New pathogens in pneumonia

0025-7125/94 $0.00 + .20

PNEUMONIA

NEW PATHOGENS IN PNEUMONIA Luis G. Guerra, MD, Hoi Ho, MD, and Abraham Verghese, MD, FRCP(C), FACP

In contrast to bacteremia, in which the cause of infection is readily established, the determination of the cause of acute pneumonia remains problematic. The emergence of newer pathogens and the recognition of new presentations of older pathogens, however, have made it apparent that it will always be necessary to pursue aggressively an etiologic diagnosis in patients with pneumonia. Empiric therapy, when it works, is useful but should never stop the clinician from asking whether this patient could have a new presentation of an old agent, an unusual presentation of a common agent, or an entirely new pathogen. GROUP A STREPTOCOCCUS

After a significant decline in the incidence of acute rheumatic fever and other serious complications of group A streptococcal infections during the 1970s, probably related to a decreased virulence of the organism, a resurgence is now taking place. In addition, group A streptococcus infections characterized by a fulminant course and a high morbidity and mortality have been increasingly recognized among young adults with competent immune systems. The two most important forms of invasive group A streptococcal infection include malignant scarlet fever and streptococcal toxic shock syndrome. Because both can have adult respiratory distress syndrome (ARDS) as the dominating syndrome, it is important to include this organism in any discussion of new pneumonia pathogens. Organism

Group A streptococci are gram-positive, facultative, anaerobic, catalase-negative organisms that in clinical specimens are seen as cocci in pairs or short chains. From the Department of Internal Medicine (LGG, HH), and the Sections of Infectious Diseases and Geriatrics (A V), Texas Tech University Health Sciences Center, El Paso, Texas MEDICAL CLINICS OF NORTH AMERICA VOLUME 78 • NUMBER 5 • SEPTEMBER 1994

967

968

GUERRA et al

Epidemiology

Typically, group A streptococcus is associated with acute pharyngitis; skin and wound infection; scarlet fever; and systemic infections, such as bacteremia, puerperal sepsis, necrotizing fasciitis, and myositis. The most common nonsuppurative complications of group A streptococci are acute rheumatic fever and poststreptococcal acute glomerulonephritis. Although it is not a common causative agent of lower respiratory tract infection, severe Streptococcus pyogenes infections have been associated with ARDS. Among the different components of the cell wall, M protein protects the organism from phagocytosis by polymorphonuclear leukocytes and makes them highly virulent. Patients who lack antibodies to the erythrogenic toxin and the antibody to the M protein are at risk for developing the streptococcal toxic shock syndrome. Clinical Presentation

Malignant scarlet fever can be either toxic or septic!5 but ARDS often dominates the picture (Table 1). In the toxic form, high fever, severe sore throat, skin rash, altered mental status, and painful adenopathy may be present. Patients with the septic form have spread of the infectious process to the soft tissues of the neck and may develop upper airway obstruction, bronchopneumonia, and otitis media. Streptococcal toxic shock syndrome45 , 46 is characterized by an infectious focus in the skin, mucous membranes, or soft tissue together with ARDS, shock, and multiple organ failure, Mortality is about 30% despite antimicrobial therapy and surgical intervention. Pain, the most common symptom, is present in almost 90% of the patients. Fever, hypotension, mental status changes, and acute renal failure are usually present. This syndrome has been associated with sinus infection, myositis, endophthalmitis, necrotizing fasciitis, peritonitis, and osteomyelitis. Group A streptococcal pneumonia4 usually occurs after a viral illness and has been well described among military recruits. Patients present with fever, productive cough, chills, dyspnea, and pleuritic chest pain, An abrupt onset is characteristic. Bacteremia is present in 10% to 15% of the patients. Chest film Table 1. STREPTOCOCCAL PULMONARY INFECTIONS Clinical Syndrome Group A streptococcus

Group B streptococcus Enterococcus

ARDS

Malignant scarlet fever Toxic form Septic form Streptococcal toxic shock Pneumonia Pneumonia in debilitated elderly Nosocomial pneumonia

= Adult respiratory distress syndrome,

Comment ARDS may dominate the clinical picture in all three Explosive pleuritis Empyema formation common Often polymicrobial and with high mortality Association with cephalosporin use, feeding tubes, debility

NEW PATHOGENS IN PNEUMONIA

969

demonstrates a bronchopneumonia; consolidation is less common. An explosive pleuritis is typical with copious amounts of serosanguineous fluid being produced; as a result, empyema is common and occurs in up to 40% of patients. Treatment

Antimicrobial therapy combined with surgical debridement in patients with necrotizing fasciitis and myositis is the treatment of choice. Penicillin remains the drug of choice. GROUP B STREPTOCOCCUS

The group B streptococcus is no longer just a pathogen of neonates or pregnant women. In adults, it is associated with urinary tract infection, soft tissue and skin infections, endocarditis, osteomyelitis, bacteremia, and pneumonia, the last-mentioned in debilitated elderly persons. Organism

Streptococcus agalactiae is a gram-positive, beta-hemolytic, facultative diplococcus that gives a beta-hemolytic reaction on blood agar. Identification of the organism is by detecting group-specific cell wall antigen. Epidemiology

Although a frequent colonizer of the genital and gastrointestinal tract of pregnant women, group B streptococci may also affect other groups of the population. Kaplan et apo found that 20% of elderly veterans carry the organism in their stools. Pneumonia owing to group B streptococci can occur; it has a predilection for elderly debilitated patients with diabetes mellitus, stroke, dementia, and malignancies (see Table 1).'6, 18,SO Clinical Presentation

The clinical course of group B streptococcus pneumoniaso is characterized by high fever, tachypnea, tachycardia, and a systolic blood pressure of less than 100 mm Hg, A brisk leukocytosis with a shift to the left is frequently present. Chest radiographic findings vary from unilateral or bilateral infiltrates to lobar consolidation with or without effusion and empyema. Occasionally, necrotizing pneumonia may develop, Group B streptococcal pneumonia is usually polymicrobial. Staphylococcus aureus, Streptococcus pneumoniae, and gram-negative rods are the most frequent associated organisms, The mortality rate of group B streptococcus pneumonia is high: 30% to 85% in different series.so Treatment

Penicillin G in high doses, usually 12 to 18 million units/day intravenously, is the recommended treatment. First-generation and second-generation cephalo-

970

GUERRA et al

sporins are also active. Ceftriaxone appears to be the most active of the thirdgeneration cephalosporins. Ampicillin, erythromycin, clindamycin, and vancomycin may be considered as alternatives; however, resistance to erythromycin and clindamycin has been reported. ENTEROCOCCUS

Originally, group D streptococci were divided into two groups: enterococcal species, which are resistant to penicillin, and penicillin-sensitive nonenterococcal species. Enterococci have been placed in their own genus with the species faecalis, faecium, and durans. Enterococcus faecalis causes the largest number of infections in humans. Organism

Enterococci are gram-positive cocci that on blood agar plates are nonhemolytic. Enterococcal species can be readily distinguished from nonenterococcal species by their ability to grow in bile-containing medium. Epidemiology

Enterococcus is a common commensal in the oral cavity and small intestine of normal adults. It was often considered a contaminant in sputum and bronchoscopy specimens? Clinical Presentation

Typically, patients are elderly and debilitated, with multiple chronic medical problems, often with feeding tubes and a prolonged hospital stay or institutionalization (see Table 1).7 Infection with this organism has also been associated with previous antimicrobial therapy, particularly cephalosporin regimens that usually do not cover enterococci?· 52 As a consequence, there is selection and overgrowth of enterococci in the stomach. The feeding tube may promote reflux and aspiration, increasing the patient's risk for developing enterococcal pneumonia. Berk et aF described two patients who received antibiotics for a communityacquired nonenterococcal pneumonia, both requiring enteral hyperalimentation. Five to six days after antibiotics were started, the patients developed high fever and a new infiltrate on chest radiograph. Transtracheal aspiration demonstrated many white blood cells and gram-positive cocci in chains; enterococcus was cultured. Treatment

The effective bactericidal treatment of enterococci combines penicillin with an aminoglycoside. For severe infection, penicillin should be administered in doses up to 20 million units/ day; the aminoglycoside dose should be adequate

NEW PATHOGENS IN PNEUMONIA

971

to have a synergistic effect against enterococci. Numerous reports have described an increasing number of aminoglycoside-resistant enterococci. MORAXELLA CATARRHALlS

Previously known as Branhamella catarrhalis, Moraxella catarrhalis has received recognition during the past decade as a causative agent of bronchitis and, less commonly, pneumonia, especially in adults with chronic lung disease. 37,49 Organism

M. catarrhalis is a small, gram-negative aerobic diplococcus. The appearance on Gram stain resembles that of a urethral smear from a patient with Neisseria gonorrhoeae infection. Epidemiology

M. catarrhalis is a normal commensal of the upper respiratory tract of children and adults. Recovery of the organism in transtracheal aspirates and the detection of antibranhamella antibodies have confirmed that M. catarrhalis is a pathogen in respiratory infections, It is considered to be a common pathogen in exacerbations of chronic bronchitis and demonstrates a striking winter seasonality, with most episodes occurring in the late fall through spring. Clinical Presentation

The clinical presentation of M. catarrhalis pneumonia differs little from that seen in patients with tracheobronchitis except for the presence of an infiltrate on the chest film. Chills, malaise, pleuritic chest pain, fever, cough, and sputum production occur. The chest film may reveal patchy bronchopneumonia or consolidation. Pleural effusion, cavitation, and empyema are rare. 37, 49 The most important risk factor for M. catarrhalis pneumonia is chronic obstructive pulmonary diseases. Patients receiving corticosteroid therapy; diabetics; and persons with multiple myeloma, alcohol abuse, renal failure, neutropenia, collagen vascular disease, and acquired immunodeficiency syndrome (AIDS) are also at risk. lO• 49 Treatment

The majority of strains now produce beta-Iactamase. A beta-Iactamase-stable antibiotic such as cefixime, cefuroxime, or amoxicillin-clavulanate is recommended. Erythromycin and the newer quinolones, such as clarithromycin, azithromycin, and roxithromycin, all have activity against this organism. ACINETOBACTER

The old name for Acinetobacter was Mima polymorpha, reflecting the organism's ability to mimic other gram-negative organisms on Gram stain, particu-

972

GUERRA et al

larly Haemophilus inJluenzae and Neisseria meningitidis. Acinetobacter has been implicated as the causative agent in community-acquired and nosocomial pneumonia?1.39 Hospital-acquired pneumonia is a well-known complication of Acinetobacter species and is frequently seen in patients receiving mechanical ventilation, who are in the intensive care unit and have received previous antimicrobial therapy.s Community-acquired pneumonia occurs less frequently but is associated with high mortality if improperly treated. Organism

Acinetobacter species are encapsulated, nonmotile, oxidase-negative, nonnitrate-reducing, aerobic gram-negative bacilli. There are two subspecies: Acinetobacter var wolffi and A. var anitratus. The former is associated with genitourinary tract infection. Epidemiology

Acinetobacter is a common organism in the environment and is frequently encountered in soil and water samples. About 25% of healthy individuals have skin colonization, and up to 7% have pharyngeal colonization. It is the most common gram-negative organism carried on the skin of hospital staff. It is also commonly found in mechanically ventilated patients in the intensive care unit. Community-acquired pneumonia usually occurs in individuals with chronic illnesses, such as alcoholics, smokers, persons with chronic renal disease, persons with chronic underlying pulmonary disease, and patients with debilitating illnesses. There has been an unexplained association of this organism with foundry workers. It is also a common cause of community-acquired pneumonia in New Guinea for unexplained reasons. Clinical Presentation

Community-acquired pneumonia presents with fever, dyspnea, cough, and pleuritic chest pain. Hypoxemia, severe respiratory distress, leukopenia, and hypotension may develop. Lobar consolidation and bronchopneumonic infiltrates are the most common chest radiograph findings; bulging of the fissures, pleural effusion, and abscess formation, and cavitation may occur.S' 19. 39 The organism is a common cause of nosocomial pneumonia and in that setting is associated with intubation or tracheostomy, prior antibiotic therapy, residence in an intensive care unit, and preexisting pulmonary disease. The subject of nosocomial gram-negative pneumonia is considered in greater detail elsewhere. Treatment

Acinetobacter is easily confused with gonococcus, meningococcus, and H. inJluenzae. This may result in the selection of antibiotics that are not effective against Acinetobacter. The antibiotic of choice for Acinetobacter pneumonia is an aminoglycoside. Beta-lactamase and plasmid-mediated antibiotic resistance is sometimes seen

NEW PATHOGENS IN PNEUMONIA

973

with gentamicin. Resistance to tobramycin and amikacin is less frequent. Piperacillin, imipenem, and ceftazidime are also active. In patients who present with an acute, fulminant gram-negative communityacquired pneumonia, Acinetobacter should be considered, and appropriate antimicrobial therapy, including an aminoglycoside, should be begun. CHLAMYDIA PNEUMONIAE

Chlamydia pneumoniae is an intracellular parasite with a pear-shaped elementary body; it contains no glycogen and is resistant to treatment with sulfonamides. Acute respiratory infections owing to C. pneumoniae are common in the adult population, and there is a high prevalence of IgG antibodies owing to past infections. 48 C. pneumoniae is a common cause of community-acquired pneumonia in the United States. Several epidemics of pneumonia have been reported, including four among military trainees in Finland from 1957 to 1985.31 C. pneumoniae is a human pathogen, and transmission may occur by respiratory secretions or aerosols. Acute infection may be totally asymptomatic or produce only mild symptoms. Frequently the first symptom is a pharyngitis with a sore throat and hoarseness; cough appears later. Fever is common during the first days of the illness. Pharyngeal erythema, rhonchi, and rales are the most common physical findings. Leukocytosis is present in fewer than 30% of patients. The chest radiograph may demonstrate a sub segmental or bilateral pneumonitis.48 A definitive diagnosis is made by isolating the organism from oropharyngeal secretions or bronchoalveolar lavage and by demonstrating a fourfold rise in IgG or IgM or a single IgM titer greater than 1:16 and an IgG titer more than 1:512. These tests, once confined to a research setting, are increasingly available. Patients with C. pneumoniae lower respiratory tract infection usually do well with outpatient care; acute hospitalization is rare. Full clinical recovery takes several weeks or months. Underlying diseases and concomitant bacterial infections are predisposing factors for severe disease. It has been suggested that chronic C. pneumoniae infection may be a risk factor for coronary heart disease. 4o Tetracycline, doxycycline, and erythromycin and the newer macrolides are the recommended antibiotics for the treatment of C. pneumoniae infection. Ofloxacin therapy has been associated with a rapid, remarkable clinical improvement in four patients with C. pneumoniae pneumonia. 33 MELIOIDOSIS

Melioidosis is a rare disease in North America, and when it does occur, it usually represents recrudescence of infection acquired years before, typically in Southeast Asia. It is an infection of humans and animals caused by Pseudomonas pseudomallei. It was first described by Whitmore and Krishnaswami in 1912. Organism

P. pseudo mallei is a small, gram-negative, motile, aerobic organism. Epidemiology

The causative organism, P. pseudomallei, is commonly found in the soil, stagnant waters, and market produce in Southeast Asia, where the infection is an

974

GUERRA et al

endemic health problem. The mechanism of infection may include wound infection by contaminated soil and nasal inhalation. High antibody titers against P. pseudomallei suggest the diagnosis of melioidosis; however, isolation of the organism is necessary for confirmation. It must be suspected in all persons who have resided in Southeast Asia. Clinical Presentation

The clinical manifestation of melioidosis varies from localized, acute suppurative infection to more chronic infections. Pulmonary infections are the most common complication. 15 Patients with acute pneumonia usually present with fever, chills, productive cough, pleuritic chest pain, and weight loss. Constitutional symptoms, such as headaches, myalgia, and anorexia, can also be present. Hemoptysis, if present, is not severe. On physical examination, the patient is tachypneic, is febrile, and has signs of consolidation on chest examination. Leukocytosis with shift to the left is commonly seen. The chest radiograph demonstrates upper lobe infiltrates with cavitation. 36 Pleural effusion may also be present. It is important that this disease be entertained in the differential diagnosis of any person with chronic lung disease who presents with fever, weight loss, hemoptysis, and pleuritic chest pain when no other cause is evident and who gives a history of residence in an endemic area for melioidosis. Recrudescence has been noted as much as 26 years after residence in an endemic area. The acute systemic form is rare in North America, but in endemic areas, it can result in abscesses in the lung, joints, liver, brain, skin, myocardium, and even the prostate. It is possible that chronic infection in such a site serves as a focus for the late recrudescence. Surgery, trauma, or intercurrent illness may play an important role in such reactivation, and hence this disease has been described as a "medical timebomb." Diagnosis is often tricky: Blood cultures are often negative, and the organism may be misidentified by the laboratory workers or overlooked unless they are forewarned. With up to 3 million persons having served in Vietnam, it is estimated that as many as a quarter of a million persons may have been infected and have the potential to reactivate. Treatment

The organism is highly resistant to many antibiotics. In a multicenter study, ceftazidime and co-trimoxazole were recommended as the drugs of choice for severe infection with P. pseudomallei."4 RHODOCOCCUS

Rhodococcus equi, formerly known as Corynebacterium equi, was first isolated in 1923 and is a common cause of pneumonia in horses and other animals. In humans, it has been associated with cavitary pneumonia, empyema, and brain abscess; the typical host has T cell dysfunction produced by lymphoma or renal transplantation or as a result of receiving immunosuppressive agents. 22, 43 R. equi has been recognized as an important respiratory pathogen in patients with AIDS. The respiratory tract is the most important route of infection in both humans and animals. 32 Frequently a history of exposure to animals is present.

NEW PATHOGENS IN PNEUMONIA

975

Organism

R. equi is an aerobic, nonmotile, gram-positive, weakly acid-fast organism, commonly found in the soil. Salmon-pink colonies are seen in the growth media. It is easily mistaken for Listeria monocytogenes or diphtheroids. Clinical Presentation

The most common clinical presentation of R. equi pneumonia includes high fever, cough, pleuritic chest pain, dyspnea, and extreme fatigue. Chest radiograph may demonstrate infiltrates, but there is no predilection for any particular lobe. Pneumonia can be necrotizing. Cavitation, pleural effusion, empyema, and pulmonary abscess may occur. 32 Pneumonia owing to R. equi may be mistaken for Mycobacterium tuberculosis or Nocardia because the organism is weakly acidfast. Bronchoscopy with biopsy, thoracocentesis, or surgery may be necessary if the diagnosis of R. equi is entertained, but the organism is not isolated on expectorated sputum. Treatment

The treatment of R. equi is difficult. The organism appears to be sensitive to vancomycin, erythromycin, chloramphenicol, and aminoglycosides. Resistance to penicillin and first-generation cephalosporins has been reported in humans. Parenteral administration of vancomycin and erythromycin appears to be the treatment of choice. Antimicrobial therapy should be continued for a prolonged period, usually 2 months. Surgery for lung abscess drainage may be indicated. PNEUMOCYST/S CAR/Nil

Pneumocystis carinii is a well-known cause of pneumonia in immunosuppressed hosts. With the beginning of the AIDS epidemic in the early 1980s, the incidence of P. carinii pneumonia rose, and it became the most common opportunistic infection in patients with AIDS. Jacobs et aF5 and Cano et a19 have described P. carinii as a cause of pneumonia in patients with no predisposing conditions. Organism

P. carinii is characterized by an ameboid appearance and, although identified by methenamine silver and Giemsa stains, does not grow in fungal media. Three stages are identified in the life cycle of P. carinii: a trophozoite form, a cyst form, and the precyst stage. Whether to consider the organism a protozoan or fungus remains controversial. Epidemiology

P. carinii is a saprophyte in the respiratory tract of humans and animals. There is a high prevalence of antibodies against P. carinii in children, most

976

GUERRA et al

probably related to a subclinical infection during childhood. Later, when an individual develops a defect in the immune system, clinical disease may develop. Whether this represents reactivation of dormant organisms or exogenous infection remains a matter of debate. Person-to-person transmission has been suggested by outbreaks in hospitals and orphanages. Autopsy surveys have revealed subclinical P. carinii infection in about 5% of patients with lymphoreticular neoplasms and rarely in healthy persons. Clinical Presentation

Cano et al9 described five healthy individuals who developed P. carmll pneumonia. They presented with high fever, chills, myalgias, progressive dyspnea, and productive cough. Tachypnea, tachycardia, cyanosis, decreased breath sounds, and diffuse bilateral rales were common physical findings. Leukocytosis, with a neutrophil predominance, and hypoxemia were present in all but one patient. The chest radiograph demonstrated alveolar and interstitial infiltrates. All patients were HIV-negative on hospital admission. Diagnosis was made by identifying the organism on specimens obtained by bronchoscopy, thoracocentesis, or needle aspiration. The mean age of the patients was 39.6 years. In contrast, Jacobs et aP5 reported a cluster of P. carinii pneumonia in a group of elderly patients; all but one was older than 70 years of age. Interestingly, these patients had a decreased lymphocyte response to T cell mitogens. Treatment

Trimethoprim/ sulfamethoxazole and pentamidine are commonly used drugs in the treatment of P. carinii pneumonia. An alternative drug for milder cases of Pneumocystis pneumonia is atovaquone, given orally in a dose of 750 mg three times daily for 21 days. Q FEVER

Q fever is an acute self-limited febrile illness. Sheep, cattle, and goats are common reservoirs for this zoonosis. Organism

lus.

Coxiella burnetii, the etiologic agent of Q fever, is a gram-negative coccobacil-

Epidemiology

Q fever is frequently an occupational disease affecting farmers, veterinarians, or abattoir workers. Q fever can be acquired by ingesting contaminated milk, being exposed to infected parturient cats, or skinning wild rabbits. Besides the self-limited febrile illness (the most common presentation), several clinical syndromes associated with Q fever have been reported, including pneumonia, hepatitis, endocarditis, and osteomyelitis.

NEW PATHOGENS IN PNEUMONIA

977

The incidence of pulmonary involvement in Q fever varies from 0% to 90%. This wide variation is probably related to many factors, such as different geographic strains, source, route, or dose of the infectious agent. Q fever pneumonia is frequently a mild illness. It can present as an atypical pneumonia, a rapidly progressive pneumonia, or, most commonly, an incidental finding in a patient with a febrile illness. Clinical Presentation

Although presenting signs and symptoms are nonspecific, severe headache is seen in about 75% of patients with Q fever pneumonia and frequently is a useful clue to the diagnosis. In contrast to the patients with rapidly progressive pneumonia who usually have signs of pulmonary consolidation, physical examination of the chest is often unremarkable in other forms of Q fever pneumonia. Chest films obtained on admission are almost always abnorma1. 35 Multiple round segmental opacities measuring 5 to 20 cm in diameter represented the most frequently observed radiographic findings (68%), especially in Q fever outbreaks. Other nonspecific findings observed on chest roentgenograms included linear atelectasis (50%), pleural effusion (35%), and lobar consolidation (25%). Pseudotumor of the lung rarely may develop during the course of a Q fever pneumonia. 26 The diagnosis of Q fever may be confirmed serologically by complement fixation, microhemagglutination or microimmunofluorescent tests. A fourfold rise in titer between the acute and convalescent serum sample is diagnostic of Q fever. A provisional diagnosis of Q fever pneumonia also can be made by demonstrating small coccobacillary bodies within the alveolar macrophages in tissues obtained by transbronchial biopsy.38 Treatment

Although C. burnetii is more sensitive to fluoroquinolones and rifampin than to chloramphenicol, doxycycline, or trimethoprim, tetracycline is the antibiotic of choice for Q fever pneumonia. 41 With a mortality of less than 1%, Q fever pneumonia is rarely a fatal disease. AEROMONAS HYDROPHILA

Organism

Aeromonas hydrophila, a gram-negative bacillus, is a well-known organism causing both gastrointestinal and extraintestinal illnesses. 51 Epidemiology

Although gastroenteritis, cellulitis, bacteremia, and peritonitis are commonly reported, pneumonia caused by A. hydrophila remains a rare clinical entity. Similar to patients with other bacterial pneumonias, A. hydrophila pneumonia patients frequently have conditions predisposing to aspiration, such as cerebrovascular accident, general anesthesia, alcohol abuse, and total or partial submersion in

978

GUERRA et al

water. ' Although A. hydrophila is not a marine bacterium, it has been implicated as the causative organism causing fulminant pneumonia in a previously healthy patient after swimming in the sea. 20 Because A. hydrophila infections are considered waterborne diseases, exposure to contaminated water, including swimming or near-drowning, is the most commonly observed precipitating condition. Underlying diseases, such as chronic alcoholic liver disease (18%), congestive heart failure (18%), or chronic pulmonary disease (12%), may play a role in the development of A. hydrophila pneumonia. ' Clinical Presentation

The presenting signs and symptoms are frequently nonspecific and similar to those of other bacterial pneumonias. A fulminant course with severe respiratory distress owing to noncardiogenic pulmonary edema, however, can occur in A. hydrophila-infected swimming or near-drowning individuals. Radiographic findings such as basilar infiltrates, lobar consolidation, and pulmonary cavitation are nonspecific. The bilateral fluffy pulmonary infiltrates suggestive of ARDS are frequently observed in near-drowning patients. A. hydrophila often can be isolated from sputum, tracheal aspirates, bronchoscopic samples, or blood. Treatment

A. hydrophila usually is resistant to ampicillin, carbenicillin, cephalothin, and cefoxitin. All isolates are sensitive to chloramphenicol, tetracycline, and aminoglycosides. Mortality rate ranges from 38% to 46% and is probably related to the severity of the precipitating conditions. LISTERIA MONOCYTOGENES Organism

Listeria monocytogenes is an intracellular gram-positive motile bacillus. Listeria has been isolated from wild and domestic animals as well as from plants and soil. Epidemiology

Although Listeria can be isolated from stool of up to 16% of asymptomatic human carriers, it remains an uncommon respiratory pathogen. It causes infections in newborns, pregnant women, the elderly, and immunosuppressed patients. Human immunodeficiency virus (HIV)-infected individuals and AIDS patients are particularly prone to Listeria infections. The Listeria infection rate in the HIV-infected group is 65 to 145 times higher than that of the general popula tion. 6, 28, 29 Clinical Presentation

The majority of patients with Listeria pneumonia have hematologic malignancies such as leukemia or lymphoma, They frequently have received chemo-

NEW PATHOGENS IN PNEUMONIA

979

therapy or steroids; the average age is 56 years. 34 Patients frequently present with fever and chills. Respiratory symptoms such as shortness of breath, pleuritic chest pain, and cough may not be obvious in obtunded patients who have concomitant meningitis.14 The white blood cell count is usually normal. Chest radiographs frequently show basilar infiltrates or pleural effusion. Listeria can be isolated either from the blood or from the pleural fluid. Treatment

The antibiotics of choice for Listeria infections include ampicillin or penicillins in combination with an aminoglycoside. Trimethoprim/sulfamethoxazole is another excellent alternative. Newer cephalosporins, including late-generation cephalosporins, have poor activity against L. monocytogenes. Besides antibiotic therapy, closed chest tube drainage may be indicated if empyema is present. In reported patients with Listeria pleuropulmonary infections, the mortality was 12.5% and probably related to the underlying diseases. BACILLUS CEREUS Organism

Organisms of the genus Bacillus are ubiquitous gram-positive, aerobic, sporeforming rods. Bacillus cereus has been found to cause a variety of syndromes, such as food poisoning, bacteremia, endocarditis, ocular infections, and musculoskeletal infections. Epidemiology

Pleuropulmonary disease caused by Bacillus has been rarely reported, probably because these organisms were considered to be contaminants. There were no organisms of the Bacillus group reported in three extensive reviews comprising 918 cases of empyema, lung abscesses, or pneumonias. 2• 3,17 B, cereus rarely is the causative agent of pneumonia in immunocompetent persons. It may cause serious bronchopulmonary infections, however, in immunocompromised patients. Clinical Presentation

Most pneumonia cases occur in patients who are neutropenic or cirrhotic or alcohol abusers. They frequently have nonspecific symptoms such as fever, cough, and chest pain. Approximately 50% of patients with B. cereus pneumonia have hemoptysis either on admission or during the course of their illnesses. Lifethreatening hemoptysis may occur in one half of these patients.s Abnormal findings on chest roentgenograms included cavitary infiltrates, pleural effusion, and rarely large pseudotumor.24 B. cereus and other Bacillus species are frequently identified in blood, but such isolation does not always indicate infection. Similarly, because it is part of the normal flora, its isolation in sputum samples may not be significant, unless it is obtained in pure culture by transtracheal aspirate and with a Gram stain that

980

GUERRA et al

shows an abundance of neutrophils together with gram-positive rods. Mortality rate is high in patients with B. cereus pneumonia (75%) and is largely related to underlying diseases. Treatment

Vancomycin is the antibiotic of choice for B. cereus infections. Because Bacillus species may produce beta-Iactamase, they should be considered resistant to the penicillins. EIKENELLA CORRODENS Organism

Eikenella corrodens is a fastidious facultative anaerobic gram-negative bacillus and is part of the normal human oral flora. Because it is a member of the normal oral flora, E. corrodens is frequently involved in human bite wounds, respiratory tract infections, or head and neck infections. Although the pathogenicity of E. corrodens appears to be low, infections resulting in abscess formation may develop when other organisms such as Streptococcus viridans coexist. Epidemiology

E. corrodens pleuropulmonary infections have been reported in patients who have conditions that either interfere with maintaining good oral hygiene or predispose to aspiration, such as cerebrovascular accident, seizure, periodontal diseases, alcohol abuse, or esophageal cancer. 47 Approximately 50% of these patients have lung cancer or lung mass. Clinical Presentation

Patients frequently present with nonspecific symptoms, such as fever, chills, cough, shortness of breath, and pleuritic chest pain. Chest radiograph shows cavitary pulmonary infiltrates and pleural effusion. In 13 reported cases of E. corrodens pneumonia, the causative organisms were isolated more frequently from transtracheal aspirates (78%) than from pleural fluid (54%)? Treatment

E. corrodens is notoriously resistant to clindamycin and metronidazole. It is susceptible to penicillin, ampicillin, antipseudomonal penicillins, second-generation and third-generation cephalosporins, and quinolones. HANTAVIRUSES Organism

Hantaviruses are the causative agents of a disease complex named hemorrhagic fever with renal syndrome (HFRS). Hantaan, Puurnala, Seoul, and Prospect

NEW PATHOGENS IN PNEUMONIA

981

Hill are the four members of the genus Hantavirus of the family Bunyaviridae. Although Hantaan, Puumala, and Seoul viruses are known human pathogens, Prospect Hill has not been found to cause disease. Epidemiology

Hantaan virus, the etiologic agent of Korean hemorrhagic fever, was the first recognized hantavirus that was isolated and reported in 1978. Nephropathia epidemica, a less dramatic disease caused by Puumala virus, is widespread in Scandinavia, the Soviet Union west of the Ural Mountains, and northwestern Europe. Although transmission of hantavirus has been recently documented among U.S. military personnel training in Korea, thousands of United Nations military personnel were clearly infected with hantaviruses during the Korean warY In the Four Corners area of the United States, a unique hantavirus has been identified as the cause of the outbreak of respiratory illness named hantavirus pulmonary syndrome (HPS)Y' 12, 23 All hantaviruses have reservoirs among free-living small rodents, such as moles, mice and rats. Peromyscus maniculatus (deer mouse), the principal rodent reservoir for US hantavirus, has a habitat that extends throughout most of the United States except the Southeast. Infection takes place by exposure to rodent excreta, either through the aerosol route or direct inoculation, The incubation period is highly variable and ranges from 2 to 4 weeks. Table 2. SCREENING CRITERIA FOR HANTAVIRUS PULMONARY SYNDROME IN PERSONS WITH UNEXPLAINED RESPIRATORY ILLNESS Potential Case-Patients Must Have One of the Following A febrile illness (temperature 2: 101° F) occurring in a previously healthy person characterized by unexplained adult respiratory distress syndrome, or bilateral interstitial pulmonary infiltrates developing within 1 week of hospitalization with respiratory compromise requiring supplemental oxygen, or An unexplained respiratory illness resulting in death in conjunction with an autopsy examination demonstrating noncardiogenic pulmonary edema without an identifiable specific cause of death Potential Case-Patients Are to Be Excluded If They Have Any of the Following A predisposing underlying medical condition (e.g., severe underlying pulmonary disease, solid tumors or hematologic malignancies, congenital or acquired immunodeficiency disorders, or medical conditions [e.g" rheumatoid arthritis or organ transplant recipients] requiring immunosuppressive drug therapy [e.g., steroids or cytotoxic chemotherapy]) An acute illness that provides a likely explanation for the respiratory illness (e.g., recent major trauma, burn, or surgery; recent seizures or history of aspiration; bacterial sepsis; another respiratory disorder such as respiratory syncytial virus in young children; influenza; or legionella pneumonia). Confirmed Case-Patients Must Have the Following At least one specimen (i.e., serum or tissue) available for laboratory testing for evidence of hantavirus infection and In a patient with a compatible clinical illness, serology (presence of hantavirus-specific IgM or rising titers of IgG), polymerase chain reaction for hantavirus RNA, or immunohistochemistry for hantavirus antigen is positive Adapted from the Centers for Disease Control: Update: Hantavirus pulmonary syndrome-United States. MMWR 42:8165,1993.

982

GUERRA et al

Clinical Presentation

There were 42 HPS cases reported to the Centers for Disease Control from July 1991 to October 1993. Case-patients' ages ranged from 12 years to 69 years (median, 32 years). During the onset of illness, patients frequently have a prodrome of fever, myalgia, headache, abdominal pain, nausea, vomiting, and variable respiratory symptoms such as cough. This is followed abruptly by respiratory failure. On admission, hemoconcentration and thrombocytopenia are present in more than 70% of patients. In contrast to the hemorrhagic manifestations and renal involvement of the clinical syndrome previously associated with hantavirus infections, the clinical features of patients with HPS were characterized by the predominance of respiratory symptoms and only limited renal complications. The hospital course is complicated by hypoxia owing to noncardiogenic pulmonary edema and profound hypotension. Diffuse bilateral pulmonary infiltrates on chest films usually develop within 2 days of hospitalization. Pleural effusion and heavy edematous lungs are frequently observed during postmortem examination. Microscopic findings such as interstitial infiltrates of mononuclear cells in the alveolar septa, focal hyaline membrane, and occasional alveolar hemorrhage occur frequently. Hantavirus antigen can be detected by immunohistochemistry in most organs, especially in the lungs. Shock and severe lactic acidosis are two prognostic markers that predict a poor patient outcome. Mortality rate is high (62%) in 42 reported cases of HPS.

Treatment

There is no specific treatment for HPS; supportive measures are the basis of therapy. Similar to the treatment of noncardiogenic pulmonary edema, overhydration and severe hypoxia should be avoided. Although previously isolated hantaviruses have demonstrated in vitro sensitivity to ribavirin, whether treatment with this investigational antiviral drug for HPS has any beneficial effect is unknown. Because there are no signs and symptoms that can reliably distinguish HPS at the time of presentation from other forms of noncardiogenic pulmonary edema, physicians should have a high index of suspicion of this disease. To standardize the investigation and laboratory assessment of persons with possible HPS in the United States, the Centers for Disease Control has issued screening criteria (Table 2). SUMMARY It appears that many commonly recognized syndromes such as the ARDS may well be caused by agents that have only recently emerged as respiratory pathogens. HPS represents one such entity. It appears likely that the increasing pressure of antibiotic use as well as the reemergence of certain pathogens will continue to challenge the clinician. Paramount to the identification and treatment of unusual pneumonias will be the degree with which an effort is made to make an etiologic diagnosis through sputum examination, transtracheal aspirate, bronchoscopy, or lung biopsy. Although pneumococcal pneumonia is the most common community-acquired pneumonia seen by practicing physicians, in alllikelihood from time to time a physician will encounter pneumonia caused by one of

NEW PATHOGENS IN PNEUMONIA

983

the unusual pathogens described in this article or else by an altogether new pathogen. References 1. Baddour LM, Baselski VS: Pneumonia due to Aeromonas hydrophilia-complex: Epidemiologic, clinical, and microbiologic features. South Med J 81:461, 1988 2. Bartlett JG, Finegold SM: Anaerobic infections of the lung and pleural space. Am Rev Respir Dis 110:56, 1974 3. Bartlett JG, Gorbach SL, Thadepalli H, et al: Bacteriology of empyema. Lancet 1:338, 1974 4. Basiliere JL, Bistrong HW, Spence WF: Streptococcal pneumonia. Recent outbreaks in military recruit populations. Am J Med 44:580, 1968 5. Bekemeyer WB, Zimmerman GA: Life threatening complications associated with Bacillus cereus pneumonia. Am Rev Respir Dis 131:466, 1985 6. Berenguer J, Solera J, Diaz MD, et al: Listeriosis in patients infected with human immunodeficiency virus. Rev Infect Dis 13:115, 1991 7. Berk SL, Verghese A, Holtsclaw SA, et al: Enterococcal pneumonias occurrence in patients receiving broad-spectrum antibiotic regimens and enteral feeding. Am J Med 74:153,1983 8. Buxton AE, Anderson RL, Werdegar D, et al: Nosocomial respiratory tract infection and colonization with acinetobacter calcoaceticus. Am J Med 65:507,1978 9. Cano S, Capote F, Pereira A, et al: Pneumocystis carinii pneumonia in patients without predisposing illnesses. Acute episode and follow-up of five cases. Chest 104:376, 1993 10. Capewell S, McLeod DT, Croughan MJ, et al: Pneumonia due to Branhamella catarrhalis. Thorax 43:929,1988 11. Centers for Disease Control: Outbreak of acute illness-southwestern United States. MMWR 42:421, 1993 12. Centers for Disease Control: Update: Hantavirus pulmonary syndrome-United States. MMWR 42:816, 1993 13. Cury JD, Harrington PT, Hosein IK: Successful medical therapy of rhodococcus equi pneumonia in a patient with HIV infection. Chest 102:1619, 1992 14. Domingo P, Serra J, Sambeat MA, et a1: Pneumonia due to Listeria monocytogenes. Clin Infect Dis 14:787, 1992 15. Everett ED, Nelson RA: Pulmonary melioidosis observations in thirty nine cases. Am Rev Respir Dis 112:331, 1975 16. Farley MM, Harvey RC, Stull T, et al: A population-based assessment of invasive disease due to group B streptococcus in nonpregnant adults. N Engl J Med 328:1807, 1993 17. Finland M, Barnes MW: Changing ecology of acute bacterial empyema: Occurrence and mortality at Boston City Hospital during 12 selected years from 1935 to 1972. J Infect Dis 137:274, 1978 18. Gallagher PG, Watanakunakorn C: Group B streptococcal bacteremia in a community teaching hospital. Am J Med 78:795, 1985 19. Glew RH, Moellering RC Jr, Kunz LJ: Infections with acinetobacter calcoaceticus (herellea vaginicola): Clinical and laboratory studies. Medicine 56:79, 1977 20. Goncalves JR, Brum G, Fernandes A, et al: Aeromonas hydrophilia fulminant pneumonia in a fit young man. Thorax 47:482, 1992 21. Goodhart GL, Abrutyn E, Watson R, et al: Community-acquired Acinetobacter calcoaceticus var anitratus pneumonia. JAM A 238:1516, 1977 22. Harvey RL, Sunstrum JC: Rhodococcus equi infection in patients with and without human immunodeficiency virus infection. Rev Infect Dis 13:139, 1991 23. Hughes JM, Peters q, Cohen ML, et al: Hantavirus pulmonary syndrome: An emerging infectious disease. Science 262:850, 1993 24. Isaacson P, Jacobs PH, Mackenzie AMR, et al: Pseudotumor of the lung caused by infection with Bacillus sphaericus. J Clin Pathol 29:806, 1976

984

GUERRA et al

25. Jacobs JL, Libby OM, Winters RA, et al: A cluster of Pneumocystis carinii pneumonia in adults without predisposing illnesses. N Engl J Med 324:246,1991 26. Janigan OT, Marrie TJ: An inflammatory pseudotumor of the lung in Q fever pneumonia. N Engl J Med 308:86, 1983 27. Javaheri S, Smith RM, Wiltse 0: Intrathoracic infections due to Eikenella corrodens. Thorax 42:700, 1987 28. Jones LW, Carswell J, Ramussen KC: Listeria pneumonia, a case report. S Afr Med J 75:188, 1989 29. Jurado RL, Farley MM, Pereira E, et al: Increased risk of meningitis and bacteremia due to Listeria monocytogenes in patients with human immunodeficiency virus infection. Clin Infect Dis 17:224, 1993 30. Kaplan EL, Johnson OR, Kuritsky IN: Rectal colonization by group B j3-hemolytic streptococci in a geriatric population. J Infect Dis 148:1120, 1983 31. Kleemola M, Saikku P, Visakorpi R, et al: Epidemics of pneumonia caused by TWAR, a new chlamydia organism, in military trainees in Finland. J Infect Ois 157:230, 1988 32. Lasky JA, Pulkingham N, Powers MA, et al: Rhodococcus equi causing human pulmonary infection: Review of 29 cases. South Med J 84:1217,1991 33. Lipsky BA, Tack KJ, Kuo e, et al: Ofloxacin treatment of Chlamydia pneumoniae (strain TWAR) lower respiratory tract infections. Am J Med 89:722, 1990 34. Mazzulli T, Salit IE: Pleural fluid infection caused by Listeria monocytogenes: Case report and review. Rev Infect Ois 13:564, 1991 35. Millar JK: The chest film findings in 'Q' fever-a series of 35 cases. Clin Radiol 29:371, 1978 36. Morrison RE, Lamb AS, Craig DB, et al: Melioidosis: A reminder. Am J Med 84:965, 1988 37. Nicotra B, Rivera M, Luman JI, et al: Branhamella catarrhalis as a lower respiratory tract pathogen in patients with chronic lung disease. Arch Intern Med 146:890, 1986 38. Pierce TH, Yuch Se, Gorin AB, et al: Q fever pneumonitis: Diagnosis by transbronchoscopic lung biopsy. West J Med 130:453, 1979 39. Rudin ML, Michael JR, Huxley EJ: Community-acquired acinetobacter pneumonia. Am J Med 67:39, 1979 40. Saikku P, Leinonen MJ, Tenkanen L, et al: Chronic Chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart study. Ann Intern Med 116:273,1992 41. Sawyer LA, Fishbein DB, McOade JE: Q fever: Current concepts. Rev Infect Ois 9:935, 1987 42. Sheedy JA, Freob HF, Batson HA, et al: The clinical course of epidemic hemorrhagic fever. Am J Med 16:619, 1954 43. Sladek GG, Frame IN: Rhodococcus equi causing bacteremia in an adult with acute leukemia. South Med J 86:244, 1993 44. Sookpranee M, Boonma P, Susaengrat W, et al: Multicenter prospective randomized trial comparing ceftazidime plus co-trimoxazole with chloramphenicol plus doxycycline and co-trimoxazole for treatment of severe melioidosis. Antimicrob Agents Chemother 36:158,1992 45. Stevens OL: Invasive group A streptococcus infections. Clin Infect Ois 14:2, 1992 46. Stevens OL, Tanner MH, Winship J, et al: Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. N Engl J Med 321:1,1989 47. Suwanagool S, Rothkopf MM, Smith SM, et al: Pathogenicity of Eikenella corrodens in humans. Arch Intern Med 143:2265, 1983 48. Thorn OH, Grayston JT: Infections with Chlamydia pneumoniae strain TWAR. Clin Chest Med 12:245, 1991 49. Verghese A, Berk SL: Moraxella (Branhamella! catarrhalis. Infect Ois Clin North Am 5:523, 1991 50. Verghese A, Berk SL, Boelen LJ, et al: Group B streptococcal pneumonia in the elderly. Arch Intern Med 142:1642, 1982 51. Von Graevenitz A, Mensch AH: The genus Aeromonas in human bacteriology. Report of 30 cases and review of literature. N Engl J Med 278:245,1968

NEW PATHOGENS IN PNEUMONIA

985

52. Yu VL: Enterococcal superinfection and colonization after therapy with moxalactam, a new broad-spectrum antibiotic. Ann Intern Med 94:784,1981 53. Zervos MJ, Bacon AE, Patterson JE, et al: Enterococcal superinfection in patients treated with ciprofloxacin. J Antimicrob Chemother 21:113,1988

Address reprint requests to Abraham Verghese, MD Texas Tech University Health Sciences Center Department of Internal Medicine 4800 Alberta A venue El Paso, TX 79905