Infection: The Real Culprit in Chronic Bronchitis and Emphysema?

Symposium on Chronic Respiratory Disease

Infection: The Real Culprit in Chronic Bronchitis and Emphysema? Wilbur Y. Hallett, M.D.*

Although chronic bronchitis, emphysema, and asthma do not appear morphologically to be infectious processes, infection has been assigned a major clinical role in the aggravation and perpetuation of the chronic obstructive pulmonary processes. Its role in pathogenesis, though uncertain, is becoming more probable as additional information is acquired, complexly relating it to many other factors. The role of infection in chronic bronchitis and emphysema must be considered in three separate contexts: (1) infection in the etiology of chronic obstructive pulmonary disease, (2) chronic infection in established chronic obstructive pulmonary disease, and (3) superinfections in advanced chronic bronchitis and emphysema.

INFECTION IN THE ETIOLOGY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Since the prevalence of chronic bronchitis and emphysema is related to smoking and air pollution"! more than to any other factors, infection appears at a casual glance to be eliminated as a significant etiologic factor. But the recognition that infection is facilitated by inhalation of pollutants 13 • 34. 35. 38, 77. 9! suggests at least a dual, synergistic causation. In animals, exposure to certain pollutants interferes with pulmonary defense mechanisms!3. 34, ;].,. lH and simultaneous inhalation of bacteria or viruses results in more frequent and severe pulmonary infectionsY5. 78, 91 In human beings the intensity of prolonged exposure to atmospheric pollutants is proportional to the frequency and duration of certain respiratory tract infections. 2;l. 67 Age-specific respiratory disease mortality is directly related to the degree of exposure to atmospheric sulfation. 10o Respiratory infections are more prevalent and more severe among cigarette smokers.91 Such evidence is additional, although indirect, affirmation of an etiologic role for infection in chronic obstructive pulmonary disease "Associate Professor of Medicine, USC School of Medicine; Currently Visiting Associate Professor of Medicine, U,C.L.A. Medical Clinics of North America- Vo!. 57, No. 3, May 1973

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(even though, disturbingly, the role of smoking in acute respiratory infection is negated by at least one reviewer).38 If chronic obstructive pulmonary disease became obvious immediately following pulmonary infection, a cause-and-effect relationship with infection would be confirmed. However, this does not happen in .man; even the focal pneumatoceles or bullae, becoming manifest after staphylococcal pneumonia,39 are quite different from diffuse emphysema. That infection does not produce "permanent" chronic obstructive pulmonary disease is erroneously suggested by clinical observations that the cough and sputum of colds and influenza, and the wheezes and reduced flow rates of bronchiolitis do disappear, even though they are sometimes long-lasting. 48 However, careful and specific pulmonary function testing may reveal a very definite, permanent "step-down" after acute "benign" respiratory infections, when compared with pre-infection values. 4 The very long delay and apparent lack of association between the common respiratory infections, beginning in early life, and overt chronic obstructive pulmonary disease, manifesting itself in middle age or later, is similarly misleading. We are, happily, provided with lungs with much greater capacity than the level at which they usually function. They tolerate much damage throughout a lifetime before major symptoms or impairment of activity becomes manifest. The part of the lung involved, the smaller airways, is not critical in overall airway resistance until a major proportion has been damaged. 41 Routine measurement of ventilatory capacities and other standard pulmonary function tests will fail to reveal damage which would be readily apparent anatomically and, to compound the problem, relatively major anatomic damage may not be apparent to any except the most expert pulmonary pathologist. 92 It now appears likely that recurrent infections, quite possibly viral, in combination or in conjunction with altered defense mechanisms and lung damage as from pollutants, produce changes, beginning in infancy, leading to varying degrees of destruction and scarring of respiratory and terminal bronchioles and alveoli/ 6 • 98 and that these recurrent processes continue completely undetected until the remaining viable alveolar parenchyma and bronchial airways are inadequate to sustain asymptomatic activity. Abundant evidence is rapidly accumulating defining the roles of certain immunoglobulins in protection from infection. 8. 94 For example, immunoglobulin A, found in secretions from the nose and lung, seems to be important in defense against airborne invaders; it is increased significantly in sputum in acute bronchitis, while a decrease in its concentration is found in far-advanced chronic bronchitis of long duration. 58 The lack of IgA appears to be another factor favoring recurrent infection in chronic bronchitis. 94 Hereditary deficiency of alpha 1 antitrypsin,51 described as a factor in the development of emphysema, suggests a possible role of infection by the release of elastolytic proteases from phagocytes which will be present in greater numbers in the presence of infection. The lung, lacking adequate amounts of protective alpha1 antitrypsin, a protease inhibitor, is damaged;43 furthermore, certain infecting organ-

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isms such as Pseudomonas and Proteus may inactivate any remaining protease inhibitors.62 Infection accordingly is a major factor, but rarely the sole culprit in the pathogenesis of chronic obstructive lung disease. MacLean 56 has implicated bronchiolitis as the basic factor in the etiology of emphysema, with other factors playing variable roles. The normal lung clears inhaled bacteria remarkably well;4H the damaged or hindered lung does not. Most evidence points to infection plus smoking, or plus industrial or urban pollution, or plus other chemical or physical irritants, or plus genetic defect, or plus a combination of these as the necessary complex, with the other factors as basic ones and infection only of secondary importance. No single specific pathogen appears responsible. Other mechanisms implicating infection have been suggested, such as altered immunologic response invoked by antigen deposition of dead bacteria with "antigen-sensitized cell" interaction leading to inflammation and additional cell injury akin to what is found in experimentally produced pyelonephritis. 6B Viral infection may play a role in the development of this hypersensitivity.32 One other possible effect of pulmonary infection is induction of "respiratory reactivity." The individual, under these circumstances, may be relatively free of chronic airways obstruction, but may develop bronchospasm under various stresses such as with exercise, coughing, laughing, or particulate inhalationY' 84 Acetylcholine or mecholyl administration will detect this state of hyperreactivity by invoking reversible bronchospasm. 29 • 84 Although some persons are "respiratory reactors" virtually all of the time, the condition is found in more individuals during infection and may lead into irreversible airways obstruction. Certain conclusions are possible at present. Respiratory infections, even those occurring at an early age, may engender airways obstruction and disease; therefore, each respiratory illness should be promptly and properly treated to a point of maximal benefit. 16 Contentment with less than optimal treatment and improvement is condemned. The complacency which once characterized medical attention to the smokers' chronic cough and phlegm still seems to exist for the child with a persistent running nose and cough. Simple, early, energetic treatment of respiratory infections in early life may be of much greater importance than realized at present. A large number of inadequately attended, early instances of chronic lung disease are being found by pediatric pulmonary specialists. 96 • 97 Ideally, exposure to inhaled pollutants - smoke, smog, or occupational inhalants - should cease during respiratory illnesses. Avoidance of all such exposures for those with genetic abnormalities known to predispose to chronic bronchitis may become routine. 61 Early vaccination may become feasible for protection from the multiple viruses known to produce respiratory illness. 16 The anti-influenza vaccines are the only ones readily available now. Whether multiple virus vaccines, when they become available, will reduce the prevalence of chronic bronchitis and emphysema requires careful prospective study.

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CHRONIC INFECTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE Infection has been assigned various roles from main star to simple supporting part in the aggravation and perpetuation of the chronic obstructive pulmonary syndromes. Chronic bronchitis has recently been described 59 as a series of superimposed, sequential, acute inflammatory insults. Two bacterial pathogens, Diplococcus pneumonia and Hemophilus influenzae, are implicated, being present in purulent sputum particularlyat the time of more obvious exacerbations 5. 10, 22, 55, 76, 89 and treatment with specific antibiotics produces improvement of the increased cough and purulent sputum. There is infiltration of the bronchial mucosa with leukocytes, plasma cells, and lymphocytes,40 and pathologic evidence of H. influenzae invading or infecting the bronchial mucosa in chronic bronchitis. 19, 89 Prophylaxis with an appropriate antibiotic over long periods, particularly in the winter months, has reduced the number of intercurrent infections and the number of days lost from work. 1, 10, 15, 18,22,33,73,74,89 The presence of antibodies in the serum of patients may be considered as evidence of active infection; in patients with chronic lung disease, antibodies against the pneumococcus were less common than specific precipitins against H. influenzae. 7 Increases in serum IgM and IgG antibodies to both have been found in acute exacerbations. 79 But there are some who question whether these pathogens even originate in the lower respiratory tract. 5, 68, 69 Exacerbations have also been found to be associated with Mycoplasma pneumoniae 12 , 47 and with viruses, particularly rhinoviruses, respiratory syncytial, influenzae, and parainfluenzae. 12 , 15,25,47,86,87 A synergistic effect of viruses and bacteria has been suggested as instrumental in the chronic bronchitic process. 52 Other observations argue against the role of infection. Pathologically, processes such as tracheobronchial mucous gland hypertrophy and increase in goblet cells, paralleled by metaplasia of the bronchial epithelium, are more prevalent than infection. 80 ,90 H. influenzae is currently regarded more as simply a saprophyte 64 albeit a potentially dangerous one. Other than in sputum, the pneumococcus is found in areas of bronchopneumonia only and is thought to be pathogenic only at the time of reversible acute superinfections. 64 Perhaps both organisms should be considered as noninvasive infectants. Stronger circumstantial evidence against the role of infection in chronic obstructive pulmonary disease has come from studies implying that antibiotic therapy or any therapy does not benefit the long-term course of the disease, at least as physiologically measurable. 8, 10, 15, 37, 85 Recently, more encouraging reports of the results of the application of energetic therapy have appeared. 70 To paraphrase Stuart-Harris,89 the purulent, bacteria-laden sputum of chronic bronchitis does not occur in normal lungs. As with pus in open wounds, the primary pathology may not be infection, but the presence of pyogeniC bacteria retards healing, produces inflammation, and often results in invasive infection. No tuberculosis-like process of a single, COB-

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tinuous, slowly extending infection is responsible for chronic bronchitis; but rather, an underlying pathologic process, however produced, allows a semi-saprophytic residence of bacteria with endless exacerbations and variable overall worsening or improvement>9 related to greater or lesser prevalence of bacteria or other microorganisms. Meanwhile, in clinical practice, office and hospital, if there is evidence of infection, it should be properly treated after adequate diagnosis .15.4;), RH

DIAGNOSIS OF CHRONIC INFECTION History Purulent sputum is the hallmark of infection in chronic bronchitis. The simple question, "Do you raise phlegm?" evokes an adequate answer from which more details can be pursued.:l1 Sputum and cough on most days for a minimum of 3 months and for not less than 2 successive years is sufficient for a tentative diagnosis of chronic bronchitis. 20 For purposes of detecting any bronchial infection, it is sufficient that sputum be present, and that it be purulent. Patient awareness of purulence is not always reliable,31 and the physician must carefully elicit the description of color and consistency. It may be simpler and more reliable to have the patient produce a specimen, when possible (often produced spontaneously during the maneuvers of a thorough chest examination). . Cough without sputum does not mean infection is absent. Women, especially, who may be more fastidious, and children, often swallow the phlegm. Successful expectoration may lessen or even be absent in more advanced obstructive lung disease, as infection occurs where damage is greatest and cough propulsion is least. Purulent mucus may inspissate, block the lumina, and lead to more infection, atelectasis, and destruction distally.36 Systemic signs of infection are often absent in chronic bronchial infection: fever does not usually appear (except during major superinfections), chills are uncommon, and leukocytosis is usually not present. 59 Some systemic effects such as sweating, particularly at night, loss of appetite, general debility, malaise, and interference with erythropoiesis do occur. Separating infection from hypoxia, hypercapnia, and other factors as a cause of symptoms in advanced COPD may be impossible.

Physical Examination The patient with chronic infection, i.e., chronic purulent bronchitis, is more likely to be, or to become, a "blue bloater" or "type B" (of chronic airway obstructive disease), in contrast to the chiefly emphysematous "pink puffer" or "type A." As a "blue bloater," he is more likely to be corpulent, less aware of dyspnea, tending toward a plethoric, cyanotic appearance, and prone to develop heart failure earlier. But many patients, including those with severe infection, will not fit a clear-cut type, manifesting varying features of each.!l.:lO Observing the sputum during the physical examination, and the way

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it is produced, is absolutely necessary. The usual source of purulent sputum is the lung, even in the patient who insists it comes from the "back of his throat" (although admittedly an ENT specialist may hold an opposite view). Examination of the nares, paranasal sinuses, and retropharynx will identify the "post-nasal dripper," but he, too, is often a bronchitic as well. In chronic bronchitis, auscultation of the lung reveals roughened breath sounds; rhonchi are usually present, but not always; rales are not usually heard consistently unless concomitant pneumonitis or interstitial fibrosis is present. In emphysema, breath sounds may be faint, even when infection is severe. X-Ray Examination Routine chest x-ray films usually fail to reveal direct evidence of bronchial infection, other than nonspecific thickening of the bronchial walls. If voluminous, purulent sputum is present, bronchiectasis should be suspected and bronchography done. In chronic bronchitis, bronchograms, although not necessary for diagnosis, would show small diverticula protruding from bronchial lumina into orifices of ectatic glands, and distortion of luminal contours by altered bronchial architecture and by filling defects from the presence of tenacious secretions. 81 The detection of emphysema by radiolucency and flattened diaphragms is not sufficient evidence of infection.

Sputum The critical procedure of sputum examination is simple and straightforward: (1) gross examination, (2) microscopic examination, and (3) culture and sensitivity. Yet many questions are asked: Is it from the lung? Does it represent an infectious process in the lung? Does culture predominance reflect pathogenicity? Are organisms cultured from the lung, or are they oral contaminants? Is antibiotic therapy contraindicated if only "normal flora" are found? GROSS EXAMINATION. The purulence of sputum should be readily apparent as small to large masses of translucent to opaque cream, yellow, green, or brown colored mucus. Purulence, per se, is not synonymous with infection; the sputum of allergic or asthmatic bronchitis may appear quite purulent, yet be found to be composed of a conglomeration of eosinophils,27 granulocytes, and lymphocytes, but without pyogenic organisms. In such instances, it is not the infection but the cellular constituents and debris which produce the purulence. There is much concern over contamination of sputum by oral flora. Bronchoscopy or transtracheal catheterization has been advocated for purest specimen collection,5, 36, 68, 69, 76 but is controversial and probably not necessary for routine use in simple exacerbations of chronic bronchitis. 46 , 55, 89 Washing the specimen in a sterile gauze with saline, or more simply in a tea strainer with tap water, has also been recommended,2 but probably is not necessary.46 If sputum cannot be easily produced, expectoration will be aided by aerosol administration of surface-active agents such as N -acetylcysteine, xyloxapol, or even distilled water. 65

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MICROSCOPIC EXAMINATION. The specimen for microscopic examination (and for culture and sensitivity) must be selected from within the thick, cell-laden mucus. Although teasing out a portion of a large mucous plug may be unpleasant, it is in omitting this careful step in selecting a specimen that a great source of error occurs. Placing the adherent mass on a slide and using the edge of another slide to "cut out" a portion is an easy procedure. Merely dipping a wire loop into a specimen and pulling it out only provides watery material that is not representative of secretions from within the lung.17 Homogenization of sputum with the same mucolytic agents as used in aerosols may facilitate the procedure and increase reliability.46.7s Direct microscopic examination of an unstained wet mount under a coverslip confirms the bronchial tree as the source if respiratory epithelial cells are found, and will also allow detection of yeasts and other fungi, and parasites (rare, yet rewarding when found). Buffered crystal violet mixed with the specimen in equal amounts improves visualizationY Thin smears should be stained by Gram and by Wright techniques. The Gram stain (of a fresh specimen) gives the best and most rapid indication of type and predominance of bacteria, and also identifies those bacteria phagocytized by histiocytes, macrophages, and leukocytes. The initial selection of antibiotics should be based on these early observations. R8 It is acknowledged that lack of confidence in the Gram stain is expressed by some. 36 The most common pathogenic bacteria found are (1) the gram-positive lanceolate, Diplococcus pneumoniae, and (2) the gram-negative, short, bacilli Hemophilus influenzae, sometimes occurring in short chains. D. pneumoniae may be difficult to distinguish from the very common "normal flora" alpha streptococcus. The other most common "normal flora" bacterium is the easier-to-detect gram-negative, biscuitshaped, diplococcus, Neisseria catarrhalis. The Wright's stained smear distinguishes eosinophils from other reticuloendothelial cells. In allergic disorders of the bronchus, eosinophils are usually found, often in large amounts. Allergy may still be present although eosinophils are absent. Sputum eosinophilia does not absolutely rule out infection since the two conditions often coexist. Leukocytes and other reticuloendothelial cells, ciliated columnar cells, goblet cells, and other cellular components of the bronchoalveolar tree may be inspected. Cellular analysis is, at present, more a research tool than routine. New useful information is being obtained, however, and cytologic examination may soon help provide a better diagnosis of chronic bronchitis and other non-neoplastic pulmonary diseases. 59 CULTURE. For culture of the selected specimen (which must be from within the purulent lung-produced mucus), blood agar plating is adequate for most pathogens. H. influenzae is best cultured on an enriched media such as "Levinthal agar," or "chocolate" agar; Saponin V disks have been recommended more recently.21 Many clinical laboratories report pneumococcal growth much more frequently than H. influenzae; quantitative studies have shown the opposite. 22 Identification of most bacteria is available in 24 hours. Standardized disk sensitivities,3 properly performed, are most practical for determining antibiotic sensitivity.

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Predominance of growth on culture is not always a true reflection of prevalence in the lung. 46 Quantitative sputum cultures-analogous to techniques standard with urine-have been recently advocated in an attempt to establish greater reliability of the infectivity of pathogenic organisms. 46 . 75 Lack of value has been found by some,36 but greater reliability, compared to usual techniques, is evident. 46 • 75 It is, however, unlikely that this tedious modification of culture technique will become routine. Often only "normal flora" are found on culture of very purulent sputum. This finding remains a problem therapeutically; viruses or myocoplasma may be suspected but are not found frequently enough to explain the findings. Therapeutic antibiotic trials often clear the sputum in such cases. Studies of anaerobic bacteria in chronic bronchitis and emphysema are conspicuous by their absence from the literature; anaerobes fail to grow in routine culture methods described, and could perhaps explain apparently infected sputum with no pathogens on culture. Other Studies Viruses, particularly the rhinoviruses,12. IS. 25. 86. 87. 89 are implicated in exacerbations of chronic bronchitis, but not to the same degree as bacteriaY Academic importance is attached to identification of these viruses by tissue culture or by antibody response. The practical value of virus identification is low at present in the absence of readily available antiviral agents, but can be an aid in differential diagnosis and perhaps in avoiding unnecessary antibacterial efforts. The expiratory flow rates of pulmonary function tests are poor predictors of the degree of chronic bronchitis54 and, by implication, of infection. Superinfections in COPD are a major cause of arterial hypoxemia l9 which could be best detected by arterial blood gas studies.

TREATMENT OF CHRONIC INFECTION In patients with chronic infection or infectious exacerbations in chronic bronchitis and emphysema, antibiotic therapy should be applied whenever infection is apparent. Initial antibiotic selection is best when guided by the Gram stain appearance of the sputum; in less urgent conditions, one may wish to wait for the sensitivity results of culture. That neither of these guides is used adequately is evident in many hospitals. 26 Ampicillin, in adequate dosages of 500 mg. four times daily, is the preferred drug in "virgin" cases. I. 18. 73 Its broad spectrum, bacteriostatic action, and easily achieved therapeutic levels with oral administration make it well suited for therapy even in instances in which sputum studies cannot be, or are not, obtained. Interference with the action of ampicillin against H. influenzae by the "indirect pathogenicity" of penicillinase-producing enterobacteria has been described. 53 Concomitant administration of penicillinase inhibitor (cloxacillin) overcame this situation. 53 Alternative choices when allergy to penicillin is present are the tetracyclines, which, before ampicillin, were found to be the most effective

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antibiotics in studies in Great Britain. 10. IH Dosages of 250 mg. four times daily have been fairly successful; larger doses may be necessary to provide adequate inhibitor concentration in bronchial secretions. 11 In long-term use, ampicillin and tetracycline have been attended by the greatest diminution in days of prostrating illness or days lost from work, and by disappearance of pathogens from the sputum. 'O • '1" Distressing reports of tetracycline-resistant pneumococci have appeared."'· H" The newer, longer-acting, slowly excreted tetracyclines have been suggested as particularly suited for use in respiratory infections,"4. g, and their once, or twice, daily only dosage should insure better patient adherence to dosage schedules. When intolerance is noted, or poor results of applied anti-infective therapy are obtained, other antibiotics should be tried; discontinuing therapy too early is a frequent error of the impatient, looking for faster results, or by the hasty, thinking maximum benefit has been obtained. Other agents found useful are cephalothin (Cephalexin),93 clindamycin, and erythromycin. Chloramphenicol has been efficacious, but its well-described hematologic toxicity makes its use, particularly in recurrent or chronic regimens, inadvisable; sulfas have been used with less success. For antibiotic usage, the following plan is recommended: 1. P.R.N. therapy (for the patient with no, or infrequent, previous treatment): An appropriate antibiotic continued long enough to eradicate evidence of infection for at least several days. Even when gram stains and culture reveal only "normal flora" such as N. catarrhalis and alpha streptococcus (and providing the sputum is not eosinophil-laden), a trial of antibiotics in adequate doses will usually provide remarkable clearing of purulence with reduction in symptoms. 2. Periodic therapy (for the patient who has frequent repeated infections, each responding to p.r.n. therapy, even though only partially): A minimum of 5 to 10 days of antibiotic therapy at timed intervals more frequent than the expected recurrence of the exacerbations, i.e., monthly antibiotic treatment periods for exacerbations usually occurring every 2 months. The same antibiotics may be used each time if the known offending organism is usually the same. Two (or more) drugs may be used alternately (or sequentially) in an attempt to control superinfections due to resistant bacteria. 3. Continuous "chemoprophylaxis" (when the procedures outlined above are not successful and exacerbations still occur in non treatment periods): Select the antibiotic to which identified pathogens have been most often sensitive. Ampicillin has the best track record for such uses, but expense is great if a 500 mg. four times daily regimen is to be maintained; tetracycline is less expensive. ANCILLARY THERAPY. Antibiotic therapy is only one aspect of the treatment of chronic bronchitis and emphysema; it will not be successful if other aspects of these diseases are ignored. Smoking or exposure to other irritants must cease, completely. Expectorants should be used where tenacious sputum is present, or suspected, in adequate dosages: 15 to 30 cc. (300 to 600 mg.) of glyceryl guiacolate four times daily is necessary (not the usual 100 to 200 mg. ad-

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vised on the label), or 15 drops of saturated solution of potassium iodide four times daily. Our use of expectorants is sadly hampered, however, by lack of adequate knowledge of action and effect. Inhalation of mucolytic agents such as N-actylcysteine should be considered. Bronchodilators should be included, for obvious reasons, in almost every instance; their dosage, route, etc., should be individualized. Physical therapy - postural drainage, cupping, etc. - is recommended as part of a comprehensive regimen. Confirmation of true benefit is controversial, but in individual cases remarkable benefit may be obtained. Steroids will reduce inflammation in resistant cases, or those complicated by hypersensitivity, and may facilitate access of the antibacterial agent to the bacteria. Caution is required because of the notorious side effects of the adrenocortical hormones, and because more frequent opportunistic infections with antibiotic-resistant organisms are encountered. The use of antibiotics and ancillary therapy may give results ranging from remarkable clinical improvement to no benefit at all. No beneficial alteration of the course of chronic bronchitis or emphysema by antibiotic or other long-term therapy is claimed by some, based on prospective studies. 8, 10,85 But specific effect of therapy as compared to nontreated controls is difficult since a control group, once identified, does not go untreated. Most investigators nevertheless recognize that acute or extreme events in these same patients respond to treatment. More recently, reports have appeared of improved status following multifaceted therapy with the admonition that maximal systematic care must be applied to all patients to find those persons who may show some degree of reversibility.70 Rational individualization based on thorough investigation is advisable, rather than "shotgun" therapy.

SUPERINFECTIONS IN SEVERE CHRONIC OBSTRUCTIVE PULMONARY DISEASE Major superinfections in patients with chronic obstructive pulmonary disease are likely to occur, the frequency and severity of the infection being proportional to the severity of the chronic obstructive pulmonary disease. In addition to lung damage and endogenous factors alluded to in the pathogenesis of COPD, other conditions facilitate infection in these patients. Any deviation from usual oxygen tension in the inspired air, high or low, has an adverse effect on mucus flow. 50 High oxygen is also toxic to alveolar macrophages. 42 High carbon dioxide levels similarly interfere with lung cleansing mechanisms. The many solutions and agents used in inhalation therapy also may have detrimental effects as yet not well identified. These superinfections tend to be of three types: (1) the usual bronchoalveolar, (2) nosocomial, and (3) opportunistic. 1. The usual bronchopneumonias are more frequent in chronic obstructive pulmonary disease and may be regarded as an extension or worsening of the exacerbations referred to above. D. pneumoniae is the pathogen most often responsible; other pathogens such as H. influenzae are less frequent. 45 Only certain salient features of diagnosis and therapy will be mentioned:

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The physical and x-ray findings of bronchopneumonia in chronic obstructive pulmonary disease may seem falsely minimal in contrast to the apparent severity of illness in the patient. In advanced emphysema, the remaining available, relatively normal parenchyma which may become infected is present only in small and widely scattered islands separated by empty and silent blebs, bullae, and emphysematous spaces. 1Ol Impairment of pulmonary function may be major, contrasting with the apparently minimal involvement by x-ray examination or auscultation. Inhalation therapy is essential for adequate oxygenation, ventilation, and clearance of infectious secretions. Antibiotic therapy must last long enough to assure complete healing, and in dosages and routes providing adequate tissue levels in poorly vascularized, often fibrotic lungs. If viral pneumonitis occurs, it may be severe, and for this reason immunization against epidemic influenza is recommended in patients with severe COPD. 2. Nosocomial infections in chronic obstructive pulmonary disease come about from bacterial (usually Pseudomonas or Klebsiella) contamination of the solutions so often used in inhalation therapy of the advanced case. 60 Pseudomonas infection is the major problem. Growth of this organism occurs in nebulizer reservoirs, a~rosol solutions, and even open distilled water containers. 28 , 63, 71 Prevention is easily accomplished by periodically nebulizing dilute acetic acid through the inhalation therapy devices (caution: the acetic acid solution must not be inhaled), anq by proper handling to keep solutions sterile.72 Treatment of Pseudomonas is necessary if clinical infection is evident by fever or pulmonary infiltrates. Parenteral therapy in the hospital with potentially dangerous antibiotics (usually nephrotoxic) is usually required. A combination of gentamycin and carbenicillin has recently been found most effective, but complete eradication is not often achieved. 99 Indeed, if purulent sputum loaded with Pseudomonas is the only evidence of infection, dangerous or exhaustive treatment may not be necessary. Nonspecific measures promoting better bronchodilation, ventilation, sputum liquefaction, and drainage may be sufficient. Immunization against Pseudomonas has been used to protect burn patients. 82 • 93 This technique may be applicable in severe COPD. Staphylococcal infections may also be similarly induced from organisms carried by hospital equipment, solutions, and personnel, but are less frequent than formerly. Penicillinase-resistant antibiotics are effective in treatment. 3. Opportunistic infections are those due to usually nonpathogenic ubiquitous organisms which become invasive in the presence of altered defense mechanisms, as in the use of immunosuppressive drugs in organ transplants, malignancy, etc. In patients very ill with chronic obstructive pulmonary disease, the use of steroids and antibiotics facilitates infections of this type. Monilia,t4 aspergillus, and other fungi have caused severe local or systemic illnesses. Aspergillus produces the complex syndrome of "bronchopulmonary aspergillosis" in asthmatics, producing bronchospasm and recurrent fever and pulmonary infiltrates. Probably more common than previously

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suspected, aspergillosis can be detected by immediate wheal response to intradermal testing followed by a delayed erythema and edema 24 to 36 hours later. Aspergillus is found in the sputum and is there probably as a noninvasive infection. Treatment with steroids alone is sufficient, surprisingly, without need for antimycotic agents to remove the offender. 44 It is more likely that when steroids and antibiotics are used in severe COPD, superinfections will be by bacteria resistant to that antibiotic. The most common offenders are Pseudomonas, Escherichia coli, Proteus, staphylococcus, and anaerobic bacteria (special cultures required). Antibiotics are determined by sensitivities of the bacteria. Treatment often becomes difficult, requiring a sequence of antibiotics to fit the most recently found offender, a game of antibiotic musical chairs. Maximum use of ancillary treatment is essential.

SUMMARY OF RECOMMENDATIONS 1. All respiratory infections in childhood or even later should be treated to maximal benefit. This may be a factor in prevention of COPD. 2. Exogenous factors, particularly smoking and to a lesser extent urban and occupational air pollution, which facilitate infection, should be avoided especially at times of infection or in those susceptible because of impaired defense mechanisms. 3. Chronic infection in chronic bronchitis and emphysema should be properly diagnosed and optimally treated with antibiotics in accordance with the plan outlined, including expectorants, bronchodilators, and other ancillary therapy. 4. Superinfections occur in proportion to the severity of the underlying lung damage and require accurate diagnosis and energetic treatment. Prevention of superinfections in hospitalized patients is possible with proper precautions. Infection remains a major factor and problem in chronic bronchitis and emphysema, but there is much debate about the exact role it plays. Knowing when and how to treat (or not to treat): that is the question.

REFERENCES 1. Allan, G. W., Fallon, R. J., Leese, A. W., et al.: A comparison between ampicillin and tetracycline in purulent chronic bronchitis. Brit. J. Dis. Chest, 60:40-43, 1966. 2. Bartiett, J., and Finegold, S. M.: Improved technique to process coughed sputum for culture. Clin. Res., 19:183 (Jan.) 1971. 3. Bauer, A. W., Kirby, W. M. M., Sherris, J. C., et al.: Antibiotic susceptibility testing by a standardized single disk method. Amer. J. Clin. Path., 45:493-496 (April) 1966. 4. Berven, H.: Studies on the cardiopulmonary function in the post-infectious phase of "atypical" pneumonia. Acta. Med. Scand., Supp!. 382,1962, pp. 71-75. 5. Brumfitt, W., Willoughby, M. L. N., and Bromley, L. L.: An evaluation of sputum examination in chronic bronchitis. Lancet, 2:1306-1308 (Dec 28) 1957. 6. Buckley, C. E., Ill, Dorsey, F. C., and Sieker, H. 0.: lmmunophysiologic correlations in chronic respiratory disease (abstract). Clin. Res., 20:635 (April) 1972. 7. Burns, M. W.: Precipitins to pneumococcal c-substance polysaccharide in the serum of patients with chronic bronchial disorders. Lancet, 1 :223-224 (Feb 3) 1968. 8. Burrows, B., and Earle, R. H.: Course of prognosis of chronic obstructive lung disease: A prospective study of 200 patients. New Eng. J. Med., 280:397-404 (Feb. 20) 1969 ..

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