Underlying Medical Conditions
Mycobacterial virulence factors and host immune defenses determine the risk of dissem-
ination. In large studies, 30% to 80% of patients with miliary TB had underlying medical
conditions (Table 1).
Tumor necrosis factor alpha (TNF-a) plays an important role in the host immune
response to TB. Not surprisingly, the increasing use of anti-TNF agents like infliximab and
etanercept has resulted in a disturbing numbers of reports of patients suffering from
pulmonary and disseminated TB.
Immunology
Adequate containment of tubercle bacilli requires an intricate interplay of different
components of the innate and the adaptive immune system. Macrophages generally represent
the first line of defense. Binding to surface toll-like receptors (TLRs) initiates a robust innate
immune response. TLR-mediated signals influence cytokine production and homing of effector
T cells to the site of infection. Engulfed bacteria are eliminated by reactive nitrogen and oxygen
intermediates. Infected macrophages process and present antigens to various T-cell subsets,
including MHC class II–restricted CD4þT-helper lymphocytes and MHC class I–restricted
cytolytic CD8þ T-suppressor lymphocytes. Processed peptides and secreted cytokines,
including interleukin (IL)–12, trigger TH1 cells to secrete cytokines including IL-2 and TNF-a,
which in a feedback loop further activate the macrophages. Dominance of TH2-type cytokines
(IL-4, IL-5, IL-10) increases the risk of dissemination by cross-inhibiting protective responses
such as granuloma formation.
Additional molecular defects also contribute to an increased risk of developing
disseminated TB. These mechanisms include impaired expansion ofgdT cells, inadequate
CD4 cell function or quantity, the presence or absence of certain HLA-phenotypes, impaired
MHC class II–restricted target cell lysis, and premature lysis of target cell macrophages.
CLINICAL PRESENTATION
Miliary TB can arise as a result of progressive primary infection, from reactivation of a latent
focus with subsequent spread, or rarely even following iatrogenic infection. Disseminated TB
has, for instance, been reported after extracorporeal shock wave lithotripsy (11,12), homograft
cardiac valve placement (13), and even catheterization of the urethra (14). Transplantation of a
solid organ not previously recognized and infected withM. tuberculosiscan also result in
miliary TB (15,16).
The clinical manifestations of miliary TB are highly variable and often nonspecific. In
immunocompromised patients or when miliary TB develops during primary infection, the
disease tends to have a more acute onset and follow a more rapid clinical course. Fulminant
disease with Landouzy sepsis, a systemic inflammatory response syndrome with refractory
shock (17,18), potentially including multiorgan system failure (19), and acute respiratory
distress syndrome (ARDS) (20–23)) may ensue. The “cytokine storm” can be quite dramatic
and result in a clinical picture resembling gram-negative septic shock. These complicated cases
are typically the patients encountered by critical care providers.
Reactivation miliary TB can present as an acute illness as well, but is more likely to be
subacute or chronic. Reinfection may have a role in highly endemic areas. At the chronic end of
the spectrum, presentation with prolonged fever of unknown origin, anorexia, weight loss,
lassitude, night sweats, and cough are frequent. In one series of 38 patients, the median
duration of illness reported was two months (24). Rarely, especially among older people,
apyrexial presentations with progressive wasting strongly mimicking a metastatic carcinoma
are seen (25,26). This is occasionally described as cryptic miliary TB (26). Rigors are unusual
but have been described (27,28).
Paradoxical worsening of lesions during effective TB therapy is known as immune
reconstitution disease (IRD). While IRD is distinctly rare in HIV-negative individuals, almost
one-third of patients with HIV/TB coinfection experience some form of IRD within days to
weeks of the initiation of highly active antiretroviral therapy (HAART). Manifestations include
fever, appearance or worsening of lymphadenopathy, new or worsening pulmonary infiltrates,
serositis, cutaneous lesions, and new or expanding CNS tuberculomas (29).
422 Albrecht