Nonresolving Pneumonia - Springer25 Nonresolving Pneumonia DAVID OST, ANNA ROZENSHTEIN, AND ALAN...

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Nonresolving PneumoniaDAVID OST, ANNA ROZENSHTEIN, AND ALAN FEIN

Introduction

Pneumonia that fails to respond to treatment is acommon problem. Although quantification of thefrequency of this problem is difficult, Feinsilver etal. (1990) reported that approximately 15% of pul-monary consultations and 8% of bronchoscopieswere done to evaluate nonresolving pneumonia. Inthe intensive care unit (ICU) up to 90% of patientswill have persistent radiographic infiltrates on chestx-ray (Augustine et al., 1992). Clinicians are con-fronted with a complex challenge when this occurs.First, it is difficult to define normal resolution, de-layed resolution, and progression of disease. A spe-cific pathogen cannot be identified in up to 50% ofcases of community-acquired pneumonia (CAP),and two or more etiologies are identified in up to5% of cases (Marston et al., 1997; British ThoracicSociety, 1993; Fang et al., 1990; Marrie et al., 1989;Mundy et al., 1995). This leads to significant diag-nostic uncertainty when patients fail to respond toempiric therapy. As a result, when pneumonia failsto respond to treatment, the question becomeswhether or not the diagnosis of pneumonia is evencorrect, since many conditions can mimic pneu-monia. It is therefore more precise to use the termnonresolving pneumonia syndrome when approach-ing these cases, since a nonresolving pneumoniamay not even be infectious.

DAVID OST, ANNA ROZENSHTEIN, AND ALAN FEIN •Columbia University College of Physicians & Surgeons, St.Luke’s–Roosevelt Hospital Center, New York, NY 10025.

Community-Acquired Pneumonia, edited by Marrie. KluwerAcademic/Plenum Publishers, New York, 2001.

The first goal in evaluating nonresolving pneu-monia is to discriminate between normal and non-resolving pneumonia in order to avoid unnecessarydiagnostic tests. This requires a clear definition ofwhat is normal and what is abnormal resolution. Ifabnormal resolution is identified, the next step is toconsider the most common infectious and noninfec-tious factors associated with the nonresolving pneu-monia syndrome. Finally, the utility of various testsin developing a diagnostic approach must be as-sessed.

Definitions

The difficulty in defining the nonresolvingpneumonia syndrome is that the normal resolutionof pneumonia is not a clearly defined process.Given this uncertainty, it is useful to consider theresolution of pneumonia as a spectrum, includingnormal resolution, slowly resolving pneumonia,and progressive pneumonia. The parameters usedto describe this spectrum include both clinical andradiographic criteria.

Clinical criteria that have been studied includefever, cough, crackles, white blood cell count, PO2

level, and C-reactive protein (Lehtomaki, 1988;Bartlett et al., 1998; American Thoracic Society,1993). Subjective response is usually noted within 3to 5 days of starting treatment (Bartlett et al., 1998).Most studies of resolution of pneumonia have notfocused on symptoms, however, but instead on ra-diographic resolution (Lehtomaki, 1988; Marrie,1992; Imboden et al., 1961; MacFarlane et al., 1984;Jay et al., 1975; Finnegan et al., 1981). Fein et al.(1991) defined this as at least 10 days of antibiotictherapy alone with “a radiographic infiltrate that

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has not resolved in an expected period of time basedon the presumptive diagnosis.” Kirkland and Win-terbauer (1991) defined slowly resolving pneumoniaas less than 50% clearing at 4 weeks associated withclinical improvement on antibiotics. Most investi-gators have chosen an arbitrary definition of 1month, but in all instances slowly resolving infec-tions have been defined by the persistence of radio-graphic abnormalities in a clinically improved host(Lehtomaki, 1988; Imboden et al., 1961; MacFar-lane et al., 1984; Jay et al., 1975; Finnegan et al.,1981; Kirkland & Winterbauer, 1991; Israel et al.,1956; Gleichman et al., 1949).

Although the ideal transition point for definingslowly resolving pneumonia varies, from a clinicalstandpoint the critical distinction lies in differen-tiating pneumonias that are progressive from thosethat are merely slow to resolve. The latter can beobserved without further testing, whereas the for-mer requires further investigation. The clinical de-cision that a patient has a nonresolving and progres-sive pneumonia must therefore take into accountfactors that affect the expected rate of resolution.These factors include comorbidities, age, severity,and type of infectious agent.

Comorbidities and Resolution ofCommunity-Acquired Pneumonia

Pneumonia frequently occurs in patients withcomorbidities or advanced age. The comorbiditiesmost commonly associated with CAP that affect therate of resolution include chronic obstructive pul-monary disease (COPD), alcoholism, diabetes melli-tus, neurological disorders, ischemic heart disease,malignancy, renal failure, immunosuppression, andHIV infection (Fein et al., 1991; Israel et al., 1956;Marrie, 1990). While patients without comorbidi-ties will usually demonstrate clearing of radio-graphic infiltrates by 4 weeks, only 20% to 30% ofpatients with these comorbidities will clear by 4weeks (MacFarlane et al., 1984; Jay et al., 1975).The frequency of these comorbidities increaseswith age and thus concurrent comorbidities aremore common in the elderly. For example, in pa-tients less than 50 years of age, COPD is present in5.7% of CAP cases. In patients older than 50 years,COPD is present in greater than 30% of CAP cases(Marrie, 1990).

Age and Resolution of Community-Acquired Pneumonia

Despite the concurrence of comorbidities andadvanced age, several studies have demonstratedthat age itself is an independent risk factor for de-layed clearing (MacFarlane et al., 1984; Jay et al.,1975; Israel et al., 1956; Van Metre, 1954). Approx-imately 90% of patients younger than 50 yearsshow radiographic resolution by 4 weeks (Mac-Farlane et al., 1984; Jay et al., 1975; Israel et al.,1956; Van Metre, 1954). However, Jay et al. (1975)demonstrated that only 30% of patients older than50 years without concurrent disease had radio-graphic resolution by 4 weeks. Similarly, Mac-Farlane et al. (1984) found that even by 9 weeksonly 50% of older patients had radiographic resolu-tion. In a study of CAP by Israel et al. (1956), onlyone third of patients were over 50 years but thisgroup accounted for two thirds of the cases of non-resolving pneumonia. Thus, age is among the mostimportant factors associated with delayed resolu-tion.

Severity and Resolution of Community-Acquired Pneumonia

Age is also associated with an increased riskfor more severe pneumonia (American ThoracicSociety, 1993; Research Committee of the BritishThoracic Society, 1987; Zweig et al., 1990; Fine etal., 1990). However, severity of disease remains anindependent risk factor for delayed resolution(Marrie et al., 1989; Research Committee of theBritish Thoracic Society, 1987; Fine et al., 1990).The time to radiographic resolution for severe CAPhas been estimated at 10 weeks, compared with 3 to4 weeks for mild to moderate pneumonia (Marrie,1992). Indeed, definitions of normal resolution varysignificantly in the literature, in part because ofwide variations in the severity of illness triggeringadmission (McMahon et al., 1989; Roos et al., 1988;Wennberg et al., 1987). This has an impact on theexpected “normal” rate of resolution, since sever-ity of disease affects the rate of resolution (Marrieet al., 1989; Mundy et al., 1995; Marrie, 1992; Re-search Committee of the British Thoracic Society,1987; Zweig et al., 1990; Sullivan et al., 1972; Whiteet al., 1981).

NONRESOLVING PNEUMONIA 389

Impact of Infectious Agents on Rateof Resolution

The rate of radiographic and clinical improve-ment also varies with the infectious agent. While afull review of each infectious agent associated withCAP is beyond the scope of this chapter, this sec-tion will focus on the features that are relevant toresolution of pneumonia with respect to the mostcommon microorganisms. These include Streptococ-cus pneumoniae, Legionella, Mycoplasma, Chla-mydia pneumoniae, and Haemophilus influenzae.

Streptococcus pneumoniae

Pneumococcal pneumonia accounts for up to65% of CAP infections, and therefore accounts formost cases of infectious nonresolving pneumoniasyndromes (Bartlett et al., 1998; American ThoracicSociety, 1993; Marrie, 1990; Pennington, 1986). It isalso the best studied of the infectious etiologies interms of the rate of resolution and the factors thataffect resolution. In normal individuals without pre-disposing illnesses, clinical improvement precedesradiographic improvement.

Clinical improvement is relatively rapid in un-complicated cases. When auscultation was the pri-mary tool for assessing response to therapy, clini-cians were able to detect abnormal findings onphysical examination in only 8% of patients at 1month (Chatard, 1910; McRae, 1910; Lord, 1925).Similarly, Van Metre (1954) demonstrated that fe-ver resolved rapidly, with only 6% of patients dem-onstrating fever beyond 20 days. Risk factors fordelayed resolution of auscultatory findings and fe-ver in this study included more severe presentationand multilobar disease.

In contrast, radiographic improvement is oftenmuch slower. Despite relatively rapid clinical im-provement, approximately 20% to 30% of patientswill have no improvement on chest radiograph atone week (MacFarlane et al., 1984). Initial worsen-ing of the chest radiograph has also been frequentlyreported (MacFarlane et al., 1984; Jay et al., 1975;Graham & Bradley, 1978). Risk factors for delayedradiographic resolution include bacteremia, persis-tent fever or leukocytosis beyond 6 days, agegreater than 50 years, COPD, and alcoholism (Mac-Farlane et al., 1984; Jay et al., 1975; Israel et al.,

1956). Radiographic clearing occurs by 1 to 3months in nonbacteremic cases and in 3 to 5 monthsfor bacteremic cases (Fein et al., 1987). Residualradiographic abnormalities are rare in nonbacte-remic cases but are present in up to 35% of bacte-remic cases (MacFarlane et al., 1984; Jay et al.,1975; Israel et al., 1956; Fein et al., 1987). Impor-tantly, bronchogenic carcinoma was not found to bea common cause of nonresolving pneumonia in anyof these studies (Jay et al., 1975; Israel et al., 1956).

Legionella pneumophila

Legionella is increasingly recognized as animportant pathogen in patients with severe CAP(Bartlett et al., 1998; American Thoracic Society,1993; Marrie, 1990). Indeed, Legionella is one ofthe three most frequent etiologic agents that causerapidly progressive pneumonias (Torres et al., 1991;VanEeden et al., 1988). It is frequently encounteredin the compromised host and in the elderly, with theestablished risk factors for Legionella being ciga-rette use, alcoholism, age greater than 65 years,immunosuppression with corticosteroids, dialysis,and bone marrow transplantation (England et al.,1980; Gump & Keegan, 1986). Many of these pre-disposing conditions are likewise risk factors fordelayed resolution, so it is not surprising that therate of resolution for Legionella is slower than thatof other organisms.

Ninety percent of Legionella infections aredue to Legionella pneumophila, and 80% of theseare due to serogroup 1 (Bartlett et al., 1998; Ameri-can Thoracic Society, 1993; England et al., 1980;Gump & Keegan, 1986; Fang et al., 1989). Thus,most of the literature on the natural history of Le-gionella infections is based on this one serogroup.As in pneumococcal infections, clinical improve-ment precedes radiographic improvement. The radio-graphic infiltrates and clinical picture are usuallyindistinguishable from severe pneumococcal infec-tions (Helms et al., 1979). There is usually an initialpatchy infiltrate that subsequently becomes conflu-ent and even bilateral, often despite appropriateantibiotic therapy (Dietrich et al., 1978; Edelstein &Meyer, 1984; Kroboth et al., 1983; Lo et al., 1983).

The distinguishing features of Legionella in-fections are the propensity for initial radiographicdeterioration, the prolonged resolution of radio-

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graphic infiltrates, and the prolonged convalescenceassociated with this infection. MacFarlane et al.(1984) noted radiographic deterioration in up to twothirds of patients with Legionella, compared with4% of patients with nonbacteremic pneumococcalpneumonia. In addition, after this initial deteriora-tion, resolution is slower than with pneumococcalinfections. Radiographic clearing only begins after2 to 3 weeks, with 50% of radiographs abnormal at10 weeks (MacFarlane et al., 1984; Lo et al., 1983).Resolution may take as long as 6 to 12 months, withresidual fibrosis evident in up to 25% of patients(Dietrich et al., 1978; Edelstein & Meyer, 1984).Even after radiographic resolution, generalizedweakness and fatigue may persist for months. In theinitial description of Legionnaires’ disease in Phila-delphia, patients frequently complained of fatigueand shortness of breath when surveyed up to 2 yearsafter the event, with half demonstrating residualabnormalities on pulmonary function testing (Lat-timer et al., 1979).

Mycoplasma pneumoniae

Mycoplasma pneumoniae is a common causeof respiratory tract infections; however, it is a rela-tively rare cause of severe pneumonia (Foy et al.,1979). M. pneumoniae infection is generally lesssevere and occurs in a younger population, so it isnot surprising that the rate of resolution is fasterthan with other types of pneumonia. Clinically ap-parent pneumonia occurs in only 3% to 13% ofpatients infected, with most patients being youngadults (Cassell & Cole, 1981; Luz et al., 1984; Mur-ray et al., 1975; Foy et al., 1971). Mycoplasma ac-counts for approximately 5% of hospitalized pneu-monias, but is unusual in those older than 65 years(Marrie, 1993).

The initial radiographic pattern is one of inter-stitial infiltrates with progression to air space dis-ease with consolidation. Multilobar involvement iscommon, occurring in 50% to 60% of cases (Finne-gan et al., 1981). Radiographic deterioration ontreatment is rare, occurring in less than 25% ofcases (Fein et al., 1987). Acute respiratory distresssyndrome (ARDS) is a rare complication of Myco-plasma pneumonia; in one series of hospitalizedpatients with Mycoplasma pneumonia, only sevenof 64 patients (10.9%) required mechanical ventila-tion (Marrie, 1993).

olution of Mycoplasma pneumonia is common(Marrie, 1992; Fein et al., 1987). There is usually arapid clinical improvement that occurs in the first 2weeks, in part reflecting the predominantly youngpopulation affected. Radiographic resolution maytake anywhere from 2 weeks to 2 months (Fein etal., 1987). Shames et al. (1970) demonstrated anaverage duration of radiographic abnormalities of 1to 2 weeks, depending on the use of antibiotics.Finnegan et al. (1981) and MacFarlane et al. (1984)found that 40% had complete radiographic resolu-tion at 4 weeks and 90% at 8 weeks. Residualscarring and fibrosis were rare in both studies.

Chlamydia pneumoniae

C. pneumoniae infection is common, with30% to 50% of young adults having serologicalevidence of infection (Grayston, 1992). Distin-guishing features of Chlamydia infection include anincreased frequency of hoarseness, lack of fever,and a prolonged period before seeking medical at-tention. Extrapulmonary manifestations includeerythema nodosum, encephalitis, and Guillain-Barré syndrome.

The disease is relatively mild and mortality israre, with prompt resolution common in youngerpatients. However, relapse is common when eryth-romycin is given for only 2 weeks, and it is there-fore advisable to treat with either 3 weeks of eryth-romycin or 2 weeks of a tetracycline (Grayston,1992). Radiographically, Chlamydia pneumonia isindistinguishable from other forms of pneumonia,with lobar and interstitial infiltrates being common.Initial radiographic deterioration is rare, with radio-logic clearing requiring 1 to 3 months (Marrie,1992; MacFarlane et al., 1984). In MacFarlane’s(1984) series, resolution was intermediate betweenMycoplasma and Legionella. Fifty percent of chestradiographs were normal by 4 weeks and up to 20%took longer than 9 weeks to clear (MacFarlane etal., 1984; Stengstrom et al., 1962). Residual radio-graphic scarring and fibrosis is seen in 10% to 20%of cases (Fein et al., 1987).

Haemophilus influenzae

Haemophilus influenzae has become an in-creasingly common cause of pneumonia and is nowrecognized as a common pathogen in the elderly, inhospitalized patients, and in cigarette smokersIn contrast to Legionnaires’ disease, rapid ris-


(Niederman, 1998). Risk factors for severe infec-tion include COPD, malignant disease, diabetes,alcoholism, and immunosuppression (Takala et al.,1990; Musher et al., 1983; Levin et al., 1977). In asurveillance study in Finland, 71% of cases oc-curred in patients who were severely immuno-compromised, and 55% of invasive cases occurredin those over the age of 50 years (Takala et al.,1990). Invasive cases are more commonly causedby encapsulated strains, which are also associatedwith a higher risk for severe sepsis and mortality(Williams & Verghese, 1991; Fein et al., 1993). Un-encapsulated strains are less frequently associatedwith mortality but are more often associated with aprolonged febrile tracheobronchitis (Williams &Verghese, 1991).

The clinical presentation of Haemophiluspneumonia is not unique and it is therefore impos-sible to reliably differentiate it from other pneu-monias, particularly pneumococcal pneumonia (Nie-derman, 1998; Takala et al., 1990; Musher et al.,1983; Levin et al., 1977; Williams & Verghese,1991; Fein et al., 1993). A multilobar pattern ofbronchopneumonia with a pleural effusion is con-sidered “classic” but this finding is by no meansspecific.

The natural history of Haemophilus infectionhas not been well studied and there are no distin-guishing features regarding the rate of resolution.Based on its propensity to infect the immuno-compromised and elderly, the rate of resolution canbe expected to be slow. Clinical improvement isalso slow, with many patients hospitalized for up to2 to 3 weeks, with only half returning to theirprevious level of function by 6 weeks (Takala et al.,1990; Fein et al., 1993; Venkatesan et al., 1990).Similarly, radiographic resolution can be expectedto be slow relative to other pneumonias.

Pneumonia of Unknown Etiology

Since half of all pneumonias will have no iso-lated pathogen, it becomes clear that the possibleupper limit of normal resolution will be quite high(Marston et al., 1997; British Thoracic Society,1993; Fang et al., 1990; Marrie et al., 1989; Mundyet al., 1995). Because S. pneumoniae and L. pneu-mophila are both common in severe CAP, the nor-mal resolution time for severe CAP may be ex-pected to range from 3 to 12 weeks. However, inmany cases no pathogen will be identified.

Based on these studies, it is apparent that thenormal time to resolution for severe CAP has abroad distribution curve, depending on a variety offactors. Many patients with a nonresolving pneu-monia will actually be within the limits of normalresolution once these other factors are taken intoconsideration. Those patients with slow radio-graphic resolution but a good clinical response canbe defined as having slowly resolving pneumonia.At some point in this spectrum, however, the patientcrosses into the area of nonresolving pneumonia.Those patients with clinical deterioration undertherapy can be defined as having progressive pneu-monia. These two categories have significant over-lap, but are useful clinical definitions, since patientswith progressive disease are more likely to warrantadditional diagnostic testing. Importantly, the termpneumonia in this situation does not necessarilyequate with infection, since many patients withclinical deterioration may have a noninfectious dis-order. Progressive disease in these cases may be dueto factors associated with infectious or noninfec-tious etiologies.

Infectious Etiologies

If the initial diagnosis of an infectious etiologyis correct, then factors that can lead to a progressiveor nonresolving pneumonia need to be assessed.These factors include those associated with thepathogen, the host, or the therapy.

Pathogen Factors

Alternative or unusual pathogens need to beconsidered in the patient who fails to respond totreatment. Although there are a potentially unlim-ited number of “unusual” pathogens that maycause a nonresolving pneumonia, several warrantspecial attention. The most important are tuber-culosis, fungi, Nocardia and Actinomyces, Coxiellaburnetii, and Pneumocystis carinii. In addition, thepossibility of a relatively “common” pathogenwith resistance needs to be considered.

Tuberculosis

There has been an increase in the incidence oftuberculosis recently, and in certain populationstuberculosis remains a significant concern (Ameri-

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can Thoracic Society, 1994; Centers for DiseaseControl, 1990a). In particular, the suspicion of tu-berculosis should be particularly high in immigrantpopulations, those with a history of intravenousdrug abuse, and in patients with AIDS (Block et al.,1989; Centers for Disease Control, 1990b). In addi-tion, the elderly should also be considered at higherrisk for tuberculosis, since the elderly still representone of the largest repositories of tuberculosis in theUnited States. Most infections in the elderly willrepresent reactivation disease, since the majoritywere infected 50 to 70 years ago. However, recentstudies of epidemic spread in nursing homes indi-cate that new infections are also possible, so a highindex of suspicion is necessary (American ThoracicSociety, 1994; Centers for Disease Control, 1990a;Creditor et al., 1988).

The clinical presentation of tuberculosis as acause of nonresolving pneumonia will often be“atypical,” especially in the elderly. Nine out of tencases of unsuspected tuberculosis in a communityteaching hospital occurred in elderly patients (Coun-sell et al., 1989). In a review of 93 patients over theage of 60 years, Morris found atypical findings suchas nonspecific mid- or lower-lobe changes to becommon (Morris, 1989). Similarly, Kahn et al.(1977) found that one third of adult patients withnewly diagnosed tuberculosis had “atypical” find-ings, irrespective of age. Thus, the classic presenta-tion of a cavitary infiltrate in the apical or posteriorsegments of one or both upper lobes may not al-ways be present.

In this setting, the diagnosis of tuberculosismay be difficult. Tuberculin testing may be nega-tive in 10% to 20% of patients with active disease,and in an even higher percentage of the elderly andpatients with AIDS (American Thoracic Society,1994; Kent & Schwartz, 1967). A two-step tuber-culin test should be considered in the elderly toovercome this waning of delayed hypersensitivity.Sputum acid-fast cultures are positive in up to 80%of cases, but sputum is not always easy to obtain,especially in the elderly (American Thoracic Soci-ety, 1994; Katz et al., 1987). Because culture resultsmay take up to 6 weeks, newer methods, includingthe BAC-TEC system, are recommended to de-crease the time needed to establish a diagnosis(Ellner et al., 1988). Polymerase chain reaction test-ing has been approved for smear-positive speci-

mens to allow confirmation of tuberculous disease,but its role in smear-negative patients remains to bedetermined (Chin et al., 1995; Brisson-Noel et al.,1991).

Fungi

Both opportunistic as well as endemic fungimimic bacterial pneumonia. Of the opportunisticfungi, Aspergillus is the most important. The spec-trum of pulmonary Aspergillus infections includesbenign mycetomas, chronic necrotizing aspergillo-sis, and invasive pulmonary aspergillosis. Of thesevarious forms, it is the chronic necrotizing andinvasive forms of disease that are most likely to bemistaken for bacterial pneumonia.

Chronic necrotizing aspergillosis represents asemi-invasive form of infection and is most com-monly seen in patients with preexisting chroniclung disease, often in the setting of chronic cor-ticosteroid use (Binder et al., 1982). It may also beseen at the interface of a mycetoma and the normallung. From a pathophysiologic standpoint, this syn-drome represents the result of a host immune re-sponse that is barely able to hold the infection incheck but not strong enough to eradicate it. Theradiographic appearance is usually chronic and pro-gressive, affecting the upper lobes more frequently.

Invasive aspergillosis is classically describedas affecting neutropenic patients taking multipleantibiotics for several days. However, it is impor-tant to realize that aspergillosis is being increas-ingly recognized in two new groups of patients. Thefirst group is older patients with chronic lung dis-ease who are taking corticosteroids. In these casesAspergillus may mimic a bacterial infection, lead-ing to significant delays in therapy. In one series,patients with invasive aspergillosis were treated anaverage of 18 days with multiple antibiotics beforethe diagnosis was made. In many of these cases thediagnosis was only established post mortem (Rodri-guez et al., 1992).

The second new group at risk for Aspergillusinfection is the AIDS population. Patients with ad-vanced AIDS are at increased risk for invasive as-pergillosis (Miller et al., 1994; Denning et al., 1991).In addition, patients with less advanced HIV infec-tion may develop one of three different patterns oftracheobronchitis that may mimic nonresolving


pneumonia. These three patterns are obstructivebronchial aspergillosis, ulcerative tracheobron-chitis, and pseudomembranous tracheobronchitis.Obstructive bronchial disease is characterized bythick mucous plugs filled with Aspergillus in theairways, with little mucosal involvement (Denninget al., 1991). Ulcerative tracheobronchitis is charac-terized by additional mucosal and cartilaginous in-volvement (Kemper et al., 1993). Pseudomembra-nous tracheobronchitis develops when there isextensive inflammation and invasion of the tra-cheobronchial tree with formation of a pseudo-membrane of hyphae and necrotic debris (Pervex etal., 1985). Thus, in addition to the traditional neu-tropenic patient, the diagnosis of Aspergillus as acause of nonresolving pneumonia should be consid-ered in elderly immunocompromised patients andin patients with advanced AIDS.

The other major group of fungal infectionsthat need to be considered as a cause of nonresolv-ing pneumonia are the endemic fungi. The endemicfungi share many common clinical characteristics,but the most important element in establishing thediagnosis is a careful history, since each fungus canbe found in certain geographic areas. Histoplasrruicapsulatum can be found in the Mississippi Rivervalley, Coccidioides immitis in the southwesternUnited States, and Blastomyces dermatitidis in theSoutheast and Midwest. In the case of both histo-plasmosis and coccidioidomycosis, most inhabi-tants of these areas will have immunologic evi-dence of prior exposure (Davies & Sarosi, 1987).These fungi can cause a nonspecific acute febrileillness, which is usually self-limited and may easilybe confused with CAP.

The more difficult cases involve those patientswho develop chronic and progressive disease, whichinvolves the upper lobes and may be cavitary, oftenleading to a misdiagnosis of tuberculosis (Goodwinet al., 1981). Although blastomycosis is classicallydescribed as mass-like and coccidioidomycosis isdescribed as producing thin-walled cavities, noneof these fungi can be reliably distinguished on thebasis of their chest radiograph findings.

In general, when the chest radiograph suggeststuberculosis but smears are negative for acid-fastorganisms, these fungal infections should be con-sidered. In addition, patients with HIV infection areat particularly high risk of disseminated infection

with both histoplasmosis and coccidioidomycosis,so early consideration of these possibilities is es-sential in this group (Wheat et al., 1990; Sarosi &Johnson, 1992; Ampel et al., 1993; Grossman et al.,1970).

A combination of potassium hydroxide smearand culture of sputum may make the diagnosis.Serology is generally not useful for histoplasmosisand blastomycosis. IgM antibodies for coccidioido-mycosis may be clinically useful, and tilers typ-ically rise in the first 2 weeks, disappearing by 1month (Davies & Sarosi, 1987). Skin testing isavailable for histoplasmosis but is not useful sinceactive infection cannot be distinguished from priorexposure and 90% of inhabitants in an endemic areacan be expected to lest positive (Davies & Sarosi,1987; Goodwin el al., 1981).

Nocardia and Actinomyces

Although Nocardia and Actinomyces are clas-sified as higher-order bacteria, both behave in amanner more consistent with the pulmonary my-coses. Both result in a chronic pulmonary diseasethat is difficult to diagnose because of the difficultyin isolating these pathogens. Nocardia can only begrown aerobically if cultures are kept and examinedfor up to 4 weeks, whereas Actinomyces requiresstrict anaerobic conditions with enriched media.Both are gram-positive organisms with branchingfilamentous pseudohyphae. Nocardia frequentlystains positive on acid–fast smear, but Actinomycesis rarely positive. Because these organisms haverelatively specific culture requirements and are dif-ficult to stain, communication with the microbiol-ogy laboratory is essential when there is clinicalsuspicion of either disease.

Patients with Nocardia present with a sub-acute or chronic syndrome, including cough, puru-lent sputum, and night sweats. Infection frequenltyoccurs in the setting of underlying malignancy orpulmonary alveolar proteinosis. Disseminated in-fection may occur, with the most serious conse-quence being central nervous system involvementwith brain abscess. The most common radiographicpresentation is that of a localized alveolar infiltratethat is usually homogenous, nonsegmental, and of-ten cavilary (Grossman el al., 1970). Actinomycosishas similar clinical and radiographic features, but

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tends to extend across fissures and to involve thechest wall.

Coxiella burnetii (Q Fever)

Coxiella burnetii, also known as Q fever, is azoonosis, with infected cattle, goats, sheep, and catsas its primary reservoirs (Babudieri, 1959). Infec-tion occurs when C. burnetii is aerosolized at thetime of parturition (Marrie et al., 1988). Most infec-tions are self-limited febrile illnesses, with pneu-monia, hepatitis, and endocarditis being rare com-plications (Sawyer et al., 1987).

The pneumonia caused by Q fever is generallymild but rarely may present as a rapidly progressivepneumonia that is refractory to antibiotics. Casesmay be part of an outbreak or may occur sporad-ically. In cases involving exposure to animals orduring a recognized outbreak there is usually littlediagnostic difficulty. Sporadic cases are much moredifficult to diagnose. Signs and symptoms thatshould raise the suspicion of Q fever include mild tomoderate pneumonia with a nonproductive coughassociated with a severe headache. Radiographicfindings include pleural based opacities, single ormultiple rounded opacities, atelectasis, and hilaradenopathy. The mean time to radiographic resolu-tion is 30 days with a range from 10 to 70 days(Gordon et al., 1984; Millar, 1978). Mortality is veryuncommon with Q fever.

Pneumocystis carinii

P. carinii pneumonia (PCP) is most likely tooccur as a nonresolving pneumonia in the setting ofunrecognized HIV infection, chronic steroid use,chemotherapy, or bone marrow transplantation.The course of PCP infection is less acute and themortality lower in HIV-positive patients than inHIV-negative patients. Patients with HIV have alonger duration of symptoms (28 days vs. 5 days),lower respiratory rate (23.4 vs. 30), and higher(69 vs. 52) (Kovacs et al., 1984). In a study byGerrard (1995), the mortality rate among HIV-positive patients was 8% versus 32% among HIV-negative patients. Among HIV-negative patients in-fection develops almost exclusively in the setting ofcombined corticosteroid and immunosuppressivetherapy. Notably, in Gerrard's (1995) series, all

cases of HIV-negative PCP occurred within 6 monthsof the initiation of immunosuppressive therapy, in-dicating that the risk for PCP infection may behigher shortly after initiation of immunosuppres-sion. In this study, PCP occurred in 12% of patientswith Wegener’s granulomatosis, 6% of patientswith renal transplants, and 4% of liver transplants.

The radiographic findings associated withPCP are quite varied. The characteristic pattern ofperihilar interstitial infiltrates is seen in two thirdsof patients, but up to 10% will have normal chestradiographs (Katz et al., 1991). There is usuallyprogression to widespread air space disease over a2- to 5-day period. Other unusual but not uncom-mon findings include unilateral focal infiltrates,nodules, mediastinal and hilar adenopathy, andpleural effusions. Thin-walled cysts are observed in10% of patients and therefore pneumothorax maybe a complication of recurrent infections. In pa-tients who have undergone prior pentamidine pro-phylaxis, the radiographic findings can be expectedto be atypical, with up to 40% demonstrating upperlobe disease. This is in contrast to a rate of 7% forpatients not taking pentamidine (Coblentz, 1992).

Resistant Pathogens

An important consideration in the approach toany pneumonia is the possibility of antibiotic resis-tance. In particular, the possibility of penicillin-resistant S. pneumoniae (PRSP) must be consideredwhen evaluating patients with nonresolving pneu-monia. PRSP was first described in the 1960s inAustralia and New Guinea. In recent surveys fromEurope, approximately 40% to 60% of pneumo-cocci demonstrate intermediate or high-level resis-tance (Linares et al., 1992; Marton, 1992). In theUnited States resistance rates are lower but arerising, mimicking the trends seen previously in Eu-rope. Among isolates of invasive pneumococcaldisease, 25% to 35% of cases currently demonstratepenicillin resistance (Hofmann et al., 1995).

The clinical impact of penicillin resistance onimmediate mortality is unclear. Bacteremia occursin 15% to 30% of patients with pneumococcal pneu-monia and carries a mortality of 36% to 43% (Afessaet al., 1995). This mortality is unaffected by anti-biotic administration in the first 5 days. Thus, riskfactors at presentation and other comorbidities may


outweigh antibiotic resistance as predictors of earlymortality. Studies from Spain demonstrated no sig-nificant difference in mortality between patientsinfected with resistant or sensitive strains of pneu-mococci (Pallares et al., 1995). Penicillin wasequivalent to other therapies as long as the mini-mum inhibitory concentration (MIC) was 2or less. Other retrospective studies have demon-strated a higher mortality in bacteremic patientswith PRSP but this was in association with otherrisk factors known to affect prognosis (Pallares etal., 1987).

In patients with nonresolving pneumonia whohave by definition survived the initial 5 days, it isreasonable to investigate the possibility of drugresistance as a contributing factor. The suspicion ofPRSP should be especially high in cases of non-resolving pneumonia associated with risk factors fordrug resistance. The risk factors for infection withPRSP include prior therapy within 6 months,pneumonia within 1 year, hospitalization in theprior 3 months, and nosocomial infection (Bedos etal., 1996; Moreno et al., 1995; Nava et al., 1994). Ofthese factors, the most significant in both univariateand multivariate analyses is prior use.

Once a PRSP is either suspected or isolated, itbecomes important to determine the level of peni-cillin resistance and the sensitivity pattern of theorganism. The majority of PRSP strains have inter-

medi and defin ed as a In the setting of intermedi-mediate resistance to penicillin, defined as an MIC

ate resistance to penicillin, increasing the dose ofpenicillin to 12 to 18 million units per day is effec-tive. Isolates with an are defined ashaving high-level resistance, and these cases shouldbe treated with agents other than penicillin based ontheir susceptibility testing.

Alternative agents include cefotaxime, ceftri-axone, imipenem, macrolides, newer fluoroquino-lones, and vancomycin. Importantly, sensitivity pat-terns for cephalosporins do not necessarily followpenicillin susceptibility patterns. Pneumococcal iso-lates that have intermediate resistance to penicillinmay have high-level resistance to cephalosporins(Jacobs, 1992; John, 1994). Therefore, sensitivity tocephalosporins and imipenem should be confirmedin cases of PRSP. Similarly, since macrolide resis-tance is less prevalent, these drugs may be usefulalternatives but their use still requires confirmation

of sensitivity. If erythromycin resistance is demon-strated, then clarithromycin, azithromycin, andclindamycin should not be used, since there is sig-nificant cross-resistance. Newer fluoroquinolones,such as trovofloxacin and levofloxacin, have dem-onstrated excellent activity against PRSP and maybe considered in cases of PRSP. Finally, vanco-mycin is the most reliable treatment for PRSP sinceresistance to vancomycin has not yet been demon-strated.

Host Factors

The effect of various host factors, includingcomorbidities such as alcoholism, diabetes, COPD,and age on the normal rate of resolution of pneu-monia has been discussed above. Most host factorscannot be altered and therefore do not necessarilydirectly affect treatment. However, certain dis-orders of immune function warrant special attentionbecause the underlying defect can be at least par-tially treated if recognized. These include AIDSand syndromes associated with deficiencies of hu-moral immunity.

AIDS

With the experience gained from the HIV epi-demic, most physicians are aware of PCP as a causeof respiratory compromise in the HIV-infected pa-tient. Indeed, PCP was among the most commondiseases associated with AIDS, being the initialmanifestation in approximately two thirds of casesin older series (Centers for Disease Control, 1989).With the use of widespread prophylaxis, the domi-nance of PCP among the pulmonary pathogens as-sociated with HIV has decreased, but it remains animportant consideration (Martin et al., 1992). Bac-terial pneumonia is now the most common initiallower respiratory tract infection in AIDS patients(Wallace et al., 1993); therefore, it is important toconsider the possibility of HIV infection in patientswith nonresolving pneumonia. If the diagnosis ofunrecognized HIV is made, the spectrum of pos-sible pathogens changes dramatically. Indeed, theInfectious Disease Society of America (Centers forDisease Control, 1989) recommends routine testingfor HIV infection in patients between the ages of 15and 54 with CAP that occurs in hospitals where the

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rate of newly diagnosed HIV infection exceeds onecase per 1000 discharges. Conditions that are muchmore likely in this setting and that need to be con-sidered in these cases include cryptococcal pneumo-nia, endemic fungal infection, tuberculosis, and PCP.

Primary Humoral Immune Deficiencies

Primary humoral immune deficiencies are dueto inherited defects in antibody production. Whilethere are many diseases associated with secondarydisorders of humoral or cellular immunity, the im-portance of identifying primary humoral immunedeficiency syndromes lies in the fact that treatmentwith intravenous immune globulin has an effect onthe incidence and resolution of pneumonia. The dis-orders most commonly associated with hypogamma-globulinemia in which intravenous immune globulin(IVIG) is indicated include X-linked agammaglobu-linemia, common variable immune deficiency(CVID), selective IgG subset deficiency, and hypo-gammaglobulinemia with hyperimmunoglobulin M.

All these disorders are characterized by defectsin the production of immunoglobulins, from intrinsicdefects within the B cell to problems with B cell/Tcell interactions. The resulting deficiencies in im-munoglobulin production lead to impaired opson-ization and complement activation. Thus, patientswith relative or absolute hypogammaglobulinemiaare prone to recurrent and refractory sinopulmonarytract infections with encapsulated organisms lead-ing to nonresolving pneumonias. Infections typi-cally begin in infancy or early childhood so thatmost cases are recognized by the time patientsreach adulthood. Importantly, certain disorders,most notably CVID and IgG subclass deficiency,may present in an atypical manner at a later age.The most common pathogens in these patients in-clude 5. pneumoniae and H. influenzae, with Myco-plasma and P. carinii being less common.

Monthly IVIG maintenance therapy markedlyreduces the incidence and severity of pneumonia inthese patients (Skull & Kemp, 1996; Buckley &Schiff, 1991; World Health Organization, 1982).Currently, protocols require maintenance infusionsevery 2 to 4 weeks to maintain a trough levelgreater than 400 mg/dL (Buckley & Schiff, 1991).When patients with primary humoral immune defi-ciencies develop pneumonia, additional supple-

mental IVIG is warranted for treatment of the acutedisease and facilitates resolution and decreases se-verity.

Another situation in which humoral immunityis commonly compromised is chronic lymphocyticleukemia (CLL). Progressive hypogammaglobulin-emia is common in CLL, and results in an increasedincidence of respiratory tract infections. IVIG hasbeen demonstrated to decrease the incidence ofthese infections by nearly 50% (Cooperative Groupfor the Study of Immunoglobulin in Chronic Lym-phocytic Leukemia, 1988). However, some investi-gators have questioned the utility of IVIG in thissetting based on its high cost. It has been estimatedthat IVIG in CLL results in a gain of 0.8 quality-adjusted days per patient per year at a cost of $6million per quality-adjusted life-year gained (Weekset al., 1991). Thus, the routine maintenance use ofIVIG in CLL is probably not warranted. However,in an individual patient with CLL with nonresolvingpneumonia and hypogammaglobulinemia, IVIGshould be considered.

Therapy-Related Factors

When pneumonia fails to respond appropri-ately to treatment, certain aspects related to therapyneed to be considered, including possible medica-tion errors as well as the concentrations of anti-biotics used.

With respect to medication errors, it is espe-cially important to carefully check dosing sched-ules, compliance, and when appropriate, drug levels.If intermediate-level resistant PRSP is present,higher doses of penicillin will be required as previ-ously discussed. Similarly, if PCP is suspected,higher doses of trimethoprim–sulfamethoxazolewill be required. When aminoglycosides are used itis important to check levels and adjust the dosingregimen accordingly. Similarly, as renal functionchanges, drug doses may similarly require readjust-ment. In addition, aminoglycosides do not penetratethe lung well so it may be necessary to aim forhigher peak concentrations when using a traditionaldosing regimen, especially when treating pseudo-monal pneumonia. The effect of decreased pulmon-ary penetration on aminoglycoside efficacy using aonce-daily dosing regimen has not yet been studiedfor pneumonia.


It is also important to ensure that adequatelevels of drug are reaching the site of infection byruling out sequestered foci of infection. The twomain forms of sequestered foci that may preventadequate resolution of pneumonia are empyemasand lung abscesses. Empyema evaluation can befacilitated by a variety of imaging techniques, in-cluding chest CT and ultrasound. In the patient withnonresolving pneumonia, demonstration of any sig-nificant amount of pleural fluid should lead to con-sideration of a diagnostic thoracentesis to rule outempyema. Although the exact criteria for definingan empyema remains controversial, in the setting ofa nonresolving or progressive pneumonia it is pru-dent to aggressively evaluate all effusions for pos-sible chest tube drainage. A pH less than 7.20,positive gram stain, positive culture, or demonstra-tion of grossly purulent fluid should prompt chesttube placement.

Pulmonary abscesses can also lead to non-resolving pneumonia. Predisposing factors thatshould raise the suspicion of abscess formation in-clude alcoholism, seizures, poor oral hygiene, andprevious aspiration. Chest x-ray typically will dem-onstrate an air-fluid level but chest CT is moresensitive and can confirm the diagnosis in difficultcases. Because most patients with lung abscessesdo well with only conservative management and aprolonged course of antibiotics, it is important toidentify those factors associated with increasedabscess-related mortality that may warrant a moreaggressive approach. Factors that adversely affectthe prognosis in patients with lung abscess includeincreased age, pediatric age, large cavity size,longer duration of symptoms prior to therapy, lowerlobe location, multiple abscesses, and associationwith malignant disease (Perlman et al., 1969; So-senko & Glassroth, 1985; Wallace et al., 1979; Har-ber & Terry, 1981). The importance of intrabron-chial aspiration as a contributing factor in fatalcases of lung abscess has also been emphasized inseveral reports (Harber & Terry, 1981). This has ledseveral investigators to recommend controlleddrainage and improved physical measures to avoidintrabronchial spread. Thus, although routine drain-age is not necessary in all patients, it should beconsidered in those at high risk and in those withnonresolving pneumonia drainage.

A variety of techniques have been used to drain

abscesses. These include bronchoscopic aspiration,CT-guided aspiration, and ultrasound-guided aspi-ration. However, some attempts at bronchoscopicaspiration have actually led to intrabronchial aspi-ration and ARDS (Harber & Terry, 1981). Thus, ifbronchoscopic aspiration is considered, it shouldprobably be limited to carefully selected patients inwhom all other methods of drainage are not possi-ble. When bronchoscopy is done for either diagnos-tic or treatment purposes, there should be minimaluse of depressant drugs and careful use of lidocaineto minimize the risk of intrabronchial spread.

Noninfectious Etiologies

Many noninfectious diseases may mimic pneu-monia by presenting pulmonary infiltrates. The ma-jor categories of disease that warrant considerationas mimics of pneumonia include neoplastic, immu-nologic, drug-induced, and vascular diseases.

Neoplastic Diseases

Neoplasms may cause a nonresolving pneu-monia syndrome either by causing a postobstructivepneumonia or abscess or by appearing as infiltrativeprocesses with air bronchograms. Neoplasms thatcause postobstructive pneumonias and abscesses aremost commonly bronchogenic carcinomas. Thosethat present as alveolar infiltrates include lym-phoma and bronchoalveolar cell carcinoma.

Postobstructive Pneumonias

In cases of postobstructive pneumonia, thetumor occludes the bronchi either by endobronchialinvolvement or extrinsic compression. Bronchos-copy remains the method of choice for detectingendobronchial obstruction, since it allows for thesimultaneous collection of biopsy and cytologyspecimens that are sensitive and specific forendobronchial malignancies. However, the overallfrequency of endobronchial carcinoma as a cause ofnonresolving pneumonia is surprisingly low, rang-ing from 0% to 8% (Feinsilver et al., 1990; Israel etal., 1956; Gleichman et al., 1949). Despite this lowprevalence, the relatively low risk associated withbronchoscopy makes it an appropriate considera-

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tion in those at especially high risk for lung cancer(e.g., cigarette smokers older than 50 years).

Carcinomatous Lung Abscess

It has been recognized for many years that asignificant proportion of lung abscesses are associ-ated with bronchogenic carcinomas, so-called car-cinomatous lung abscesses (Perlman et al., 1969;Sosenko & Glassroth, 1985; Wallace et al., 1979).The reported incidence of carcinoma in this settingis high, ranging from 7.6% to 17.5% (Sosenko &Glassroth, 1985; Wallace et al., 1979). The identi-fication of this subset of nonresolving pneumoniasis particularly important, since identification ofconcurrent carcinoma may allow for curative resec-tions and since carcinomatous lung abscess is asso-ciated with greater mortality than is simple lungabscess. Unfortunately, distinguishing carcinoma-tous from simple abscesses can be difficult.

Although a number of radiographic findingshave been described as being suggestive of car-cinomatous abscess, such as mural nodules andipsilateral hilar node enlargement, none of theseradiographic criteria have been demonstrated toclearly distinguish between carcinomatous andsimple lung abscesses. Indeed, when Wallace et al.(1979) applied radiographic criteria to cases of lungabscess, the diagnostic accuracy was only 70%,with a 16% false-negative rate and a 14% false-positive rate. Radiographic location is also nothelpful, since lobes that are classic for aspiration(i.e., posterior segments of the upper lobes or supe-rior segments of the lower lobes) account for 50%to 60% of carcinomatous abscesses. The exceptionto this is the rare occurrence of an anterior segmentabscess, which strongly suggests the possibility ofcarcinoma (Sosenko & Glassroth, 1985; Wallace etal., 1979).

Direct visual findings at the time of bronchos-copy are similarly not helpful in identifying mostcases of carcinomatous lung abscess, with only 15%to 21% of cases demonstrating an endobronchiallesion (Perlman et al., 1969; Sosenko & Glassroth,1985; Wallace et al., 1979). The most common find-ing is nonspecific inflammation and edema of theaffected bronchus. Although bronchoscopy in thesetting of lung abscess can be associated with sig-nificant risk, cytology and transbronchial biopsyhave diagnostic yields as high as 80% (Wallace et

al., 1979). Thus, the best test to identify carcinoma-tous abscess remains bronchoscopically obtainedcytology and transbronchial biopsy samples. Giventhe risk of bronchoscopy in this setting, it is advis-able to attempt bronchoscopy only in those patientswith carcinomatous lung abscesses and to avoidbronchoscopy in those with simple abscesses.

Clinical features associated with carcinomaabscess include older age, rapid onset, lack of sys-temic symptoms, no predisposition to aspiration,lower white blood cell count, lower oral tempera-ture, and less extensive infiltrates on chest radio-graph. Patients with three or more of these factorscan be considered at high risk for carcinoma, andbronchoscopic examination should be considered(Sosenko & Glassroth, 1985). Similarly, those withmediastinal or hilar adenopathy or very limited in-filtrates surrounding the abscess should also be con-sidered for bronchoscopy. Patients without any ofthese risk factors, especially if they are less than 45years of age and are nonsmokers, are at relativelylow risk for carcinoma and can be managed conser-vatively unless healing is delayed or the course isotherwise atypical of anaerobic infection (Sosenko& Glassroth, 1985).

Bronchoalveolar Cell Carcinoma

Bronchoalveolar cell carcinoma is tradition-ally characterized as a subtype of adenocarcinomaof the lung that is slow-growing and frequentlyassociated with the small peripheral airways andalveolar spaces. It may present as a focal alveolarinfiltrate, often with air bronchograms, mimickingthe radiographic appearance of pneumonia. Consol-idation occurs in up to one third of cases, involvingboth segmental and lobar areas (Ludington et al.,1972). Other radiographic appearances include pul-monary nodules and diffuse or multicentric alveolarinfiltrates. The nodular form has a good prognosis,whereas the resectable diffuse and multicentricforms have a worse prognosis (Dumont et al.,1998).

Lymphoma

Lymphoma in the lung may present as focalalveolar infiltrates with air bronchograms, mimick-ing the radiographic appearance of pneumonia.When lymphoma affects the lung parenchyma, it


may occur either as part of a systemic disease or asa true primary pulmonary lymphoma. Lymphomararely presents with radiographic evidence of pul-monary parenchymal involvement; only 10% ofHodgkin’s and 4% of non-Hodgkin’s lymphomaspresent with initial parenchymal pulmonary in-volvement (Berkman & Breuer, 1993). However, inboth cases, as the disease progresses, lung involve-ment becomes progressively more common, risingto 38% of Hodgkin’s and 24% of non-Hodgkin’scases (Berkman & Breuer, 1993). If pulmonaryHodgkin's lymphoma is suspected, CT scan of thechest may be especially useful, since mediastinallymphadenopathy is almost invariably present. Im-portantly, in cases of non-Hodgkin’s lymphoma aswell as Hodgkin’s disease associated with HIV,mediastinal lymphadenopathy may be absent in upto 50% of cases (Berkman & Breuer, 1993; White &Matthay, 1989). Confirming the diagnosis of pul-monary lymphoma requires an adequate core oftissue for histologic examination; thus, percutane-ous fine-needle aspirates are frequently nondiag-nostic. Similarly, bronchoscopy with transbron-chial biopsy may provide the diagnosis but only ifan adequate sample size can be obtained. In thissetting, immunophenotyping, immunoelectropho-resis, and analysis of monoclonal markers may beof diagnostic benefit when traditional light micros-copy is not definitive (Oka et al., 1988; Schwaiger etal., 1991). If these tests are still nondiagnostic,open-lung biopsy may be required to establish thediagnosis.

Immunologic Diseases

Many immunologic diseases can be associatedwith some pulmonary manifestations, but this discus-sion will be limited to diseases that present with anacute onset, have frequent pulmonary manifestations,and present with few extrapulmonary symptoms.These include systemic vasculitis, bronchiolitisobliterans organizing pneumonia, the eosinophilicpneumonia syndromes, acute interstitial pneumo-nia, pulmonary alveolar proteinosis, and sarcoid.

Systemic Vasculitis

Fever, dyspnea, and pulmonary infiltrates maybe the initial manifestation of systemic vasculitis ora connective tissue disorder and may be easily mis-

taken for CAP. In most patients, extrapulmonarysymptoms will be prominent and a prior history ofvasculitis will be present. However, when extra-pulmonary symptoms are lacking, differentiatingpulmonary vasculitis from severe CAP may be dif-ficult. Furthermore, patients with a previously es-tablished diagnosis of vasculitis are frequently onimmunosuppressive therapy for their vasculitis andare therefore prone to opportunistic infections. Dis-tinguishing a nonresolving infectious process fromworsening vasculitis can be especially difficult inthese immunocompromised patients.

While many types of vasculitis have varyingdegrees of pulmonary involvement, this discussionwill focus only on those that have a propensity toinvolve the lung and that may mimic CAP. Theseinclude Wegener's granulomatosis and the alveolarhemorrhage syndromes.

Wegener´s Granulomatosis. Wegener’sgranulomatosis (WG) is a form of small- andmedium-vessel granulomatous vasculitis that pri-marily involves the upper and lower respiratorytracts and kidneys. Other organ systems that may beinvolved include the joints, eyes, skin, nervous sys-tem, and heart. Less commonly involved are thegastrointestinal tract, subglottic area, trachea, thy-roid, and liver (Hoffman et al., 1992). The “lim-ited” form of WG accounts for up to 25% of casesand is characterized by isolated upper respiratorytract and lung involvement (Hoffman et al., 1992;Duna et al., 1995). WG typically occurs in middle-aged men, but it has been noted in all age groups.

Upper respiratory tract involvement is themost common manifestation, and pulmonary symp-toms are rare in the absence of upper respiratorytract symptoms. A history of recurrent upper respi-ratory tract problems should raise the possibility ofWG when evaluating patients with a nonresolvingpneumonia syndrome. Common upper respiratorytract manifestations of WG include sinusitis, rhi-norrhea, purulent nasal discharge, oral and nasalulcers, and otitis (Hoffman et al., 1992).

Extrapulmonary manifestations may be espe-cially useful in distinguishing WG from an infectiousetiology of nonresolving CAP. The most commonextrapulmonary manifestations include segmentalnecrotizing glomerulonephritis, ocular involve-ment with uveitis, joint manifestations with arthral-gias and arthritis, central or peripheral nervous

400 CHAPTER 25

system involvement, and cardiac involvement. Skininvolvement may be evident as well, including pal-pable purpura, ulcers, vesicles, papules, or subcuta-neous nodules (Hoffman et al., 1992). Importantly,many or all of these extrapulmonary findings maybe absent in the limited form of WG.

Lower respiratory tract manifestations of WGare nonspecific and include cough, hemoptysis,dyspnea, and pleuritic pain. Pulmonary function isalso nonspecific and may demonstrate either a re-strictive or obstructive pattern. Chest radiographicfindings are variable, including nodules, diffusehazy infiltrates, alveolar infiltrates, and pleuralopacities (Cordier et al., 1990; Buschman et al.,1990). The nodules encountered in WG may beeither well circumscribed or hazy, and up to onehalf will be cavitary. Nodules range in size fromseveral millimeters up to several centimeters.

Laboratory findings are generally nonspecificin WG and include leukocytosis, thrombocytosis,anemia, and an elevated sedimentation rate, any ofwhich can be seen in other causes of nonresolvingpneumonia. The most useful diagnostic laboratorytest in differentiating WG from infectious causes ofnonresolving pneumonia is the antineutrophil cyto-plasmic antibody (ANCA) test (Kallenberg et al.,1994). WG is now classified as one of the ANCA-associated vasculitides. There are two main formsof ANCA, cytoplasmic or c-ANCA and perinuclearor p-ANCA. Most patients with WG have thec-ANCA form, which is directed against a serineproteinase. Ninety percent of patients with activeWG with both renal and pulmonary involvementwill be ANCA-positive (Duna et al., 1995; Kallen-berg et al., 1994). However, in patients with limitedWG without glomerulonephritis, or in inactive dis-ease, the sensitivity of c-ANCA decreases to 65%(Rao et al., 1995). Similarly, false-positive tests dooccur, most notably with microscopic polyarteritis,polyangiitis overlap syndrome, idiopathic crescen-teric glomerulonephritis, Churg-Strauss syndrome,or classic polyarteritis nodosa (Kallenberg et al.,1992). Thus, it remains controversial whether thediagnosis of WG can be established with just anabnormal radiograph, the clinical history, and apositive ANCA. Some clinicians advocate treatingin these instances even without histologic confirma-tion. Since the disorders most likely to cause a

false-positive ANCA are generally treated with im-munosuppressive regimens similar to that for WG,this is often a reasonable option. However, whenconcurrent infection is a concern, tissue biopsy be-comes imperative.

Alveolar Hemorrhage Syndromes. Thesyndrome of diffuse alveolar hemorrhage (DAH)may be a manifestation of a wide variety of dis-eases, including Goodpasture’s syndrome, connec-tive tissue disorders, systemic vasculitis, drug tox-icity, coagulopathy, mitral stenosis, and a variety ofpulmonary infections. The clinical presentation ofalveolar hemorrhage is relatively similar irrespec-tive of the cause and includes fever, dyspnea, andalveolar infiltrates that are easily mistaken forpneumonia. Differentiating DAH from infectiousetiologies of nonresolving pneumonia is critical be-cause the treatment for many of the syndromesassociated with DAH includes immunosuppressiveagents. This discussion will focus on those featuresof DAH that distinguish it from other causes ofnonresolving pneumonia and the etiologies of DAHthat are most likely to mimic pneumonia.

DAH may present at any age because of thewide variety of diseases that lead to the syndrome.The typical onset is fairly rapid, with cough, fever,and dyspnea being common but nonspecific symp-toms. Physical examination and routine laboratorytests are nonspecific and reflect the extrapulmonarymanifestations of the underlying cause of the DAH.Respiratory distress may be severe, leading to rapiddeterioration and the need for mechanical ventila-tion. Hemoptysis is common but is not necessarilymassive and is absent in up to one third of patients,so careful attention to the serum hemoglobin levelis important. A rapidly falling hemoglobin in theabsence of gastrointestinal bleeding with diffusepulmonary infiltrates should raise the possibility ofDAH. When hemoptysis is not obvious, bronchos-copy with sequential bronchoalveolar lavage (BAL)will demonstrate progressively hemorrhagic fluidcharacteristic of DAH. This finding is not specificfor any particular etiology of DAH and is seenirrespective of the cause of DAH.

Radiographic findings are nonspecific, withpatchy bilateral alveolar infiltrates being the mostcommon finding. If the patient has had previous


episodes of DAH an interstitial infiltrate secondaryto pulmonary fibrosis may also be present. Sim-ilarly, chest CT scan is usually nonspecific, oftenreflecting the underlying disease associated withthe DAH.

After the presence of DAH is established, it isimperative to establish the specific underlyingcause. A careful history and physical along withsome specific serologic tests will rule out mostcauses of DAH, including drug use, exposure tocytotoxic agents, bone marrow transplantation, andvasculitis or collagen vascular disease. In mostcases, extrapulmonary manifestations of diseasewill be present to help in establishing the diagnosis.This is particularly helpful in differentiating DAHfrom infectious causes of nonresolving pneumonia.

However, in some cases the clinician will onlybe able to rule out drug exposures, environmentalfactors, coagulopathy, and neoplasms, and therewill be no extrapulmonary findings to help guidethe diagnostic evaluation. These cases are mostlikely to be mistaken for pneumonia because of thepaucity of extrapulmonary manifestations. In thesecases, in the absence of other systemic findings,there are four causes of DAH that need to be consid-ered. These include p-ANCA-associated vasculitis,isolated pulmonary vasculitis without associatedantibodies, anti-glomerular basement membranedisease, and idiopathic pulmonary hemosiderosis.

p-ANCA-associated vasculitis and isolatedpulmonary vasculitis are truly forms of pulmonarycapillaritis (Mark & Ramirez, 1985; Leatherman,1988; Travis et al., 1990). Both syndromes are dis-tinct from the usual classification of vasculitis syn-dromes. Indeed, follow-up evaluation of isolatedpulmonary capillaritis indicates no evidence of sub-sequent systemic disease. Both are treated similarto WG, with cytoxan and corticosteroids.

Anti-glomerular basement membrane disease(anti-GBM), or Goodpasture’s syndrome, is distinctfrom these two forms of pulmonary capillaritis andrepresents the classic form of immune-mediatedpulmonary injury. Patients with Goodpasture's syn-drome usually present with concurrent renal in-volvement, but isolated lung injury can occur with-out renal disease (Tobler et al., 1991). In these cases,in contrast to typical anti-GBM disease, circulatinganti-GBM antibodies are often absent. The only

way to establish the correct diagnosis in these casesof limited Goodpasture's syndrome is to demon-strate linear immunofluorescence in lung tissue.

Bronchiolitis Obliterans OrganizingPneumonia

Bronchiolitis obliterans organizing pneu-monia (BOOP) is characterized by the proliferationof granulation tissue in the respiratory bronchiolesand alveolar ducts associated with chronic inflam-mation in the adjacent alveoli (Cordier, 1993).BOOP may occur in association with a variety ofother disorders, in which case it is a secondary formof BOOP. It may also occur in an isolated form,idiopathic BOOP, also referred to as cryptogenicorganizing pneumonia. This discussion will focuson the idiopathic form of BOOP, emphasizing thosepoints that help to distinguish it from other mimicsof pneumonia.

BOOP typically occurs in the fifth or sixthdecade of life, with men and women equally af-fected. The onset is typically subacute, with 75% ofpatients having symptoms for less than 2 months atthe time of diagnosis (Cordier, 1993; Cordier et al.,1989). The typical presentation of BOOP beginswith a flu-like illness mimicking CAP, with fever,malaise, fatigue, dyspnea, and dry cough. Rales arecommon and are present in approximately 75% ofpatients, but wheezes are rare as is clubbing (Cor-dier et al., 1989). Laboratory tests are nonspecific,with an elevated sedimentation rate and leuko-cytosis the most common findings.

The chest radiograph demonstrates bilateral,diffuse alveolar infiltrates, often with a peripheraldistribution. Up to half of all patients will haverecurrent or migratory infiltrates. Linear, intersti-tial, and cavitary lesions are rare, as are pleuraleffusions and pleural thickening. The CT scan typ-ically reveals patchy, alveolar infiltrates with con-solidation, ground-glass changes, and bronchialwall thickening (Cordier et al., 1989; Muller et al.,1990).

The diagnosis of BOOP requires demonstra-tion of the characteristic histologic pattern in theabsence of other concurrent disease. Transbron-chial biopsy is often insufficient to establish thisdiagnosis, since the histologic features of BOOP

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can be seen with a variety of other disorders. There-fore, open-lung biopsy remains the gold standardtor diagnosing BOOP.

Eosinophilic Pneumonia Syndromes

The common pathologic feature of the eosino-philic pneumonia syndromes is the collection ofeosinophils in the interstitial and alveolar spaces.Other pathologic findings that may be present tovarying degrees include lymphocytic interstitialpneumonia, bronchiolitis obliterans organizingpneumonia, and usual interstitial pneumonia. Thehypereosinophilic syndrome as well as allergicangiitis and granulomatosis (Churg-Strauss syn-drome) both belong to this category of disease.However, both of these rare disorders have promi-nent extrapulmonary symptoms that serve to differ-entiate them from infectious pneumonia. Only twodiseases within this category are rapidly progres-sive and limited to the pulmonary system such thatthey are frequently mistaken for CAP. These arechronic eosinophilic pneumonia and acute eosino-philic pneumonia.

Chronic Eosinophilic Pneumonia. Theterm “chronic eosinophilic pneumonia” (CEP) wasfirst used by Carrington et al. (1969) to describe asyndrome of concurrent blood eosinophilia and pul-monary eosinophilic infiltrates. CEP may often pre-sent as a fulminant illness with cough, fever, dys-pnea, weight loss, wheezing, night sweats, andradiographic infiltrates (Jederlinic et al., 1988).With this constellation of findings, it is frequentlymistaken for CAP.

CEP occurs most commonly in middle-agedadults, although it can occur at any age. Women areaffected twice as often as men. Atopy is common,occurring in up to 50% of patients. Asthma or asth-matic symptoms occur in 30% to 50% of patients,and are usually of recent onset (Jederlinic et al.,1988; Allen & Davis, 1994). The onset is insidiousand the course variable, with symptoms present forweeks prior to the time of diagnosis. Peripheralblood eosinophilia is present in more than 80% ofpatients and may be very severe. Other nonspecificlaboratory abnormalities include an elevated sedi-mentation rate and IgE levels, thrombocytosis, andiron deficiency anemia.

The chest radiograph demonstrates patchy,nonsegmental, alveolar infiltrates that tend to sparethe central and basilar regions, resulting in a patterntermed the “photographic negative of pulmonaryedema” (Gaensler & Carrington, 1977). CT scansometimes better delineates this peripheral patternof disease, but the pattern is not pathognomonic andis not always present (Ebara et al., 1994). However,this photonegative pulmonary edema pattern is suf-ficiently rare that its presence should at least promptconsideration of the diagnosis of CEP. Other radio-graphic patterns that can be seen in CEP includediffuse bilateral infiltrates and lobar consolidation.

The diagnosis of CEP is usually suspected onclinical grounds based on the chest x-ray pattern,blood eosinophilia, and clinical history. However,tissue is still necessary to confirm the diagnosis.The distinctive feature of CEP is elevated BALeosinophilia, typically in the 20% to 70% range(Allen & Davis, 1994). Transbronchial biopsy usu-ally demonstrates interstitial and alveolar eosino-phils and histiocytes. Multinucleated giant cellswith a granulomatous component may be present aswell. The sensitivity of BAL eosinophilia and trans-bronchial lung biopsy is such that open-lung biopsyis rarely needed to establish the diagnosis.

Less than 10% of patients will improve with-out treatment (Allen & Davis, 1994; Yoshida et al.,1994; Naughton et al., 1993). Corticosteroids are themainstay of therapy, with complete remission beingthe rule. Radiographic and clinical improvementcan be expected within 2 to 3 days, and radio-graphic resolution by 3 weeks. Lack of a promptresponse to corticosteroids should prompt reevalua-tion and consideration of alternative diagnoses. Re-lapse occurs in up to 80% of cases after eithercessation or tapering of steroids (Jederlinic et al.,1988). Thus, corticosteroids often have to be con-tinued for prolonged periods after the initial treat-ment period.

Acute Eosinophilic Pneumonia. Acuteeosinophilic pneumonia (AEP) as a cause of acuterespiratory failure was first described by Badesch etal. (1989). Although it is characterized by eosino-philic infiltration of the lung parenchyma similar tothat seen in CEP, the two syndromes seem to bedistinct clinical entities.

AEP occurs most commonly from the ages of


20 to 40 years, although it can occur at any age.Men are affected twice as often as women. There isno relationship to smoking, and unlike CEP, mostpatients do not give a history of asthma or atopy(Badesch et al., 1989; Allen et al., 1989). In contrastto CEP, the onset of AEP is rapid, usually manifest-ing in less than 7 days. AEP typically presents withthe onset of fever, nonproductive cough, dyspnea,and pleuritic chest pain. Constitutional symptomsare common, including malaise, myalgias, andnight sweats. The most common findings on physi-cal examination are fever, tachypnea, occasionalrhonchi, and bibasilar crackles. Laboratory findingsare similarly nonspecific. The peripheral eosinophilcount usually becomes markedly elevated duringthe course of disease, but may be normal at presen-tation (Umeki & Soejima, 1992). Erythrocyte sedi-mentation rate and IgE levels are also elevated inthe majority of patients but are nonspecific (Umeki& Soejima, 1992; Pope-Harman et al., 1996).

Early in AEP, the chest radiograph may onlyshow subtle reticular or ground-glass infiltrates.High-resolution CT is more sensitive, demonstrat-ing progressive, bilateral, patchy, ground-glass in-filtrates, often located along the bronchovascularbundles. As the disease progresses, bilateral diffusealveolar and reticular changes are seen (Umeki &Soejima, 1992; Pope-Harman et al., 1996). UnlikeCEP, the infiltrates are not localized to the periph-ery. Small effusions occur in up to two thirds ofpatients and are frequently bilateral. If a thoracen-tesis is done, these effusions typically demonstratea high pH with marked eosinophilia (Allen &Davis, 1994).

The distinctive feature of AEP is the markedlyelevated number of eosinophils in the BAL fluid.Typically >25% of BAL cells are eosinophils,along with an increased proportion of BAL lym-phocytes and neutrophils (Allen & Davis, 1994;Umeki & Soejima, 1992; Pope-Harman et al., 1996).Transbronchial biopsy usually demonstrates exten-sive eosinophilic parenchymal involvement, fre-quent diffuse alveolar damage, an organizing fi-brinous exudate, hyaline membranes, type II cellhyperplasia, and the absence of granulomas or hem-orrhage. As with CEP, open-lung biopsy is rarelynecessary to establish the diagnosis, given the goodsensitivity of BAL and transbronchial biopsy.

The diagnosis of AEP is a diagnosis of exclu-

sion. In addition to BAL eosinophilia and biopsyevidence of eosinophilic parenchymal infiltrates,other known causes of eosinophilic pneumonia syn-dromes should be ruled out. These include drugreactions, asthma, and infections (Allen & Davis,1994). In addition, the diagnosis is in part estab-lished by the rapid and complete response to treat-ment, which consists of corticosteroids. Responseto corticosteroids is frequently dramatic, occurringwithin 48 hours, and failure to respond shouldprompt the consideration of alternative diagnoses.In contrast to CEP, there should be no further epi-sodes of relapse during long-term follow-up.

Acute Interstitial Pneumonia

Acute interstitial pneumonia (AIP) is a rare,idiopathic form of diffuse alveolar damage. Ham-man and Rich (1935) classified it with idiopathicpulmonary fibrosis. However, it is now recognizedthat AIP is separate and distinct from idiopathicpulmonary fibrosis and probably corresponds to asubset of idiopathic ARDS.

AIP typically occurs in young healthy adults.There are no known risk factors and both sexes areaffected equally. The median age is 43 years (range,7–83 years). AIP typically presents after a pro-dromal period of up to 14 days with the abrupt onsetof fever, cough, and dyspnea (Olson et al., 1990).Chest radiographs usually demonstrate bilateral airspace disease. CT scan of the chest typically revealspatchy or diffuse areas of ground-glass attenuation(Primack et al., 1993). The disease is similar toARDS but unlike ARDS there are none of the usualrisk factors such as sepsis, shock, trauma, or pneu-monitis. Unlike idiopathic pulmonary fibrosis, theonset and progression of the disease is very rapid.Most patients develop hypoxic respiratory failure,and mechanical ventilation is often required. Mor-tality is high, ranging from 60% to 100% in severalseries, with an average of approximately 70%. It isunclear whether or not corticosteroids are beneficialin AIP, although most clinicians would favor a trialof corticosteroids once infectious etiologies havebeen ruled out (Olson et al., 1990).

The distinguishing features of AIP are theclinical syndrome of idiopathic ARDS without riskfactors and pathologic evidence of diffuse alveolardamage. Thus, AIP requires an open or thoraco-

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scopic lung biopsy to confirm the diagnosis. Themost common findings on biopsy are diffuse alveo-lar damage, including alveolar-septal thickening,inflammatory cellular infiltration, type II cell hyper-plasia, collapse of adjacent alveoli, and hyalinemembranes (Katzenstein et al., 1986). These fea-tures of diffuse alveolar damage are nonspecific andother diagnoses must be ruled out.

Pulmonary Alveolar Proteinosis

Pulmonary alveolar proteinosis (PAP), alsoknown as pulmonary alveolar phospholipoprotein-osis, is a rare diffuse lung disease characterized bythe abnormal accumulation of lipoproteinaceousfluid in the distal air spaces (Wang et al., 1997;Prakash et al., 1987). PAP probably represents ahistopathologic syndrome caused by multiple eti-ologies. Histopathologic findings similar to PAPcan be found in cases of silicoproteinosis, alumi-num dust exposure, titanium exposure, hematologicmalignancies, immunosuppressive disorders, andopportunistic infections. However, despite these as-sociations, the majority of cases of PAP are notassociated with any of these risk factors and fallinto the category of idiopathic PAP.

Tests that can help differentiate PAP fromother causes of nonresolving pneumonia includechest radiography, high-resolution CT, serum sur-factant proteins, BAL fluid analysis, and eitheropen-lung biopsy or transbronchial biopsy. Chestradiographs typically demonstrate nonspecific cen-tral alveolar opacities in the mid- and lower-lungzones with marked sparing of the areas adjacent tothe diaphragm and heart. High-resolution CT willoften reveal a ground-glass appearance with thick-ening of the intralobular and interlobular septa in apattern of polygonal shapes, frequently referred toas a “crazy paving” appearance. Elevated serumlevels of surfactant proteins A and D have beendemonstrated in PAP (Honda et al., 1993, 1995;Kuroki et al., 1993). These are not specific to PAPand can also be found in idiopathic pulmonary fi-brosis. While none of these findings are diagnosticof PAP, they should raise the suspicion of PAP andcan narrow the diagnostic possibilities.

BAL, transbronchial biopsy, or open biopsycan make the diagnosis. BAL demonstrates charac-teristic findings of PAP, including milky appearing,

periodic acid-Schiff (PAS)-positive fluid, macro-phages filled with PAS-positive material, and acel-lular eosinophilic granules. Transbronchial biopsyis distinctive for preserved alveolar architecturewith minimal thickening of the septa and scantinflammatory infiltrates. Terminal bronchioles andalveoli are flooded with a PAS-positive lipopro-teinaceous fluid consisting of phospholipids.

In contrast to many of the other noninfectiousmimics of pneumonia, there is no role for immuno-suppressive agents or corticosteroids in PAP. Themost effective treatment is whole lung lavage(Hoffman et al., 1989). Indeed, PAP may exist withconcurrent infections and predisposes patients tosuperinfections with Nocardia, opportunistic fungi,and mycobacteria. It is therefore critical to rule outconcurrent infection, and corticosteroids should beavoided since there have been reports that they mayincrease mortality.

Sarcoidosis

Sarcoidosis is a chronic granulomatous dis-ease of unknown etiology that affects multiple or-gan systems, most frequently the lungs, skin, andeyes. Because sarcoidosis usually has extrapulmon-ary organ system involvement, it is rarely confusedwith other causes of nonresolving pneumonias. Ev-idence of extrapulmonary disease that should raisethe suspicion of sarcoidosis includes extrathoraciclymphadenopathy, skin lesions such as erythemanodosum, lupus pernio, or sarcoid plaques, anduveitis. Clinically significant extrapulmonary in-volvement in other organ systems is much lesscommon, with asymptomatic histologic evidence ofinvolvement being the rule. Chest radiographs typ-ically demonstrate hilar adenopathy in more than70% of cases but parenchymal infiltrates in theabsence of adenopathy may be present in up to 25%of cases (Thomas & Hunninghake, 1987). Histol-ogy typically demonstrates a nonspecific pattern ofnoncaseating granulomas with multinucleated giantcells and lymphocytes. In contrast to many otherinterstitial lung diseases, bronchoscopy with trans-bronchial biopsy has an excellent diagnostic yield,in the range of 75% to 95%. The natural history ofsarcoidosis is quite variable, with many patientsundergoing spontaneous remissions. Other patientsmay have a chronic relapsing course. Hunninghake


et al. (1994) demonstrated that withholding therapyuntil there is objective evidence of deteriorationdoes not adversely affect outcome. Since the find-ing of noncaseating granulomas is relatively non-specific and may be found in other infectious andnoninfectious granulomatous disorders, reservingtherapy for those patients with severe or progres-sive disease is prudent. Therapy in such cases typ-ically consists of corticosteroids given for severalweeks to months. The optimal dose and duration arenot known. Other infectious etiologies should beexcluded prior to initiating corticosteroid treatment.

Drug-Induced Pneumonitis

The number of drugs and therapeutic agentsthat may cause pulmonary toxicity is large and evergrowing. Mechanisms of injury include direct toxiceffects, idiosyncratic reactions, and immune-mediatedmechanisms. With some exceptions, the diagnosisof drug-induced lung disease is one of exclusion.Clinical findings, histology, chest radiographs, andeven high-resolution CT scans are relatively non-specific. Most reactions are not dose-related butsome reactions can occur weeks to years after themedication is discontinued. Thus, to effectivelyrule out drug-induced lung disease in the setting ofa nonresolving pneumonia requires careful evalua-tion of every drug that the patient is receiving or hasrecently received. This section focuses on a few ofthe classic agents that produce unusual or charac-teristic patterns that may mimic pneumonia. Theseinclude amiodarone, methotrexate, and bleomycin.

Amiodarone

Amiodarone is associated with a wide varietyof pulmonary presentations, including interstitialpneumonitis, mass lesions, BOOP, hypersensitivitypneumonitis, eosinophilic pneumonitis, diffuse al-veolar hemorrhage, asthma-like syndromes, pleuraleffusions, and lymphocytic interstitial pneumonitis(Rosenow et al., 1992). One unusual association ofamiodarone toxicity is that with postoperativeARDS. There are a number of reports of ARDSoccurring after surgery in patients taking amioda-rone, typically within 18 to 72 hours (Kennedy,1990). Some investigators have observed unilaterallung injury postoperatively, with only the venti-

lated lung being involved. Whether or not this rep-resents potentiation of amiodarone toxicity by sup-plemental oxygen remains unclear.

The exact incidence of these complications isdifficult to define, with most estimates around 5%in the literature. There are no good ways to identifythose patients at particularly high risk for amio-darone toxicity. Males are affected more commonlythan females, and pulmonary toxicity is more com-mon in those with other pulmonary comorbidities.Most patients who develop toxicity are taking 400mg per day or more for 2 or more months (Ken-nedy, 1990). As with most forms of drug toxicity,clinical and radiographic findings are otherwisenonspecific. Symptoms may be acute or insidious inonset. Pleurisy is uncommon, occurring in 10% ofcases, with pleural effusions also uncommon butreported. The chest radiograph is nonspecific, rang-ing from focal alveolar infiltrates to peripheral infil-trates to mixed alveolar-interstitial patterns. Be-cause amiodarone is an iodinated compound, itsdensity on noncontrast high-resolution CT scanmay be increased (Rosenow et al., 1992; Kennedy,1990). Although it is not sensitive, this is one of thefew highly specific radiographic findings that whenpresent can definitively establish a diagnosis. Treat-ment for suspected amiodarone toxicity is cortico-steroids and discontinuation of the drug. In thoserare instances where there are no suitable alterna-tive antiarrhythmic agents, administration of cor-ticosteroids combined with reducing amiodarone tothe lowest possible dose may be effective.

Methotrexate

Methotrexate has been associated with manysyndromes that may mimic pneumonia, includingbronchospasm, BOOP, pleural effusions, eosino-philic pulmonary infiltrates, noncardiogenic pul-monary edema (from intrathecal methotrexate), anda hypersensitivity type of pneumonitis (Rosenow,1994). Because opportunistic infection is a well-documented complication with even low-dosemethotrexate, it is particularly important to rule outconcurrent infection and to look for signs that maydifferentiate drug toxicity from infection. In pa-tients receiving chemotherapeutic doses of metho-trexate there are well-described cases of a hyper-sensitivity pneumonitis-like reaction, with about

406 CHAPTER 25

half of patients reporting both lung and blood eo-sinophilia (Zitnick & Cooper, 1990). Granulomasare also frequently associated with this reaction,and occasionally hilar adenopathy has been re-ported. Patients receiving lower doses of metho-trexate for anti-inflammatory purposes have aslightly different presentation. About 5% of patientsreceiving chronic low-dose methotrexate develop asubacute interstitial process with fever, hypoxia,rales, and cough (Carson et al., 1987). Eosinophiliain this syndrome is rare, but poorly formed granu-lomas are still seen on biopsy. Nitrofurantoin poten-tiates this syndrome, and deaths have been reported(Rosenow, 1994; Carson et al., 1987). Treatmentconsists of withdrawal and corticosteroids.

Bleomycin

Bleomycin has been associated with a widevariety of complications, including pulmonary f i -brosis, BOOP, eosinophilic infiltrates, pulmonaryveno-occlusive disease, and an acute pneumonitisreaction similar to hypersensitivity. Up to 20% ofpatients taking bleomycin develop pulmonary reac-tions, and 1% die of pulmonary complications(Rosenow, 1994). Risk factors include age above 70years and dose greater than 450 units. There is amarked synergy between bleomycin and high levelsof inspired oxygen. This is often encountered aftergeneral anesthesia, typically manifesting about 18hours later as ARDS. Other reported synergisticinsults include the concurrent use of granulocytecolony-stimulating factor (GCSF) (Rosenow et al.,1992; Rosenow, 1994). Treatment in all cases in-cludes minimizing inspired oxygen content and ad-minister corticosteroids.

Vascular Syndromes

Vascular conditions that may mimic pneu-monia include pulmonary embolism and congestiveheart failure. Pulmonary embolism (PE) is a com-mon problem with radiographic and clinical find-ings that may easily be mistaken for pneumonia.There are no specific or typical clinical signs andsymptoms. Dyspnea is observed in 80% of patients,pleuritic pain in up to 75%, hemoptysis in 20%, andwheezing in 15% (PIOPED Investigators, 1990;Stein, 1996). Chest radiographs show infiltrates in

up to 30% of cases, with effusions in 20% (PIOPEDInvestigators, 1990). Other radiographic findingsinclude diaphragmatic elevation in 60%, focal oli-gemia in 10%, enlarged pulmonary arteries in 20%,and normal radiographs in 30%. The classic Hamp-ton's hump is rarely seen (PIOPED Investigators,1990; Stein, 1996). Infiltrates from PE may takeseveral weeks to resolve and thus are easily mis-taken for slowly resolving pneumonias. Althoughthe chest radiographic does not correlate with theseverity of PE, the alveolar–arterial gradient onblood gas correlates linearly with the severity of PE(Stein et al., 1995). The possibility of PE as thecause of a nonresolving pneumonia syndrome shouldbe raised when hypoxia is out of proportion toradiographic findings and fails to improve despitelack of radiographic progression.

Although the diagnosis of congestive heartfailure is usually apparent, occasionally unusualradiographic patterns of cardiogenic pulmonaryedema may mimic pneumonia. In particular, atypi-cal pulmonary edema patterns have been well de-scribed in patients with bullous lung disease and inpatients with mitral regurgitation. Because pulmon-ary edema principally develops in areas of maximalperfusion, patients with marked COPD may mani-fest asymmetric pulmonary edema patterns. Sim-ilarly, if the regurgitant jet associated with mitralvalve insufficiency is directed at one of the pulmon-ary veins, unilateral and focal pneumonia edemapatterns may occur. In this setting echocardiogra-phy may be of help to identify the severity anddirection of the mitral regurgitation. In borderlinecases, Swan–Ganz catheterization may be necessaryto further clarify the issue and is usually definitive.

Approach to Nonresolving Pneumonia

In developing a diagnostic approach, it is im-portant to first understand the capabilities as well asthe limitations of the most commonly used diagnos-tic tests. Careful consideration of the diagnosticyield, risks, and benefits is critical in decidingwhether additional invasive tests are warranted.The diagnostic tests that are most commonly usedin evaluating nonresolving pneumonia are chest ra-diographs, chest CT scans, and fiber-optic bron-choscopy.


Radiographic Differential Diagnosis

As is clear from the previous descriptions,radiographic findings alone are almost never spe-cific for any one diagnosis. However, radiographicstudies are useful in narrowing the differential diag-nosis and suggesting groups of diagnostic possi-bilities for consideration. The primary radiographictools in assessing nonresolving pneumonia arechest radiographs and chest CT scans. The evalua-tion of nonresolving pneumonia has further benefit-ted from the development of high-resolution chestCT (HRCT). HRCT involves using thin-sectionscanning at 1- to 2-mm collimation combined with ahigh spatial reconstruction algorithm. HRCT is su-perior to conventional techniques in several keyareas that affect the management of nonresolvingpneumonia. Compared to conventional chest x-ray,HRCT allows superior detection of parenchymalabnormalities including emphysema, air space dis-ease, interstitial disease, and nodules. Detection ofthese structural abnormalities may narrow the dif-ferential diagnosis or suggest new possibilities.Certain conditions, such as amiodarone toxicity andlymphangitic spread of malignancy have specificHRCT characteristics that may suggest a diagnosiswith reasonable specificity. In addition, the greatersensitivity of HRCT allows for better precision inassessing a patient’s response to therapy over time.This is especially useful when there is preexistinglung disease, such as in idiopathic pulmonary fi-brosis, that makes it difficult to distinguish acutefrom chronic changes. CT also improves detectionof localized collections, such as abscesses and em-pyemas. Finally, the ability to better localize dis-ease helps direct biopsy procedures and may im-prove diagnostic yield.

Bronchoscopy

The role of fiber-optic bronchoscopy (FOB) inthe diagnosis of nonresolving pneumonia dependslargely on the clinical scenario. The best acceptedindication for FOB in the diagnosis of pneumonia isin the immunocompromised host with diffuse pul-monary infiltrates. In this setting different organ-isms that require markedly different treatments mayhave similar or indistinguishable clinical presenta-tions. While clinical and radiographic patterns may

narrow the set of diagnostic possibilities, abnormalhost factors, poor baseline cardiopulmonary re-serve, and the wide spectrum of possible pathogensoften make an empiric trial risky and therefore jus-tify early FOB. Similarly, in cases of nonresolvingpneumonia, the relative ease and low risk of FOBmake this an appealing diagnostic procedure in apopulation of patients with a similarly wide spec-trum of possible infectious and noninfectious eti-ologies.

Despite the frequency of its use for this indica-tion, there are few studies that document the diag-nostic yield of FOB for nonresolving pneumonia. Ina retrospective analysis of FOB for nonresolvingpneumonia, Feinsilver et al. (1990) demonstratedthat FOB successfully diagnosed 86% of patientswho eventually had a specific diagnosis estab-lished. FOB was more likely to establish a specificdiagnosis in younger, nonsmoking patients withmultilobar involvement and prolonged duration ofdisease. Patients older than 55 years, smokers, andthose with immune defects were more likely tohave a nondiagnostic bronchoscopy and were sub-sequently shown to have slowly resolving pneu-monia.

The utility of FOB in nonresolving pneumoniaalso depends on the disease possibilities being con-sidered and the population being studied. FOB ismost useful in diagnosing unusual pathogens, someimmunologic disorders such as chronic and acuteeosinophilic pneumonia, and neoplastic diseases.Depending on the diseases being considered, trans-bronchial biopsy may or may not be necessary. Inother situations, FOB may have a relatively lowdiagnostic yield but may provide useful informa-tion in ruling out infectious processes. This is espe-cially important if immunosuppressive therapy isbeing considered.

The role of bronchoscopy in ruling out bacte-rial infections in the setting of nonresolving pneu-monia is unclear. Most recommendations are basedon extrapolating data from studies of CAP andnosocomial pneumonia. Since the causative organ-ism in CAP is not isolated in more than 40% ofcases, the initial rule of FOB is limited (BritishThoracic Society, 1993; Bartlett et al., 1998; Basel-ski & Wunderink, 1994). FOB for CAP, particularlyif done prior to antibiotic therapy, increases thepercentage of cases with a defined etiology. How-

408 CHAPTER 25

ever, the additional pathogens that are isolated arealmost always covered by routine empiric antibiotictherapy. Therefore, the role of FOB in identifyingbacterial pathogens in nonresolving CAP is not eas-ily defined. Unless unusual pathogens such as My-cobacterium tuberculosis are present, the diagnos-tic sensitivity and specificity for pathogens in thispopulation is probably limited.

Based on studies of ventilator-acquired pneu-monia (VAP), however, several recommendationscan be made. First, unprotected collection tech-niques, such as tracheal aspirates and unprotectedBAL, are of little value for identifying bacterialpathogens. Physician accuracy on predicting VAPbased on unprotected endotracheal aspirates andclinical information ranges from 71% to 82% (Fagonet al., 1993). Diagnosis with protected broncho-scopic techniques demonstrates sensitivity andspecificity in excess of 85% (American ThoracicSociety, 1995). While multiple protected broncho-scopic techniques have been used, each with itsown particular advantages and disadvantages, it isunclear whether any one technique is markedly su-perior. Techniques include protected specimenbrush and protected BAL with quantitative culture.The important point with all of these techniques isto obtain specimens from the distal alveolar or res-piratory bronchiole with minimal proximal airwaycontamination. Controversy exists as to whetherdiagnostic bronchoscopy should be performed onall patients with VAP, since multiple studies haveshown no survival benefit compared to empirictherapy alone (American Thoracic Society, 1995).Whether this applies to nonresolving pneumonia isunclear. Certainly FOB that detects noninfectiousetiologies would be expected to alter therapy andpresumably affect survival. Given this limited data,it still best to use a protected specimen technique ifbacterial pathogens are suspected, realizing the lim-itations of the technique.

Summary

The diagnostic evaluation of nonresolvingpneumonia begins with a careful history, physicalexamination, and review of the medical record. Thegoal is to determine whether the rate of resolution iswithin the range of expected norms, taking into

consideration the patient’s underlying host factors,comorbidities, severity of illness, and any knownpathogens. If the patient is stable or slowly improv-ing and has other comorbidities or host factors thatare known to delay the rate of resolution of pneu-monia, careful observation and continued therapy iswarranted for 4 to 8 weeks. If there is no resolutionor progression of disease, then a more aggressivediagnostic approach is warranted.

The physician must first determine whetherthe nonresolving pneumonia is due to an infectiousor noninfectious etiology. The initial evaluationshould include a chest CT to look for unsuspectednodules or localized collections of fluid. Any sig-nificant pleural collections should be biopsied ordrained. If this is unrevealing, bronchoscopy shouldbe considered.

Several factors should be considered when de-ciding on whether to proceed with FOB. As men-tioned previously, in patients with stable but non-resolving pneumonia with impaired host defensesit is reasonable to observe the patient, since theinfection can be expected to take a longer time toclear. When infection fails to resolve in a patientwithout impaired host defenses or if there is clinicalprogression, FOB should be pursued. Similarly, ifnoninfectious etiologies or unusual pathogens aresuspected. FAB is warranted. Positive results fromFOB can serve to modify or optimize treatmentregimens. Similarly, a negative result has signifi-cant value. Patients with a negative FOB have agood chance of merely having a slowly resolvingpneumonia and if they are stable can be observed.Similarly, a negative FOB will narrow the differen-tial diagnosis for patients with progressive disease.Diseases that typically are not diagnosed with FOBthat are progressive include pulmonary vasculitissyndromes, BOOP, and the various forms of diffusealveolar damage. In these cases a negative bron-choscopy with progressive symptoms should promptconsideration of an open-lung biopsy.

While definitive recommendations on the de-cision to proceed to open-lung biopsy cannot bemade, several factors need to be considered whendeciding whether to proceed with open-lung bi-opsy. These factors include disease progression, thediagnostic possibilities being considered, and theeffect that a positive open-lung biopsy will have ontreatment. In general, if the disease is relatively


stable, a period of careful observation may be war-ranted. If there is a high likelihood for a disease thatwould necessitate a dramatic change in therapy,then open-lung biopsy is warranted. Diseases in thiscategory generally include most vasculitis syn-dromes (WG) and inflammatory lung diseases(AIP) that require immunosuppressive therapy. Inthese cases, the risk of immunosuppression in apatient who is currently infected requires a specifictissue diagnosis. The more potent the immunosup-pression required, the more the open-lung biopsy iswarranted. Similarly, FOB in these cases can helpto rule out concurrent infection, but open-lung bi-opsy remains the gold standard to establish thediagnosis.

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