generalized malaise and hyponatremia while she was initiated on anti-TB treatment has also been described (75).
Tuberculin Skin Test
Tuberculin anergy is more common in miliary TB than in pulmonary TB and extrapulmonary TB; tuberculin skin test conversion may occur following successful treatment. In various published pediatric series, tuberculin anergy has ranged from 35% to 74% (11–13, 28, 41); in published adult series, the corresponding figures have been 20% to 70% (30–33, 35–40, 98). However, a positive tuberculin skin test only indicates infection with Mycobacterium tuberculosis and does not always indicate active disease.
Interferon Gamma Release Assays
The in vitro T-cell-based interferon gamma release assays (IGRAs), available in enzyme-linked immunosorbent assay and enzyme-linked immunospot assay formats, may be useful for patients with miliary TB, especially children, BCG-vaccinated individuals, and persons living with HIV infection and AIDS (104, 105). A positive IGRA result, however, does not distinguish between latent TB infection and active disease, but a negative IGRA result may be helpful in ruling out a diagnosis of TB (106).
Pulmonary Function and Gas Exchange Abnormalities
Miliary TB is associated with abnormalities of pulmonary function typical of interstitial lung disease, and these may be of a greater magnitude than might be anticipated from the chest radiograph (107–109). Impairment of diffusion is the most common abnormality and may sometimes be severe (109, 110). Other abnormalities include a mild reduction in flow rates suggestive of peripheral airway involvement (110). During the acute stage, arterial hypoxemia due to widening of the alveolar-arterial oxygen gradient and hypocapnia due to tachypnea are also observed (111).
Cardiopulmonary Exercise Testing
Patients with miliary TB have abnormal cardiopulmonary exercise performance with lower maximum oxygen consumption, maximal work rate, anaerobic threshold, peak minute ventilation, breathing reserve, and low maximal heart rate (2–5, 98, 111, 112). Other abnormalities include higher respiratory frequency, peak minute ventilation at submaximal work, and high physiological dead space/tidal volume. A demonstrable fall in oxygen saturation (to 4% or more) with exercise has been observed. Following successful anti-TB treatment, these abnormalities had reversed in most of the patients, though they persisted in some of them (111, 112).
Immunological Abnormalities and BAL Fluid
A few reports on the cellular characteristics of BAL fluid in patients with miliary TB have been published, and these have shown conflicting results (18, 110, 113). The proportion and absolute number of lymphocytes are substantially increased in BAL fluid. Although a raised CD4+ CD8+ T-lymphocyte ratio and B lymphocytes were reported for BAL fluid in one study (108), a decrease in CD4+ CD8+ T-lymphocyte ratio was reported in another (110). The small number of patients studied could partly be the reason for these differences. Polyclonal hypergammaglobulinemia with increases in immunoglobulin G (IgG), IgA, and IgM was observed in peripheral blood and BAL fluid in one study (108). These findings probably result from increased local synthesis by activated B lymphocytes. Increased BAL fluid fibronectin and serum C3 levels as acute-phase response to ongoing inflammation were observed (108, 114). Lymphocytic alveolitis and increased IgG and IgA levels persisted following anti-TB treatment (108).
Imaging Studies
A miliary pattern on the chest radiograph is often the first clue suggestive of miliary TB. Several other imaging modalities, such as ultrasonography, CT, and magnetic resonance imaging (MRI), help to discern the extent of organ involvement and are also useful in evaluation of response to treatment.
Chest radiograph
A miliary pattern on chest radiograph (1–5, 8) is the classical feature of miliary TB and is observed for a majority of patients. Subtle miliary lesions are best delineated in slightly underpenetrated films, especially when the diamond-shaped areas of the lung in between the ribs are carefully scrutinized using bright light (9, 115). The chest radiographic abnormalities in miliary TB are listed in Table 10 (2–5, 98). Some patients may have normal chest radiographs initially and the classical miliary pattern may evolve over the course of the disease (Fig. 5), emphasizing the importance of periodic repeat chest radiographic examination in patients with pyrexia of unknown origin (2–5, 42).
TABLE 10
| Common | Uncommon | Rare |
|---|---|---|
| Classical miliary pattern (50%)a | Nonmiliary patterns (10%–30%)a | Other associated findings (<5%)a |
| Asymmetrical nodular pattern | Intrathoracic lymphadenopathy | |
| Coalescence of nodules | Pleural effusion | |
| Mottled appearance | Empyema | |
| “Snow storm” appearance | Pulmonary parenchymal lesions and cavitation | |
| Airspace consolidation | Segmental consolidation | |
| Thickening of interlobular septa | ||
| Pneumothorax | ||
| Pneumomediastinum | ||
| Pericardial effusion |
FIGURE 5
When patients with miliary TB develop ARDS (Fig. 6), the chest radiograph findings may be identical to those seen in ARDS due to other causes (83, 85). The majority of the patients (88%) in the study reported by Sharma et al. (42) had chest radiographs consistent with miliary TB; in some, these classical radiographic changes evolved over the course of the disease. The diagnosis of miliary TB is easier when the patient presents with classical miliary shadowing on chest radiograph in an appropriate setting. However, the diagnosis may be difficult in situations in which chest radiograph does not show classical miliary shadows.
FIGURE 6
In the pre-CT scan era, for up to 50% of the patients, the classical miliary pattern would not be discernible on the chest radiograph, being evident only at the time of autopsy (21, 24, 25, 30, 38, 115, 116). Steiner (115) reasoned that when caseous material, collagen, or both were present in the tubercles, they became visible on the chest radiograph. The classical miliary pattern on the chest radiograph represents a summation of densities of the tubercles that are perfectly aligned; imperfectly aligned tubercles result in curvilinear densities and a reticulonodular pattern (117). Rarely, lymphatic obstruction or infiltration can result in a ground-glass appearance (118).
Ultrasonography
Ultrasonography helps in detecting associated lesions such as ascites and pleural effusion (which may sometimes be loculated), focal hepatic and splenic lesions, and cold abscess. Ultrasonography guidance also facilitates diagnostic thoracic or abdominal paracentesis to procure pleural or peritoneal fluid for diagnostic testing, especially if the fluid is loculated.
Computed tomography and magnetic resonance imaging
HRCT and thin-section multidetector row CT have considerably improved the antemortem diagnosis of miliary pattern. HRCT reveals a mixture of both sharply and poorly defined, <2-mm nodules that are widely disseminated throughout the lungs, associated with diffuse reticulation (119, 120). HRCT may reveal a classical miliary pattern, even when the chest radiograph looks apparently normal (2–5, 42), and also facilitates identification of intrathoracic lymphadenopathy, calcification, and pleural lesions. Air trapping has been described on HRCT both at presentation and during follow-up (120) and occurs due to endobronchial involvement of peripheral airways. The interlobular septal thickening or intralobular fine network that is evident on HRCT in miliary TB seems to be caused by the caseation necrosis in the alveolar walls and interlobular septa. Sometimes in subjects with active postprimary disease, centrilobular nodules and branching linear structures giving a “tree-in-bud appearance” may be evident (119, 120).
Pipavath et al. (121), in a recent publication, reported the following changes on HRCT in patients with miliary TB (n = 16): miliary pattern (n = 16); intrathoracic lymphadenopathy (n = 8); alveolar lesions, such as ground-glass attenuation and/or consolidation (n = 5); pleural and pericardial effusions (2 patients each); and peribronchovascular interstitial thickening and emphysema (1 patient each). In that study (121), nodules were randomly distributed in both lung fields in miliary TB, whereas in sarcoidosis, the findings included peribronchovascular interstitial thickening and perilymphatic distribution of the nodules (122). A higher prevalence of interlobular septal thickening, necrotic lymph nodes, and extrathoracic involvement has also been observed in HIV-seropositive patients with miliary TB (122).
MRI and CT have been useful in identifying miliary lesions at extrapulmonary sites. Abdominal CT has been useful in identifying lesions in the liver and spleen, lymphadenopathy, and cold abscesses (2–5). Unlike the CT of the chest, in which the classical <2-mm nodular lesions are evident, miliary lesions in the liver and spleen may appear as discrete hypodense lesions, a few of which may be confluent, sometimes with irregular peripheral rim enhancement (123). MRI of the brain and spine is very useful in the initial evaluation and follow-up of miliary TB patients with TBM or spinal TB and also protects from radiation exposure (2–5).
Image-guided radiological procedures, such as fine-needle aspiration for cytological examination (FNAC) and biopsy under CT or MRI guidance, are useful for procuring tissue and body fluids for diagnostic testing.
Echocardiography
Two-dimensional transthoracic echocardiography helps to diagnose associated pericardial effusion.
Bronchoscopy
Fiberoptic bronchoscopy, BAL fluid, bronchoscopic aspirate, brushings, and transbronchial lung biopsy specimens are useful in confirming the diagnosis of miliary TB. The cumulative diagnostic yield for various bronchoscopic specimens by smear and culture methods in published studies has been found to be 46.8% (Table 8) (29, 35, 36, 40, 42, 124, 125).
Laparoscopy
When associated abdominal involvement is present, laparoscopy provides an opportunity to visualize the lesions with the naked eye and facilitates biopsy from the liver, peritoneum, omentum, and mesenteric lymph nodes for diagnostic confirmation (126).
Serodiagnostic, Molecular, and Other Methods
Detection of mycobacterial antigens, antibodies, and immune complexes in the blood and body fluids by enzyme-linked immunosorbent assay has been used for diagnosis of miliary TB; however, these methods are not being used currently (2–5). PCR of cerebrospinal fluid, tissue biopsy specimens, and blood (especially from HIV-infected patients) may be useful for confirmation of diagnosis (18). The Xpert MTB/RIF (Cepheid, Sunnyvale, CA), a cartridge-based nucleic acid amplification test, has been found to be useful in the early diagnosis of pulmonary (3–5) and extrapulmonary (127) TB and can detect the presence of Mycobacterium tuberculosis complex and provide information regarding rifampin resistance in 90 min. Line probe assays facilitate rapid detection of Mycobacterium tuberculosis and mutations associated with resistance to rifampin, isoniazid, and second-line anti-TB drugs in under 24 h. Adenosine deaminase and interferon gamma level estimations in ascitic fluid and pleural fluid can be helpful in confirming the diagnosis of TB (128–132).
Positron Emission Tomography
Positron emission tomography CT (PET-CT) using the radiopharmaceutical 18F-labeled 2-deoxy-d-glucose has been found to be useful to assess the activity of various infectious lesions, including pulmonary TB (133, 134). The utility of PET-CT in assessing the activity of lesions (Fig. 7) that might persist following anti-TB treatment in miliary TB needs to be studied further.
FIGURE 7
The algorithm for the workup of a patient suspected to have miliary TB is shown in Fig. 8.
FIGURE 8
TREATMENT
Miliary TB is uniformly fatal if not treated (1–5). Standard anti-TB treatment is the cornerstone of management. There is no consensus regarding the optimum duration of treatment in patients with miliary TB. In several parts of the world, patients with miliary TB get treated under national TB control program, with directly observed treatment using short-course chemotherapy (135, 136). However, there are no published randomized controlled trials assessing the efficacy of the standard World Health Organization (WHO) treatment regimens (135, 136) that are widely used in national TB control programs worldwide. Even less is known regarding the efficacy of standard treatment regimens in the treatment of HIV and miliary TB coinfection.
The American Thoracic Society, CDC, and Infectious Disease Society of America (137) guidelines, National Institute for Health and Clinical Excellence (138) guidelines, and the 2015 report of the Committee on Infectious Diseases, American Academy of Pediatrics (AAP) (139) from the United Kingdom recommend 6 months of treatment (2-month intensive phase with isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin, followed by a 4-month continuation phase with isoniazid and rifampin) for newly diagnosed cases of miliary TB without meningeal involvement.
In the WHO guidelines for the treatment of TB (136), patients are categorized as “new patients” or “previously treated patients.” In these guidelines (136), miliary TB is classified as pulmonary TB because there are lesions in the lungs. New patients with miliary TB receive 6 months of daily or intermittent treatment as described above. The current WHO policy (140) suggests that HIV-coinfected patients with TB and all TB patients in HIV-prevalent settings should receive daily treatment during both the intensive and the continuation phases (strong recommendation, high-quality evidence). For previously treated patients, the WHO guidelines (136) advocate that specimens for culture and drug susceptibility testing (DST) be obtained from all previously treated TB patients at or before at the start of treatment. DST should be performed for at least isoniazid and rifampin, and in settings where rapid molecular DSTs are available, the DST results should guide the choice of regimen. Although this duration of treatment may be sufficient for many, each patient needs to be assessed individually, and wherever indicated, treatment duration may have to be extended.
The evidence-based INDEX-TB guidelines (127) advocate treatment for at least 9 months when TBM is present, and other guidelines (136–138) suggest that treatment be extended for 12 months. When TB meningitis is present, the recent AAP Committee on Infectious Diseases recommendations advocate an initial intensive phase with isoniazid, rifampin, pyrazinamide, and ethionamide [or an aminoglycoside (in place of ethambutol)] for 2 months, followed by a continuation phase of 7–10 months with isoniazid and rifampin (139). The WHO guidelines (136) indicate 9 months of treatment when bone and joint TB is also present. The evidence-based INDEX-TB guidelines (127) suggest that when spinal TB and other forms of bone and joint TB are present, a total treatment duration of 12 months (extendable to 18 months on a case-by-case basis) is indicated.
Corticosteroids
No study has specifically evaluated the role of adjunct corticosteroid treatment in patients with miliary TB; only limited evidence is available, showing conflicting results. A beneficial response was observed in some studies (141), although such benefit could not be documented in others (142). While associated adrenal insufficiency is an absolute indication for their administration, adjunctive corticosteroid treatment may be beneficial in miliary TB with TB meningitis, large pericardial or pleural effusion, dyspnea, and/or disabling chest pain, IRIS, ARDS, immune complex nephritis, and histiocytic phagocytosis syndrome (2–5, 81, 143).
Antiretroviral Drugs
Coadministration of rifampin may result in dangerously low levels of antiretroviral agents by inducing the hepatic cytochrome P450 pathway. The current WHO recommendations (144) and the British HIV Association guidelines regarding the timing of starting antiretroviral drugs, the choice of drugs, and the timing of initiation in relation to institution of anti-TB treatment (145) are shown in Fig. 9.
FIGURE 9
Mechanical Ventilation
Surgery
Surgery is often required to procure specimens for diagnostic testing and to ameliorate complications, such as small bowel perforation, for which it may be lifesaving.
Mortality
Prognostic Factors
Several factors have been identified as predictors of poor outcome in patients with miliary TB (Table 11). In patients with ARDS due to miliary TB (85), an acute physiological and chronic health evaluation (APACHE II) score greater than 18 or a score less than or equal to 18 in the presence of hyponatremia and ratio of arterial oxygen tension (PaO2) to fraction of inspired oxygen (FIO2) less than or equal to 108.5 have been identified to be predictors of death. Identification of these factors can alert the clinicians managing patients with miliary TB.
TABLE 11
| Study (year) (reference) | Predictors of poor outcome |
|---|---|
| Gelb et al. (1973) (32)a | Stupor, meningismus, increasing age, cirrhosis of liver, leukopenia, leukocytosis |
| Grieco and Chmel (1974) (33) | Increasing age, presence of underlying disease, history of cough, night sweats |
| Kim et al. (1990) (35) | Female gender, altered mental status |
| Maartens et al. (1990) (36) | Age greater than 60 yrs, lymphopenia, thrombocytopenia, hypoalbuminemia, elevated transaminase levels, treatment delay |
| Sharma et al. (1995) (42) | Dyspnea, chills, temp of >39.3°C, icterus, hepatomegaly, hypoalbuminemia, hyponatremia, elevated serum alkaline phosphatase |
| Long et al. (1997) (14) | Presence of one or more predisposing conditionsb |
| Mert et al. (2001) (37) | Male sex, presence of atypical chest radiographic pattern, delay in instituting anti-TB treatment |
| Hussain et al. (2004) (34) | Presence of altered mental status, lung crackles, leukocytosis, thrombocytopenia, and the need for ventilation |
| Kim et al. (2008) (86) | High nutritional risk scorec |
a
No statistical analysis was performed.
b
Listed in Table 3.
c
A four-point nutritional risk score was defined according to the presence of four nutritional factors: low body mass index (<18.5 kg/m2), hypoalbuminemia (serum albumin < 30 g/liter), hypocholesterolemia (serum cholesterol < 2.33 mmol/liter), and severe lymphocytopenia (<7 × 105 cells/liter). Each risk factor was assigned a value of 1 if present or 0 if absent. Patients with 3 or 4 points were classified as having a high nutritional risk score.
PREVENTION
BCG vaccination is effective in reducing the incidence of miliary TB, especially in children (146). However, it is not effective in individuals who have latent TB infection and should not be administered to immunosuppressed hosts. Targeted tuberculin testing is practiced in countries with a low prevalence of TB, such as the United States (137, 147), but anti-TB drug-induced hepatotoxicity is a potential risk with the treatment of latent TB infection. Ongoing research (148, 149) has yet to provide a more effective vaccine than BCG.
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Published In
Microbiology Spectrum
Volume 5 • Number 2 • 30 April 2017
eLocator: 10.1128/microbiolspec.tnmi7-0013-2016
Editor: David Schlossberg, Philadelphia Health Department, Philadelphia, PA
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© 2017 American Society for Microbiology.
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Received: 1 October 2016
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Published online: 10 March 2017
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Philadelphia Health Department, Philadelphia, PA
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Miliary Tuberculosis. Microbiol Spectr
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