What are the primary risk factors for developing tuberculosis (TB), especially in patients with compromised immune systems, such as those with Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) or diabetes?

Risk Factors for Tuberculosis

HIV infection is the single most powerful risk factor for developing active TB, with rates of 35-162 cases per 1000 person-years—representing up to a 170-fold increased risk compared to the general population. 1

Highest-Risk Immunocompromised Conditions

HIV/AIDS (The Dominant Risk Factor)

• HIV-infected individuals with positive tuberculin tests have an annual TB risk of 45 cases per 1000 person-years, compared to 1.1 per 1000 in the general population 1
• HIV-coinfected injection drug users face even greater risk at 76 cases per 1000 person-years 1
• Risk remains elevated indefinitely in HIV patients due to progressive immunosuppression, unlike immunocompetent persons where risk declines after 2 years 1
• Mortality is significantly higher in HIV-positive TB patients, particularly those with very low CD4+ counts who present with disseminated disease 1, 2

Other Severe Immunocompromising Conditions

• Silicosis carries approximately 30-fold increased risk (68 cases per 1000 person-years), requiring extended treatment duration of 8-12 months due to impaired drug penetration and macrophage dysfunction 1
• Chronic renal failure with hemodialysis: 10-25 times greater risk than general population 1
• Solid organ transplant recipients: 15-fold increased risk 1
• Stem cell transplant recipients: 8-12-fold increased risk 1

Diabetes Mellitus

• Diabetic patients have 2-4-fold increased TB risk, with even higher risk in insulin-dependent or poorly controlled diabetes 1
• The American Thoracic Society identifies diabetes as a key risk factor due to its high prevalence in the U.S. population 1
• Standard TB regimens remain adequate, though rifampin reduces serum levels of sulfonylurea oral hypoglycemics requiring dose adjustment 1, 2

Immunosuppressive Medications

TNF-α Antagonists

• All three licensed TNF-α antagonists (infliximab, etanercept, adalimumab) carry 5-7-fold increased TB risk 1
• Screening for latent TB is mandatory before initiating these agents 1

Corticosteroids

• Prednisone ≥15 mg/day for 2-4 weeks represents the threshold dose that suppresses tuberculin reactivity and predisposes to TB reactivation 1
• Higher doses for prolonged periods carry greater reactivation risk, especially in high-risk populations 1

Other Immunosuppressive Therapy

• Hematologic malignancies (leukemia, lymphoma, Hodgkin's disease) increase risk 1, 3
• Head/neck carcinomas and lung cancer are associated with active TB 1

Recent TB Infection and Prior Disease

• Infection within 1 year: 12.9 cases per 1000 person-years—representing the highest risk period after initial infection 1
• Infection 1-7 years past: 1.6 cases per 1000 person-years 1
• Radiographic fibrotic lesions consistent with prior healed TB: 2.0-13.6 cases per 1000 person-years 1
• Among immunocompetent persons, approximately 50% of the 5-10% lifetime risk occurs within the first 2 years after infection 1

Malnutrition and Weight Loss

• Being >15% underweight carries 2.6 cases per 1000 person-years—more than double the risk of normal weight individuals 1
• Underweight by 10-14%: 2.0 cases per 1000 person-years 1
• Overweight by >5%: 0.7 cases per 1000 person-years (protective effect) 1
• Gastrectomy with malabsorption and jejunoileal bypass increase risk through weight loss mechanisms 1

Injection Drug Use

• HIV-seronegative injection drug users: 10 cases per 1000 person-years 1
• This elevated risk reflects increased transmission, more recent infection, and the immunologic effects of drug use itself 1

Additional Medical Conditions

• Chronic peptic ulcer disease with malnutrition 1, 3
• Chronic malabsorption syndromes 1, 3
• Carcinomas of oropharynx and upper GI tract preventing adequate nutrition 1, 3
• End-stage renal disease 1, 3

Epidemiologic and Social Risk Factors

• Close contacts of newly diagnosed infectious TB cases (≥5 mm tuberculin test threshold) 1, 3
• Recent immigrants from high-prevalence countries 1, 3
• Residents of congregate settings: homeless shelters, correctional facilities, nursing homes 1
• Healthcare workers with TB exposure 1

Age-Related Considerations

• Infants <2 years face particularly high risk for life-threatening tuberculous meningitis or miliary TB 1
• All children <4 years with >10 mm tuberculin reaction are candidates for preventive therapy 3
• Older age >60 years increases susceptibility 1

Substance Use

• Smoking: 45 pack-years or heavy smoking increases risk 1, 4
• Alcohol use increases risk, though difficult to isolate from other confounding factors 1

Critical Clinical Pitfall

The presence of multiple risk factors compounds TB risk exponentially rather than additively—for example, an HIV-positive injection drug user with diabetes faces dramatically higher risk than any single factor alone would predict. 1 Screen aggressively and maintain high clinical suspicion in patients with any combination of these conditions.