Implications/Analysis of Family History

No mention has been made of family history, presumably because there was nothing remarkable. George is often in close proximity with people who are “at risk” for certain community-acquired infections (e.g., tuberculosis) simply because he is living in hostels.

Implications/Analysis of Clinical History

Malignancy, autoimmunity, or a chronic infection could help explain this symptomatology.

The weight loss/night sweats and cough would be consistent with a malignancy such as a lymphoma. It is unlikely that he has an HIV infection because there is no evidence of intravenous drug use, homosexual behavior, or previous transfusions. You should, however, confirm that these are not considerations.

George is afebrile right now so it is unlikely that he has a fulminant (acute) infection, but a chronic infection is a possibility. The fact that George is a nonsmoker should “steer you away” from a lung malignancy, although the primary pathology certainly seems to be in the lungs. A vasculitic type process in the lungs, such as occurs in autoimmune disorders, might present in this fashion. However, there are no obvious precipitants (e.g., drug-antibody complexes) for such a reaction. The emphasis on “no travel” excludes infections that are unique to “hot spots” or specific locales, such as aspergillosis resulting from contact with moldy hay in farming areas or blastomycosis resulting from inhalation of the Ajellomyces dermatitidis (formerly Blastomyces dermatitidis) conidia (spores) present in soil in the Mississippi Valley area of the United States.

Implications/Analysis of Laboratory Investigation

Several of the tentative assumptions just described can be ruled out on the basis of the laboratory investigations. The fact that the blood sugar value is normal rules out diabetes, whereas a normal blood cell count and differential rules out a lymphoma and acute viral or bacterial infection. An abnormal chest radiograph in the absence of overt fever, along with hypoxia (poor oxygenation), is suggestive of a chronic infection with slower-growing organisms.

Additional Laboratory Tests

Indigent elderly alcoholics represent a population at risk for numerous chronic infectious diseases, one of the more important of which is tuberculosis (TB). A Mantoux test should be given to check for an immune response to M. tuberculosis, the causative agent of TB. Chronic viremias (e.g., hepatitis B/C and HIV) could present this way and can be ruled out using ELISAs to detect antibodies specific for the various antigens. In this case, George had a positive reaction to the Mantoux test.

A Mantoux (tuberculin) test, consisting of purified protein derivative (PPD) isolated from cultures of M. tuberculosis, is injected intradermally to assess prior exposure to M. tuberculosis. A positive test manifests as a local area of cytokine (IFNγ)-induced erythema and induration reaching a maximum at 24 to 48 hours. Unlike edema there is no pitting when pressure is applied to this region. This reaction is referred to as a delayed-type hypersensitivity reaction (DTH). As a word of caution, a negative Mantoux test could indicate that the individual is immunosuppressed and has not generated an immune response to the infection. Therefore, a positive control using Candida antigen should be administered in the “other” arm. Virtually everyone has been exposed to Candida, which is the rationale for using this antigen as a positive control. To confirm infection with M. tuberculosis, an acid-fast smear of George’s sputum and a polymerase chain reaction (PCR) assay to detect the presence of the M. tuberculosis was performed. Both tests were positive.

Host Response

Phagocytes play a central role in host defense to M. tuberculosis. Recognition may be indirect (opsonin mediated) or direct (e.g., TLR-2 and TLR-4; see Case 7). Phagocytosis of M. tuberculosis by alveolar macrophages results in the formation of a phagosome, a vesicle that is normally the site of microbial destruction (see Case 6). Included in the host defense armamentarium are lysosomal enzymes, reactive oxygen intermediates, and nitric oxide. M. tuberculosis has evolved immunoevasive strategies, however (see later), that allow it to thrive in the phagosome.

As well as the products just listed, phagocytes express a “natural resistance associated macrophage protein 1” (NRAMP1) that may play a role in phagocyte host defense. This protein is an integral membrane protein that becomes part of the phagosome during phagocytosis and as such functions as a divalent-metal efflux pump at the phagosomal membrane. In so doing, NRAMP1 limits the availability of some divalent cations required for survival of bacteria within the phagosome. Studies in West Africa to examine susceptibility to tuberculosis have shown that reduced expression of NRAMP1 increased susceptibility.

Infection by M. tuberculosis

M. tuberculosis bacteria that thrive within the phagosome will ultimately cause lysis of the macrophage, resulting in the production of cytokines and a number of chemical mediators (chemokines) whose actions result in the attraction of monocytes and other leukocytes to the region. Recruited monocytes differentiate to macrophages that phagocytose M. tuberculosis, and the process is repeated. The bacteria continue to thrive until activated CD4+ T cells (secreting type 1 cytokines and chemokines) arrive at the site of inflammation. Interferon gamma (IFNγ), a type 1 cytokine, enhances the activity of NADPH oxidase and the inducible nitric oxide synthase (iNOS). Tumor necrosis factor (TNF), another type 1 cytokine, functions as a second signal for activation of iNOS and NADPH oxidase during some bacterial infections. The net effect of T cell–derived cytokines is the reduction of bacterial growth and formation of granulomas that may contain the infection to this site for years, but necrosis of tissue, as a result of the inflammatory reaction, may lead to dissemination even years later.

Often the disease will be dormant until the host becomes immunosuppressed (decrease in CD4+ T cell–derived type 1 cytokines), at which time the disease is reactivated. When the infection is not successfully contained, large numbers of organisms may escape into the bloodstream resulting in miliary tuberculosis, the most serious manifestation of this infection.

Immunoevasive Strategies

M. tuberculosis has evolved several evasive strategies to avoid the host immune attack. One such strategy includes an ability to inhibit fusion of lysosomes with the phagosome, thereby excluding the lysosomal contents from the site of microbial destruction. Furthermore, Mycobacterium species secrete proteins that “mop up” (scavenge) reactive oxygen intermediates generated after activation of NADPH oxidase and the accompanying respiratory burst. Consequently, the macrophages are deprived of much of the armamentarium required to destroy these bacteria, which proliferate and cause the destruction of the alveolar macrophages.