include suppressor and cytotoxic T cells. On exposure to specific antigens, both CD4+ and CD8+ cells produce a variety of cytokines that interact with other components of the immune system, particularly B lymphocytes and macrophages.
One important role for the cellular immune system is to protect against bacteria that have a pattern of intracellular growth, especially M. tuberculosis (see discussion of tuberculosis in Chapter 25). In addition, the cellular immune system has a critical role in the handling of many viruses, fungi, and protozoa.
Although separating the immune protection of the lung into different categories is important for discussion purposes, these functions are deeply intertwined, and dysfunction in one aspect will likely cause problems in other parts of the system. Development of a respiratory infection generally indicates that a number of defense mechanisms have been overcome by the infecting organism.
Failure of respiratory defense mechanisms
Clinically important deficiencies have been recognized for each of the major categories of respiratory defense mechanisms. As a result, respiratory infections may ensue, and an analysis of the specific types of infections associated with each type of defect is clinically useful.
Impairment of physical clearance
The simplest impairment of physical clearance to understand is the inability to cough effectively. Three factors are required to generate the high velocities of an effective cough: (1) a large inspiration, (2) an increase in intrathoracic pressure against a closed glottis, and (3) a coordinated expiratory blast during which the glottis opens. Considering each of these steps, it becomes easier to appreciate why certain patients have difficulty with clearing inhaled particles and respiratory secretions. The patient with a weakened or paralyzed diaphragm will not be able to take a deep breath. The patient with weak expiratory muscles, such as the person with quadriplegia, will not be able to generate the large increase in intrathoracic pressure. The patient with a chronic tracheostomy or paralyzed vocal cord will not be able to effectively close the glottis to increase intrathoracic pressure. All these patients are prone to respiratory tract infections, even if the underlying immune systems are normal.
Other physical or anatomic factors that influence deposition and clearance of particles include genetic abnormalities and environmental factors affecting the mucociliary transport system. Especially interesting information has been provided by a genetic abnormality termed primary ciliary dyskinesia, also sometimes called either the dyskinetic cilia syndrome or the immotile cilia syndrome. In this disorder, a defect in ciliary structure and function leads to absent or impaired ciliary motility and hence to ineffective mucociliary clearance. More than 20 types of defects are recognized, but the most common is the absence of dynein arms on the microtubules (Fig. 22.1). Clinically, the impairment in mucociliary clearance is associated with chronic sinusitis, chronic bronchitis, and bronchiectasis. In males, the sperm tail, which has a structure similar to that of cilia, is abnormal, resulting in poor sperm motility and infertility. The disorder called Kartagener syndrome, which consists of the triad of chronic sinusitis, bronchiectasis, and situs inversus, is a variant of primary ciliary dyskinesia (see Chapter 7). Normal ciliary motion in a specific direction is believed to be responsible for the normal rotation of the heart and positioning of intraabdominal organs during embryogenesis. When ciliary function is significantly disturbed, positioning of the heart and intraabdominal organs becomes random, thus accounting for the situs inversus found in approximately 50% of patients with primary ciliary dyskinesia.
Causes of impaired mucociliary clearance:
1.Primary ciliary dyskinesia
2.Viral respiratory tract infection
3.Cigarette smoking
4.High concentrations of O2 for prolonged periods
5.General anesthesia
Viral respiratory tract infections frequently cause temporary structural damage to the tracheobronchial mucosa. The injured mucosa is associated with impaired mucociliary clearance, which may retard the transport of invading bacteria out of the tracheobronchial tree. This is one of the mechanisms by which viral respiratory tract infections predispose the individual to complicating bacterial superinfections.
Environmental factors also may cause impairment of mucociliary clearance. Exposure to cigarette smoke is the most important clinically and probably contributes to the predisposition of heavy smokers to recurrent respiratory tract infections. Some atmospheric pollutants, such as sulfur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3), appear to depress mucociliary clearance, but the clinical consequences are not entirely clear. High concentrations of O2, such as 90% to 100% inhaled for more than several hours, appear to be associated with impaired mucociliary function. Here, the consequences may be relevant to patients with respiratory failure who require these extremely high concentrations. In addition, general anesthesia with inhalational drugs administered during surgery is associated with short-term ciliary dysfunction and contributes to the increased risk of pneumonia in patients during the postoperative period.
Management of patients with respiratory failure often involves the insertion of a tube into the trachea (an endotracheal tube) and the support of gas exchange with a mechanical ventilator (see Chapter 30). Endotracheal tubes pose a significant risk for bacterial infection of the lower respiratory tract, often called ventilator-associated pneumonia, in part by preventing glottic closure, a critical component of the sequence of events leading to an effective cough. In addition, the endotracheal tube provides a direct conduit into the trachea for bacteria that have colonized or contaminated the ventilator tubing or the endotracheal tube itself.
Impairment of antimicrobial peptides
There is substantial overlap in function of the antimicrobial substances present in the sol layer. Thus, an isolated defect in any one component is unlikely to cause catastrophic consequences. Deficiencies of lysozyme have been associated with an increased risk of acute bacterial bronchitis. In patients with cystic fibrosis, the high sodium and chloride content in their respiratory secretions appears to inactivate defensins and contributes to the severe respiratory infections that commonly occur. In animals, defects in SP-A or SP-D are associated with an increase in respiratory infections, but analogous problems in humans have not been identified.
Impairment of phagocytic and inflammatory cells
Clinical problems result from deficiencies in the number or function of the two major phagocytic and inflammatory cell types: alveolar macrophages and PMNs. One of the more important ways in which macrophage function can be impaired is by viral respiratory tract infections. These infections may paralyze the ability of the macrophage to kill bacteria, another reason why patients with viral infections are more susceptible to superimposed bacterial bronchitis or pneumonia.
Cigarette smoking depresses the ability of alveolar macrophages to take up and kill bacteria. Hypoxia,
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HIV infection, starvation, alcoholism, and cold exposure similarly appear to be conditions in which impaired bacterial killing is at least partly due to depressed macrophage function. Treatment with corticosteroids, given for myriad diseases, seems to depress migration and function of macrophages, and this may compound additional adverse effects of steroids on lymphocytes and the immune system. HIV can infect alveolar macrophages, both serving as a reservoir for viral particles and resulting in impaired macrophage function in patients with AIDS, likely complicating the other host defense defects recognized in the disease (see Chapter 27).
Clinical situations that potentially depress macrophage function include:
1.Viral respiratory tract infections
2.Cigarette smoking
3.Alcoholism
4.Starvation
5.Cold exposure
6.Hypoxia
7.Corticosteroid therapy
8.HIV/AIDS
PMNs are reduced in number in several clinical circumstances, often due to underlying bone marrow disease (e.g., leukemia) or to the treatment administered. Chemotherapeutic agents used to treat malignancy commonly destroy rapidly proliferating cells of the bone marrow, resulting in temporary loss of PMN precursors and marked depression in the number of circulating PMNs. When PMNs are present at abnormally low concentrations, the risk of bacterial infection begins to rise, becoming particularly marked when the count drops below 500/mm3. Although opportunistic fungal infections are generally associated with impairment of cellular immunity rather than with neutropenia, the fungus Aspergillus is an important respiratory pathogen in the neutropenic patient.
Causes of decreased numbers of PMNs:
1.Bone marrow replacement by tumor
2.Cancer chemotherapeutic agents
Defects in the adaptive immune system
The adaptive immune system is subject to defects in function that affect its humoral and cellular components. In comparison with innate immunity, there is much less redundancy in the adaptive immune system, and as a general principle, defects in adaptive immunity result in a much greater risk of infection. Deficiencies in the humoral immune system, such as decreased or absent immunoglobulin production (i.e., hypogammaglobulinemia or agammaglobulinemia), are associated with recurrent bacterial and viral respiratory infections, often leading to bronchiectasis. The risk of infection is best defined for individuals with IgG or global immunoglobulin deficiency. Although some individuals with selective IgA deficiency seem to have an increased risk of respiratory infections, either viral or bacterial, this risk may be at least partly related to a coexisting deficiency of one of the four recognized IgG subclasses. The majority of patients with selective IgA deficiency do not develop recurrent sinopulmonary infections, likely because of redundancy in the immune system.
Causes of adaptive immune deficiency:
1.Humoral: decreased or absent immunoglobulins
2.Cellular: corticosteroids, cytotoxic drugs, Hodgkin disease and other lymphomas, HIV/AIDS
Cellular immunity is disturbed most frequently by treatment with corticosteroids, cytotoxic agents, or other immunosuppressive drugs and in some well-defined disease states, such as Hodgkin lymphoma and AIDS. A number of congenital immunodeficiency syndromes are characterized by profound impairments in cellular immunity as well. Unlike most other deficits in respiratory defenses, problems with cellmediated immunity may lead to infection with a specific group of microorganisms, including intracellular bacteria (especially mycobacteria), fungi, Pneumocystis, and certain viruses, particularly cytomegalovirus. Some of these organisms, such as Pneumocystis and several of the fungi, rarely affect individuals with normal cellular immunity, whereas other organisms, such as M. tuberculosis, can affect individuals without any defined defects in cellular immunity.
In summary, the defense mechanisms available to protect the respiratory tract from invading microorganisms are varied and complex. These defenses can be thwarted by exposure to damaging influences, such as cigarette smoke and ethanol. Equally important, pharmacological and other forms of treatment provided by physicians can disrupt host defense mechanisms, making it essential that physicians be aware of the potential infectious complications of therapy.
In the clinical setting, deficiencies in immunoglobulins and PMNs are strongly associated with an increased risk of bacterial infections. Although problems with mucociliary clearance and macrophage function are somewhat less well defined in terms of the specific infectious risk, bacterial infections also appear to be prominent in these settings. In contrast, disturbances in cellular immunity are characterized by an increased risk of a different subset of infections, especially those caused by mycobacteria, Pneumocystis, fungi, and certain viruses.
Augmentation of respiratory defense mechanisms
Importantly, there are significant opportunities to augment defense mechanisms and protect against some forms of respiratory tract infection. Immunization against certain respiratory pathogens has induced the production of antibodies against the organisms and has conferred either relative or complete protection against infection by these microbes.
Perhaps the most notable examples are immunization against SARS-CoV-2 (which causes COVID-19), influenza viruses, and many subtypes of the common bacterium Streptococcus pneumoniae (pneumococcus) as well as to toxins of Bordetella pertussis (which causes whooping cough). Appropriate vaccination is critical for any patient with an underlying condition which increases their risk for severe disease. At the time of publication, SARS-CoV-2 vaccination is recommended for all individuals 5 years and older. Universal immunization against pertussis is recommended during childhood and a booster shot recommended for all adults. Annual influenza vaccination is indicated for all individuals aged 6 months and older. Pneumococcal vaccination is now recommended universally both for young children and for adults older than 65 years. Pneumococcal vaccination is also recommended for individuals outside of those age groups who are at increased risk of invasive pneumococcal disease.
Suggested readings
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Pulmonary host defenses
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Augmentation of respiratory defense mechanisms
Centers for Disease Control and Prevention (CDC). Prevention and control of seasonal influenza with vaccines: Recommendations of the Advisory Committee on Immunization Practices — United States, 2021-22 influenza season MMWR RR-5, 2021;70: 1-28.
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