Overwhelming pneumonia

-\ i Y@-

John Segreti, MD., graduated summa cum laude from Loyola University in Chicago before receiving his medical education from Rush Medical College. While a resident in internal medicine at Rush-Presbyterian-St. Luke’s he received the Department of Medicine Award for Outstanding Medical Resident. Dr. Segreti completed a 2-year fellowship in infectious diseases at Rush-Presbyterian-St. Luke’s in 1985. He is presently a member of the faculty as Instructor and an attending physician in the Department of Medicine, Section of Infectious Diseases.

Roger C, Bone, M.D., is a graduate of the University of Arkansas School of Medicine. After completing an internship and residency in internal medicine at Parkland Memorial Hospital in Dallas, he undertook a fellowship in the Cardiopulmonary Section of the Department of Medicine at the University of Texas Southwestern Medical School. Dr. Bone returned to the University of Arkansas School of Medicine to join the faculty, where he received the Outstanding Teacher Award on three occasions. In 1984$ he joined the faculty of Rush Medical College where he is presently Ralph Crissman Brown Professor and Chairman of Medicine and Chief of the Section of Pulmonary Medicine and Critical Care. Dr. Bone is board-certified in internal medicine and pulmonary medicine. He is Chairman of the American College of Chest Physicians Fellowship Award Committee, on the American Board of Internal Medicine Subspecialty Board on Pulmonary Diseases, President of the Chicago Thoracic Society and, with this issue, Editor-in-chief of Disease-a-Month. 10

OVERWHELMING

PNEUMONIA

Despite recent advances in diagnosis and therapy, pneumonia remains a major cause of morbidity and mortality. While pathogens usually associated with pneumonia, such as Streptococcus pneumoniae, Mycoplasma pneumoniae, and viruses, remain important etiologic agents, a wide variety of “new” pathogens, organisms once thought to be “non-pathogens,” and microbes with changing antimicrobial susceptibilities are increasingly isolated from both “normal” and immunocompromised hosts (Table 11.’ We will review the etiologies of overwhelming pneumonia that can lead to acute respiratory failure. We will examine the currently available diagnostic modalities, review the etiology and therapy of community-acquired pneumonia, and discuss nosocomial pneumonia and pneumonia in the immunocompromised host. Pneumonia occurs when a microbe invades the normally sterile lung parenchyma. An organism may arrive hematogenously from an extrapulmonary source, or may be introduced directly, as by penetrating chest wounds. Most commonly, organisms are introduced by aspiration of one’s own oropharyngeal secretions. Once present in the lower respiratory tract, microbes must overcome an elaborate array of defenses in order to proliferate and cause clinical disease. In the upper airway, these defense mechanisms include anatomic barriers (such as nasopharyngeal filtration and the epiglottis) that protect the lower respiratory tract from aspiration of large particles.’ An adhesion barrier exists that resists mucosal colonization of potential pathogens in the upper airway. The normal upper respiratory flora also prevents colonization. Saliva contains proteases, lysozymes, and IgA that may help prevent colonization.’ In the lower respiratory tract, tracheobronchial sensitivity allows the patient to cough and expel aspirated respiratory secretions from the trachea. A mucociliary clearance mechanism exists that physically removes bacteria from the lung. A variety of humoral substances, such as immunoglobulin and complement, may be important for bacterial opsonization and lysis. Bronchoalveolar lymphocytes, alveolar macrophages, and the influx of granulocytes into the lung tissue constitute the cellular components of lower airway defense! When functioning properly, invading microbes are eliminated and clinical disease is DM,January1987

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TABLE Agents

1. Causing

viruses

Bacteria

Overwhelming

Pneumonia

“NORMAL”

HOST

Influenza Adenovirus Respiratory

A & B syncytial

“IMMUNOCOMPROMISED” HOST

virus

Streptococcus pneumoniae Staphylococcus aureus Hemophilus injluenzae Legionella sp. Mixed anaerubes Francisella tularensis Streptococcus pyogenes Yersinia pestis Pseudomonas pseudomallei

Bacteria-like organisms

Mycoplasma pneumoniae Chlamydia psittaci Co)tiella burnetti

Fungi

Coccidioides Histoplasma Blastomyces

immitis capsulatum dermatitidis

Herpes simplex Cytomegalovirus Adenovirus Legionella sp. Enterubacteriaceae Pseudomonas aeruginosa staphylococcus JK bacillus Nocardia sp. Listeria monocytogenes

sp.

candida sp. Aspergillus

sp. cryptococcus

neoformans Mucor sp. Sporothri)r schenkii Mycobacteria

Parasites

Mycobacterium tuberculosis

Mycobacterium tuberculosis Mycobacterium-avium intracellulare Pneumocystis Strongyloides stercoralis

carinii

avoided. Pneumonia results when these defenses are impaired, or when they are overcome by a large number of organisms or by organisms of unusual virulence. Invading microbes adhere to alveolar macrophages, and a chemotactic substance relatively specific for neutrophils is released by the macrophages.3’4 Once summoned, these neutrophils release proteases which can, in turn, activate the complement cascade, the kinin system, and fibrinolysis. Products of the kinin system, such as bradykinin, induce a capillary leak resulting in accumulation of exudated fluid in the interstitium and alveoli.5 Consequently, gas exchange in these areas is severely compromised. Although blood flow to this area decreases, a ventilation-perfusion mismatch may result, which, if severe, can lead to arterial hypoxemia. The interstitial fluid causes diminished lung compliance and thus increases the work of 12

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1987

breathing, potentially leading to respiratory muscle fatigue and hypoventilation. The proteases released by the neutrophils may also activate various mediators of inflammation that have been implicated in the pathogenesis of the intense inflammatory response in the lung, resulting in the clinical syndrome known as the adult respiratory distress syndrome L4RDS).6 The lower respiratory tract infections that result can be described in terms of pathologic appearance, radiologic appearance, or clinical presentation. While all these classifications are useful to some degree, every effort should be made to identify the specific etiologic agent. Once identified, specific antimicrobial therapy can be substituted for a “shotgun” approach. A definitive etiologv can be ascribed when a microbe is isolated from blood. If blood cultures are negative, a variety of noninvasive and invasive tests may be required to establish a diagnosis. NONINVASIVE

DIAGNOSTIC

TECHNIQUE3

Sputum Gram’s stain and culture are the traditional methods used to diagnose the bacterial cause of pneumonia. Both are noninvasive, and, although the sputum culture requires 18 to 24 hours, the Gram’s stain can give valuable information in a matter of minutes. Prior to initiation of antibiotics, Gram-stained samples should be examined for leukocytes and squamous epithelial cells.“’ The presence of more than 25 epithelial cells per field at 100 X magnification indicates contamination with oral flora (Fig 1). On the other hand, finding less than 10 epithelial cells per field, along with more than 25 leukocytes per field, suggests that the specimen actually represents lower respiratory tract secretions.’ In a study at the Mayo Clinic, Rochester, Minn., however, only 25% of the sputum specimens submitted to the clinical microbiology laboratory fit the latter criteria.7 The morphology and the staining characteristics of bacteria seen in the leukocyte-predominant fields should be noted and the preponderant organism recorded. This method has proved useful for the identification of Streptococcus pneumoniae in the sputum.’ Sputum should be read as positive only if more than ten gram-positive lancet-shaped diplococci are seen per oil immersion field (1,000 X magnification) or there is a predominance of this organism on the slide (Fig 21.” Whether this approach is equally useful for the identification of other causes of pneumonia is unclear. Stains for acidfast bacteria, a potassium hydroxide preparation, and a methanamine silver nitrate stain should be performed on sputum if mycobacteria, fungi, or Pneumocystis carinii, respectively, are possible etiologies. Cultures of expectorated sputum are less reliable than microscopic examination.‘* Not only can fastidious organisms such as S. pneumoniae and Hemophilus influenzae be missed, but cultures ofDM,

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13

FIG 1. The presence contamination

of more than 25 epithelial cells per low-power field indicates and makes the results of sputum culture meaningless.

oropharyngeal

FIG 2. Finding more than tive of pneumococcal 14

10 gram-positive pneumonia.

diplococci

per oil-immersion

field

is strongly

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ten yield multiple organisms, several of which are potential pathogens.ll Unfortunately, it is difficult to tell whether these bacteria are the etiology of the pneumonia or are merely colonizing the upper respiratory tract. This may result in initiation of unnecessary or inappropriate antibiotics. Semiquantitative cultures, washing of sputum samples, and the use of mucolytic agents have been proposed to improve the clinical utility of sputum cultures; however, results have been variable and the practicality of these techniques for routine use has been questioned.“’ l3 INVASIVE

DIAGNOSTIC

TECHNIQUES

Transtracheal aspiration (ITA) has been suggested as an alternative method of obtaining lower respiratory secretions.14815 When done correctly and in the proper clinical setting, TI’A has been shown to be safe and the cultures obtained are more reliable than expectorated sputum cultures.14’ l5 In general, TTAs are less often contaminated.7 Nonetheless, false-positive cultures do occur.15-‘7 Transtracheal aspiration is not without risk. Cases of fatal hemorrhage, sudden death, paratracheal infection, pneumothorax, and mediastinal emphysema have been described.1~20 This procedure should not be performed on patients with significant hemostatic abnormalities, especially thrombocytopenia.21 Caution should be observed in patients with uncontrollable cough and patients who cannot or will not cooperate. Transtracheal aspiration should be done only by a properly trained physician thoroughly familiar with the technique. Even then, TTA is sufficiently traumatic that it is best reserved for the obtunded patient who is unable to produce an adequate sputum sample.14 If a pathogen is not isolated with the above techniques, or the patient fails to respond to empiric antibiotic therapy, more invasive diagnostic procedures must be considered. Percutaneous lung biopsy, fiberoptic bronchoscopy and biopsy, and open lung biopsy are all potentially useful in this setting. Percutaneous lung biopsy allows the sampling of the lower respiratory tract without fear of upper airway contamination. Needle aspiration, needle biopsy, and trephine biopsy of the lung represent the techniques available. Current opinion, however, favors the use of needle aspiration under fluoroscopic guidance in the diagnosis of localized pulmonary disease because of the high rate of complications with needle and trephine biopsy.21’22 Sappington and Favorite were the first to demonstrate the clinical and microbiologic utility of pulmonary needle aspiration.23 Later, Davidson et al. compared the usefulness of lung aspiration, ‘ITA, and expectorated sputum in 25 Navajo Indians with acute, untreated community-acquired pneumonia.16 Twenty lung aspirations resulted in the culture of a pathogen, 17 of which grew S. pneumoniae. MulDM,

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tiple organisms were grown in all the expectorated sputum cultures and in 41% of the ITA cultures. Twenty-seven percent of the TTA cultures grew more than one potential pathogen. When done on a compliant patient and under fluoroscopy, aspiration lung biopsy has a relatively low rate of complication.21’24-26 The most common complication is pneumothorax, which occurs in approximately 25% of patients. About one half of the patients with pneumothorax will require chest tube drainage. Hemoptysis may occur in up to 5% of patients, but is almost always self-limited. Bleeding is more common in patients with thrombocytopenia and/or a prolonged prothrombin time. Extension of infection to the pleura with subsequent empyema formation has been reported, but is exceedingly rare.‘l An unusual but life-threatening complication is air embolism. But this risk is decreased considerably by carefully instructed breathing on the part of the patient.‘l The incidence of pneumothorax is highest in needle aspiration of mediastinal lesions and cavitating lesions.26 Lesions along the pleural surface and in the periphery of the lung have the fewest complications at biopsy.26 It is advisable to avoid lung aspiration on patients with bullous lung disease and patients requiring ventilatory supportzl Flexible fiberoptic bronchoscopy (FFB) is a safe, common, easily performed procedure that is well tolerated by most patients. The endobronchial tree is visualized directly and specimens may be obtained for culture. However, the reliability of bronchoscopy as a method of obtaining culture material is doubtfuLz7 Flatauer et al. have stressed the importance of examining a Gram stain of bronchoscopic secretions, and others have suggested the use of quantitative cultures and antibody coating as means of increasing the reliability of bronchoscopic cultures.28z2g Recently Wimberley et al. introduced a bronchoscopic technique utilizing a plugged telescoping catheter brush (ETTCB).30In vivo and in vitro trials demonstrated little or no contamination with oral pharyngeal organisms. Subsequent reports, however, have shown variable results. Higuchi et al. had a false-positive rate of only 10% in a primate pneumonia model and a false-negative rate of 30% .31 Others have found false-positive rates of 63% to 84% .32J33Such disparity may be attributed to differences in technique, such as in the delivery of topical anesthesia, method of suctioning, and whether quantitative cultures are performed.34’35 In addition to sampling lower respiratory secretions, FFB affords the opportunity to biopsy lung tissue. Transbronchial biopsy (TBB) provides a specific diagnosis in 26% to 68% of patients, with most investigators reporting true positive yield of 38% to 46Y0.~“~’ Generally, a higher diagnostic yield is obtained in patients with diffuse rather than focal pulmonary lesions on chest roentgenogram.41 Flexible fiberoptic bronchoscopy is a safe procedure. Postbronchoscopy fever with increasing infiltrates may be noted. Arterial hy16

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poxemia is common during bronchoscopy, and the use of supplemental oxygen has been stressed.‘l Pneumothorax may follow transbroncheal biopsy, but only 11 deaths were reported in two retrospective studies reviewing 72,000 procedures.43’44 Significant hemorrhage correlates with platelet count under 1OO,OOO/cumm, an abnormal prothrombin or a partial thromboplastin time, and the presence of the uremia.‘l When ‘ITA, FFB, and TBB do not yield the diagnosis, open lung biopsy may be considered. The diagnostic yield ranges from 55% to 91% and averages about 60% .21J40,45,46 Pneumothorax, aside from that expected at the time of thoracotomy, is the most common complication. Hemorrhagic complications are rare, presumably because bleeding can be controlled locally at the time of surgery. The overall complication rate was 11% in six combined series, a rate similar to that of FFB.‘* Matthay and Moritz were able to find only two definite biopsy-related deaths in 288 procedures-a mortality rate of only 0.6%? Recently, there has been growing interest in the detection of specific microbial antigens and bod.y fluids utilizing immunologic methods. This approach is not only very rapid, but potentially more specific than cultural techniques. These methods will be reviewed below. COMMUNITY-ACQUIRED Pneumococcal

PNEUMONIA

Pneumonia

STREPTOCOCCUS PNEUMONLAE Streptococcus pneumoniae is the most common cause of bacterial community-acquired pneumonia (CAP) accounting for more than 50% of cases in most studies.47-52 In some series pneumococcal pneumonia represents close to 80% of all the bacterial pneumonias .52 Pneumococci are common inhabitants of the human upper respiratory tract and have been isolated in 5% to 70% of normal adults .53 Carriage rates are highest in preschool children and adults in crowded conditions (such as barracks and open dormitories). The incidence of nasopharyngeal carriage decreases with age, and adults without children have lower carriage rates. The organism spreads via droplets, and pneumonia occurs when a carrier aspirates the colonizing bacteria.53 Following the introduction of the pneumococcus into the lower respiratory tree, there is an incubation period of one to three days. Many patients present with a single shaking chill, but the use of antipyretics often alters this classic presentation. Temperature is usually elevated, in the range of 102 to 106OF. Cough productive of purulent sputum is common, as is pleuritic chest pain. Signs and DM,

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symptoms at presentation may be more insidious in elderly and debilitated patients.54 In these patients temperature may be only slightly elevated if at all, and, occasionally, hypothermia is present.55 Chest auscultation often reveals evidence of consolidation, and a pleural friction rub may be heard. Patients with lower lobe pneumonias may also have abdominal symptoms such as abdominal pain and distention. Laboratory findings are not specific. Leukocytosis with a shift to immature forms is common and arterial blood gases often reveal decreased Paoz and Paco,.53 The chest roentgenogram may show lobar consolidation or patchy bronchopneumonia.56 Rarely, S. pneumoniae may cause a necrotizing or cavitating pneumonia.57’ 58 Since pneumonia follows aspiration, the initial lesion occurs in dependent lung segments. Usually, only a single lobe is involved, though two lobes can be involved in up to 25% of the patients, and three or more lobes in about 1% of the patients.56 Up to 50% of the patients will have pleural effusions if decubitus chest films are done; however, clinical empyema is ram5’ Although not generally recognized, patients with pneumococcal pneumonia can develop ARDS. Fruchtman et al. described ten patients with pneumococcal pneumonia who developed ARDS.” Five of these patients died despite institution of appropriate antibiotics and respiratory support. The authors suggest that ARDS may be more common than generally believed in the setting of bacteremic pneumococcal pneumonia, and that the development of ARDS may explain the persistent 25% mortality of this disease in the antibiotic era.61 The difficulty in identifying a specific bacterial etiology of pneumonia has been discussed. Cultures of expectorated sputum are often unreliable, and ‘ITA, bronchoscopy, and lung aspiration may be necessary in the severely ill patient. If the pneumococcus is isolated from blood or pleural fluid then the diagnosis is definite, but blood cultures are positive in under one third of patients and thoracentesis is rarely required.53 Various approaches have been attempted to improve the accuracy of the sputum examination in patients with presumed pneumococcal pneumonia. The quellung reaction provides rapid identification of the pneumococcus .62863 Others have advocated the use of counterimmunoelectrophoresis (CIE) or coagglutination for the identification of pneumococci in sputum.64 A potential problem with sputum CIE is the high rate of false positives in asymptomatic pneumococcal pharyngeal carriers.65 An advantage of sputum CIE or coagglutination is the continued ability to detect antigen after onset of antimicrobial therapy.66 It must be stressed that the reliability of antigen detection is dependent on an adequate sputum sample. The standard treatment of pneumococcal pneumonia consists of procaine penicillin G given intramuscularly at a dose of 300,000 to 600,000 units every 12 hours.53 Brewin et al. were unable to discern 18

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any advantage in the use of high-dose (20 million units per day) intravenous (IV) penicillin G in severely ill patients with pneumococcal pneumonia who did not have evidence of metastatic disease.67 Patients allergic to penicillin may be treated with erythromycin.53 In recent years antibiotic-resistant S. pneumoniae have been increasingly identified. Some pneumococci are intermediately resistant to penicillin G with minimum inhibitory concentrations (MIC) of 0.1 to 1.0 gnVm1.68’6g These are ten to one hundred times greater than the MIC of susceptible pneumococci. Although some patients with intermediately penicillin-resistant pneumococci respond to standard therapy, most patients, especially those with meningitis, require much higher doses of penicillin G or a different antibiotic.6s Even more frightening has been the emergence of multiply resistant pneumococci in South Africa in 1977.” These organisms were found to be resistant to penicillin, methicillin, ampicillin, cephalothin, erythromycin, chloramphenicol, tetracycline, and gentamicin. They were sensitive to vancomycin, &unpin, bacitracin, and novobiocin. Following the identification of the index case, a 3-year-old boy with pneumonia, 19% of the patients and 2% of the staff in one hospital were found to be asymptomatic nasopharyngeal carriers of this resistant organism. These bacteria do not produce a beta-lactamase, rather the mechanism of resistance seems to be due to alteration of penicillin-binding proteins (PBP), especially PBP 3.‘l The penicillin molecule is unable to bind to this protein and thereby is unable to interfere with cell wall production. Fortunately, penicillin resistance is uncommon in the United States, accounting for only about 3% of isolates.6g Since it is cumbersome for most clinical laboratories to perform tube or agar dilution assays on all pneumococci to determine in vitro susceptibilities, it is recommended that a 5 pg oxacillin disk be used to screen for penicillin resistance.6s A penicillin susceptible organism will have a zone of inhibition of greater than 20 mm, while resistant organisms have a diameter of less than 12 mm.72 The emergence of resistant pneumococci and the inability to alter the mortality of bacteremic pneumococcal pneumonia underscores the importance of prophylaxis. The currently available vaccine contains 23 different capsular polysaccharides, which accounts for approximately 90% of bacteremic pneumococcal pneumonia in the United States.73 It is recommended for patients with chronic underlying diseases, patients 60 years of age and older, patients 2 years of age and older with splenic dysfunction, and elderly institutionalized patients. It is not recommended for patients under 2 years of age or for pregnant women. Though the vaccine may not be as effective in elderly patients and immunosuppressed patients as it is in healthy young people, we still recommend it because the morbidity and mortality associated with pneumococcal pneumonia outweigh the low toxicity of the vaccine. Severe local and systemic reactions have DM, January 1987

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been common among adults given a second dose, thus most patients who have received the 14-valent pneumococcal vaccine should not be revaccinated.73

STREPTOCOCCUS

PYOGENES

Today S. pyogenes is a rare cause of pneumonia and when it occurs is usually associated with a preceding viral infection.74 Epidemics of this illness have been described in military recruits.74’75 The onset of symptoms is usually abrupt and can include high fever, chills, cough productive of purulent sputum, pleurisy, and, at times, hemoptysis. Empyema occurs in 30% to 40% of the cases and appears very early in the course of the disease.7b77 Blood cultures are positive in about 15% of cases. Mortality is low with penicillin therapy and drainage of the empyema, but prolonged antibiotic therapy may be required.

Legionnaire’s

Disease

Legionnaire’s disease came to the attention of the medical community and the U.S. public in 1976, when 182 cases of the disease occurred in an epidemic in Philadelphia.” Investigation of that outbreak demonstrated a wide spectrum of disease ranging from a mild flu-like syndrome to a severe pneumonia with ABDS requiring ventilatory support. The overall mortality rate was 17%. Subsequently, the bacterial etiology of this disease has been confirmed.7s A gramnegative bacterium was grown from the lungs of four patients at autopsy and was named Legionella pneumophila. Currently there are 11 recognized serotypes of L. pneumophila and several other species of Legionella causing human disease.8”-85 Legionella pneumophda can survive for long periods of time in water and has been found in moist soil.‘” This may explain the epidemiologic relation of the disease with recent excavation, air conditioner cooling towers, hospital shower heads, hospital humidifiers, respiratory devices, and even common tap water.87-8g Person to person spread was not demonstrated in either the Philadelphia or subsequent outbreaks, but may have a potential role in the pathogenesis of sporadic disease.Yo The incidence of community acquired Legionnaires’ disease has been estimated at 12/100,000 population/year in the United States, but this is probably a low figure.g1 Geographic variation is known to occur.52’ 92.93 Yu et al., in a prospective study at the Pittsburgh Veterans Administration, found Legionnaire’s disease to be responsible for 22.5% of community-acquired pneumonias attributable to a single pathogeng3 Legionnaires’ disease seems to be more frequent among males, persons 50 years of age and older, persons requiring renal dialysis or transplantation, smokers, immunosuppressed pa20

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tients, and persons with a co-morbid disease such as chronic bronchitis, emphysema, or diabetes mellitus.“, ” Legionella pneumonia can neither be diagnosed nor distinguished from non-Legionella disease solely on clinical or radiologic critefia.96, 97 A frequently used diagnostic tool is the indirect fluorescent antibody (IFA) assay. The diagnosis is established if a fourfold rise in antibody titer is demonstrated.” Some think that a presumptive diagnosis can be made if the IFA titer is greater than l/256, but such elevated titers have been found in 3% to 12% of normal controls.g2,s(C101 False-positive serology may occur in plague, tularemia, and leptospirosis,lo2 and the antibody rise may be delayed for up to three or more weeks.” Nonetheless, this test is positive in 80% of patients with Legionnaires’ disease.” A direct fluorescent antibody (DFA) staining procedure has been described for the rapid diagnosis of Legionnaires’ disease.lo3 Sputum or tissue can be examined by DFA and is positive in approximately 50% of patients with Legionnaires’ disease.” The DFA remains positive for about three days after the institution of appropriate antibiotic therapy.” False-positive DFA can occur with certain Pseudomonas species as well as other gram-negative bacteria, but the magnitude of this problem is uriclear.103 Culture of L. pneumophila from sputum and blood is possible, but few community hospitals routinely do this.” Rapid diagnosis of Legionnaires’ disease can also be made by detection of antigen in the urine of affected patients. Latex agglutination, radioimmunoassay WA) and ELISA methods have been developed for this purpose.104-‘06 Antigen can be detected in the urine even after antibiotics have been given, and the sensitivity of urinary antigen is reported to be about 80%.‘04-107 The mortality of Legionnaires’ disease ranges from 10% to 20% in the general population, but is over 80% in immunosuppressed patients.78’ 94,108,1’SIn vitro, L. pneumophila is sensitive to a variety of antibiotics, but such susceptibility studies are not standardized.“’ Erythromycin and tetracycline were shown retrospectively to diminish mortality in the Philadelphia outbreak, and erythromycin effectively decreased mortality in the Vermont epidemic.78, 7g Rifampin is very effective in vitro and in a guinea pig model of Legionnaires’ disease,11&112 but it should not be used as a single agent because of the potential danger of developing resistance. Legionella pneumophila can multiply within human phagocytes and thereby avoid killing.l13 Miller et al. demonstrated the ability of erythmmycin to penetrate the cytoplasm of human granulocytes and kill ingested L. can be given orally if the patient is not pneumophiZa.‘14 Erythmmycin very ill, but we recommend IV therapy, 1 gm every six hours, for the severely ill patient. Oral erythromycin may be substituted once the patient improves. Generally, erythromycin is given for two to three weeks. Unfortunately, there are no controlled studies to determine the optimal dose or duration of therapy. DM,

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Hemophilus

Influenzae

Hemophilus influenzae is more frequently recognized as an important cause of pneumonia accounting for 2% to 18% of all CAP.115,116 This may reflect either improved microbiologic technique or a true increase in the incidence of H. influenzae pneumonia. Hemophilus influenzae is an aerobic gram-negative pleomorphic organism that colonizes the sputum of 50% to 80% of otherwise healthy patients with chronic obstructive pulmonary disease.l17 While encapsulated strains, especially type b, predominate in pediatric pneumonia, nonencapsulated organisms are more likely to cause pneumonia in adults .ll’, “’ There are no clinical or roentgenographic criteria that distinguish H. influenzae pneumonia from other causes of CAP.120The use of CIE to identify antigen in sputum and blood is of uncertain efficacy due to the high incidence of colonization and the high frequency of nontypeable organisms causing disease. The treatment of H. injluenzae pneumonia is complicated by the increasing incidence of ampicillin resistance, which is due to production of a beta-lactamase.117’121 The incidence of resistance is up to 25% and is subject to geographical variation.lzl Therefore, it is prudent to be aware of the frequency of ampicillin resistance in the local community and hospital. Chloramphenicol is an alternative drug if the organism is ampicillin-resistant, and it is the drug of choice in penicillin-allergic patients.lzl The recently released second- and third-generation cephalosporins are very beta-lactamase stable and most H. infkenzae are exquisitely sensitive.122J123 Other effective agents include tetracycline and trimethoprim-sulfamethoxazole (TMP-SMX) .lzl

Staphylococcal

Pneumonia

Staphylococcus aureus pneumonia results from the aspiration of oropharyngeal secretion or from bacteremic spread and accounts for 2% to 10% of bacterial CAP.47,48 During outbreaks of influenza, S. aureus may be responsible for up to 20% of CAP.lz4 Indeed, the emergence of a few cases of S. aureus pneumonia in the community should suggest a possible influenza epidemic.lz5 There are no clinical or radiologic features typical of S. aureus pneumonia except possibly rapid cavitation of a bronchopneumonia and the development of an empyema.lz5 Hematogenous pneumonia is seen in the setting of right-sided endocarditis or venous septic thrombophlebitis, which should be considered in IV drug abusers, patients undergoing hemodialysis, and patients on home IV therapy.lz5 The diagnosis is based on identification of the organism in empyema fluid, blood, or lung aspirate. Sputum culture and Gram stain are unreliable, since up to 40% of adults are asymptomatic carriers.lz6 22

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Once S. azzreus pneumonia is suspected, IV therapy with a semisynthetic penicillin should be initiated. About 20% of community acquired S. aureus are penicillin G sensitive.lz5 For these organisms, penicillin G is more effective than the semisynthetic penicillins and remains the drug of choice.‘25 The recent identification of methicillin-resistant S. azzreus (MRSA) complicates matters somewhat. Although these organisms are usually nosocomially acquired, community-acquired MRSA infection can occur.127, *” The MRSA infections occur primarily in IV drug abusers and patients with severe underlying illnesses. The primary infections in drug abusers are cellulitis, endocarditis, and bacteremia.128 In non-drug abusers, on the other hand, pneumonia is common.128 The mechanism of resistance seems to be due to low affinity of the drug to PBP.lzg When methicillin resistance is suspected, initial therapy should include IV vancomycin.1308 13’ Although in vitro studies may show that these organisms are sensitive to first-generation cephalosporins, clinical response is generally poor.‘27, 13’ Other Bacteria A variety of gram-negative bacteria may occasionally cause community-acquired pneumonia. ZZZebsieZZapneumoniae is most often considered, but Escherichia coli, Acinetobacter, Yersinia, Serratia, Pseudomonas, and many other aerobic gram-negative rods may also cause disease.132-136 Although these organisms can infect previously healthy patients, they are more likely to cause disease in older patients and patients with chronic underlying diseases. Residents of nursing homes, diabetics, and alcoholics are more likely to have a community-acquired gram-negative pneumonia.13’ These patients have a higher frequency of pharyngeal colonization with gram-negative rods.137-142 The pathogenesis of gram-negative pneumonia is usually aspiration of oropharyngeal secretions. Less commonly, exogenous aspiration of aerosolized particles from a contaminated reservoir or bacteremic spread from an extrapulmonary source can occur.lyI There is little to distinguish among the various gram-negative bacilli causing pneumonia and indeed from other causes of CAP.143 The patient is often elderly and a history of recent hospital discharge or residence in a nursing home may be obtained. The classic findings of a bulging fissure on chest roentgenogram and currant jelly sputum are uncommon. Early necrosis and abscess formation may suggest a gram-negative bacterial etiology, but these can also be seen with pneumococcal, staphylococcal, LegioneIZa, and even myBlood cultures should be obtained, as 20% coplasma pneumonia.l‘@ to 30% of these patients are bacteremic. Mortality is very high, approaching 80% .I@ Initial therapy with an aminoglycoside with or DM, January 1987

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without a cephalosporin is usually adequate, but optimal therapy is based on identification of the specific organism and determination of antibiotic susceptibility. Tularemia, plague, and melioidosis are rare etiologies of pneumonia in the United States. However, it is important to consider these diseases, since they may be rapidly fatal and frequently do not respond to the usual empiric antibiotic therapies. Tularemia is due to Francisella tularensis, a small gram-negative coccobacillus found primarily in wild animals and blood-sucking arthropods.145 Humans can acquire tularemia either by direct contact with an infected animal, usually a rabbit, or a bite from an infected arthropod, usually a tick.145 Pulmonary involvement is seen in up to 20% of cases and may present an ARDS.145z146Tularemia pneumonia may present as a bronchopneumonia, lobar pneumonia, pleural effusion, cavity, or with a miliary patternI* The diagnosis requires a high level of suspicion. Patients should be questioned about exposure to wild animals and ticks. The organism is rarely seen on Gram stain and cultures are often negative, since the organism does not grow on ordinary media.‘jt5 Definitive diagnosis is almost always made retrospectively by demonstrating a fourfold rise in tularemia tube agglutination or microagglutination titers.‘& Streptomycin is the drug of choice, though gentamicin may be an acceptable alteror chloramphenicol may be used, but clinical native .145Tetracycline relapse is more likely than with streptomycin.145 Plague is a rare cause of human disease today, but it still occurs. The disease is due to Yersinia pestis, a pleomorphic gram-negative bacillus. Plague occurs worldwide, affecting a variety of mammals and arthropods. In the United States; infection is most likely in small mammals such as deer, mice, chipmunks, prairie dogs, and rabbits.147 Disease is spread by infected fleas. Human infection follows the bite of an infected flea or the handling of infected wild animals. Recently, domestic cats have been implicated as sources of infection.148’ ‘49 Most cases in the United States are reported in inhabitants or recent travelers to the southwestern states. More cases are reported in the spring and summer. Pulmonary involvement is noted in about 17% of human cases.147 Most are due to hematogenous spread rather than primary pneumonia.147 The diagnosis of plague pneumonia requires a high level of suspicion and the proper epidemiologic c1ues.147-14g Blood cultures should be obtained, as they are often positive.147 In fact, the bacteria can be noted on examination of Wright’s stain of peripheral blood smears.15’ All patients with plague pneumonia should be isolated since their sputum is very infectious. Streptomycin (30 mg/kg/day), tetracycline (30 to 50 mgkg/day), or chloramphenicol (50 to 75 mg&g/day) are usually effective. Acute pulmonary melioidosis is due to Pseudomonas pseudomallei and is potentially life-threatening.1”1’152 Melioidosis is endemic in the area between 20’N and ZOOSlatitude. This includes southeast Asia 24

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and northern Australia.152 In the United States, infection occurs only in persons who have traveled in endemic areas and includes the 2,500,OOO U.S. citizens who served in Vietnam. Illness may be acute, subacute, or chronic. Infection may remain latent for a number of years.151 It usually involved upper lobes, may cavitate, and thus imitate tuberculosis. The diagnosis requires a high level of suspicion and should be considered in travelers to endemic areas, especially in patients with roentgenographic appearance of tuberculosis from whom mycobacteria cannot be demonstrated. Blood cultures may be positive, as may cultures of pulmonary tissue. Severely ill patients should be treated with TMP-SMX and a third-generation cephalosporin such as ceftazidime.15’ Therapy should be continued for 30 days or longer.151 Aspiration

Syndromes

Aspiration pneumonia is almost always associated with an underlying condition that reduces the level of consciousness, interferes with esophageal motility, or mechanically disrupts the lower esophageal sphincter.153 Aspiration is common, but usually well tolerated. The development of pulmonary complications due to aspiration depends on the frequency, volume, and character of the aspirated material. Three distinct aspiration syndromes are generally defined: aspiration of toxic fluids, aspiration of particulate matter, and aspiration of bacteria.153 Mendelson was the first to recognize the importance of acidity in determining the extent of pulmonary injury independent of infection.155 In animal studies, lung injury was worse when the pH of the aspirate was less than 2.5.155,156 The volume and distribution of the acid aspirate was also important in determining the extent of injury. Toxic effects of this chemical burn are immediate. A capillary leak develops with exudation of fluid and protein into the alveoli and bronchi. Pulmonary edema and diminished lung compliance follow, as may severe hypotension. Within minutes, hypoxemia develops with arterial oxygen tensions of 35 to 50 torr and clinical ARDS often develops.153 In most clinical and animal studies, mortality ranges from 35% to 60%. ls3,156-15sTherapy of acid aspiration demands correction of hypoxia, which usually requires ventilatory support and positive end expiratory pressure (PEEP) .160Intravenous fluid support is important and a flow-directed pulmonary catheter is often critical to aid in optimal fluid therapy. Since the damage is almost immediate and since acid is neutralized within minutes, installation of buffering solutions is not advised.153 The empiric use of prophylactic antibiotics after an observed episode of aspiration is controversial. Although well-controlled clinical studies are lacking, retrospective reviews do not support this practice.157-16g2 lCil It seems logical to withhold antiDM,

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25

biotics initially and treat only if clinical evidence of infection occurs. When antibiotics are given, gram-negative bacilli, staphylococci, and mouth anaerobes should be treated. The use of steroids in the setting of aspiration pneumonia is controversial, but most recent studies do not support their use.16’-lM Aspiration of particulate matter causes variable degrees of respiratory obstruction. Large particles may lodge in the larynx or trachea and cause sudden respiratory distress and death.153 Smaller objects may reach the peripheral airways and cause bronchial irritation and obstruction followed by bacterial pneumonia, lung abscess, bronchiectasis, or empyema. Therapy involves relief of the obstruction and institution of antibiotic therapy if necessary.‘53 In contrast to the dramatic presentation of acid aspiration and the aspiration of particulate matter, aspiration of pathogenic bacteria usually is insidious in onset.153 The initial episode is seldom observed, but the diagnosis is suspected when a susceptible patient presents with fever, anemia, weight loss, and cough productive of foul-smelling sputum. Diseased gums and poor dental hygiene are often present.ls3 The chest roentgenogram may show either a bronchopneumonia or an abscess, depending on how recently aspiration has occurred. The posterior segments of the upper lobes and the superior segments of the lower lobes are most commonly affected if the patient aspirated in the supine position.153 Anaerobic bacteria are recovered from over 80% of the patients and are the exclusive isolate in about 50% of the patients.‘65 The mortality rate for anaerobic lung disease is about 10%.'"6-'66 Poor prognostic signs include old age, large abscess size, long duration of symptoms, serious underlying illness, and the presence of multiple abscesses.167 The treatment of anaerobic lung abscesses and empyema in the preantibiotic era consisted primarily of postural or surgical drainage .153While surgical drainage of an empyema remains an important treatment modality, surgical drainage of a lung abscess is often contraindicated because of the possible spread of infection and asphyxiation from spillage of cavity contents.‘6s Penicillin G is generally regarded as the preferred drug for treatment of anaerobic lung infection.153’165 Bacteroides fhgilis is present in up to 15% of patients with aspiration pneumonia or lung abscess and is resistant to penicillin G. Yet even these patients usually respond.‘65 Treatment of anaerobic pneumonia requires IV penicillin G, 10 to 20 million units per day for seven to ten days.165 A longer duration of therapy is indicated for treatment of anaerobic abscesses. Duration of treatment varies, but is usually continued until the chest roentgenogram clears or shows only small residual lesions.165 Parenteral antibiotics are given initially until the patient is afebrile, then oral medications may be substituted. A recently published study by Levison et al. questions whether penicillin G is the drug of choice for anaerobic lung disease.“’ In 26

DM, January 1987

this study only eight of 15 patients treated with penicillin G were

cured,whereas all13patientstreatedwith clindamycinwere cured,

Despite some criticisms ofstudy design, thesrnd number ofpa* tients, and a possible problem with noncompliance among the outpatients, the study was prospective, randomized, and had predetermined criteria with which to judge outcome.171 That penicillin G had such a high failure rate while clindamycin was uniformly successful may be explained by the increasing recognition of penicillin-resistant anaerobes causing pulmonary infections.172 Also, the incidence of penicillin G resistance has increased among many previously sensitive organisms such as Bacteroides rneZaninogenicus.17Z However, most clinical laboratories are not able to routinely perform in vitro anaerobic susceptibilities. Therefore, the physician must often make therapeutic decisions on clinical grounds. The patient with anaerobic lung abscess who is not seriously ill should probably still receive penicillin G.16’ This drug is much cheaper and has a long, favorable record. If the patient does not improve within seven to ten days, clindamycin, 600 to 900 mg IV every eight hours, should be substituted. Clindamycin should be considered as initial therapy of the seriously ill patient and for the penicillin-allergic patient.16’ Metronidazole has excellent in vitro activity against strict anaerobic bacteria, but most microaerophilic streptococci are resistant.16s Therefore, it is not surprising that it is less effective than clindamycin when used as a sole agent in anaerobic lung infection.173 Finegold recommends penicillin G in combination with clindamycin or metronidazole as initial therapy of serious anaerobic lung disease.16’ Chloramphenicol has activity against all anaerobes and represents another option, but clinical and microbiologic failure of chloramphenicol have been reported.1”g’ 174The efficacy of cefoxitin, moxolactam, imipenem, ureido and carboxy-penicillins, the new quinolone drugs, and other new beta-lactam antibiotics remains unclear due to lack of comparative studies. Tuberculosis

The incidence of tuberculosis has declined markedly over the past century, as has its morbidity and mortality.‘75 Nevertheless, tuberculosis remains an important health problem in the United States, with over 21,000 new cases reported in 1984.176 Most cases of active tuberculosis are due to reactivation of dormant infection.“’ Tuberculosis is primarily a disease of the elderly, of whom 10% to 25% have evidence of healed infection.177 Reactivation is also more frequent among alcoholics, patients who have undergone gastrectomy, diabetics, patients with silicosis, and patients given immunosuppressive or cytotoxic drugs.17’ Although the typical patient with active disease presents with nonspecific systemic symptoms such as anorexia, fatigue, weight loss, fever, or night sweats, the clinician DM,

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1987

27

must remain observant for atypical roentgenographic and clinical presentations of tuberculosis in order to avoid unnecessary morbidity and mortality. Such atypical features may be more common than previously expected, especially among elderly patients.17’ Patients may present with syndromes indistinguishable from CAP, with infiltrates involving primarily the middle and lower lung fields without apical disease.17s181 Patients with miliary TB may present with a syndrome reminiscent of ARDS (Fig 3).18’ Patients with typical cavitary tuberculosis may also develop ARDS, perhaps secondary to endobronchial spread must be considered in the of the disease.ls3 Therefore, tuberculosis patient presenting with respiratory failure and fever who does not respond to the usual antibacterial therapy.lW The definitive diagnosis of tuberculosis requires the growth and identification of Mycobacterium tuberculosis from sputum or tissue. Unfortunately, M. tuberculosis rarely grows in less than two weeks and so culture information is rarely available during the initial patient evaluation. Since active pulmonary or miliary tuberculosis can be associated with anergy, nonreactivity to purified protein derivative does not ex-

FIG 3. A 68-year-old roentgenogram but autopsy 28

woman presented with respiratory failure and died within revealed a miliaty pattern. Sputum smears did not show revealed miliary tuberculosis.

24 hours. acid-fast

uhf,

JanUsry

Chest bacilli,

1987

elude tuberculosis.175”84 Similarly, failure to demonstrate acid-fast organisms on even multiple sputum smears does not rule out active pulmonary tuberculosis .184J Is5 Flexible fiberoptic bronchoscopy and transbronchial biopsy may be useful in evaluating patients with negative smears who are suspected of having tuberculosis.185 If the diagnosis of tuberculosis cannot be discounted, empiric antituberculous therapy may be indicated. Isoniazid (INH) (300 mgday), and rifampin (600 mgday), are the preferred drugs for initial therapy of severely ill patients.ls6 If a trial of therapy is desired, the narrow spectrum provided by INH and ethambutol may be preferable. If drug resistance is suspected, then three or four drugs should be given initially (rifampin and INH plus ethambutol, streptomycin, or pyrazainamide) .la6 Drug resistance should be suspected in (1) patients with a history of previous intermittent use of antituberculous drugs, (2) patients from Mexico, Haiti, Southeast Asia, and Africa, and (3) patients in areas of the United States with known high incidence of drug resistance.1861g0 Steroids have been used successfully in the treatment of ARDS associated with miliary TB, or bronchogenie spread of cavitaty TB, but reliable clinical studies are lacking.ls3 Mycoplasma Mycoplasma pneumoniae is a common cause of CAP, accounting for 10% to 40% of infections.1g1’1s2 Although most patients are young, up to 20% of pneumonias in patients over 40 years of age may be due to this agent.1g3”W Most infections are uncomplicated upper respiratory tract infections such as tracheitis or bronchitis.lg5 Clinically apparent pneumonia occurs in only 3% to 10% of the patients and it is often ‘catypical.“1g6~1’“7 Recently, several authors have stressed the protean manifestations of M. pneumoniae infection.193p 194,198 Mycoplasma pneumoniae has been associated with lung abscess, bronchiectasis, lobar consolidation, pneumatocoeles, and ARDS.1g9-202 Pleural effusions are seen in up to 20% of these patients if decubitus films are obtained.‘03 The most serious manifestations of this disease appear in patients with sickle cell disease, and in immunocompromised hosts.“04 However, fatal fulminant mycoplasma pneumonia has been reported in normal hosts.2oz Since most laboratories are unable to culture M. pneumoniae, the diagnosis must be made serologically. Antibody titers greater than l/128 or a fourfold rise in titer is considered diagnostic.205,206 Elevation of cold agglutinins to a titer of greater than l/64 or a fourfold rise in titer is observed in 30% to 70% of patients.‘06 Antibiotic therapy with tetracycline or erythromycin has been shown to improve symptoms and decrease the duration of illness.1g5’205 Since relapse has been noted in patients treated for less than two weeks, two to three weeks of therapy should be given. Therapy should be given intravenously if the patient is severely ill. DM,

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1987

29

Viral Pneumonia Viral pneumonias account for 10% to 30% of all CAP requiring hospitalization.207 Although much more frequent in children, viral pneumonia, especially influenza pneumonia, remains a significant problem in adults. Viral pneumonias typically present subacutely, but may have an acute onset with severe pulmonary damage and ABDSzo8 Primary influenza A pneumonia first became well documented during an epidemic in the late 1950s.20g Five to 10% of all influenza cases have pulmonary involvement, but the rate increases with age and approaches 70% in patients over 70 years of age.‘l’ Pulmonary involvement is also more common in patients with underlying chronic conditions, especially cardiovascular disease and COPD. Nonetheless, cases do occur in healthy young adults.208 The virus spreads by inhalation. Following the typical onset of flu symptoms (such as fever, chills, headache, myalgia, malaise, and anorexia), cough, dyspnea, and respiratory failure may rapidly ensue.‘l’ Chest roentgenographic appearance is not diagnostic.208 During epidemics of influenza there is an increase in the incidence of bacterial pneumonias .‘12 Patients with such secondary bacterial pneumonia are usually older and have underlying chronic diseases such as COPD. They initially have typical flu symptoms followed by one to four days of symptomatic improvement. A recurrence of fever and the development of signs and symptoms of pneumonia then folpneumoniae, S. aureus, and H. infruenzae are low.211 Streptococcus most frequently isolated.z12 The definitive diagnosis of influenza pneumonia requires isolation of the virus from sputum or nasopharyngeal swab. More commonly, the diagnosis is made when a fourfold rise in complement-fixing antibodies is demonstrated two to three weeks after the onset of acute symptoms.‘ll As serologic information is often not clinically helpful at the time of the acute illness, the diagnosis often must be made epidemiologically. Amantadine and rimantadine have been shown to be effective in preventing influenza A infection.‘13 Amantadine is also effective in relieving symptoms and allows a more rapid recovery.214’2*5 Unfortunately, there have been no controlled studies of the efficacy of amantadine in primary influenza A pneumonia. Supportive care including intubation, PEEP, oxygen, and fluid and electrolyte management are important. The clinician must be aware of the danger of secondary bacterial pneumonia and be prepared to empirically treat these infections if a definite diagnosis cannot be made and the patient’s condition worsens. Because of the severity of infection, annual vaccination is recommended for chronically ill patients and persons 65 years of age or older, especially those in chronic care facilities.‘15 Health care work30

DM,

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1987

ers with extensive contact with high-risk patients and persons providing essential community services should also consider vaccination.‘15 Epidemics of influenza B occur less frequently than those of influenza A, and it is widely accepted that influenza B infection is less severe. However, during an epidemic in 1976 to 1977, influenza B infection was found to be very severe in the elderly and was associated with excess mortality.216 Amantadine is not efficacious in the prophylaxis or treatment of influenza B infection.2*3 Recently, aerosolized ribovarin was shown to be effective in speeding symptomatic recovery of young healthy patients with mild disease.‘l’ Whether it will be similarly effective in older, more symptomatic patients is unkKlOWn.

Respiratory syncytial virus commonly causes potentially severe lower respiratory tract infections in infants.218~21s In older children and young adults, reinfections typically cause a mild common coldlike syndrome.21s Recently, Hall et al. described a more serious and protracted illness in adults.“’ These patients had altered airway reactivity for up to eight weeks after the acute infection. An outbreak in a nursing home indicates that RSV may be a common pathogen in older adults and may cause an illness indistinguishable from influenza A.“l Aerosolized ribovarin has been found to be effective in improving signs of lower respiratory infection in infants and young adults.2Z2J 223 A variety of other viruses can also cause life-threatening pneumonias. Adenovirus may cause up to 10% of respiratory disease in children and has been shown to cause outbreaks in military recruits.224 Although uncommon, fulminant necrotizing pneumonia and ARDS can occur.225 Pneumonia is especially likely to occur in adolescents and young adults with atypical measles.226~227 This illness is characterized by fever, respiratory symptoms, and a hemorrhagic, petechial or vesicular skin rash. It occurs in patients previously vaccinated with inactivated measles vaccine.“’ Respiratory infections in these patients range from asymptomatic infiltrates on chest roentgenogram to acute respiratory failure. Chickenpox is another childhood disease that is occasionally seen in the adult. While generally a mild disease in children with infrequent pulmonary complications, chickenpox is more severe in adults. Pneumonia is clinically apparent in up to 16% of adults and may be fulminant and rapidly fatalzz8 Fungal Pneumonia In endemic areas, such as the central United States, infection with Histoplasma capsdatum is almost universalzzs Scattered areas of histoplasmosis have been reported in 31 states of the continental United States and throughout the temperate zones of the world.22s DM,

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1987

31

Isolates from soil are especially frequent in bat and bird habitats.2zg Human infection results from inhalation of airborn organisms, and a heavy inoculum may be necessary. In most instances, the infection, often asymptomatic, slowly subsides as the host becomes immune.“’ When symptomatic infection does occur, symptoms range from mild malaise to severe, life-threatening disease.“’ Roentgenographic findings range from a normal chest x-ray in 75% to patchy bronchopneumonia, hilar adenopathy, and a diifuse miliary picture in the remaining 25% .“’ In a recent outbreak involving 488 symptomatic patients, 60 had evidence of disseminated disease and 19 died. The only apparent risk factors for dissemination and death were age over 54 years and immunosuppression.230 The diagnosis of histoplasmosis depends on maintaining a high degree of suspicion. A history of possible exposure to H. capsulatum should be sought. Elevated complement-fixing antibody titers of greater than %Z or a fourfold rise in titer is confirmatory and represents the usual method of diagnosis.“’ Lymph node biopsy or transbronchial biopsy may reveal the organism histologically or on cultUreS.z2g Histoplasmin skin testing is neither sensitive nor specific for acute infection?g rather it remains an epidemiologic tool. Recently, Wheat et al. described a radioimmunoassay for the detection of H. capsdatum in urine and serum that may represent a rapid method for diagnosis of disseminated histoplasmosis.231 The otherwise normal patient with mildly symptomatic infection almost never requires specific therapy. Normal patients with severely symptomatic pulmonary disease have been successfully treated with “low-dose” amphotericin B (500 mg total dose).22g Patients with disseminated disease require treatment with amphotericin B for six weeks or a cumulative dose of 2 to 3 grn.“’ Ketoconazole, a new oral antifungal drug, is much less toxic than amphotericin B, and shortterm success has been achieved in the treatment of pulmonary and disseminated disease.232 However, the optimal dose and duration of therapy are unclear. Currently, the recommended dose is 400 mg/ day as a single dose for about one year.232 The clinician should be cautious when using ketoconazole in immunosuppressed patients, as animal studies suggest a higher failure rate and incidence of relapse in the immunocompromised host.233 Infection with Coccidioides immitis is a common fungal disease in the United States, with more than 100,000 new cases reported each United States, but year. 234 The disease is endemic in the southwest with a large number of tourists to this area and with the rapid modes of travel, coccidioidomycosis can appear in virtuaIly any locale. Infection requires inhalation of as few as ten arthrospores.234 Of the infected patients, only about 40% are symptomatic.235 There is a wide spectrum of clinical disease ranging from an influenza-like syndrome to ARDS.236 Findings on chest roentgenogram are not specific. 32

DM,

January1987

Alveolar infiltrates of varying size are present and hilar lymph nodes majority of patients, the may be enlarged.237 In the overwhelming disease is self-limited with complete roentgenographic and clinical resolution in six to eight weeks.235 In some patients, especially diabetics and immunocompromised hosts, chronic pulmonary disease develops with cavitary lesions visible on chest roentgenogram.234 The disease may wax and wane over time with activity dependent on the underlying disease or state of immunosuppressionz3 In otherwise healthy patients, chronic pulmonary disease tends to be indolent. In less than 0.5%, infection disseminates hematogenously in extrapulmonary sites such as bones, meninges, and skin235 Since this organism is almost never a nasopharyngeal contaminant, a sputum smear or culture yielding this yeast is virtually diagnostic.235 About 40% to 70% of patients with primary disease have a positive sputum culture.Z37 Serologic diagnosis can be made by demonstrating elevated serum IgM precipitins or elevated titers of complement fixing antibodies.235 The complement-fixing antibody titer parallels the course of the disease and increasing titers represent a bad prognostic sign.‘% Most patients recover without chemotherapy. Patients with dissemination, patients with persistent symptoms or persistently elevated antibody titers, pregnant women, and patients with severe underlying disease usually need treatment with amphotericin B. A cumulative dose of 1 to 2 gm is generally recommended.234 Miconazole or ketoconazole may be alternative drugs for nonmeningeal disease, but the optimal daily dose and duration of therapy for these drugs needs to be determined.z34’238-240 Blastomyces dermatitidis seems to be endemic in the southeast United States, in the south central United States along river banks, and in the midwest along the Great Lakes.%l Infection probably results from inhalation of the organism, and the yeast may then disseminate hematogenously to other organs. The clinical manifestations of pulmonary disease are varied and range from a self-limited pneumonia to ARDS.242 Acute respiratory failure may be seen with miliary spread of the disease or following endobronchial spread of the organism.243’ 244 The definitive diagnosis requires growth of the organism, but visualization of the characteristic 8 to 15 i.~yeast with a thick, highly refractile cell wall and broad-based buds allows one to make a presumptive diagnosis (Fig 4).241 Serologic and skin tests are neither sensitive nor specific, though immunodiffusion may be superior to complement fixation.241 Mortality is quite high in patients with ARDS secondary to blastomycosis, and amphotericin B therapy should be initiated in these patients if the diagnosis is deemed likely. Most authors recommend a cumulative dose of 1.5 to 2.5 gm?’ Ketoconazole may be an alternative drug for less symptomatic patients, but results are not uniformly successfu1,245,246

DM,

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1987

33

FIG 4. A 28-year-old man presented to an outlying hospital with a two-day history of fever and dyspnea. The admission chest roentgenogram revealed a miliary pattern. He required emergency intubation and institution of positive end expiratory pressure. Broad-spectrum antibacterial and mycobacterial antibiotics were given but the patient died the next morning. At postmortem, the lungs were filled with 8-15 k yeasts with thick, highly refractile cell wall and broad-based buds in giant cells indicative of blastomycosis.

NOSOCOMIAL

PNEUMONIA

Nosocomial infections are best defined as infections neither present nor incubating on admission to the hospital.247,248 Nosocomial pneumonia represents about 10% to 25% of all such infections. Not only does this complication increase hospital stay and cost, it is also associated with increased mortality.Z49-251 When a person enters the hospital, various aspects of the respiratory defense mechanisms are affected that can ultimately predispose the patient to pneumonia. During hospitalization and other stressful conditions, such as respiratory failure, surgery, and starvation, the upper airway is colonized with potentially pathogenic gram-negative rods.25Sz54 Adherence of these organisms to the upper respiratory tract seems to be related to a diminished quantity of fibronectin on the surface of the buccal epithelial cells2” When the patient is given antibiotics, the normal residual bacteria are suppressed, allowing gram-negative rods to colonize this area.256 The source of these gram-negative rods is unclear. They may represent the patient’s own 34

DA4, January

1987

fecal flora, organisms in the hospital environment, organisms colonizing hospital personnel or other infected patients, or organisms transmitted via the hands of hospital workers.257 If a patient is given an anesthethic or narcotic drug, laryngeal function is impaired and allows aspiration to occur. If the patient is intubated or undergoes tracheostomy, infectious secretions are introduced directly into the lower respiratory tract. Additionally, patients with a tracheostomy develop tracheobronchial colonization with gram-negative rods, probably secondary to enhanced adhesion.254,257 Nebulizers, humidifiers, and respiratory assistance devices aerosolize bacteria, especially Legionella, and may directly introduce them into the 1ung.25s-261 Finally, the administration of steroids or cytotoxic drugs may alter alveolar macrophage and polymorphonuclear leukocyte number and function, further predisposing the patient to infection. The organisms that commonly cause nosocomial pneumonia are aerobic gram-negative bacilli (especially E. co/i, ZZZebsielZa, Serratia, Pseudomonas) and staphylococci.251, “‘, 263 However, many different organisms may be responsible. The prevalence of a particular organism in the environment of a hospital has a dramatic effect on the incidence of these pneumonias. For example, MRSA, Legionelk, and Aspergillus may be more common in certain hospitals.264-266 Nosocomial pneumonia is often difficult to diagnose.z67 Underlying lung disease, congestive heart failure, or ARDS limits the usefulness of chest films.2”3, “’ In addition, the patient may be so debilitated that the ability to mount a fever response or leukocytosis is blunted. The difficulty in diagnosing nosocomial pneumonia is especially pronounced in patients with ARDS. A recent study showed that nosocomial pneumonia is misdiagnosed in about 40% of these patients.z68 This is very disconcerting, since patients with ARDS seem to be prone to nosocomial pneumonia, and up to 75% of patients dying with ARDS have acquired a nosocomial pneumonia.2W Unfortunately, it is difficult to tell to what extent nosocomial pneumonia causes, is associated with, or results from ARDS. In a primate ARDS model, though, bacterial superinfection was shown to markedly worsen lung function.26g Because of the variety of possible pathogens and the diversity of possible therapy, every attempt should be made to identify a specific organism. The difficulty in making a specific diagnosis is compounded by the high incidence of upper airway colonization with pathogenic organisms.252”54 Thus, sputum Gram stain and culture are often unreliable. Transtracheal aspiration is not helpful in patients with tracheostomies or endotracheal tubes because of tracheal colonization.z53’ 254 Blood cultures should be obtained, but are too techniques has been often negative.263 The utility of bronchoscopic discussed. However, transbronchial biopsy may not be possible in patients with a coagulopathy or who require positive pressure venLIM,January1937

3s

tilation. Similarly, percutaneous lung aspiration is not advised for patients on a ventilator. Open lung biopsy may remain the only alternative. Serologic studies may be used to diagnose some of the causes of the nosocomial pneumonia retrospectively, but they are rarely helpful in the acute situation. Often an empiric therapeutic decision must be made before bacteriologic data are known or in the absence of such data. The choice of empiric therapy depends on: (1) the patient’s present antibiotic regimen, (2) the status of the patient’s immunity, (3) the prevalent organism in the hospital or geographic locale, (4) knowledge of a recent outbreak in the community, and (5) a history of aspiration. In general, antibiotic coverage should be broad enough to cover gramnegative bacteria (especially Pseudomonas) and staphylococci. This generally means that the patient should receive an aminoglycoside plus a semisynthetic penicillin, an aminoglycoside plus clindamycin, or a cephalosporin plus an aminoglycoside. If MRSA are possible pathogens, the patient should receive vancomycin. When a history of aspiration is obtained, clindamycin or high-dose penicillin should be added. The duration of therapy tends to be prolonged and depends on how quickly the patient responds. Prevention of nosocomial pneumonia has received much attention. Possibly the best prevention is strict hand washing by the medical staff but too few comply.27o Some have studied the use of prophylactic topical antibiotics with or without parenteral antibiotics.271 Airway colonization and the number of pneumonias were diminished, but at the expense of inducing higher levels of resistance. Finally, the importance of environmental surveys and infection control should not be forgotten. Helms et al. were able to decrease the frequency of isolation of L. pneumophila from the water supply and decrease the incidence of Legionnaire’s disease by intermittent elevation of hot water temperatures and continuous chlorination2” Much of what has been written about nosocomial pneumonia also pertains to pneumonia in the immunocompromised patient. The “immunocompromised” condition is variably defined. For our purposes, the term refers to an underlying disease or therapy that impairs normal host defense to infection. Infection, especially pneumonia, is very common in these patients and is a frequent cause of death.273-286 Host defenses may be impaired by a variety of illnesses and therapies. Neutropenia seems to be the most important variable responsible for infection.273-286 The risk of infection begins to rise when the neutrophil count dips below 1,000 cells per cubic millimeter, but below lOO/cu mm, infection, usually with gram-negative bacilli, S. aureus, Can&da, or Aspergillus, becomes the ru1e.273-286Defects in granulocyte function, such as chemotaxis, mobilization, and killing ability, may be present.287’ 288If the monocyte count falls, as seen in hairy 36

DA4, January1987

cell leukemia, an increased risk exists for infection with atypical myimmunity prediscobacteria and fungi.287 Defects in cell-mediated pose to infection with intracellular pathogens such as Listeria monocytogenes, cytomegalovirus, non-typhi Salmonella, Nocardia, Toxoplasma, and M. tuberculosis, to name a few.287 Abnormalities in pulmonary macrophage number or function also predispose to infection with intracellular pathogens.287 Defects in humoral immunity are common in multiple myeloma and chronic lymphocytic leukemia. Patients with these diseases are susceptible to infection with encapsulated organisms, as are asplenic and hyposplenic patients.287 Adrenocortical steroids are often used in patients with cancer, organ transplant patients, and patients with various autoimmune diseases. Large doses of steroids inhibit the formation of granulomas and also may cause a monocytopenia and/or lymphopenia. Thus such patients are prone to illnesses such as tuberculosis and infection due to other intracellular pathogens.287 Cytotoxic drugs predispose to infection, primarily by inducing myelosuppression.287’288 However, cytotoxic drugs also affect humoral and cell-mediated immunity.287,288 Radiation therapy may result in neutropenia and abnormal granulocyte function.287~ 288 Cytoxic chemotherapy and radiation therapy may also cause defects in mechanical barriers to infection. Mucositis or gastrointestinal tract ulceration are often sites of colonization and may serve as portals of entry for viruses, bacteria, and fungi.287,288 Central nervous system dysfunction, whether attributable to the primary disease or to its therapy, can cause defects in the gag reflex, resulting in aspiration pneumonia.z87 Finally, a tumor mass may obstruct a bronchus and cause pneumonia.288 Though pneumonia is a common infection, with a high mortality rate, it is often difficult to diagnose in this patient population. Fever is usually present, but few other signs or symptoms point to the lung as the source of infection.274-286 To compound the problem, noninvasive tests are often negative or misleading, and the chest roentgenogram may be entirely normal initially.274’28~z86 Serologic tests are of limited utility in the acute situation, and if a significant humoral defect is present, the patient may be unable to mount an antibody response. The difficulty in making a specific diagnosis is further compounded by the wide variety of noninfectious etiologies of fever and pulmonary infiltrates in the immunosuppressed host (Table 2). Thus, it is often necessary to resort to invasive diagnostic techniques, especially when the patient fails to respond to empiric broad-spectrum anti-bacterial therapy. The various invasive diagnostic modalities currently available have been reviewed. However, a few comments should be made about open lung biopsy. Open lung biopsy remains the best premortem method to diagnose the etiology of pneumonia in these patients.289-2g3 Though false-negatives occur, false-positive results are rare. Some have argued that open lung biDM,

January

1987

37

TABLE

2.

Non-infectious Causes Immunocompmmised

of Pneumonitis Patients

in

Idiopathic pneumonitis Tumor invasion Leukagglutination Tumor lysis Radiation Pulmonary embolism Drug reaction Hemorrhage

opsy is of limited value because it rarely changes the ultimate outcome.2g4-2s6 Such variable results are explained by differences in incidence of infectious etiologies and differences in underlying disease. Thus, it is difficult to compare these studies. In our opinion, open lung biopsy remains a valuable tool in selected patients. It is recommended that the immunocompromised pneumonia patient be given empiric broad-spectrum antibacterial therapy initially, since the most common causes of pneumonia are gram-negative bacilli.2g7 This strategy has effectively diminished the mortality due to bacteria. An unfortunate but expected consequence has been the emergence of fungi as significant pathogens.zg7 AspergiZZus and Candida species are the most common isolates.2s8~2gg Aspergihs is a ubiquitous mold that can colonize or invade lung tissue. Infection is caused by inhalation, and many hospitals can culture it from the air year-round.266 In the severely granulocytopenic patient, AspergiZZus may gain entrance from corneal or skin abrasions.300 Clinical pneumonia is characterized by acute onset of high fever with few other signs or symptoms. The roentgenographic appearance is not specific, though the presence of a wedge-shaped defect is suggestive of this organism, which has a propensity to cause infarcts by invading blood vessels.2sg Scattered case reports exist of invasive pulmonary aspergillosis in apparently normal patients, but typically, patients have less than 500 granulocytes per cubic millimeter, or have received cytotoxic or high-dose steroid therapy.300 Invasive pulmonary aspergillosis is rarely diagnosed premortem.300 Isolation of AspergiZZus from sputum or bronchoalveolar lavage must be interpreted with care. Multiple positive cultures from a typical patient are suggestive of true infection?00 At one institution, positive nasopharyngeal cultures correlated with the development of invasive disease.3o1 Blood cultures are almost never positive for AspergiZZus, and serologic studies are equally unrevealing.300 Recently, attempts have been made to detect AspergiZZus antigen in the sputum or bron38

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1987

choalveolar lavage .302,303 The definitive method of diagnosis remains lung biopsy with demonstration of tissue invasion (Fig 5). Amphotericin B remains the cornerstone of therapy. The usual dose is 0.5 to 0.7 m#l@day. Although the optimum dose is unknown, a dose of 1 to 2 gm is often required. The ultimate factor predicting survival is attaining remission of the underlying disease. Much like invasive pulmonary aspergillosis, Candida pneumonia is primarily seen in profoundly granulocytopenic patients. The clinical and roentgenographic presentations are not specific, and blood cultures are often negative .“‘, 304 Definitive diagnosis requires the demonstration of yeast forms invading tissue (Fig 6). However, in the typical patient, frequent isolation of Candida from sputum is suggestive, and it is prudent to initiate empiric therapy with amphotericin B while awaiting histologic confirmation.2g7 As with aspergillosis, the ultimate efficacy of therapy depends on attaining remission of the underlying disease with normalization of the granulocyte count. A variety of viral pneumonias are seen in the immunocompromised patient. Cytomegalovirus is a common pathogen, especially in patients undergoing allogeneic bone marrow transplantation.305 Disease is probably a result of reactivation of dormant infection and it

FIG 5. The definitive sue invasion. DM,

January

diagnosis of invasive pulmonary aspergillosis requires Here Aspergillus is shown invading a pulmonary blood 1987

demonstration vessel.

of tis-

33

FIG 6. The pseudohyphae patient.

of

Candida are shown

invading

the lung

tissue

of a granulocytopenic

typically presents as a bilateral interstitial pneumonia and correlates with total-body radiation therapy.30s Diagnosis requires culture of the virus from lung tissue or visualization of the typical intranuclear inclusions. Cytomegalovirus pneumonia is almost always fatal and effective therapy is lacking.305 The drug 9-0,3-dihydroxy-&propoxymethyl1 guanine (DHPG) has been recently used to treat serious CMV infections in immunodeficient patients. However, patients with CMV pneumonia responded poorly.306, 307 Adenovirus has recently emerged as another cause of pneumonia in immunocompromised patients.308’ 3og It is mostly seen in those undergoing bone marrow transplantation and seems related to the severity of acute graft-vs.-host disease.3o8 Like cytomegalovirus, disease is probably due to reactivation of endogenous infection.308 Herpes simplex is another cause of pneumonia in these patients.310’ 311 Disease may be due to direct spread of mucocutaneous lesions or from hematogenous dissemination. A localized pneumonia suggests the former pathogenesis, while a diffuse bilateral appearance is a clue for hematogenous spread. Most patients with diffuse pneumonia have evidence of mucocutaneous disease.310 The diagnosis depends on culture of lung tissue or histologic evidence. Treatment with acyclovir is often effective. 40

DM,

January1987

PULMONARY COMPLICATIONS OF ACQUIRED IMMUNODEFICIENCY SYNDROME In mid-1981 the medical community became aware of a new disease in previously healthy persons characterized by multiple opportunistic infections and unusual malignancies.31Z316 Between June 1, 1981 and January 1986, close to 17,000 U.S. cases of this acquired immunodeficiency syndrome (AIDS) had been reported to the Centers for Disease Contro1.317 A retrovirus, the human T-cell lymphotrophic virus IIVlymphadenopathy-associated virus (HTLV-III/LAW is now known to cause AIDS. Acquired immunodeficiency syndrome has been identified virtually worldwide.31S In the United States, the majority of AIDS patients are reported in New York, California, New Jersey, and Florida.317 Homosexual and bisexual males account for about 75% of the cases and another 15% are IV drug abusers317 Other high-risk groups include hemophiliacs, heterosexual contacts of high-risk patients, and transfusion recipients .317,31gAbout 4% of all cases do not fit into any of the above groups.317 Acquired immunodeficiency syndrome is diagnosed clinically. Excluded are patients receiving immunosuppressive therapy and patients with preexisting diseases causing immunosuppression. Patients must have a disease predictive of defective cellular immune function3” Almost half of the patients present with Pneumocystis carinii pneumonia (PCP), about 25% have Kaposi’s sarcoma, and about 7% have both.31s The remaining patients have other opportunistic infections or malignancies such as primary central nervous system lymphoma, fungal or viral esophagitis, progressive multifocal leukoencephalopathy, chronic mucocutaneous herpes simplex, chronic Cryptosporidium enteritis, and disseminated Mycobacterium In the absence of these diseases, a diagnosis avium-intracellulare.321 of AIDS can be made if a patient has a positive serologic or virologic test for HTLV-IWLAV in addition to one of the following diseases: (1) disseminated histoplasmosis, (2) isosporiasis causing chronic diarrhea, (3) bronchial or pulmonary candidiasis, (41 non-Hodgkin’s lymphoma of high-grade pathologic type, or (5) Kaposi’s sarcoma in patients over 60 years of age.320 Diffuse pneumonia is very common in AIDS patients, either as the initial presentation or as a complication of AIDS (Table 3).322 By far the most common cause of pneumonia in this syndrome is P. carinii. Even when other pathogens or disease processes are found in the lungs, P. carinii is often also present.3z2 Pneumocystis carinii is a protozoan parasite that traditionally infected children with acute lymphoblastic leukemia, patients with lymphoma, and organ transplant patients.323 As in these groups, PCP in AIDS is probably the result of reactivation?24 Serologic data from normal children suggests that infection is nearly universal within the first two years of life.325 Unlike previous cases of PCP, patients with AIDS often have a more OM, January 1987

41

TABLE Etiologies

3. of Pneumonia

in AIDS

INFECTIOUS

NONINFECTIOUS

Pneumocystis carinii Mycobacterium avium-intracellulare Cytomegalovirus Pyogenic bacteria Toxoplasma go&ii Candida sp. Crytococcus neoformans Coccidioides immitis Histoplasma capsulatum Cryptosporidium Nocardia sp. Listeria monocyto,qenes

Lymphocytic interstitial pneumonitis Kaposi’s sarcoma Lymphoma

prolonged clinical prodrome, with pulmonary symptoms for about three weeks prior to presentation.326 A few have a rapid onset of respiratory failure. Chest roentgenogram usually shows diffuse bilateral titrates, but the diagnosis requires demonstration of the organism in tissues or in bronchial secretion (Fig 7). The diagnosis can

FIG 7. A 25-year-old homosexual man presented tory of progressive dyspnea and low-grade stitial infiltrate. Bronchoalveolar lavage (B) 42

to the emergency room with a three-weelc hisfever. Chest film (A) revealed a bilateral interrevealed cysts typical of Pneumocystis carinii. DM,

January

1987

be made on bronchoscopy in over 90% of patients, but negative results do not rule out PCP.3278328Complications of flexible fiberoptic bronchoscopy in patients with AIDS are minimal.327’ 328 The treatment of PCP, in addition to appropriate supportive measures, consists of parenteral (TMP-SMX) or pentamidine.32g Each is equally effective, but there is a high incidence of side effects to TMPSMX in AIDS patients (especially neutropenia, drug fever, and rash) that require discontinuation of therapy.330’331 Patients with AIDS have a slow response to therapy and are also more prone to relapse and require retreatment .326,32g Trimethoprim-sulfamethoxazole is given in a dose of 20 mg/kg/day of TMP. The optimal duration of therapy is unclear, but probably more than two weeks is necessary. If there is no improvement after 14 days of therapy, re-biopsy is recommended to rule out a second pathogen. Pentamidine is given in a dose of 4 mg/kg/day either as single intramuscular injection or slowly Iv over 60 minutes.332 Patients receiving pentamidine must be observed for hypotension, hypoglycemia, renal insufficiency, and the development of sterile abscesses. If PCP is unresponsive to these drugs, or the patient cannot tolerate the side effects, therapy with difluoromethylornithine may be attempted.333 The prognosis is poor in these patients. The mortality rate for the initial bout of PCP is approximately 30% .32sIf AIDS patients with PCP develop acute respiratory failure requiring intubation and ventilatory support, the mortality rate approaches 90% .322 Mycobacterium avium-intracelhlare and cytomegalovirus (CMV) are two other common pulmonary pathogens in AIDS patients.322 Mycobacterium avium-intracellulare infection may be diagnosed by blood culture, but usually requires finding the organism in the sputum or in tissue sections.334 Disease caused by Mycobacterium avium-intracellulare is a serious problem in this population. Therapy often requires simultaneous use of five or six antimycobacterial drugs because of the high incidence of drug resistance.335 Two promising drugs undergoing clinical trials are clofazamine and ansamycin.336 Since ansamycin is a rifampin-like drug, it need not be used in combination with rifampin. It is unclear what role CMV plays in AIDS patients, but it is certain that in AIDS patients CMV can cause infection ranging from chorioretinitis to pneumonitis.332j 337As noted above, therapy of CMV pneumonia is often ineffective. Surprisingly, M. tuberculosis is relatively uncommon in the usual AIDS patient, except for Haitians in whom there is a high incidence of drug resistance.338 A variety of other infectious and noninfectious processes, whether alone or in combination with P. carinii, may also affect the AIDS patient. A recent report by Polsky et al. documents the incidence of community-acquired bacterial pneumonias in patients with AIDS.33s This diversity of microbes and noninfectious diseases alone with the potentially dangerous therapies for these conditions underscores the importance of making a specific diagnosis. DM,

January

1987

43

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