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| THIS WEEK'S TEACHING TOPICS |  | | | | | | | | |
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TEACHING TOPIC
1. Immunology in Chronic Obstructive Pulmonary Disease
REVIEW ARTICLE, Mechanisms of Disease: Immunologic Aspects of Chronic Obstructive Pulmonary Disease, M.G. Cosio, M. Saetta, and A. Agusti, Extract | Full Text | PDF | PPT Slide Set
Pulmonary damage caused by cigarette smoke and other environmental toxins can incite inflammatory and immunologic reactions that culminate in chronic obstructive pulmonary disease (COPD). Inflammation mediated by T cells in the lung, which may persist for years after cessation of smoking, has been identified as a key component of COPD. This suggests that COPD could be an autoimmune disease triggered by cigarette smoking.
Clinical Pearl
 Why Some Smokers Evade COPD
Immune regulation, genetic susceptibility, and the environment are factors that provide protection against or induce a predisposition to autoimmune diseases, and these factors may be important in COPD. With time, the lungs of all smokers are damaged and release material with the potential for eliciting an immune response. Not all smokers have a reaction to these antigens, however, and among those who do have a reaction, its intensity varies. These differences probably account for the wide range of disease severity in response to similar amounts of exposure to cigarette smoke.
| Morning Report Questions | | Q: |  |
What is the most likely cause of disease progression in COPD? | | A: | |
Current thinking suggests that progression of the disease is the result of T-cell–mediated inflammation. T cells could be activated by antigens released during smoking-induced lung injury. Exposure to infectious or environmental insults, tissue trauma, oxidative stress, or cell death could release sequestered autoantigens, modify proteins, damage mitochondria, and release DNA from apoptotic cells. The adaptive immune system can recognize these products as foreign antigens and trigger an immune reaction.
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What are the different steps in disease progression of COPD? | | A: | |
Step 1 is the initial response to cigarette smoke, in which macrophages and dendritic cells produce cytokines and chemokines that orchestrate the inflammatory conditions required to activate the adaptive immune system. The hallmark of step 2 is T-cell proliferation. Disease progression and severity are, at this point, determined by the ability of dendritic cells to stimulate T cells. The final phase, step 3, is an adaptive immune reaction. The resulting immune inflammation, induced by CD4+ Th1 T cells along with cytolytic CD8+ T cells and B cells, leads to cellular necrosis and apoptosis, immune and complement deposition, tissue injury with airway remodeling, and emphysema. In most smokers, the disease process will not advance to step 2 and 3 if innate inflammation is minimized.
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Figure 3. Initial Response to Cigarette Smoke — Step 1 in the Process Leading to COPD.
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Figure 4. Proliferation of T Cells — Step 2 in the Process Leading to COPD.
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Figure 5. The Adaptive Immune Reaction — Step 3 in the Process Leading to COPD.
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TEACHING TOPIC
2. Case: Multiresistant Tuberculosis and AIDS
CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL, Case 18-2009: A 24-Year-Old Woman with AIDS and Tuberculosis with Progressive Cough, Dyspnea, and Wasting, D. Wilson, R.M. Hurtado, and S. Digumarthy, Extract | Full Text | PDF | PPT Slide Set
A 24-year-old woman with acquired immunodeficiency syndrome (AIDS) and pulmonary tuberculosis was admitted to a hospital in South Africa because of progressive cough, dyspnea, and wasting. A diagnosis of tuberculosis had been made 7 months earlier and HIV infection 6 months earlier. Cough and positive sputum smears persisted during antituberculosis treatment, and despite broad-spectrum antibiotic therapy and supportive care, her condition worsened and she died on the 20th hospital day. Results of a diagnostic test were received 3 months post mortem.
Clinical Pearls
Diagnosis of Drug-Resistant Tuberculosis in Resource-Limited Settings
Delayed diagnosis is the most common roadblock to accessing appropriate second-line antimycobacterial therapy for patients coinfected with HIV and drug-resistant tuberculosis in resource-limited settings. Lack of clinical response and the presence of smear-positive disease after two or more months of therapy should prompt sputum cultures and drug susceptibility testing. However, these tests require a long time interval to establish diagnosis (22 to 68 days). More rapid diagnostic methods that are under evaluation in resource-limited settings include the microscopic-observation drug-susceptibility (MODS) assay and line-probe assays. A two-step strategy, which could have been used for this patient, would involve the use of rapid diagnostic tests to screen for multidrug resistant tuberculosis, followed by expedited referral of the isolate, once drug resistance was detected, for expanded second-line drug susceptibility testing.
Management of Drug-Resistant Tuberculosis in Resource-Limited Settings
Documentation of multidrug resistance is required before the initiation of treatment for multidrug resistant tuberculosis, since unregulated use of second-line antimycobacterial agents can lead to the development of extensively drug-resistant tuberculosis. Strategies for multidrug resistant tuberculosis include an induction phase with the use of at least four active drugs, use of an injectable drug for a minimum of 6 months (preferably at least 6 months after conversion to a negative culture), continuation of therapy for a minimum of 18 months after culture conversion, and supervised therapy. If an adequate antimycobacterial regimen is used concomitantly, corticosteroids can be beneficial in patients with tuberculosis who have respiratory distress.
| Morning Report Questions | | Q: | |
What are the most common causes of nonresponse to antituberculosis therapy in HIV-infected adults? | | A: | |
Persistent sputum smears positive for acid-fast bacilli indicate non-response to antituberculosis therapy. Factors to be considered include nonadherence to antituberculosis therapy, resistance to antimycobacterial drugs, post-tuberculosis lung disease (bronchiectasis), superimposed infection or tumor, progression of HIV disease, immune reconstitution syndrome after starting antiretroviral therapy, and deterioration due to other conditions (e.g., heart failure, renal disease, or diabetes).
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In this patient with extensive lung disease, positive sputum smears, and clinical deterioration, progressive tuberculosis was the most likely diagnosis.
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Table 3. Causes of Nonresponse to Antituberculosis Therapy in HIV-Infected Adults.
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When should fluoroquinolones not be used for respiratory tract infections? | | A: | |
Fluoroquinolones should never be used for the treatment of bacterial infections of the respiratory tract in settings with a high incidence of tuberculosis, because they have activity against Mycobacterium tuberculosis and their use in patients with undiagnosed tuberculosis can promote the development of resistance.
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