Miliary Tuberculosis: A Comprehensive Review of Epidemiology, Clinical Manifestations, Diagnosis, Treatment, and Complications

Abstract

Miliary tuberculosis (TB) represents a potentially fatal form of disseminated TB resulting from the lymphohematogenous dissemination of Mycobacterium tuberculosis. Although accounting for approximately 1–2% of all TB cases in immunocompetent adults, its mortality rate exceeds 30%. This review screened peer-reviewed, original research studies via four databases (PubMed, EMBASE, MEDLINE, and CENTRAL) to synthesize up-to-date evidence. Key risk factors include human immunodeficiency virus (HIV) co-infection, anti-tumor necrosis factor-α (TNF-α) agents and chronic malnutrition. The clinical presentation of miliary TB is notoriously nonspecific, with fever, night sweats, weight loss, and constitutional symptoms predominating. Over 60% of patients have extrapulmonary complications, with central nervous system (CNS) involvement in 10–30%, abdominal involvement in 15–30%, and skeletal involvement in up to 17%. Laboratory abnormalities are common, including elevated erythrocyte sedimentation rate (ESR), anemia, lymphopenia, and nearly universal C-reactive protein (CRP) elevation. Diagnoses remain difficult due to paucibacillary lesions; novel molecular assays and a validated CNS prediction scoring system greatly improve diagnostic efficiency, while multiple microbiological and invasive tissue sampling modalities are briefly summarized for comprehensive clinical reference. Standard 6-month isoniazid, rifampicin, pyrazinamide ethambutol and isoniazid, rifampicin (HRZE-HR) regimens apply to isolated pulmonary miliary TB, whereas 9–12-month extended therapy plus adjunctive dexamethasone is required for CNS complications. Drug resistant cases demand 18–24-month individualized regimens with high blood-brain barrier penetration. Severe complications including tuberculous meningitis and high mortality acute respiratory distress syndrome (ARDS) are fully discussed, and TNF-α antagonists act as salvage therapy for steroid-refractory tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS). Bacillus Calmette–Guérin (BCG) vaccination provides substantial protection against miliary TB in children, with efficacy of approximately 77% and favorable cost-effectiveness. Existing reviews lack integrated post-pandemic epidemiological data, cutting-edge molecular diagnostics and modern extrapulmonary treatment algorithms; this paper fills such gaps to offer balanced clinical guidance for frontline clinicians.

Introduction

Tuberculosis (TB) remains a major global health problem, with an estimated 10.6 million people falling ill and 1.6 million deaths in 2021 alone.^1,2 The World Health Organization (WHO) Global Tuberculosis Report 2023 indicated that approximately 7.5 million people were diagnosed with TB in 2022—the highest number since WHO began global monitoring in 1995—and an estimated 10 million new cases occurred in 2023.³ The COVID-19 pandemic has caused unprecedented disruption to TB services worldwide, leading to increased TB incidence and mortality for three consecutive years (2020–2023), reversing the previous downward trend and consequently setting back decades of efforts in the global fight against TB.^2–4 TB has once again become the leading cause of death from a single infectious agent, with mortality more than twice that of HIV/AIDS.² An estimated 1.26 million TB deaths occurred in 2023, with nearly 700,000 excess TB-related deaths during 2020–2023.³

Among the various forms of TB, miliary tuberculosis represents one of the most severe and potentially lethal manifestations, resulting from the massive lymphohematogenous dissemination of Mycobacterium tuberculosis from a primary focus.^5,6 The term “miliary,” derived from the Latin word miliarius meaning related to millet seed, was first coined by John Jacob Manget in 1700 to describe the resemblance of gross pathological findings to innumerable millet seeds in size and appearance.^7,8

Historically considered predominantly a disease of infants and children in the pre-antibiotic era, miliary TB has undergone a significant epidemiological shift over the past three decades and is now increasingly recognized in adults as well.^5,9 This changing demographic pattern reflects several factors, including the global HIV/AIDS pandemic, increased use of immunosuppressive therapies, organ transplantation, chronic hemodialysis programs, and the introduction of biological agents such as anti-tumor necrosis factor-α (anti-TNF-α) therapies.^10–12 The COVID-19 pandemic has further exacerbated the TB burden through healthcare disruptions, delayed diagnoses, and increased vulnerability in affected populations.^3,4

The clinical manifestations of miliary TB are notoriously protean and nonspecific, often leading to diagnostic delays that contribute to its substantial mortality. Fever, night sweats, weight loss, and constitutional symptoms predominate, but the disease can involve virtually any organ system, with extrapulmonary complications occurring in over 60% of cases.^13,14 The central nervous system, abdomen, and skeletal system are particularly frequent sites of dissemination, each associated with significant morbidity and mortality.^15–17 Additionally, ARDS is a rare but devastating complication that dramatically increases mortality.^18–21

Diagnosis remains challenging due to the paucibacillary nature of the disease and the frequent absence of classic radiographic findings, particularly in early stages.²² While the classic miliary pattern on chest radiography is present in only 50–90% of cases, high-resolution computed tomography (HRCT) has substantially improved diagnostic sensitivity, revealing randomly distributed micronodules even when plain films appear normal.^23,24 A recently developed scoring system utilizing readily available clinical and laboratory parameters offers a non-invasive approach to evaluate CNS involvement in miliary TB patients, potentially reducing the need for lumbar puncture and neuroimaging in selected cases.²⁵

Despite the availability of effective anti-tuberculosis therapy, mortality from miliary TB remains substantial, ranging from 15–20% in children to 25–30% in adults, with even higher rates when complications such as ARDS or tuberculous meningitis supervene.^26–29 Treatment follows standard anti-tuberculosis regimens, though the optimal duration remains debated, particularly when extrapulmonary involvement is present. Adjunctive corticosteroids have demonstrated benefit in specific complications, including tuberculous meningitis, pericarditis, and immune reconstitution inflammatory syndrome (IRIS).^30–32

Although previous reviews have summarized the epidemiology, clinical features, and management of miliary tuberculosis, most existing literatures were published prior to the COVID-19 pandemic and fail to address the evolving challenges of this severe disease in the post-pandemic era. The global disruption of tuberculosis healthcare services, delayed case detection, altered transmission dynamics, and worsened immunosuppressive comorbidities following the COVID-19 outbreak have substantially changed the clinical spectrum, diagnostic timeliness, and prognostic outcomes of miliary tuberculosis. Furthermore, recent advances in molecular diagnostics, individualized anti-tuberculosis regimens, complication-targeted interventions, and host-directed therapies have not been systematically consolidated in current reviews focused on miliary tuberculosis. Critical knowledge gaps remain regarding the early identification of high-risk populations, standardized diagnostic workflows for occult central nervous system involvement and acute respiratory distress syndrome, and optimized therapeutic strategies for drug-resistant cases and post-infectious inflammatory complications under modern post-COVID-19 clinical settings. Therefore, this updated review aims to comprehensively synthesize the latest evidence on the clinical characteristics, early diagnostic strategies, individualized management protocols, and prognostic evaluation of miliary tuberculosis, filling the post-pandemic research void and providing practical, up-to-date clinical guidance for the standardized diagnosis and treatment of this life-threatening tuberculosis subtype.

Epidemiology

Global Burden and Impact of COVID-19

Miliary tuberculosis accounts for approximately 1–2% of all tuberculosis cases in immunocompetent adults and up to 20% of all extrapulmonary TB cases in clinical studies.^4,33,34 In autopsy studies, the proportion is considerably higher, with miliary TB documented in 0.3–13.3% of all autopsies and 11.9–40.5% of all TB cases.^35–37 According to US Centers for Disease Control and Prevention data from 2012–2014, miliary TB accounted for 3.5–3.8% of all reported TB cases and 11.2–12.2% of all reported extrapulmonary TB cases.³⁸

In late HIV infection, extrapulmonary TB accounts for more than 50% of all TB cases, and miliary TB is encountered with substantially greater frequency.^39,40 Among HIV-infected individuals with TB, disseminated disease occurs in up to 38% of cases, particularly when CD4+ T-cell counts fall below 200 cells/μL.^41,42

The COVID-19 pandemic has significantly altered the global TB landscape. The WHO 2022 and 2023 TB reports documented a rise in estimated new TB cases for three consecutive years post-2020, reversing the previous downward trend.^2,3 In 2023 alone, over 1.26 million TB deaths occurred, and nearly 700,000 excess TB-related deaths were estimated during 2020–2023.³ The case fatality rate, which had been falling, rose again, particularly in high-burden countries.^2,3 Although miliary TB is not separately reported in global statistics, it reflects the overall TB burden and is disproportionately affected by delays in diagnosis and treatment caused by pandemic-related healthcare disruptions.^3,4

Demographic Trends

Age Distribution

In the pre-antibiotic era, miliary TB was predominantly a disease of infants and children.^5,43 Currently, two distinct peaks are evident: one involving adolescents and young adults (20–40 years), and another later in life among elderly individuals (>60 years).^6,9,44,45 A recent study comparing miliary TB patients with and without CNS involvement found that those with CNS disease were significantly younger (mean age 23.7 vs 30.5 years, P=0.046), suggesting that younger patients may be more susceptible to hematogenous dissemination to the CNS.²⁵

Sex Distribution

Males appear to be more frequently affected by miliary TB in both pediatric and adult series, with male-to-female ratios ranging from 1.3:1 to 3:1 in various studies.^45–48 However, in miliary TB patients with CNS involvement, a female preponderance has been observed (58% female vs 42% male).²⁵ Some recent adult series have also described a female preponderance in overall miliary TB, possibly reflecting increased healthcare-seeking behavior or referral patterns.^49,50

Geographic and Ethnic Variation

In the United States, a higher incidence of miliary TB has been described among African Americans in some earlier publications, though such trends are less evident in recent data.^5,6,51 Whether this reflects true ethnic variation, socioeconomic factors, nutritional status, comorbid illnesses, or host genetic factors remains unclear. In regions with high TB incidence, such as Southeast Asia and sub-Saharan Africa, miliary TB constitutes a proportionally greater burden.^52,53 These regions have also been disproportionately affected by COVID-19-related TB service disruptions.³

Predisposing Conditions

Multiple predisposing and associated conditions have been identified in patients with miliary TB (Table 1). In various series, 24–66% of patients have at least one identifiable predisposing condition.^{9,48,49,54,55}

Table 1.

Predisposing and Associated Conditions in Miliary Tuberculosis

Condition Category	Specific Conditions	Approximate Frequency*
Infectious	HIV/AIDS	14-47% in endemic areas
	Childhood infections (measles, pertussis)	Variable
Immunosuppressive conditions	Malignancy (hematologic, solid organ)	3-10%
	Organ transplantation	2-4%
	Chronic kidney disease/dialysis	5-8.5%
	Connective tissue diseases	3-10%
Iatrogenic	Corticosteroid therapy	7-18%
	Immunosuppressive/cytotoxic drugs	5-8%
	Anti-TNF-α therapy	1-3% of treated patients
Metabolic/nutritional	Diabetes mellitus	5-38%
	Malnutrition	Variable
	Alcoholism	12-37%
Other	Post-gastrectomy	Rare
	Silicosis	Rare
	Pregnancy/postpartum	2-5%

Note: *Based on data from references6,9,10,45,48,54–58.

Abbreviation: TNF-α tumor necrosis factor-alpha.

The introduction of immunomodulatory biological agents, particularly anti-TNF-α therapies, has emerged as an important risk factor for miliary TB.^10,59 In a prospective study from the British Society for Rheumatology Biologics Register, disseminated and miliary TB accounted for 27.5% of all TB cases and 44% of extrapulmonary TB among patients receiving anti-TNF therapy.¹⁰ The rate of TB development was significantly higher for adalimumab (144 events/100,000 person-years) and infliximab (136/100,000 person-years) compared with etanercept (39/100,000 person-years). The median time to TB development was shortest for infliximab (5.5 months) compared with etanercept (13.4 months) and adalimumab (18.5 months).

Iatrogenic dissemination has also been associated with various procedures, including ureteral catheterization, extracorporeal shockwave lithotripsy, laser lithotripsy, cardiac valve homograft replacement, and intravesical BCG therapy for bladder carcinoma.^60–64

Pathogenesis and Immunopathology

Mechanisms of Dissemination

Miliary tuberculosis results from the massive lymphohematogenous dissemination of M. tuberculosis from a pulmonary or extrapulmonary focus, with subsequent embolization to the vascular beds of various organs.^6,65 Organs with high blood flow and abundant phagocytic cells—particularly the spleen, liver, lungs, bone marrow, kidneys, and adrenals—are most frequently affected.^35,36,66

Multiple distinct pathological pathways facilitate hematogenous and lymphatic dissemination of Mycobacterium tuberculosis, as summarized in previous research.^6,67 The first pathway refers to early generalization that takes place in the setting of primary tuberculosis infection, characterized by abrupt clinical onset and rapid disease advancement. The second mechanism is late generalization arising from post-primary tuberculosis lesions; this process can present as rapidly advancing acute miliary tuberculosis, intermittent episodic spread, or slow, long-standing chronic miliary tuberculosis. Thirdly, simultaneous reactivation of multiple latent mycobacterial foci distributed across different visceral organs triggers systemic bacterial dissemination. Reinfection constitutes another vital transmission pathway, which plays a prominent role in regions with extremely high tuberculosis endemicity. The final route involves direct vascular leakage of liquefied caseous necrotic substances originating from extrapulmonary tuberculous lesions, which directly enters the circulatory system and triggers widespread miliary lesions throughout the body.

Immunopathogenesis

The development of miliary TB reflects inadequate effector T-cell (Teff) response in containing M. tuberculosis.^68–71 Current understanding suggests that miliary TB represents the Th2 end of the immunological spectrum, with chemokine-directed selective homing of Th2 cells playing a critical role.^72,73

Role of Regulatory T Cells

Regulatory T cells (Treg cells; CD4(+)CD25(+)FoxP3(+)) appear to play a crucial role in the immunopathogenesis of miliary TB by suppressing effector immune responses at pathologic sites.^70,73 In patients with miliary TB, FoxP3+ Treg cells obtained from bronchoalveolar lavage (BAL) fluid predominantly produce interleukin-10 (IL-10) and suppress autologous T-cell proliferation in response to M. tuberculosis antigen.⁷⁰ When the balance of homing shifts toward Treg cells, local immunosuppression occurs, facilitating disease dissemination.^6,70,71

Th1/Th2 Balance

While Th1 responses characterize protective immunity, Th2 responses appear to exert counter-regulatory effects. Interleukin-4 (IL-4), through its ability to downregulate inducible nitric oxide synthase (iNOS), toll-like receptor 2 (TLR2), and macrophage activation, may determine whether infection becomes latent or progressive.^68,69,74,75

Probable Molecular Basis of Dissemination

Several molecular mechanisms have been implicated in the development and progression of miliary tuberculosis.^{6,72,73,76–87} An important immunological factor involves an immunomodulatory imbalance of γ/δ T-cells, which disrupts early immune recognition and containment of Mycobacterium tuberculosis, thereby contributing to hematogenous dissemination.^72,76 Inadequate generation and maturation of effective cell-mediated immunity also plays a critical role, as impaired cellular immune responses fail to control mycobacterial proliferation and prevent systemic spread.⁷³

Specific human leukocyte antigen (HLA) genotypes are closely associated with susceptibility or resistance to miliary TB. Disease susceptibility is significantly increased in individuals carrying HLA-Bw15, HLA-DRB1*15/16, DRB1*13, DQB1*050301, DQB1*0601, DQB1*0602, DQB1*0201 and DRB1*04.^{77,78,81,82,84,85,87} Conversely, protection against developing miliary tuberculosis is associated with the absence of HLA-Cw6, HLA-DRB1*10, DQA1*02:01, DQB1*0501, and DPB1*1501, suggesting that these genotypes may confer favorable immune regulation against disseminated disease.^78,83,85 Additional pathogenic mechanisms include impaired major histocompatibility complex (MHC) class II-restricted target cell lysis, which reduces the ability of immune effector cells to eliminate infected macrophages.^77,79 Conversely, over-exuberant lysis of target macrophages may trigger excessive tissue necrosis and promote uncontrolled mycobacterial release into the bloodstream, further accelerating dissemination.^77,79 Furthermore, multiple gene polymorphisms have been linked to increased susceptibility, including LTA₊₃₆₈ G/A, IL10₋₁₀₈₂/IL10₋₅₉₂, Interferon-γ gene+874T-A, NRAMP1 and vitamin D receptor (VDR) gene polymorphisms, all of which compromise protective anti-tuberculosis immune function.^78,80,86

Pathological Findings

Gross examination reveals small, punctate, gray to reddish-brown, rounded lesions of relatively uniform size (approximately 2 mm in diameter) scattered throughout affected organs, resembling millet seeds.^5,6 Histopathologically, the tubercle constitutes the hallmark of miliary TB, typically consisting of central caseous necrosis surrounded by epithelioid cells, Langhans giant cells, and lymphocytes.^88–90

The nature and morphological characteristics of tuberculous lesions in miliary TB vary significantly depending on the tempo and severity of hematogenous dissemination.^6,89,90 In cases of acute massive hematogenous dissemination, pathological examination typically reveals “soft” or “exudative” tubercles, which are characterized by active inflammation and easily detectable acid-fast bacilli (AFB) within the lesions. By contrast, in patients with chronic or episodic mycobacterial dissemination, the lesions predominantly consist of “hard” tubercles, often with a minority of admixed soft exudative lesions, and acid-fast bacilli are rarely detectable on microscopic examination. When miliary tuberculosis is complicated by ARDS, the pathological features include not only typical miliary granulomas but also prominent hyaline membrane formation accompanied by diffuse inflammatory cellular infiltration in the alveolar spaces. In individuals co-infected with human immunodeficiency virus (HIV), miliary TB exhibits distinct pathological alterations characterized by poorly formed granulomas, minimal inflammatory cellular reaction, extensive tissue necrosis, and abundant acid-fast bacilli, reflecting severe impairment of host cellular immunity.

Organ System Involvement

The distribution of visceral lesions in miliary tuberculosis exhibits prominent discrepancies between autopsy series and prospective clinical cohort research, which can be largely attributed to differences in patient populations, disease progression timelines, and diagnostic accessibility during life.^6,35,36,91 Organs with abundant microvascular perfusion and dense resident phagocyte populations bear the highest risk of hematogenous mycobacterial seeding, as circulating bacilli readily lodge within capillary beds to initiate granuloma formation; these organs include the lungs, spleen, and liver, which consistently rank at the top of involvement frequency in both autopsy and clinical datasets (Table 2). Nevertheless, Mycobacterium tuberculosis possesses the capacity to disseminate to nearly every human visceral organ system through systemic blood and lymphatic circulation, and less commonly affected sites such as the pancreas, reproductive organs, and adrenal glands still develop miliary granulomas in a notable subset of patients with prolonged untreated disease or severe immunosuppression. Autopsy specimens often capture full-spectrum multi-organ involvement that fails to be identified via ante-mortem imaging and laboratory testing, explaining why the detection rates of splenic, bone marrow, and adrenal lesions are markedly higher in post-mortem analyses compared with clinical observational data collected from living patients. This divergent pattern of organ lesion prevalence highlights the limitations of routine clinical evaluation in capturing the full pathological extent of disseminated miliary tuberculosis and underscores the value of cross-referencing clinical data with autopsy-derived epidemiological statistics to fully characterize the systemic spread pattern of this lethal disease.

Table 2.

Frequency of Organ Involvement in Miliary Tuberculosis

Organ System	Autopsy Series (%)*	Clinical Series (%)†
Lungs	63–100	87–96
Liver	55–100	72-88
Spleen	79–100	44
Kidneys	24–64	37
Lymph nodes	33–80	35
Central nervous system	22–73	10–30
Bone marrow	14–77	17
Adrenals	12–53	12
Gastrointestinal tract	11–28	11
Pancreas	12–20	8.5
Reproductive organs	5–13	7

Note: *Based on references;^{35,36,91–94} †Based on references.^{13,14,47,95–97}

Clinical Manifestations

General Features and Constitutional Symptoms

The clinical presentation of miliary TB is notoriously protean and nonspecific, often leading to diagnostic delays. Classically, patients present with fever of several weeks’ duration, anorexia, weight loss, weakness, and cough.^5,6,98 Over 80% of patients present with fever, cough, and sputum production.^13,14 Night sweats are common, occasionally so profuse as to produce the “damp shadow sign,” where sweat engraves the patient’s silhouette on the bed.⁹⁹ Approximately 30% report symptoms such as headache and hemoptysis, and about 20% exhibit shortness of breath and fatigue.^13,14,100

In a substantial proportion of patients, particularly the elderly, fever may be absent, and patients may present with progressive wasting strongly mimicking metastatic carcinoma-a presentation termed “cryptic miliary TB”.^98,101,102 In the pre-CT era, such cases were often diagnosed only at autopsy; however, HRCT has substantially improved antemortem diagnosis.^23,103

Table 3 summarizes the frequency of various symptoms and signs in miliary TB from major series, incorporating data from a recent study comparing patients with and without CNS involvement.²⁵

Table 3.

Frequency of Clinical Manifestations in Miliary Tuberculosis

Manifestation	MTB (%)*	MTB +CNS (%)†	Overall Adult Series (%)‡	Pediatric Series (%)§
Symptoms
Fever	90	77	89–100	61–98
Cough	66	35	53–83	17–90
Sputum	34	19	30–50	Variable
Night sweats	16	13	50–100	8–75
Fatigue	20	23	48–91	14–54
Weight loss	6	3	47–100	4–60
Headache	22	68	18–43	2-8
Nausea	10	39	5–15	3–10
Vomiting	10	26	5–20	2–8
Dyspnea	22	13	13–79	7–25
Chest pain	6	0	4–79	1–3
Abdominal pain	–	–	5–19	3–15
Hemoptysis	–	–	2–16	1
Signs
Tachypnea	–	–	30–47	Variable
Rales/crackles	–	–	28–50	34–72
Hepatomegaly	–	–	12-37	39–82
Splenomegaly	–	–	6–32	24–54
Lymphadenopathy	–	–	5–30	5–30
Altered mental status	–	–	8–32	2–8
Meningeal signs	–	–	3–21	19-–35
Choroidal tubercles	–	–	2-13	2–5
Ascites	–	–	4–9	6–9

Notes: *Data from Xiao et al 25 (n=50 MTB without CNS) ^†Data from Xiao et al 25 (n=31 MTB with CNS) ^‡Compiled from references9,13,45–48,54,55,98,104–107 §Compiled from references.^108–111

Central Nervous System Involvement

CNS involvement represents one of the most devastating complications of miliary TB, occurring in 10–30% of adult patients and 20–40% of children.^6,15,112 Conversely, approximately one-third of patients presenting with tuberculous meningitis (TBM) have underlying miliary TB.¹¹³ Patients with CNS involvement are significantly younger than those without (mean age 23.7 vs 30.5 years, P=0.046) and more frequently female.²⁵

Tuberculous Meningitis

Results from the rupture of a subependymal or subpial Rich focus into the subarachnoid space, releasing mycobacterial antigens and initiating an intense inflammatory response.^114,115 The resultant exudative arachnoiditis mainly targets the basal cisterns and triggers a series of pathological sequelae.^116,117 Hydrocephalus represents another frequent complication, accounting for 80% communicating cases and 20% obstructive cases among patients with tuberculous meningitis.

The clinical progression of tuberculous meningitis (TBM) generally develops in three successive phases.^118,119 The initial prodromal stage lasts for one to two weeks and is marked by general malaise, low-grade fever, persistent headache and altered personality. The subsequent meningitic stage presents with unrelenting headache, vomiting, meningeal irritation, confusion, cranial nerve paralysis and hemiparesis. In the final paralytic stage, patients develop stupor, coma, recurrent seizures, multiple cranial nerve impairments and hemiplegia.

Among patients with TBM, headache (68%), nausea (39%), and vomiting (26%) are significantly more common than in miliary TB without CNS involvement.²⁵ Cranial nerve involvement occurs in 20–50% of patients, with the sixth nerve most commonly affected, followed by the third and fourth.^120,121 Optic nerve involvement occurs in up to 35% of cases and carries a poor prognosis.^122–128

Abdominal Involvement

Abdominal tuberculosis occurs in 15–30% of patients with miliary TB and represents the sixth most common form of extrapulmonary TB.^16,129,130 The abdomen may be involved through several mechanisms: hematogenous dissemination, lymphatic spread, ingestion of infected sputum, or direct spread from contiguous infected lymph nodes or fallopian tubes.^131,132 Table 4 summarized the frequency of abdominal involvement in miliary tuberculosis. The peritoneum, intestines, liver, spleen, and lymph nodes are frequently involved, with presentations ranging from ascites and abdominal pain to obstruction or hepatosplenomegaly. These manifestations are often nonspecific, underscoring the need for clinical vigilance to ensure timely diagnosis and management.

Table 4.

Frequency of Abdominal Involvement in Miliary Tuberculosis

Site	Frequency (%)*	Clinical Features
Peritoneum	10–15	Abdominal pain, distension, ascites, low-grade fever, night sweats, weight loss
Intestines	8–11	Chronic abdominal pain, diarrhea, constipation, obstruction, perforation
Liver	26–72	Hepatomegaly, right upper quadrant pain, elevated alkaline phosphatase, jaundice (rare)
Spleen	20–44	Splenomegaly, left upper quadrant pain, hypersplenism
Mesenteric lymph nodes	20–35	Abdominal pain, palpable masses, obstructive symptoms
Pancreas	2–8	Abdominal pain, weight loss, jaundice, mass lesions mimicking malignancy
Genitourinary	7–17	Flank pain, dysuria, hematuria, sterile pyuria, menstrual abnormalities, infertility

Note: *Based on references.^{13,16,95,96,129,133–137}

Skeletal Involvement

Skeletal tuberculosis complicates up to 17% of miliary TB cases, though it accounts for less than 5% of all TB cases overall.^17,138,139 Hematogenous dissemination from pulmonary or extrapulmonary foci seeds the skeletal system, with the spine being the most common site (50% of skeletal TB), typically presenting with back pain, kyphosis, and paraspinal abscesses.^140,141 Other sites include the hips, knees, and long bones. Although skeletal TB itself has low mortality, its presence signals disseminated disease and warrants prompt diagnosis to prevent deformities or neurological complications (Table 5).

Table 5.

Distribution of Skeletal Tuberculosis

Site	Frequency (%)*	Clinical Features
Spine (Pott’s disease)	50	Back pain, gibbus deformity, paraplegia (10–30%), paraspinal cold abscess
Hip	10–15	Hip pain, limp, limitation of motion
Knee	10–15	Pain, swelling, effusion, synovial thickening
Sacroiliac joint	5–10	Buttock pain, sacroiliac tenderness
Ribs	5–10	Chest wall mass, pain
Long bones	5–10	Bone pain, pathologic fracture
Multiple sites	10–15	Variable

Note: *Based on references.^{17,138,142–145}

Genitourinary Involvement

Genitourinary tuberculosis occurs in 7–17% of miliary TB patients and represents the most common form of extrapulmonary TB in some series.^13,146,147 The kidney is usually infected hematogenously and is the most frequently affected site, with subsequent spread to the ureters, bladder, and genital organs (Table 6).^148,149

Table 6.

Genitourinary Tuberculosis in Miliary TB

Site	Frequency (%)*	Clinical Features
Kidney	74–96	Flank pain, hematuria, sterile pyuria, renal failure (bilateral disease)
Ureter	8–29	Stricture, hydronephrosis, obstruction
Bladder	1–16	Frequency, urgency, dysuria, contracture
Epididymis/testis	4–13	Scrotal swelling, pain, discharge, fistula
Prostate	1–3	Perineal pain, obstructive symptoms, nodularity
Female genital tract	7	Infertility, pelvic pain, menstrual abnormalities, tubo-ovarian masses

Note: *Based on references.^{13,95,146,147,150,151}

Acute Respiratory Distress Syndrome (ARDS)

ARDS is a rare but devastating complication of miliary TB, occurring in approximately 8% of patients, yet carrying a mortality rate of 40–80%.^{18,19,152,153} The pathogenesis involves diffuse alveolar damage from massive bacillary seeding and an intense inflammatory response, leading to increased alveolar-capillary permeability and non-cardiogenic pulmonary edema.^18,154

Clinical Features

Patients typically present with rapidly progressive dyspnea, hypoxemia, and bilateral pulmonary infiltrates evolving over days to weeks.^19,155 The onset may be fulminant, occasionally preceding the classic miliary radiographic pattern.^18,156 Risk factors for developing ARDS include alcoholism, cirrhosis, hypoalbuminemia, delayed diagnosis, and underlying immunosuppression.^26,157

Radiographic Findings

Chest radiography shows diffuse bilateral alveolar or ground-glass opacities that may obscure the underlying miliary nodules.^18,19 CT typically reveals diffuse ground-glass attenuation, consolidation, and septal thickening superimposed on a miliary pattern.¹⁵⁸

Special Populations

HIV-Infected Individuals

Patients with advanced HIV infection, defined as CD4+ T-cell counts below 200 cells/μL, exhibit a distinct spectrum of clinical manifestations when complicated by miliary tuberculosis.^39,40,159 These patients are prone to extrapulmonary lesions, including those occurring at rare atypical anatomical sites, and disseminated cutaneous miliary tuberculosis can be detected in 5% to 10% of cases. Intrathoracic lymphadenopathy is observed in 40%–60% of affected individuals, while tuberculin skin test anergy occurs in 60%–80% of this population. Sputum smear testing yields positive results at a lower rate of only 20%–30%, whereas mycobacteremia is far more prevalent, affecting 30%–40% of patients. Histopathological examination typically reveals inadequate granuloma formation. Collectively, these characteristic alterations contribute to faster disease deterioration and substantially elevated mortality among HIV-associated miliary TB patients.

Children

The clinical manifestations of childhood miliary tuberculosis differ markedly from those seen in adult patients.^{108–111,160} Children are less likely to develop chills, night sweats or hemoptysis compared with adult counterparts. Peripheral lymphadenopathy is far more prevalent in pediatric cases, occurring in 40% to 60% of patients, while hepatosplenomegaly can be identified in 60%–80% of affected children. Tuberculous meningitis develops in 20%–40% of children with miliary TB, a proportion higher than the 15%–30% observed in adults. BCG vaccination provides 73% protective efficacy against childhood miliary tuberculosis,¹⁶¹ and the overall mortality rate among pediatric patients ranges from 15% to 20%, which is substantially lower than that of adults.

Pregnancy and IVF-ET

An increasing number of cases have been reported in pregnant women after in vitro fertilization and embryo transfer (IVF-ET), often presenting with miliary TB during the first or second trimester.^162–164 These patients have poor pregnancy outcomes, with high rates of spontaneous abortion and fetal loss.^165,166 Risk factors include untreated prior pulmonary TB and tubal factor infertility.^167,168

Anti-TNF-α Therapy

Patients receiving anti-TNF-α agents (infliximab, adalimumab, etanercept) for inflammatory conditions are at increased risk of miliary TB, which may manifest as a paradoxical IRIS after treatment withdrawal.^56,59,169 Management requires high-dose corticosteroids and careful monitoring.¹⁷⁰

Laboratory Abnormalities

Hematological Findings

A wide spectrum of hematological abnormalities occurs in miliary TB, though their diagnostic significance is limited (Table 7).^{9,13,25,45,47,48,55,105} Table 7 summarizes the spectrum of hematological abnormalities observed in patients with miliary tuberculosis. The most frequent finding is elevated erythrocyte sedimentation rate (89–95%), reflecting systemic inflammation. Anemia is highly prevalent, affecting 76–86% of patients, followed by lymphopenia (48–76%), which may indicate impaired cell-mediated immunity. Leukocytosis and leukopenia occur in 11–27% and 17–26% of cases, respectively, while thrombocytosis (10–32%) and thrombocytopenia (8–24%) are also common. Less frequent abnormalities include monocytosis (8–30%), pancytopenia (3–12%), leukemoid reaction (1–5%), and disseminated intravascular coagulation (1–3%). These findings highlight the broad impact of miliary tuberculosis on the hematopoietic system. Their presence should prompt consideration of miliary TB in the appropriate clinical context, and they may serve as adjunctive markers for disease severity and prognosis.

Table 7.

Hematological Abnormalities in Miliary Tuberculosis

Abnormality	Frequency (%)*
Elevated ESR	89–95
Anemia	76–86
Lymphopenia	48–76
Leukopenia	17–26
Thrombocytosis	10–32
Monocytosis	8–30
Leukocytosis	11–27
Thrombocytopenia	8–24
Pancytopenia	3–12
Leukemoid reaction	1–5
Disseminated intravascular coagulation	1–3

Note: *Based on references.^{9,13,25,45,47,48,54,55,105,171–173}

Abbreviation: ESR, erythrocyte sedimentation rate.

Biochemical Abnormalities

Table 8 outlines the key biochemical derangements in miliary tuberculosis. Elevated C-reactive protein (>90%) is nearly universal, indicating a robust acute-phase response. Hypoalbuminemia (71–75%) serves as a negative prognostic marker and correlates with malnutrition and chronic inflammation. Hyponatremia (26–68%) is particularly important as it may signal tuberculous meningitis or syndrome of inappropriate antidiuretic hormone secretion. Elevated alkaline phosphatase (32–67%) and transaminases (38–55%) suggest hepatic granulomatous involvement, often with disproportionate increases in alkaline phosphatase. Hyperbilirubinemia is uncommon (8–11%) and usually mild, whereas hypercalcemia (0–13%) results from extrarenal 1,25-dihydroxyvitamin D production by activated macrophages within granulomas. These biochemical abnormalities, while nonspecific, provide valuable clues for diagnosing miliary tuberculosis and anticipating complications.

Table 8.

Biochemical Abnormalities in Miliary Tuberculosis

Abnormality	Frequency (%)*	Comments
Hyponatremia	26–68	May indicate tuberculous meningitis; predictor of mortality
Hypoalbuminemia	71–75	Negative prognostic factor
Elevated transaminases	38–55	Asymptomatic elevation common; correlates poorly with histology
Elevated alkaline phosphatase	32–67	Suggests hepatic involvement
Hyperbilirubinemia	8–11	Usually mild; fulminant hepatic failure rare
Hypercalcemia	0–13	Granulomatous production of 1,25-dihydroxyvitamin D
Elevated CRP	>90	Nonspecific acute phase response

Note: *Based on references.^{9,13,25,45,47,48,54,55,105,106,171,174,175}

Comparative Laboratory Parameters in Miliary TB with and Without CNS Involvement

A recent comparative study by Xiao et al²⁵ provided detailed laboratory data comparing miliary TB patients with and without CNS involvement. This study of 81 patients (50 without CNS, 31 with CNS) revealed significant differences in several parameters (Table 9). Patients without CNS involvement had significantly lower hemoglobin and albumin levels, and significantly higher ESR and CRP levels, suggesting a more intense systemic inflammatory response. In contrast, patients with CNS involvement had relatively preserved nutritional status and less systemic inflammation, which may reflect different immunological mechanisms or timing of dissemination. These findings highlight the importance of considering CNS involvement when interpreting laboratory results in miliary TB patients. The scoring system derived from these parameters (see Molecular Diagnostics) provides a practical tool to integrate clinical and laboratory data for early identification of CNS complications.

Table 9.

Laboratory Parameters in Miliary Tuberculosis with and Without CNS Involvement

Parameter	MTB without CNS (n=50)	MTB with CNS (n=31)	P value
Hemoglobin (g/L)	115.6 ± 20.8	126.9 ± 18.1	0.015
Serum albumin (g/L)	31.7 ± 6.7	40.0 ± 6.4	<0.001
Total protein (g/L)	60.9 ± 12.2	68.4 ± 11.8	0.015
ESR (mm/h)	49.8 ± 32.3	27.9 ± 24.3	0.005
CRP (mg/L)	29.0 ± 51.2	7.3 ± 12.7	0.013
ALT (U/L)	40.2 ± 33.8	51.3 ± 65.1	0.321
AST (U/L)	49.0 ± 74.7	48.1 ± 79.6	0.961
GGT (U/L)	69.5 ± 69.3	86.0 ± 88.7	0.392
White blood cells (×109/L)	6.81 ± 2.72	6.60 ± 2.80	0.737
Platelets (×109/L)	244.5 ± 104.1	223.7 ± 89.9	0.363
ADA (U/L)	29.0 ± 36.5	17.6 ± 7.9	0.134

Abbreviations: ADA, adenosine deaminase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GGT, gamma-glutamine transaminase.

Diagnostic Imaging

Chest Radiography

The radiographic hallmark of miliary TB is the miliary pattern—a collection of tiny (1–3 mm) discrete pulmonary opacities uniformly distributed throughout both lungs.^176,177 This pattern is present in 50–90% of patients at presentation, though it may take 2–6 weeks to become radiographically apparent after symptom onset.^9,23,45,47 However, as summarized in Table 10, chest radiographic findings can be variable. A classical miliary pattern is observed in 50–90% of cases, while 10–30% of patients may present with an asymmetrical nodular pattern. Nodular coalescence occurs in 10–20%, and reticulonodular or ground-glass opacities are seen in 5–15% of patients. Air-space consolidation and pleural effusion are less common, each occurring in 5–20% of cases. Intrathoracic lymphadenopathy is observed in 10–35% of patients, with higher frequencies in HIV-infected individuals. Importantly, 10–30% of patients may have a normal chest radiograph at presentation, underscoring the need for more sensitive imaging modalities such as high-resolution computed tomography when clinical suspicion remains high.

Table 10.

Chest Radiographic Findings in Miliary Tuberculosis

Finding	Frequency (%)*
Classical miliary pattern	50–90
Asymmetrical nodular pattern	10–30
Coalescence of nodules	10-20
Reticulonodular pattern	5–15
Ground-glass opacities	5–10
Air-space consolidation	5–15
Intrathoracic lymphadenopathy	10–35 (higher in HIV)
Pleural effusion	5–20
Normal chest radiograph	10–30

Note: *Based on references.^{9,23,45,47,98,103,178,179}

High-Resolution Computed Tomography

HRCT is more sensitive than plain radiography and may demonstrate miliary nodules even when the chest radiograph appears normal.^23,103,180 Multiple typical HRCT features can be identified in patients with miliary tuberculosis.^24,181,182 Lesions present as nodules measuring 1 to 4 mm in diameter with either clear or indistinct borders, scattered randomly across bilateral lung fields accompanied by thickened intra- and interlobular septa. The tree-in-bud sign, defined as centrilobular nodules attached to branching linear opacities, is also a common manifestation, and ground-glass opacities tend to emerge during the acute phase of infection. Intrathoracic lymphadenopathy can be detected in 10% to 40% of cases, while air trapping may be observed on follow-up imaging examinations.

Abdominal Imaging

Ultrasonography

Serves as a valuable imaging modality for identifying multiple pathological lesions associated with abdominal miliary tuberculosis.^183,184 It can visualize free or loculated ascites, as well as focal hypoechoic nodules within the liver and spleen. Intra-abdominal lymphadenopathy, which typically appears hypoechoic and may be complicated by central necrosis, can also be clearly recognized via ultrasound scanning. In addition, the technique enables detection of cold tuberculous abscesses and allows real-time guidance for diagnostic aspiration procedures to obtain lesion specimens.

Computed Tomography

Can demonstrate a series of characteristic abdominal manifestations of miliary tuberculosis.^{134,185–187} Diffuse heterogeneous hepatosplenomegaly is frequently observed, accompanied by numerous 1–5 mm small hypodense nodules scattered throughout the liver and spleen. Intra-abdominal lymph nodes often show peripheral contrast enhancement paired with central hypodensity indicative of caseous necrosis. Additional CT features include mesenteric thickening and omental caking, focal thickening of the intestinal wall predominantly at the ileocecal segment, free intraperitoneal ascites, and tubo-ovarian masses in female patients.

Central Nervous System Imaging

Magnetic resonance imaging is superior to CT for evaluating CNS involvement and should include the entire neuraxis.^188–190 Table 11 summarizes the neuroimaging findings in patients with central nervous system tuberculosis. Basal meningeal enhancement is the most common abnormality, observed in 38–89% of cases, reflecting the intense exudative inflammation in the basal cisterns. Hydrocephalus occurs in 60–80% of patients and may require cerebrospinal fluid (CSF) diversion. Cerebral infarcts, seen in 15–41% of cases, typically involve the basal ganglia and internal capsule due to vasculitis. Tuberculomas appear in 5–27% of patients as ring-enhancing lesions with surrounding edema. Miliary brain tubercles, representing hematogenous dissemination, are visible in 5–15% of cases as multiple tiny enhancing nodules. Spinal arachnoiditis, seen in 10–20%, may cause nerve root clumping and CSF loculations. These findings underscore the importance of contrast-enhanced MRI for comprehensive evaluation of CNS tuberculosis, as early detection of these abnormalities guides timely intervention and improves outcomes.

Table 11.

Neuroimaging Findings in CNS Tuberculosis

Finding	Frequency (%)*	MRI Characteristics
Basal meningeal enhancement	38–89	Post-contrast T1 enhancement of basal cisterns
Hydrocephalus	60–80	Ventricular dilatation, periventricular edema
Cerebral infarcts	15–41	Diffusion restriction, T2/FLAIR hyperintensity in basal ganglia, internal capsule
Tuberculomas	5–27	Ring-enhancing lesions, hypointense on T2 (caseous), hyperintense on T2 (non-caseous)
Miliary brain tubercles	5–15	Multiple tiny enhancing nodules
Spinal arachnoiditis	10–20	Clumping of nerve roots, CSF loculations

Note: *Based on references.^{15,116,122,187,189,191–194}

Microbiological and Molecular Diagnosis

Sputum Examination

Though not all patients with miliary TB produce sputum, when available, it should be examined.^6,195 Sputum examination, though readily available, has a relatively low sensitivity, with acid-fast bacilli (AFB) smear positivity ranging from 26–36% and culture positivity from 49–76%. Bronchoalveolar lavage and bronchial washings provide improved diagnostic yield, with culture positivity rates of 54–67%. Post-bronchoscopy sputum examination offers the highest yield, with culture positivity approaching 100%.

Bronchoscopy

Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL), bronchial washings, brushings, and transbronchial lung biopsy (TBLB) is useful when sputum examination is negative.^196,197 The cumulative diagnostic yield in published studies is approximately 47–83%.^{9,47,198,199,200} TBLB reveals granulomas in 63–95% of cases.^47,197,201

Bone Marrow Examination

Bone marrow aspiration and biopsy are valuable in miliary TB, particularly when hematological abnormalities are present.^6,202 Granulomas are found in 41–82% of cases, and culture positivity ranges from 27–50%.^{9,13,45,47,105,203} The procedure is safer than liver or lung biopsy in patients with coagulation disorders or thrombocytopenia.⁶

Liver Biopsy

Liver biopsy has the highest diagnostic yield among invasive procedures, with granulomas found in 88–100% of cases, though AFB are demonstrated in only 0–44%.^{9,13,45,47,105,204} Elevated alkaline phosphatase, even without hepatomegaly or abnormal liver function tests, suggests hepatic involvement and increases biopsy yield.^205,206

Lymph Node Biopsy

Peripheral lymph node biopsy reveals granulomas in 75–100% of cases, with caseation in 92% and culture positivity in 43–83%.^{9,13,45,47,105,207} It is particularly useful when lymphadenopathy is present.

Other Extrapulmonary Specimens Examination

Cerebrospinal fluid analysis, essential for diagnosing tuberculous meningitis, has limited sensitivity, with smear positivity in only 1–10% and culture positivity in 25–50%. Urine, pleural fluid, and ascitic fluid cultures may provide diagnostic confirmation in 25–70% of cases but require high clinical suspicion. In HIV-positive patients, blood cultures can detect mycobacteremia in 20–40% of cases. These findings underscore the importance of obtaining multiple specimen types and utilizing both microbiological and molecular techniques to maximize diagnostic yield in paucibacillary miliary tuberculosis. (Table 12).

Table 12.

Diagnostic Yield of Various Specimens in Miliary Tuberculosis

Specimen	AFB Smear Positivity (%)*	Culture Positivity (%)*
Sputum	26–36	49–76
Gastric aspirate	25–50	61–75
Bronchoalveolar lavage	9–33	54–67
Bronchial washings	33	67
Post-bronchoscopy sputum	50	100
Cerebrospinal fluid	1–10	25–50
Urine	7–15	25–59
Pleural fluid	5–10	14–30
Ascitic fluid	3–5	30–70
Blood (HIV-positive)	N/A	20–40
Bone marrow aspirate	9–17	27–50

Note: *Based on references.^{9,13,45,47,48,55,105,198,208,209}

Modified Ziehl-Neelsen Staining

A modified Ziehl-Neelsen (MZN) staining technique incorporating cytospin preparation and Triton X-100 permeabilization was developed to enhance detection of intracellular mycobacteria in CSF.^210,211 Initial studies from China reported remarkable sensitivity (82.9% vs 3.3% for conventional ZN staining) and modest specificity (85.0%).²¹¹ However, a subsequent prospective multicenter study in Vietnam, South Africa, and Indonesia involving 618 patients failed to replicate these findings, showing comparable sensitivity for conventional and modified ZN staining (33.9% vs 34.5%) with 100% specificity for both.²¹² The reasons for this discrepancy remain unclear but may relate to differences in patient populations, CSF volumes, and laboratory techniques.

Molecular Diagnostics

Xpert MTB/RIF and Xpert Ultra

The Xpert MTB/RIF assay, an automated cartridge-based nucleic acid amplification test, simultaneously detects M. tuberculosis complex and rifampicin resistance.^213,214 Against a clinical gold standard, sensitivity in CSF ranges from 25–60%, with specificity approaching 100%.^212,215,216 Xpert Ultra, with a 10-fold lower limit of detection, increases sensitivity to approximately 70%.^217–219 The WHO recommends Xpert MTB/RIF as the initial diagnostic test for suspected TBM.²²⁰

Line Probe Assays (LPAs)

These assays detect M. tuberculosis and mutations conferring resistance to rifampicin and isoniazid within 24 hours, with sensitivity and specificity exceeding 95% for resistance detection.^221,222

Next-Generation Sequencing (NGS)/Whole-Genome Sequencing (WGS)

Recent advances in genomic sequencing technologies have further strengthened the precision and comprehensiveness of tuberculosis molecular diagnosis, with next-generation sequencing (NGS) and whole-genome sequencing (WGS) emerging as powerful adjunctive tools in clinical practice. Compared with conventional nucleic acid amplification tests that only target limited gene loci, NGS enables high-throughput, unbiased detection of Mycobacterium tuberculosis genetic variations, while WGS provides full genomic coverage of the pathogen. These cutting-edge techniques allow comprehensive identification of both known and novel mutations associated with drug resistance across first-line and second-line anti-tuberculosis drugs, facilitating early and accurate detection of multidrug-resistant and extensively drug-resistant tuberculosis, which is particularly critical for optimizing individualized treatment for severe miliary TB cases. Furthermore, WGS offers high-resolution genomic typing capability, enabling differentiation between disease relapse and reinfection, tracing transmission chains, and clarifying epidemiological characteristics of sporadic or clustered miliary TB outbreaks. Despite superior diagnostic performance, the clinical application of NGS and WGS is still limited by higher costs and rigorous technical and bioinformatics requirements, restricting their widespread use in resource-limited endemic regions.

Scoring System for CNS Tuberculosis in Miliary TB Patients

A significant advance in the diagnostic approach to miliary TB with suspected CNS involvement is the development of a clinical scoring system by Xiao et al²⁵ This system was derived from a retrospective analysis of 81 patients with confirmed miliary TB (50 without CNS involvement, 31 with CNS involvement). Using multivariate logistic regression, seven independent predictors of CNS involvement were identified: cough (negative predictor), nausea (positive), headache (positive), hemoglobin (positive at ≤131.5 g/L), serum albumin (positive at ≤38.85 g/L), ESR (negative at >38 mm/h), and CRP (negative at >5.35 mg/L). The scoring system assigns weighted scores based on regression coefficients (Table 13).

Table 13.

Scoring System for CNS Tuberculosis in Miliary TB Patients²⁵

Variable	Cutoff	Score Assigned
Cough	Present	−1.5
Nausea	Present	+2
Headache	Present	+2
Hemoglobin	≤131.5 g/L	+1.5
Serum albumin	≤38.85 g/L	+2.5
ESR	>38 mm/h	−1.5
CRP	>5.35 mg/L	−1.5

Abbreviations: CRP, C-reactive protein; ESR, Erythrocyte Sedimentation Rate.

The total score is calculated by summing the assigned values. Receiver operating characteristic (ROC) analysis demonstrated an area under the curve (AUC) of 0.86 (95% CI 0.77–0.95). At a cutoff score of 0.75, the system achieved a sensitivity of 81.5% and specificity of 81.4% for confirming CNS involvement. A score ≥2.75 provided 95.3% specificity, while a score ≤-0.75 gave 88.9% sensitivity for excluding CNS involvement.

This clinical scoring system possesses multiple practical strengths in routine clinical practice. All variables incorporated within the model consist of routinely collected clinical indicators and standard laboratory test results that are easily accessible in general hospitals. Based on the total calculated score, clinicians can spare patients with extremely low or high risk from unnecessary invasive examinations including lumbar puncture and neuroimaging scans. Meanwhile, the scoring tool helps identify individuals who require urgent cerebrospinal fluid testing and cranial imaging for timely diagnosis. Overall, its application effectively shortens diagnostic waiting periods and cuts down relevant medical expenditures for patients suspected of miliary tuberculosis combined with central nervous system involvement.

However, the authors caution that this system is a statistical model and cannot replace definitive diagnostic tests. It requires prospective validation in larger, multicenter cohorts before widespread clinical adoption. Nevertheless, it represents an important step toward personalized diagnostic algorithms in miliary TB.

Adenosine Deaminase

Adenosine deaminase (ADA) is an enzyme produced by activated T lymphocytes that serves as an indirect marker of cell-mediated immunity.^223,224 In tuberculous meningitis, a meta-analysis reported pooled sensitivity of 79% and specificity of 91% at a cutoff of 8 U/L, though significant heterogeneity across studies limits standardization.²²⁵ CSF ADA cannot reliably distinguish TBM from bacterial meningitis but may be useful as a rule-out test in high-prevalence settings.²²⁶ All summarized in Table 14.

Table 14.

Diagnostic Accuracy of CSF ADA in Tuberculous Meningitis

Cutoff (U/L)	Sensitivity (%)	Specificity (%)
5	93	80
8	79	91
10	81–92	86–97
15	58	86

Note: Based on references.^{117,227–230}

Serodiagnostic Tests

Commercial serodiagnostic tests have poor and variable accuracy and should not be used for diagnosis of pulmonary or extrapulmonary TB, including miliary TB.^231,232 The WHO strongly recommends against their use.²³³

The diagnostic algorithm for miliary tuberculosis is shown in the Figure 1 below.

Figure 1.

Diagnostic algorithm for miliary tuberculosis. This stepwise algorithm integrates clinical, radiological, and microbiological assessments to guide the diagnosis of miliary tuberculosis (TB). The diagnostic process begins when a patient presents with characteristic constitutional symptoms (fever ≥2 weeks, night sweats, weight loss, cough, fatigue), particularly in high-risk populations. Initial investigations include a chest radiograph, which may reveal a classic miliary pattern (1–3mm nodules) in 50–90% of cases, alongside routine laboratory tests and sputum AFB smear and culture. If the chest radiograph is negative but suspicion persists, HRCT is mandatory due to its superior sensitivity. For patients with confirmed or highly suspected miliary nodules on imaging, definitive microbiological confirmation is pursued through sputum examination, BAL, and, when indicated, biopsies (e.g, bone marrow, liver, lymph node) or CSF analysis. All specimens should undergo AFB smear, culture, and molecular testing using the Xpert MTB/RIF or Xpert Ultra assay. A confirmed positive laboratory result, or suspicious findings with high clinical probability, establishes the diagnosis. Conversely, the absence of miliary nodules on HRCT, along with negative laboratory results and low clinical probability, should prompt consideration of alternative diagnoses.

Treatment

Anti-Tuberculosis Chemotherapy

Miliary tuberculosis is uniformly fatal within 1 year if untreated.^6,234 Standard anti-tuberculosis treatment is the cornerstone of management, though no randomized controlled trials have specifically evaluated regimens in miliary TB.^235,236 The recommended treatment regimens for miliary tuberculosis provided has summarized in Table 15. Major guidelines uniformly recommend 6 months of anti-tuberculosis therapy for miliary TB without CNS involvement, consisting of a 2-month intensive phase (HRZE) followed by a 4-month continuation phase (HR). When CNS involvement is present, treatment is extended to 9–12 months (HRZE for 2 months, followed by HR for 7–10 months) due to poor penetration of some drugs across the blood-brain barrier and the higher risk of relapse. This distinction underscores the critical importance of accurately diagnosing CNS involvement in miliary TB patients, as it directly determines treatment duration and influences clinical outcomes.

Table 15.

Recommended Treatment Regimens for Miliary Tuberculosis

Guideline	Intensive Phase	Continuation Phase	Total Duration
WHO234/ ATS/CDC/IDSA235/ NICE (UK)236/ INDEX-TB (India)237	2 months HRZE	4 months HR	6 months
AAP238	2 months HRZE	7–10 months HR	9–12 months
With CNS involvement:
Guideline	Intensive Phase	Continuation Phase	Total Duration
WHO234/ ATS/CDC/IDSA235/ INDEX-TB237	2 months HRZE	7–10 months HR	9–12 months

Abbreviations: CNS, central nervous system; E, ethambutol; H, isoniazid; R, rifampicin; Z, pyrazinamide.

Several core factors should be taken into account when designing therapeutic regimens for miliary tuberculosis with central nervous system involvement.^31,239–242 First, differences in cerebrospinal fluid (CSF) penetration capacity among anti-tuberculosis agents are notable: isoniazid and pyrazinamide achieve CSF penetration rates of 80% to 100%, rifampicin only reaches a moderate penetration level of 10% to 20%, whereas ethambutol displays limited CSF penetration at merely 20% to 30%. Second, if isoniazid resistance is confirmed, the treatment course must maintain high-dose rifampicin at 15 mg/kg combined with levofloxacin and pyrazinamide throughout the whole therapy period. Third, patients diagnosed with multidrug-resistant tuberculosis necessitate second-line anti-tuberculosis medications that exhibit favorable central nervous system permeability, including levofloxacin, moxifloxacin, linezolid and ethionamide. Finally, therapeutic drug monitoring is recommended for cases with suspected poor therapeutic response or gastrointestinal malabsorption of anti-tuberculosis drugs.

Corticosteroids

To date, there have been no systematic prospective or retrospective analyses regarding the use of corticosteroids in the treatment of miliary tuberculosis and its extrapulmonary complications; all current treatment recommendations for tuberculosis are based on data from guidelines or review articles.

Tuberculous Meningitis

A randomized controlled trial in 545 patients demonstrated that dexamethasone (0.4 mg/kg/day tapered over 6–8 weeks) reduced mortality from 41% to 32% (RR 0.78; 95% CI 0.62–0.98).³⁰ Benefit was greatest in stage I disease, with no mortality benefit in stage III. A 2016 Cochrane review confirmed that corticosteroids reduce mortality in HIV-negative patients with TBM but not long-term neurological disability.³²

Tuberculous Pericarditis

Corticosteroids reduce mortality and progression to constriction.^243,244 The recommended regimen is prednisolone 60 mg/day tapered over 11 weeks.²⁴⁵

TB-IRIS

Corticosteroids are beneficial in both HIV-associated and anti-TNF-α-associated IRIS.^246,247 In a case series of anti-TNF-α-induced TB-IRIS, 50% of patients received corticosteroids, with doses ranging from 0.5–1.0 mg/kg/day prednisolone equivalent.¹⁷⁰

ARDS

No controlled trials exist, but corticosteroids are commonly used based on expert opinion.^28,248 In a case series of miliary TB with ARDS, corticosteroid therapy (prednisolone 0.5–1.0 mg/kg/day or equivalent) was associated with rapid clinical improvement and resolution of pulmonary infiltrates.^19,20,152

Table 16 summarizes the recommended corticosteroid regimens for managing complications associated with tuberculosis. For tuberculous meningitis, dexamethasone (0.4 mg/kg/day tapered over 6–8 weeks) is supported by randomized controlled trial evidence showing reduced mortality. Tuberculous pericarditis benefits from prednisolone (60 mg/day tapered over 11 weeks), also based on trial data. For TB-IRIS, prednisolone (0.5–1.5 mg/kg/day tapered over 4–12 weeks) is used, supported by case series. However, despite these well-established regimens for general TB complications, specific data on corticosteroid use in miliary tuberculosis (MTB) with extrapulmonary involvement remain extremely limited. In particular, for the most devastating complication—ARDS in the setting of MTB—evidence is scarce. A small retrospective study of 13 patients with MTB complicated by ARDS provides the only available data, demonstrating that steroid pulse therapy (methylprednisolone 500–1000 mg/day for 3 days) significantly improved short-term survival (HR 0.136, 95% CI 0.023–0.815), with 75% of treated patients surviving at 3 months compared to only 20% in the non-treatment group.²⁴⁸ These findings suggest that steroid pulse therapy may be a beneficial adjunctive treatment for MTB-ARDS, though larger prospective studies are urgently needed to confirm these results.

Table 16.

Corticosteroid Regimens in Miliary Tuberculosis Complications

Indication	Drug	Dose	Duration	Evidence
TBM (adults)	Dexamethasone	0.4 mg/kg/day IV, taper over 6–8 weeks	6–8 weeks	RCT30
TBM (children)	Prednisolone	2-4 mg/kg/day, taper over 6–8 weeks	6–8 weeks	Expert opinion
	Dexamethasone	0.6 mg/kg	6–8 weeks	Guideline (Review)
TB pericarditis	Prednisolone	60 mg/day, taper over 11 weeks	11 weeks	RCTs243,244
TB-IRIS	Prednisolone	0.5–1.5 mg/kg/day, taper over 4–12 weeks	4–12 weeks	Case series245,246
ARDS	Methylprednisolone	1 mg/kg/day or pulse therapy	Variable	Expert opinion
		500–1000 mg/d	3 days	Small retrospective study248

Abbreviations: ARDS, acute respiratory distress syndrome; TB, tuberculosis; TB-IRIS, tuberculosis-immune reconstitution inflammatory syndrome; TBM, tuberculous Meningitis.

Management of Specific Complications

Distinct management strategies are indicated for two subtypes of tuberculous hydrocephalus.^{249,250–252} Communicating hydrocephalus can be managed with acetazolamide, serial lumbar punctures, or external ventricular drainage as primary interventions. For obstructive hydrocephalus, ventriculoperitoneal shunt placement and endoscopic third ventriculostomy are the main therapeutic options recommended in existing studies.

Clinical management of hyponatremia complicating miliary tuberculosis relies on distinguishing two distinct underlying etiologies, namely syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and cerebral salt wasting, as documented in prior literature.^253,254 SIADH is characterized by euvolemia and concentrated urine, which is managed via fluid restriction; hypertonic saline infusion is reserved for severe cases. In contrast, cerebral salt wasting presents with hypovolemia and requires aggressive fluid resuscitation, sodium supplementation, and adjunctive fludrocortisone therapy.²⁵⁵

Multiple interventions are available to relieve elevated intracranial pressure. Intravenous mannitol at a dose of 0.25–1.0 g/kg and 3% hypertonic saline serve as first-line medical therapies.²²⁷ When concurrent hydrocephalus exists, cerebrospinal fluid diversion procedures should be performed. For patients with severe intracranial hypertension, intracranial pressure monitoring may be considered to guide further treatment.²⁵⁶

Multiple standardized therapeutic strategies are applied for the management of ARDS secondary to miliary tuberculosis. Lung-protective ventilation with a tidal volume of 6 mL/kg ideal body weight is adopted as a fundamental ventilation strategy, accompanied by conservative fluid management to alleviate pulmonary edema. Prone positioning is recommended for patients with severe ARDS, while extracorporeal membrane oxygenation (ECMO) can be considered for those with refractory and critical conditions.²²⁸ Additionally, corticosteroids are administered as effective adjunctive therapy to improve patient outcomes.^19,20,257

Treatment of Drug-Resistant Tuberculous Meningitis

Multidrug-resistant TBM carries a catastrophic prognosis, with mortality approaching 100% in some series.^229,230 According to the 2022 WHO drug-resistant tuberculosis treatment guidelines, the 6-month BPaLM regimen is not recommended for patients with central nervous system tuberculosis, including TBM, due to limited efficacy and safety data.²⁵⁸ Core principles for the management of drug-resistant miliary tuberculosis with CNS involvement cover multiple key aspects.^113,241,258 Clinicians should prioritize rapid detection of drug resistance using molecular diagnostic tools including Xpert MTB/RIF and line probe assays to guide early individualized treatment. A well-tailored therapeutic regimen containing no fewer than five effective anti-tuberculosis drugs is required for optimal treatment efficacy. Priority should be given to medications with favorable central nervous system penetration, including levofloxacin or moxifloxacin with a CSF penetration rate of 70% to 80%, linezolid with a penetration rate ranging from 30% to 70%, ethionamide or prothionamide and cycloserine or terizidone both achieving 80% to 90% penetration. High-dose isoniazid can be adopted for cases with inhA mutation, and pyrazinamide should be administered throughout the entire treatment course. In terms of treatment course duration, a minimum treatment period of 18 to 24 months is recommended for such drug-resistant cases.

Prognosis and Predictors of Outcome

Mortality

Despite effective antimicrobial therapy, mortality associated with miliary tuberculosis remains considerable and varies widely by clinical presentation.^{6,9,47,48,55,105} Mortality rates range from 14% to 28% among patients with uncomplicated miliary TB, 30% to 50% for those with tuberculous meningitis, 40% to 80% for cases complicated by acute respiratory distress syndrome, and 35% to 60% in patients co-infected with HIV. Mortality reaches 100% in untreated cases and exceeds 80% in those with multidrug-resistant tuberculous meningitis.

Predictors of Poor Outcome

Table 17 summarizes the key predictors of poor outcome in patients with miliary tuberculosis, which span multiple domains. Demographic factors include advanced age and male sex. Clinical predictors encompass altered mental status, meningismus, dyspnea, high fever, coma, and seizures. Laboratory abnormalities associated with worse prognosis include hyponatremia, hypoalbuminemia, elevated transaminases and alkaline phosphatase, high neutrophil–lymphocyte ratio leukocyte abnormalities (leukopenia or leukocytosis), lymphopenia, thrombocytopenia, and pancytopenia. Radiological findings such as atypical chest radiographic patterns and extensive bilateral involvement also predict poorer outcomes. Treatment-related factors include delayed or absent therapy, while complications like ARDS, hydrocephalus, stroke, and IRIS significantly increase mortality risk. Finally, underlying comorbidities including chronic diseases, cirrhosis, and HIV infection further worsen prognosis. These predictors highlight the multifactorial nature of risk assessment in miliary tuberculosis and underscore the need for comprehensive evaluation and timely intervention.

Table 17.

Predictors of Poor Outcome in Miliary Tuberculosis

Category	Factors
Demographic	Increasing age, male sex, female sex (variable)
Clinical	Altered mental status, meningismus, dyspnea, temperature >39.3°C, coma, seizures
Laboratory	Hyponatremia, hypoalbuminemia, elevated transaminases, elevated alkaline phosphatase, high neutrophil–lymphocyte ratio, leukopenia, leukocytosis, lymphopenia, thrombocytopenia, pancytopenia
Radiological	Atypical chest radiographic pattern, extensive bilateral involvement
Treatment-related	Treatment delay, failure to treat
Complications	ARDS, hydrocephalus, stroke, IRIS
Comorbidities	Any underlying comorbid disease, cirrhosis, HIV infection

Note: Based on references.^{6,9,47,48,54,55,95,105,259–262}

In the scoring system study, patients with CNS involvement (higher scores) had significantly higher mortality risk, emphasizing the importance of early diagnosis and treatment of this complication.²⁵

Multiple scoring systems are available to evaluate the prognostic risk of patients with severe miliary tuberculosis and tuberculous meningitis. The APACHE II score greater than 18 serves as a predictive indicator of mortality in patients diagnosed with miliary tuberculosis complicated with ARDS.²⁶ The MRC staging system is widely applied to stratify the mortality risk of tuberculous meningitis, with reported mortality rates of 15% for stage I, 30% for stage II, and 50% for stage III disease.^30,31,118 Additionally, a nutritional risk score based on multiple laboratory and anthropometric parameters, including a body mass index below 18.5, serum albumin level lower than 30 g/L, serum cholesterol level less than 2.33 mmol/L, and lymphocyte count below 7×10⁵/L, can effectively predict adverse clinical outcomes; a total score of 3 or higher is significantly correlated with increased mortality.²⁶³

Immune Reconstitution Inflammatory Syndrome

HIV-Associated TB-IRIS

IRIS occurs in approximately 18–32% of HIV-infected patients starting antiretroviral therapy (ART) within days to weeks of anti-tuberculosis treatment.^264,265 Two distinct phenotypes of IRIS have been identified in patients with tuberculosis following ART initiation.²⁶⁶ Paradoxical IRIS is characterized by the clinical deterioration of pre-existing tuberculosis lesions after the commencement of ART. In comparison, unmasking IRIS manifests as the newly emergent presentation of previously subclinical tuberculosis following ART initiation.

Clinical manifestations range from isolated fever to new or worsening lymphadenopathy, pulmonary infiltrates, serositis, cutaneous lesions, and CNS mass lesions.^267,268 CSF analysis typically shows neutrophilic pleocytosis with elevated protein.²⁶⁹ Standard management strategies for tuberculosis-associated immune reconstitution inflammatory syndrome cover multiple core interventions.²⁷⁰ Continuous administration of anti-tuberculosis therapy and ongoing antiretroviral therapy are generally maintained, unless patients develop life-threatening adverse events that necessitate ART discontinuation. Corticosteroid treatment with prednisolone at a daily dose of 1.0–1.5 mg/kg, followed by a gradual dose tapering over 4 to 12 weeks, serves as a major therapeutic measure. Nonsteroidal anti-inflammatory drugs can be applied to alleviate symptoms in mild cases, and therapeutic abscess drainage is performed when clinically indicated.

Anti-TNF-α-Induced TB-IRIS

Anti-TNF-α-induced TB-IRIS was first described in 2005 and occurs in approximately 7% of patients developing TB during anti-TNF therapy.^271,272 The mechanism involves immune reconstitution following drug withdrawal, analogous to HIV-associated IRIS.^273,274

Table 18 summarizes 45 reported cases (15 adults, 30 children) of severe paradoxical reaction (PR) or IRIS during tuberculosis treatment managed with TNF-α antagonists. Neuromeningeal tuberculosis was predominant (84.4%), with PR/IRIS manifestations including new or enlarging tuberculomas (73.3%), cerebral vasculitis (17.8%), and hydrocephalus (6.7%). First-line treatment was high-dose corticosteroids in 95.6% of cases. TNF-α antagonists were used as salvage therapy: infliximab (66.7% of adults), adalimumab (20.0%), and thalidomide (26.7% of adults, 100% of children). Clinical improvement was observed in 88.9% of patients, though 33.3% had residual neurological sequelae and 6.7% died. Thalidomide was associated with peripheral neuropathy (10% of children), and its use has declined in favor of infliximab in recent years. Among these, 6 patients (13.3%) had miliary tuberculosis (4 adults and 2 children), all with associated neuromeningeal involvement. The miliary TB patients developed PR/IRIS manifestations including new or enlarging tuberculomas (n=5), cerebral vasculitis (n=3), and hydrocephalus (n=2). All miliary TB patients received first-line high-dose corticosteroids followed by TNF-α antagonists as salvage therapy: infliximab (n=4), thalidomide (n=1), and adalimumab (n=1). Clinical improvement was observed in all 6 miliary TB patients, though 3 (50%) had residual neurological sequelae (cognitive impairment, cranial nerve palsy, and limb paresis). No deaths occurred in the miliary TB subgroup. Notably, one miliary TB patient with HIV coinfection developed severe IRIS requiring sequential infliximab and adalimumab, ultimately achieving full recovery. These findings suggest that TNF-α antagonists, particularly infliximab, are effective salvage options for corticosteroid-refractory PR/IRIS in tuberculosis, though neurological sequelae remain common and close monitoring is required.

Table 18.

Summary of Reported Cases of Anti-TNF-α-Induced TB-IRIS

Characteristic	Adults (n=15)	Children (n=30)	Total (N=45)
Demographics
Male sex, n/N (%)	4/14 (28.6)	14/29 (48.3)	18/43 (41.9)
Age, median (range)	40 years (19–63)	6 years (8 months–14 years)	–
HIV infection, n/N (%)	3/15 (20.0)	7/30 (23.3)	10/45 (22.2)
Tuberculosis characteristics
Neuromeningeal involvement, n/N (%)	12/15 (80.0)	26/30 (86.7)	38/45 (84.4)
Pulmonary involvement, n/N (%)	5/15 (33.3)	8/30 (26.7)	13/45 (28.9)
Miliary TB, n/N (%)	4/15 (26.7)	2/30 (6.7)	6/45 (13.3)
Drug-susceptible TB, n/N (%)	15/15 (100)	28/28 (100)	43/43 (100)
PR/IRIS characteristics
Time from TB treatment to PR/IRIS onset, median (IQR)	6 weeks (4–9)	4 weeks (2–8)	5 weeks (3–8)
Time from ART start to IRIS onset (HIV+), median (range)	2 weeks (2–3)	3.5 days (2–7)	–
PR/IRIS manifestations, n (%)
New/enlarging tuberculomas	8/15 (53.3)	25/30 (83.3)	33/45 (73.3)
Cerebral vasculitis/infarcts	5/15 (33.3)	3/30 (10.0)	8/45 (17.8)
Hydrocephalus	2/15 (13.3)	1/30 (3.3)	3/45 (6.7)
Leptomeningeal enhancement	2/15 (13.3)	7/30 (23.3)	9/45 (20.0)
Lymphadenitis	4/15 (26.7)	0/30 (0)	4/45 (8.9)
Treatment
First-line corticosteroids, n/N (%)	14/15 (93.3)	29/30 (96.7)	43/45 (95.6)
TNF-α antagonist used, n (%)
Infliximab	10/15 (66.7)	0/30 (0)	10/45 (22.2)
Adalimumab	3/15 (20.0)*	0/30 (0)	3/45 (6.7)
Thalidomide	4/15 (26.7)	30/30 (100)	34/45 (75.6)
Outcomes
Clinical improvement, n/N (%)	15/15 (100)	25/30 (83.3)	40/45 (88.9)
No response, n/N (%)	0/15 (0)	2/30 (6.7)	2/45 (4.4)
Full recovery, n/N (%)	5/15 (33.3)	17/30 (56.7)	22/45 (48.9)
Alive with sequelae, n/N (%)	8/15 (53.3)	7/30 (23.3)	15/45 (33.3)
Death, n/N (%)	1/15 (6.7)	2/30 (6.7)	3/45 (6.7)
TNF-α antagonist-related severe AEs, n/N (%)	2/15 (13.3)†	3/30 (10.0)‡	5/45 (11.1)

Notes: *One patient received infliximab followed by adalimumab ^†Peripheral neuropathy (thalidomide, n=1); hypersensitivity (infliximab, n=1) ^‡Peripheral neuropathy (thalidomide, n=3) Data compiled from references.^{170,271–279}

Abbreviations: AEs, adverse events; ART, antiretroviral therapy; PR/IRIS, Paradoxical reaction/ immune reconstitution inflammatory syndrome; TNF-α, tumor necrosis factor-α.

Prevention

BCG Vaccination

BCG vaccination is effective in reducing the incidence of miliary TB and tuberculous meningitis, particularly in children.^161,280,281 A meta-analysis estimated that BCG vaccination prevents approximately 30,000 cases of childhood TBM annually, with a protective efficacy of 73% (95% CI 67–79%) against TBM and 77% (95% CI 58–87%) against miliary TB.^161,282 The cost per DALY gained is approximately US$200 in high-burden settings, making BCG a highly cost-effective intervention.¹⁶¹

BCG vaccine provides substantial and consistent protection against miliary tuberculosis, with efficacy estimates ranging from 64% to 90% across multiple meta-analyses.^{161,280–282} Protection is highest when vaccination occurs in infancy (approximately 90% efficacy) and in individuals without prior sensitization to environmental mycobacteria.^281,282 Global BCG vaccination programs prevent an estimated 11,500 cases of miliary tuberculosis annually among children under 5 years, at a cost of approximately US$206 per disability-adjusted life year gained, making it a highly cost-effective intervention.²⁸⁰ The vaccine’s efficacy against severe childhood tuberculosis has been consistently demonstrated across diverse geographic settings, supporting its continued use in high-incidence countries.^{161,280–282}

Latent TB Infection Treatment

Targeted tuberculin testing and treatment of latent TB infection (LTBI) is practiced in low-prevalence countries.^232,283 However, anti-TB drug-induced hepatotoxicity is a potential risk.²⁸⁴ In candidates for anti-TNF therapy, screening and treatment of LTBI reduces TB risk by 74–89%.^285,286

Infection Control

Miliary TB patients with pulmonary involvement are potentially infectious.²⁸⁷ Standardized infection control strategies cover both hospital-based clinical management and community-based public health interventions to block tuberculosis transmission comprehensively.²⁸⁸ In healthcare settings, core preventive measures include the placement of infectious patients in negative pressure isolation rooms, and mandatory use of N95 respirators by healthcare workers during clinical contact with infected individuals. All targeted infection prevention precautions should be continuously implemented until patients obtain negative sputum smear conversion results to terminate endogenous transmission risks. Beyond clinical environments, community-focused infection control is equally essential to reduce household and societal transmission. Active case screening and contact tracing for close household and social contacts of confirmed miliary TB patients enable early identification of undiagnosed latent or active infections, facilitating timely intervention and interrupting transmission chains. In addition, health education regarding respiratory hygiene, cough etiquette, and regular indoor ventilation should be widely promoted among patients and community residents. Infected individuals are advised to wear surgical masks during outdoor activities and avoid crowded public spaces during the infectious period. Targeted public health monitoring and standardized home isolation guidance further minimize community-wide dissemination of Mycobacterium tuberculosis, forming a complete infection prevention system complementary to hospital management.

Conclusions and Future Directions

Miliary tuberculosis constitutes a rare yet highly fatal tuberculosis subtype, with poor clinical outcomes primarily attributed to atypical clinical manifestations, delayed diagnosis, and life-threatening complications, particularly CNS tuberculosis and ARDS. This review highlights clinically actionable strategies to improve early recognition, diagnosis, and management of the disease. Targeted identification of high-risk populations, including younger patients, female individuals, and people living with advanced HIV infection, enhances clinical vigilance and facilitates timely screening for severe complications. Integrative interpretation of characteristic laboratory abnormalities, typical chest and abdominal imaging features, and standardized prognostic scoring systems enables non-invasive, early recognition of CNS involvement and other critical complications, avoiding excessive invasive examinations while shortening diagnostic delays. Current standardized management regimens cover optimized anti-tuberculosis treatment tailored for drug resistance, CNS-penetrating antimicrobial agents, and targeted interventions for ARDS, intracranial hypertension, hyponatremia, and IRIS. Adjunctive therapies including corticosteroids and TNF-α antagonists serve as effective salvage strategies for refractory inflammatory complications. Despite these advances, miliary tuberculosis management remains constrained by limited pathogen load, insufficient disease-specific high-quality clinical evidence, and the lack of optimized short-course regimens, resulting in prolonged and complex treatment courses. Future prospective multicenter studies are essential to validate novel point-of-care diagnostic tools and refine individualized therapeutic protocols, while host-directed therapies represent a promising direction to further improve the survival and prognosis of patients with severe miliary tuberculosis.

Funding Statement

Gansu Provincial Natural Science Foundation (23JRRA542). Gansu Provincial Health Industry Research Plan Project (GSWSKY2021-053).

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no competing interests.