PNEUMONIA J.L. Wright DEFENSE MECHANISMS A. Aerodynamic Filtration i) Nose - Filtration is initiated in the nose, where particles greater than 10æm are removed. The coarse hairs in the anterior nares remove the very large particles. The surface area then increases markedly over the turbinates, which, combined with the narrow width of the airstream at this point, provides maximal opportunity for impaction of particles in the nasal mucous. This area is provided with a rich population of mucous glands and goblet cells. At the nasopharynx, the airstream must make a 90? change in direction, causing the remainder of the large particles to impact on the posterior pharyngeal mucosa. ii) Bronchi - As the airstream proceeds into the bronchial segments, there is a pronounced decrease in flow as a result of the large increase in cross sectional area. It is in this region the particles of 5 - 0.2æm are removed, due to sedimentation and impaction. Because of the low flow, the particles tend to fall to the mucous floor, as the gravitational forces act upon their mass density. The cough reflex is a major protective mechanism of the lung. During the cough manoeuvre, the intrapleural pressure can be raised to over 10 cm Hg, causing partial collapse of the major extrapulmonary airways. This is most noticeable in the trachea, which demonstrates at least partial membranous wall invagination. The constricted lumen results in a very high linear velocity, which may approach the speed of sound. The secretions within the airway now occupy a large volume and can be propelled towards the pharynx. Because of low flow rates in the smaller airways, such a mechanism cannot operate, but the high transpulmonary pressures may result in a milking action on the airways propelling the mucus into the larger bronchi. The mucociliary escalator is a major protective mechanism in the bronchial tree. From proximal trachea to terminal bronchioles, the epithelium is pseudostratified tall columnar and ciliated in type. The respiratory mucus is produced by submucosal glands and by goblet cells, which distally decrease in number. Each ciliated cell contains approximately 200 cilia, with an average length of 6æm. Each cilium contains longitudinal contractile elements in a 9+2 arrangement. The peripheral fibres join towards the basal ends and, by means of advanced matrix, mesh with the basal body. Ciliary motion is in one plane, with a fast effector stroke and a slower recovery stroke. The cilia beat in a bi-layer of mucus, with the apices in contact with the superficial gel layer only at the peak of the power stroke. This glycoprotein is produced by the submucosal glands and the goblet cells. The lower, or peri-ciliary layer, is known as the sol layer. Although of unknown origin, it may be secreted by bronchiolar cells, may result from the liquifaction of the gel phase, or may be due to active water transport across the epithelium. Apart from transport of impacted particles, the mucus acts to absorb noxious bases, which come into contact with the mucus and thus partially prevent alveolar damage. This action, however, allows continued contact of the gas up the tracheo-bronchial epithelium. This is important in the inhalation of gases, such as NO2 and H2S, which form their acids after interaction with water. It may also be an important factor in carcinogenesis. Ciliary dysfunction can be seen in many disease states, including the congenital states, such as Kartagener's syndrome, but is probably most common due to cigarette smoke. B. Cellular Action The small particles of 0.5-0.1 æm are able to pass the bronchial defense mechanisms and enter into the alveoli. Here, the major defense mechanism is the alveolar macrophage. It acts to isolate and detoxify particles, as well as acting as a vehicle for their removal. The alveolar macrophage is derived from the bone marrow monocyte. It is a large cell, with plentiful cytoplasm and contains a large number of lysosomal granules. The removal of the particle by the macrophage may take place by two major routes: migration from the alveolus up to the terminal bronchioles onto the escalator, or movement to the lymphatics. This is easily remembered by thinking where the carbon pigment is deposited in the lung; along the area of the terminal bronchioles in the centre of the lobule, or the linear anthracotic pigment noted on the subpleural surface of the lung in the areas of the interlobular septa.. Pneumonia Pneumonia is defined as :"inflammation of the lung: Thus, it is possible to have a number of entities which include an inflammatory reaction with the term pneumonia in the name. For example, usual interstitial pneumonia, hypersensitivity pneumonia. When pneumonia is used to indicate an inflammatory reaction induced by organisms, it can be classified in at least two different ways: a) The general type of infecting organism: bacterial, fungal, parasitic, viral, and further sub-classified under each of these headings as to the individual organism. For example, bacterial pneumonias could be classified as streptococcal, tuberculous, hemophilus, mycoplasma, legionella etc. b) The gross pattern of the inflammatory process: lobar pneumonia, bronchopneumonia, interstitial/ARDS, miliary pattern. Each classification has its own benefits and deficits, and they should probably be best used together to give the maximum treatment benefit to the patient. As an example, if a physician speaks of miliary tuberculosis, a different investigative and treatment plan comes to mind that when the topic is tuberculous lobar pneumonia. Lobar vs bronchopneumonia Invasion by standard bacterial organisms evokes an acute inflammatory reaction with dilatation and increased permeability of the capillaries, with associated neutrophil and subsequent macrophage chemotaxis. Since the exudate tends to make the lung parenchyma solid, the term "consolidation" is used. Older literature includes the term "hepatization" since the lung parenchyma had the red appearance and rubbery consistence of liver. When the inflammatory process is relatively localized to the lung parenchyma around the small airways, the term "bronchopneumonia" is used to reflect this patchy distribution. When the inflammatory process is extensive and has spread to involve almost the entirely of the lobe, or lobe segment, the term "lobar pneumonia" is used. These two terms only reflect distribution of the inflammatory process; the inflammatory process itself is identical. A lobar distribution is indicative of the virulence of the organism and the ability (or lack thereof) of the host to overcome the infection. Some organisms, such as streptococcus pneumonia and klebsiella have a thick mucoid encapsulation which hampers their phagocytosis, and allows them to spread in a rapid fashion from alveolus to alveolus via the pores of Kohn. Common inflammatory process with associated gross and microscopic appearance 1. Acute inflammatory reaction: The affected lung is congested because of the vascular engorgement of the capillaries. In addition, the capillaries have increased permeability, and there is leakage of both proteins and fluid from the vasculature into the alveoli. Leakage of red blood cells accounts for the "rusty" sputum found in patients with pneumonia. There is neutrophil chemotaxis and activation. It is at this stage that the term "red hepatization" has been used as a gross descriptor, but it is probably best just to use the term "acute consolidation". The microscopic appearance at this time would reflect the acute inflammatory process described above, with the alveolar airspaces filled with protein rich fluid and neutrophils. If the inflammatory reaction is adjacent to the pleura, there may be an associated pleural reaction, with pleural effusion, or a more limited fibrinous pleuritis. 2. As the inflammatory reaction proceeds towards resolution, there is chemotaxis of the macrophages so that there is a mixture of PMN and macrophages in the airspaces. The macrophages are responsible for phagocytosis of the inflammatory debris, including the red blood cells. The congestion of the vasculature diminishes as lesser amounts of kinins, TNFà, and the other vasodilatory substances are secreted. The lung at this stage has a grey and rather dry appearance, and the term "grey hepatization" has been used to describe this appearance, but it is probably best just to use the term "organizing pneumonia". If the inflammatory process does not resolve in this fashion, progressive acute inflammation occurs with necrosis of the lung parenchyma and damage to the airways. If the pleura was involved, the inflammatory process and bacterial proliferation can accentuate and become an empyema. 3. Continued resolution of the inflammatory process involves diminution of the numbers of PMN, and continued activity of the macrophages until the inflammatory debris has been cleared. At this stage, the process is termed "resolution". If there is continued activity of the macrophages, there will be subsequent activation and proliferation of fibroblasts. The alveolar airspace becomes filled with granulation tissue, and the lung interstitium is also thickened with fibroblasts and increased collagen. The lung parencyhmal architecture becomes reorganized and there is scarring. Complications: 1. Dissemination of infection to other distant organs. Depending on the organ involved, there can be endocarditis, cerebral and renal abscesses, or septic arthritis. 2. Empyema - bacterial invasion through the pleura 3. Lung abscess - necrosis of the lung parenchyma 4. Bronchiectasis - inflammation, necrosis and distortion of the airways, allowing them to dilate irreversibly. 5. Pulmonary scarring with honeycombing Clinical: 1. Symptoms related to lungs: There is cough which tends to be productive of sputum. The sputum may have a rusty appearance reflecting leakage of red blood cells from the vessels. If the pleura is involved, there may be pleural pain and a pleural rub can be heard on auscultation. A chest radiograph will demonstrate airspace infiltrates in the affected portions of the lung. 2. Symptoms related to generalized reaction: The patient will feel ill and tired (generalized malaise). They will usually have a fever. 3. Clinical course: With effective antibiotic therapy, the acute phase of the illness can be controlled within 48 to 72 hours. Obviously, it is important to identify the organism using sputum smears with gram and/or acid fast stains, or culture, and determine its susceptibility to various antibiotics in order to choose the most appropriate therapy. Some patients will have increased airway reactivity after an infection; it is important to realize that this is probably not full blown asthma, and will resolve after a few months. Specialized inflammatory process: Tuberculosis Incidence / prevalence: Tuberculosis is an ancient infection with historical evidence of its existence dating back to 8000 B.C. It is the single most important bacterial infection in the world. Approximately 1/3 of the world's population are infected, with 20,000,000 active cases, and annual infection of 50-100 million people each year, with an annual mortality of 3 million people. Tuberculosis is thus endemic, and there are periodic epidemics when it is (re)introduced into a susceptible population. Tuberculosis epidemics occur in waves with a 300 to 500 year cycle. In the highly developed Western world, there was a progressive decrease in T.B. since the early 20th Century. However, this trend is beginning to reverse with increasing numbers of cases of M. tuberculosis that are multi-drug resistant, and a large increase in the numbers of infections with tuberculosis avium/intracellulare, the latter largely in the AIDS population. Classification: The tuberculosis bacillus was discovered by Koch in 1882. There are at least 54 species in the genus Mycobacterium. Runyon has classified them according to their growth rate and pigment production into four groups. Causes of mammalian infections I. M. tuberculosis M. bovis - in prepasteurization days, this was the most common cause of GI tuberculosis Atypical (unclassified, anonymous mycobacterium) : These are widely distributed in nature. II. M. leprae III. - slow growing M. kansasii - lung, bone and joint infections M. avium/intracellulare: - common pathogen, very common in AIDS - now most common cause of intestinal T.B. M. scrofulaceum M. marinum - swimming pool granuloma IV. - fast growing M. fortuitum-chelonei Epidemiology: High risk groups: Tuberculosis is common in areas where there is poverty, malnourishment, and lack of medical facilities. In North America, there is an increased incidence in aboriginal populations, originally because they were susceptible hosts, and now largely because they constitute a group with low income and crowded habitat. Other groups considered high risk are persons living with those who have active T.B., people with previously active T.B. but who have not have received, or who have received inadequate chemotherapy, immigrants from high prevalence countries, and populations with low income and crowded settings (usually urban). There is an increased incidence of T.B. in people with diseases producing a decrease in immunological status such as diabetes, congenital heart disease, people at the extremes of age, patients with chronic debilitating diseases, congenital heart disease, patients with anticancer chemotherapy, and patients with HIV disease. Health care workers are considered high risk because of increased chances of exposure. Transmission: Tuberculosis bacilli can remain in viable form for many years in the tissues of health people, a condition termed dormancy. Transmission occurs most commonly through the inhalation by a susceptible host of a sufficient load of viable bacilli, usually by inhalation of sputum droplets which have been aerosolized by cough. Since pulmonary tuberculosis is usually chronic and protracted, there is ample time for transmission to occur. The bacilli are hardy and can remain viable in wet sputum for months and in dried sputum for weeks. Pathogenesis: The tubercle bacillus is a slow-growing organism that does not produce toxins or cytotoxic enzymes. After its inhalation, it is regarded as an inert particulate, and the initial response is a non-specific PMN infiltrate. The bacteria grow locally, and enter the lymphatics and vasculature, traveling to other body sites. Within 48 hours, macrophages begin to accumulate at the sites of bacteria growth, but the bacteria continue to live and grow in the macrophages, probably because of the protective qualities of their waxy cell wall. After approximately 6-8 weeks, an infiltrate of T-lymphocytes is seen, and this represents the development of delayed hypersensitivity. This is a TYPE IV immunological reaction, and is characterized by the final formation of a granuloma. As a result of the immunological reaction, there is both central caseous necrosis within the granulomata, and tissue destruction. IT IS THE HOST IMMUNOLOGICAL RESPONSE TO THE ORGANISM THAT PRODUCES THE LUNG DESTRUCTION SEEN IN TUBERCULOSIS. Resistance to the tubercle bacillus is now increased, and there is greater capacity to both phagocytose the organism, and to prevent its intracellular replication. Healing of the inflammatory foci occurs, with fibrosis and dystrophic calcification. It is important to remember that dormant bacilli can remain within these granulomata, particularly within the caseous debris. Clinical Classification Primary tuberculosis: This is the term used to describe the infection of a individual who has not been previously infected with the tubercle bacillus. The lungs are the usual site, with the pathogenic mechanism as described above. Infection occurs predominately in the lower lobes, representing the fact that a greater proportion of ventilation occurs in the lower lobes. The combination of the initial pulmonary infective site with its granuloma, and the spread to hilar lymph nodes with granuloma formation there is known as a Ghon complex (focus). The majority of cases of primary T.B. heals, without the infection becoming clinically apparent. However, in some cases it may not be localized and either miliary T.B. or progressive pulmonary T.B. may result. These developments need massive infection and some degree of immune compromise. Miliary tuberculosis: This occurs as the result of heavy hematogenous spread. There is progressive development of lesions throughout the body. Miliary T.B. may occur as a component of primary T.B., or of secondary (reactivation/reinfection) T.B. The patients are usually ill with systemic signs of fever, anaemia and weight loss. The pathological features of miliary T.B. are innumerable small yellow-white lesions which grossly resemble millet seeds. Histologically, these nodules are composed of granulomata. Secondary tuberculosis: This occurs in people who have been previously infected with the tubercle bacillus, and is usually due to reactivation of a previously walled off infective focus (there is a 5- 10% lifetime risk of developing clinical disease from a previous infection). However, it may also be due to re-exposure and re-infection from an exogenous source. Sites of secondary T.B. reflects the fact that the bacillus prefers a high level of oxygenation, and lesions are therefore most commonly found in the apices of the lung and in tissues with a high vascular supply (kidneys, meninges). There are two consequences: healing (fibrocalcific tuberculosis); and progressive pulmonary T.B. in which the lesions progress with extensive and progressive pulmonary involvement and dissemination to other organs. In fibrocalcific T.B., the destruction of lung parenchyma is again as a consequence of the immunological reaction, with scarring and calcification. In progressive pulmonary T.B., the lesions enlarge and caseate. There is subsequent erosion into adjacent structures such as bronchus, vasculature, or pleura. Erosion into a bronchus produces cavitation, increasing the growth of the bacilli and producing a situation in which contacts may become exposed and infected. Laryngeal or gastrointestinal T.B. may be produced by coughing up and swallowing organisms. Tuberculosis pneumonia (Galloping Consumption) may result from spread of organisms into distal lung parenchyma. Progressive T.B. can also be found in organs other than the lung. Involvement of subcutaneous lymph nodes produces the clinical picture of scrofula; bones produces Pott's disease with intervertebral disk destruction; adrenal involvement produces Addison's disease; and other sites such as kidneys, meninges, fallopian tubes and epididymis have the expected clinical symptoms. Diagnosis: Symptoms: Symptoms are organ specific and will vary with the extent and severity of disease. Primary T.B. is usually asymptomatic unless there is pleural involvement. Constitutional symptoms are nonspecific and include weight loss, malaise and fever. The fever has a characteristic afternoon peak with defervescence at night accompanied by sweats. Allergic symptoms may occur in primary T.B. at the onset of the immune response, and can be suggested by erythema nodosum of the skin, nonspecific fever and joint aches. Laboratory data: WBC is usually normal, although patients with primary infection may have an eosinophilia at the beginning of the immune response. Chronic anaemia may be found in patients with longstanding progressive disease. Nonspecific findings including an increase in serum gamma globulin or alpha macroglobulins may be found. Effusions (pleural or ascitic) will have an increased number of lymphocytes, increased protein, and decreased glucose, helping to distinguish them from carcinomatous or infective effusions. Chest X-Ray: In primary T.B., there may be localized areas of consolidation in any segment of lung. There may be hilar or paratracheal lymphadenopathy, usually unilateral. Pleural effusions are found in only 3% of patients and are usually unilateral. After healing, the Ghon complex can be recognized because of calcification. In reinfection/reactivation T.B., the typical lesions are in the apex of the lung and superior segments of the lower lobe. Progressive T.B. has consolidation and cavitation, while healing fibrocaseous T.B. has fibrosis and volume loss. Mantoux skin test: This test is based on the principle that delayed hypersensitivity is induced after tubercle bacillus infection. After an intracutaneous injection of 0.1 ml antigen, T-cells should accumulate in the injection site as an indicator of this reaction. The Mantoux is read in 48-72 hours, measuring the indurated area and ignoring the adjacent red skin. The standard dose is 5 TU, although doses of 1 and 250 TU are available. An indurated area of 10 mm diameter is considered positive. Reactivity is significant only in that it recognizes a previous exposure to T.B. antigen. Cross-reactivity with other mycobacterium is possible, as well as previous BCG immunization. A booster effect is also possible if a recent test has been performed. False negative reactions can be found in patients with steroid medications, immunodeficiency states, malnutrition, malignancies, sarcoidosis, overwhelming illness (including T.B.), viral infections, and chronic renal failure. If the test was performed improperly (subcutaneous injection, low TU), a false negative may result. If the patient is in the pre-allergic stage of primary infection, a false negative may be found. Culture: Mycobacterium is not fastidious, but does require K, Mg, PO4, S, and N2. It grows best at a pH of 6.5 to 7.0 and is a strict aerobe. Staining: Mycobacterium is acid fast because of their waxy cell wall. The principles behind the acid fast stains are that if either an aniline dye or a fluorochrome dye can be forced into the wall using combinations of strong dye (carbol fuchsin), phenol, and heat, then it bacillus will not decolorize with acid alcohol. The fluorochrome auramine-rhodamine stain is more sensitive than the Ziehl- Neelson stain, but has the disadvantage of staining non-viable organisms. Treatment: There is no need to isolate a patient unless they are noncompliant with covering their cough and isolating their sputum. Fomites are not a problem unless contaminated with sputum. Hospitalization is not necessary unless the patient is extremely ill. Combination chemotherapy should be used, using at least one bactericidal drug in addition to INH, and covering those which will kill actively growing extracellular bacilli, slowly growing intracellular bacilli, and slowly growing organisms in a neutral pH (caseous material), and supported by a bacteriostatic drug. The choice of chemotherapy depends on the type of patient, severity of disease, and the resistance of the organism. Ideal patients may enjoy a short course of 3-4 drugs for only 6 to 9 months. Noncompliant patients, those with slow bacterial sputum conversion, or immunosuppressed patients require long term therapy. Treatment failure may be due to noncompliant patients, faulty drug regimes (divided doses, insufficient number of drugs), or failure to recognize drug resistance. Since spontaneous resistance occurs in 1 in 106 organisms, actively growing organisms have a greater chance of developing resistance. It must be remembered, however, that drug toxicity is not rare. Isoniazid will induce a toxic hepatitis, ethambutol an optic neuritis, rifampin severe gastrointestinal symptoms, and pyrazinomide a hepatitis. Prophylaxis: Chemoprophylaxis: This therapy is directed against those patients who are already infected as shown by Mantoux conversion, and do not have active disease. These include associates of potentially infectious patients, people who have converted within the past 2 years, people with previous T.B. who were not adequately treated, people less than 35 years old with a positive Mantoux, and positive Mantoux in people with diseases which would make them more susceptible to T.B. INH is the drug of choice, and usually a 12 month course is given. BCG administration: Bacille Calmette-Guerin is manufactured by serial culture of live M. bovis organisms on ox bile medium, producing an attenuated bacillus. The rationale behind this therapy is that a susceptible person will receive a non-pathogenic infection and therefore induce sensitivity to the bacilli. When they become infected, hypersensitivity will already exist, thereby decreasing dissemination. BCG is recommended for children living in poor and crowded conditions, children with families who have had persistent or inadequately treated T.B., groups with high rates of new infections, newborns whose mothers have active T.B., and health workers. The latter group is controversial, and probably depends on type of practice. Specialized inflammatory process: Viral pneumonia (and some parasites and fungi) The majority of viral infections induce an inflammatory reaction which, in its lesser stages, can be termed "interstitial pneumonia" and in its full appearance is known pathologically as diffuse alveolar damage and clinically as Adult Respiratory Distress Syndrome. In the interstitial phase, the interstitium is thickened by an infiltrate of inflammatory cells with the mononuclear cells rather than the PMN as a dominant cell type. The reaction may be limited to the interstitium in some infections, such as mycoplasma. Viral infections and toxoplasma (parasitic infection) usually have some component of diffuse alveolar damage, with the characteristic hyaline membranes. The majority of infections which are associated with this type of alveolar reaction also affect the small airways, and have a similar mononuclear cell inflammatory component. If the reaction is not cleared the airways can become narrowed and fibrotic, or dilated and tortuous. The term interstitial pneumonia is not to be encouraged since it allows for confusion with the idiopathic interstitial pneumonias which are a group of interstital fibroses. It is probably best to refer to the pneumonias as "mycoplasma, viral, toxoplasma, etc" pneumonia rather than to group them under this term. Complications: 1. Death, especially if diffuse alveolar damage is present 2. Bronchiectasis - inflammation, necrosis and distortion of the airways 3. Superinfection with bacterial organisms to produce an additional bacterial pneumonia. Clinical: 1. Symptoms related to lungs: Cough is variable, but shortness of breath is usual and is probably related to abnormal diffusing capacity. 2. Symptoms related to generalized reaction: Flu-like symptoms of malaise, headache, muscle aches and pains and fever predominate. 3. Clinical course: This depends on the severity of the infection and the infecting agent. In general, most patients recover. In major viral pandemics, a huge mortality and morbidity rate was experienced. Immunocompromised host: A wide variety of infections other than those described above can be identified in patients with a compromised immune system. Fungal infections, particularly pneumocystis carinii, but also the standard mycelial fungal organisms of candida, aspergillus, and mucormycosis are common, as are the dimorphic fungi such as cryptococcus. Cytomegalovirus and herpes virus are seen; cytomegalovirus can often be identified in the lungs, unaccompanied by any inflammatory reaction, and in this situation the significance is unknown. Toxoplasma is also found with increased frequency in an immunocompromised patient. 10 Wright - Pneumonia 10