Are patients with Acquired Immune Deficiency Syndrome (AIDS) or a low CD4 (Cluster of Differentiation 4) count, specifically less than 200 cells per cubic millimeter, susceptible to infection by Mycobacterium tuberculosis and other mycobacteria due to the impaired activation of macrophages by CD4 cells, which are necessary for forming granulomas to contain intracellular pathogens?

From the Guidelines

Yes, patients with AIDS or a CD4 count less than 200 are susceptible to tuberculosis and other mycobacterial infections primarily because CD4 T cells are essential for activating macrophages to form granulomas that contain these intracellular pathogens. CD4 T cells, particularly Th1 cells, produce interferon-gamma which is crucial for macrophage activation 1. When activated, macrophages can effectively kill or contain mycobacteria through various mechanisms including production of reactive oxygen species, nitric oxide, and antimicrobial peptides. Additionally, activated macrophages form the core of granulomas, which are organized structures that wall off the infection and prevent dissemination. In HIV infection, as CD4 counts decline below 200 cells/mm³, this cell-mediated immune response becomes severely compromised, leading to ineffective granuloma formation and maintenance. This allows mycobacteria to replicate unchecked and disseminate throughout the body. The impaired immunity also leads to atypical presentations of tuberculosis, with increased extrapulmonary disease and disseminated infections.

Some key points to consider in the management of these patients include:

• The importance of testing for M. tuberculosis infection by either a tuberculin skin test (TST) or by an interferon-γ release assay (IGRA) upon initiation of care for HIV-infected patients without a history of tuberculosis or a prior positive tuberculosis screening test 1.
• The recommendation to treat for latent M. tuberculosis infection after active tuberculosis has been excluded in patients with positive test results 1.
• The consideration of repeat testing in patients with advanced HIV disease who initially had negative TST or IGRA results but subsequently experienced an increase in the CD4 cell count to >200 cells/µL on ART 1.
• The use of prophylaxis against mycobacterial infections in advanced HIV disease, typically with medications like isoniazid for latent tuberculosis or azithromycin for Mycobacterium avium complex.

The most recent and highest quality study, which is the 2016 official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America clinical practice guidelines, supports the use of antiretroviral therapy (ART) during antituberculosis treatment to reduce mortality rates significantly for those with advanced HIV disease and decrease the risk of developing AIDS-related conditions 1. This guideline recommends that patients with tuberculosis and HIV infection receive ART during antituberculosis treatment, with the ideal start time being within 2 weeks for those patients with a CD4 count <50 cells/μL and by 8–12 weeks for those with a CD4 count ≥50 cells/μL.

From the Research

CD4 Cells and Macrophage Activation

• CD4 cells play a crucial role in the immune system, and their count is a key indicator of the health of HIV-infected individuals 2.
• A lower CD4 cell count, particularly less than 200 cells/µl, is associated with a higher risk of opportunistic infections, including Pneumocystis jirovecii pneumonia (PCP) 3, 4, 5, 6.
• However, the provided studies do not directly address the relationship between CD4 cells, macrophage activation, and granuloma formation in containing intracellular pathogens like Mycobacteria.

Immune System and Opportunistic Infections

• The immune system of individuals with low CD4 counts is compromised, making them more susceptible to opportunistic infections like PCP, toxoplasmosis, and salmonellosis 5.
• Trimethoprim-sulfamethoxazole (TMP-SMX) is commonly used as prophylaxis for PCP in HIV-infected individuals, and its use has been shown to reduce the risk of other infectious diseases as well 5.
• The provided studies focus on the diagnosis, treatment, and prophylaxis of PCP and other opportunistic infections in HIV-infected individuals, but do not specifically discuss the role of CD4 cells in activating macrophages to form granulomas.

Limitations of the Provided Studies

• The studies provided do not directly address the question of how CD4 cells activate macrophages to form granulomas to contain intracellular pathogens like Mycobacteria.
• The studies primarily focus on the epidemiology, diagnosis, treatment, and prophylaxis of opportunistic infections in HIV-infected individuals, particularly those with low CD4 counts.