Invasive Fungal Infections

Invasive Fungal Infections The Use of Serologic Tests in Diagnosis and Management Robert L. Penn, MD; Ronald S. Lambert, MD; Ronald B. George, \s=...
Author: Leon Boone
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Invasive Fungal Infections The Use of Serologic Tests in

Diagnosis and Management

Robert L. Penn, MD; Ronald S. Lambert, MD; Ronald B.

George,

\s=b\ Serologic tests are useful in providing a presumptive diagnosis of invasive fungal infection, allowing early institution of specific therapy. The judicious use of these serologic tests for circulating antibodies or antigens also may aid in analyzing response to treatment and in assessing prognosis. This review summarizes the currently available serologic tests

for common invasive mycoses and discusses their relative usefulness and reliability. (Arch Intern Med 1983;143:1215-1220)

Tnvasive mycoses

are

being recognized with increasing

frequency.1 Blastomycosis, coccidioidomycosis, and histoplasmosis continue to be significant problems in their endemic areas2; and infections caused by opportunistic fungi have become common nosocomial complications of immunosuppression, antimicrobial chemotherapy, and in¬ travenous hyper alimentation.3,4 Definitive diagnosis of deep fungal infection is difficult and often requires a biopsy specimen to demonstrate organisms in tissue. In some however, serologie tests may allow for a presumptive diagnosis and the early institution of effective therapy. cases,

The

common

invasive mycoses

are

classified

as

follows

according to whether the causative fungus is pathogenic or opportunistic: Pathogenic Fungi Blastomyces dermatitidis Coccidioides immitis

Cryptococcus neoformans Histoplasma capsulatum

Opportunistic Fungi Aspergillus species Candida species

While pathogenic fungi can infect normal hosts, the oppor¬ tunistic fungi usually cause infections in immunocompromised hosts or in special situations such as the presence of indwelling catheters.2 In this brief review, important Accepted for publication Dec 28, 1982. From the Department of Medicine, Louisiana State University Medical Center (Drs Penn, Lambert, and George) and the Veterans Administration Medical Center (Drs Penn and George), Shreveport. Reprint requests to Veterans Administration Medical Center, 510 E Stoner Ave, Shreveport, LA 71130 (Dr Penn).

MD

invasive mycoses with useful serologie tests are discussed in alphabetical order for the purpose of easy reference. ASPERGILLOSIS

Aspergillus species

most

commonly

cause

superficial

infections restricted to a skin or mucosal surface, such as external otitis, allergic bronchopulmonary aspergillosis, and pulmonary aspergilloma. In only a minority of patients, usually the immunocompromised, do aspergini penetrate host tissues to cause invasive aspergillosis.5"7 Rapid de¬ tection of invasive aspergillosis is essential to the effective therapy of this otherwise fatal infection.8,9 Serologie tests are of established usefulness in confirm¬ ing a diagnosis of noninvasive forms of aspergillosis.10 Immunodiffusion (ID), complement fixation (CF), counterimmunoelectrophoresis (CIE), enzyme-linked immunosorbent assay (ELISA), and passive hemagglutination assay (PHA) methods successfully detect antibodies to Aspergil¬ lus antigens."13 Serum samples are tested against crude antigens prepared from Aspergillus fumigatus, Aspergil¬ lus flavus, and Aspergillus niger culture filtrates.10 The ID test is most widely available and it will reliably detect precipitins, often in multiple bands, in over 90% of patients with pulmonary aspergilloma and in about 70% of patients with allergic bronchopulmonary aspergillosis. Serologie methods for detection of invasive aspergillosis are unsatisfactory.14 Invasive aspergillosis can be diagnosed with certainty only by the histologie demonstration of As¬ pergillus organisms within tissues. Because tissue speci¬ mens may be difficult to obtain in these severely ill patients, various attempts have been made to improve the serodiagnosis of invasive aspergillosis. The Table summarizes se¬ lected experience with these approaches.12"17 Young and Bennett14 noted no true-positive reactions in their 15 pa¬ tients with autopsy-proved invasive aspergillosis. Others also have found that some patients with proved invasive aspergillosis will not have detectable Aspergillus antibod¬ ies, perhaps due in part to the underlying state of immunosuppression. The report by Prystowsky et al17 is of interest because their patients had cutaneous portals of entry for

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Selected Experience With the Serodiagnosis of Proven Invasive Aspergillosis

Source, yr Young and Bennett,'4

1971

Antigens Aspergillus fumigatus (2 strains)

No. True Test Positive/ Methods" No. Tested

Not stated

Meyer et al,151973

ID CF CIE I FA

ID

0/5 0/10 0/3 0/10 5/14 1 false-

(plus

positive) Schaefer et

al,16 1976

A

fumigatus

ID

7/10 3 false-

(plus

positives)

Prystowsky et ai," 1979 Holmberg étal,12 1980

A

Gold et al,'3 1980

Aspergillus niger A fumigatus,

Not stated

fumigatus (2 strains), Aspergillus

ID

0/3

CIE ELISA

7/10 8/10

flavus, and

A flavus, and A

ID PHA

17/55 18/55

niger *ID indicates immunodiffuslon; CF, complement fixation; CIE, counterimmunoelectrophoresis; IFA, indirect fluorescent antibody assay; ELISA, en¬ zyme-linked immunosorbent assay; and PHA, passive hemagglutination assay.

invasive aspergillosis, and despite relatively prolonged illness none had positive serologie reactions. Two of the studies included in the Table detected false-positive reac¬ tions.15,16 This is not surprising since some healthy persons may have detectable Aspergillus antibodies, and a positive reaction may persist for months.13,16 In the appropriate clinical setting the usefulness of a positive antibody reaction is improved by regular serial testing of high-risk patients to detect recent seroconversions.9,12,13 The detection of Aspergillus antigens in serum or other sites may become useful in the serodiagnosis of invasive as¬ pergillosis. These methods detect the presence of the fungus and are independent of host immune response.18"21 At present, however, these promising techniques remain re¬ search tools and are available only in a few specialized

laboratories,

BLASTOMYCOSIS

by dermatitidis are definitively diagnosed by demonstrating the organism in smears or cultures. Serologie tests for blastomycosis are considered unreliable because they lack both sensitivity and specif¬ icity.22"26 Currently available serologie tests include CF and ID methods.10 Although CF and ID tests may be performed with either mycelial- or yeast-phase antigens, the yeastphase antigens appear to be more reliable.24,27 The CF test is considered positive when the titer is 1:8 or greater.10 However, positive CF tests occur in less than 50% of patients with proved blastomycosis.28 In at least two reported series of cases of active blastomycosis, the inci¬ dence of positive CF antibody to H capsulatum was as high or higher than that for dermatitidis.222S Cross-reactions Infections caused

also occur with C immitis. Elevated CF titers are useful in this situation primarily for providing evidence of a fungal infection, but they are not specific due to cross-reactivity. Promising refinements in the ID test have been reported by workers at the Centers for Disease Control, Atlanta

(CDC).27 Using a double ID test, Kaufman et al27 found two significant precipitin bands, the A band (closer to the antigen well) and the band (closer to the serum well). They tested serum samples from 113 patients with proved blastomycosis and found either the A band alone, or a combination of A and bands, in 79%; in no case was the band found alone. In a subsequent report, serum samples from seven of ten patients with active blastomycosis sub¬ mitted to the CDC were positive for the A band.30 Impor¬ tantly, false-positive results have not been reported, and the few convalescent serum samples tested after cure have been negative.27,30 A positive ID test, ie, the presence of an A band, may be interpreted as a marker of current or recent blastomycosis. A commercial ID kit has not proved to be clinically useful.24 CANDIDIASIS

Candida organisms normally occur as commensals in the human mouth, alimentary canal, and female genital tract. They also may colonize any body surface whose usual de¬ fenses have been altered, for example, the bladder of a catheterized patient. The major challenge facing the clini¬ cian is distinguishing benign colonization from invasive infection.31 Invasive infections may remain localized, as with esophagitis or abdominal abscess, or may disseminate in the bloodstream. In immunocompromised patients, hematogenous dissemination often occurs in the absence of positive blood cultures.3234 Routine microbiologie studies thus are frequently insufficient to establish the diagnosis of systemic candidiasis.35 Serologie techniques of most value for the diagnosis of systemic candidiasis are ID, CIE, and latex agglutination (LA).10 Other tests, such as whole-cell agglutination, CF, and ELISA, are not recommended because they are less reliable when compared with other methods.10,36"39 The ID test takes 48 to 72 hours, and is not quantitative (any detectable precipitin is considered a positive reaction). The LA and various CIE tests take less than 24 hours and may be quantitated. The detection of conversion from a negative to positive reaction, a fourfold or greater rise in antibody titer, a single titer of 1:8 or more, an increasing number of precipitin bands, or precipitins to antigens other than mannan are regarded as results most indicative of invasive candidiasis.10,37,40 There is an extensive literature evaluating the usefulness of these and other tests for Candida antibodies, and contro¬ versy exists concerning their true value.35,41 The lack of standardized reagents, different patient populations stud¬ ied, and difficulties in defining invasive candidiasis make a meaningful distillation of the literature virtually impossi¬ ble. However, the following similar conclusions have been reached by a number of investigators10,36,38,41: (1) The predic¬ tive value of tests for Candida antibodies is maximal when the disease prevalence is high in the population being studied34; thus, serologie tests are of most benefit in the diagnosis of invasive candidiasis when applied to patients at greatest risk for the infection. (2) False-negative reactions have been documented in up to 50% of high-risk patients with proved systemic candidiasis,41,42 and thus a negative reaction does not exclude the diagnosis of invasive can¬ didiasis; in addition, serum samples containing antibodies against Candida krusei may give negative reactions in the standard tests that use Candida albicans antigens.10 (3) False-positive reactions are noted with all tests for can¬ didai antibodies, and their frequency increases as the sensitivity of the tests increase.3 0 Patient groups yielding the highest rates of false-positive reactions are those with candidai colonization, Torulopsis glabrata infection, bacte-

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rial endocarditis, and those recovering from open heart surgery. Titration of positive reactions has eliminated some false-positives, but at the expense of reducing test sensitiv¬ ity. Therefore, a positive reaction for candidai antibodies must be interpreted in the context of the clinical setting, and a positive reaction by itself does not establish a diagnosis of invasive candidiasis. Gas-liquid Chromatographie detection of increased amounts of circulating arabinitol or mannose, metabolic products Candida growth, have been reported to indicate the presence of systemic candidiasis.43,44 However, more recent evaluations of these methods have questioned their reliability and specificity.45,46 Reports of the detection of circulating Candida antigens by hemagglutination inhibi¬ tion,47·48 radioimmunoassay (RIA),49 CIE,50 ELISA,39,51 and LA52 in patients with invasive candidiasis perhaps offer more promise as future aids in the rapid diagnosis of this

enigmatic

Skin Test

100 90

CF Test

80 70 60 50

I

_

40 30

_

/

20

Precipitin

10

lili

infection.

JL

COCCIDIOIDOMYCOSIS

In contrast to the other infections discussed in this review, serologie tests for detecting antibodies to C immitis have assumed an important role in the diagnosis and prog¬ nosis of coccidioidomycosis. Antibodies to mycelial-arthrospore phase antigens (coccidioidin) and to spherule-endospore phase antigens (spherulin) have been detected in a variety of body fluids using tube precipitin (TP), LA, ID, CF, and CIE techniques.10,53 Reactions to coccidioidin are currently of most clinical usefulness.53 Primary inhalation of C immitis arthrospores is followed by the development of a symptomatic illness in about 40% of patients.53 In asymptomatic individuals, a positive skin test reaction to coccidioidin develops, while serologie reactions for antibody are only transiently, if ever, positive. In symptomatic infections, positive serologie reactions de¬ velop in a characteristic temporal relationship, as illus¬ trated in the Figure. Circulating IgM antibodies are detect¬ able with the TP test in about 90% of patients during the second and third weeks of illness and are almost invariably absent four to six months later (Figure). The LA test is more sensitive but is less specific, having a false-positive rate of 6% to 10%.26,54 An ID method using heated coc¬ cidioidin (IDTP test) also detects IgM precipitins, and it has a sensitivity between that of the TP and LA methods.10 The LA and IDTP tests are useful screening procedures be¬ cause of their speed and sensitivity, but a positive reaction should be confirmed with the TP test. A positive TP reac¬ tion is virtually diagnostic for recently acquired coccidi¬ oidomycosis; a negative reaction does not exclude the diag¬ nosis. The TP test is not quantitative, has no prognostic significance, and is never performed on CSF. Complement-fixing IgG antibodies are usually detect¬ able in symptomatic patients and not detectable in asymp¬ tomatic patients. They appear later than the IgM pre¬ cipitins (Figure), and within months fall to low levels or disappear if recovery takes place.58 Coccidioidomycosis can be diagnosed presumptively when a fourfold rise in CF titer is observed. Dissemination of infection to sites other than the meninges is marked serologically by rapidly rising or persistently high CF titers. With the method originally evaluated by Smith and colleagues,55,56 CF titers of 1:32 or more usually indicated nonmeningeal disseminated infec¬ tion. Since such a "critical titer" today will vary among laboratories using different methods, it is best to interpret a CF titer of 1:16 or more as suggestive of disseminated or complicated infection.10,53 Complement fixation titers of 1:8 or less may occur in very recent, localized pulmonary, or disseminated C immitis infections. Low CF titers also are

Months of Illness

Timing of positive results of coccidioidin skin test reactivity, comple¬ ment-fixing (CF) antibody titers, and tube precipitins following infection with Coccidioides immitis.

compatible with remote quiescent coccidioidomycosis, and may result from cross-reactions caused by blastomycosis or histoplasmosis. In these cases, ID tests help to determine the likelihood of coccidioidomycosis.10 A definitive diag¬ nosis, however, is made by microscopic or cultural demon¬ stration of the organism in infected tissue.

Meningeal coccidioidomycosis may occur with or without CF antibodies.57 Any titer of CF antibodies in CSF, however, is indicative of meningeal infection until proved otherwise.57 Parameningeal involvement without menin¬ gitis may occasionally cause false-positive CF reactions in CSF.58 False-negative reactions in CSF occur in about 5% of patients even when an overnight incubation is used, so that a negative reaction does not exclude meningeal involve¬ serum

ment.67 An ID method using ultrafiltered coccidioidin (IDCF test) and a recently described CIE test detect the same IgG antibodies as does the CF test, although the resultant titers may differ.10,53,59 The IDCF test is commercially available in kit form.53 These tests are useful screening procedures because they are simpler and quicker than the CF method; however, neither method is recommended for testing of CSF. Any positive IDCF or CIE reaction on other speci¬ mens must be confirmed with CF test. Serologie testing is of most prognostic value when cou¬ pled with skin testing. Patients with a positive skin test and a falling or absent CF antibody titer have the best prog¬ nosis. A poor prognosis is heralded by a negative skin test and a rapidly rising or very high CF titer. Skin tests with C immitis antigens do not affect serologie tests for coccidi¬

oidomycosis.53

CRYPTOCOCCOSIS

Cryptococcus neoformans is the only cryptococcus patho¬ genic for man. Although it is occasionally a saprophyte,60 its isolation usually indicates invasive disease. Inhalation of the yeast may be followed by hematogenous dissemination to the bones, joints, skin, urinary tract, or CNS. Most symptomatic infections involve the respiratory tract or meninges. A definite diagnosis of cryptcoccosis requires the demonstration of organisms in host tissues. Testing for cryptococcal polysaccharide capsular antigen is the most important serologie aid in the diagnosis of

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cryptococcosis. Antigen is most often sought in CSF and serum; however, any body fluid may be assayed for its presence. Although LA, CF, CIE, and ELISA methods successfully detect cryptococcal antigen, the highly sensi¬ tive and rapid LA test is recommended for widespread laboratory use.10,6163 Reliable commercial LA test kits are

available.10 The LA methods must include a control to caused by the presence of rheumatoid factor.61,64 In cases of proved cryp¬ tococcal meningitis, LA has detected cryptococcal antigen in 94% of CSF and in 70% of the serum samples,65 with positive serum samples virtually always occurring in pa¬ tients with positive CSF.60 Spinal fluid testing also has been helpful in the diagnosis of smear- and culture-negative cryptococcal meningitis.66,67 The LA test on serum is less often positive in patients with nonmeningeal infections, but has proved helpful in some cases of cryptococcal pneu¬ monia68 and disseminated cryptococcosis without menin¬ gitis.60,69 In the proper clinical setting, LA titers of 1:8 or more are considered diagnostic and those less than 1:8 are considered highly suggestive of cryptococcal infection.10 False-positive reactions are uncommon, have titers less than 1:8, and have occurred in patients with bacterial men¬ ingitis, CNS malignant neoplasms, other chronic meningitides, and in a single case of Klebsiella paravertebral abscess with osteomyelitis.10,61,70,71 Subsequent CIE studies have confirmed a weak cross-reactivity between rabbit anticryptococcal globulin and three of five Klebsiella strains tested.62 Equivocal specimens should be sent to a reputable reference laboratory for confirmation with LA and CF

identify nonspecific agglutination reactions

testing.61

False-negative spinal fluid LA tests are most likely to patients with very early infection (positive cultures abnormalities), and in patients with prolonged illness.65 A single negative test does not rule out the possibility of cryptococcal infection, and repeated testing is advised in any patient otherwise suspected of having cryp¬ tococcal meningitis.10,66 A specimen with a high antigen titer may yield a negative reaction at low dilutions ("prozone occur in and no other

phenomenon").72 Routine testing for antibodies to cryptococcal capsular polysaccharide is not recommended because of frequent false-negative and false-positive reactions.73"76 Using a sen¬ sitive RIA, anticryptococcal antibodies were detectable in 89% of 185 normal volunteers, as opposed to 41% of 51 pa¬ tients cured of cryptococcal meningitis.74 Furthermore, eight cured patients vaccinated with purified cryptococcal polysaccharide antigen manifested a significantly blunted antibody response when compared with vaccinated normal volunteers.74 These preliminary studies suggest an immu¬ nologie basis for the observation that cryptococcal antibody testing is of limited usefulness in the diagnosis and prog¬ nosis of cryptococcal infection. Prognosis in cryptococcosis also can be estimated on the basis of serologie testing. Poor prognosis and increased risk for relapse is indicated by very high (>1:32) antigen titers before therapy and persistence of antigen titers greater than 1:8 after therapy.73,77 Since the presence of detectable antigen often is associated with the absence of detectable antibody, it is not surprising that some studies found the absence of antibody to be an indicator of poor progno10.69,73,75 „:„

SljSa

HISTOPLASMOSIS

Serologie tests are useful in the diagnosis of histoplasmosis. Although a definitive diagnosis is made by the isolation of H capsulatum from clinical specimens, this may require weeks of incubation or may only rarely be accom-

pushed in some forms of infection.2 Thus, serologie tests are essential to the proper treatment of some patients with histoplasmosis. The most commonly available serologie test is the CF test for antibodies to yeast-phase or mycelial-phase (histoplasmin) antigens.10 Skill and experience are essential to obtain reliable quantitative CF test results.10 A single

serum CF reaction of 1:32 or more, or a fourfold or greater rise in titer during illness is highly suggestive of active histoplasmosis. Rising CF titers are demonstrable in over 95% of patients with primary infection; however, elevated titers are less common in the severe disseminated form of primary infection.2 Positive reactions in CSF have been used to presumptively diagnose Histoplasma meningitis.78 Serum titers of 1:8 and 1:16 are more difficult to interpret; values less than 1:8 are considered normal or negative. In a recent study at our institution, 25 of 104 healthy young blood donors from an endemic area had CF titers of 1:8 or 1:16 to one or both antigens (R.S.L. et al, unpublished data, 1983). None of the individuals in our series had titers greater than 1:16. Complement fixation titers of 1:8 and 1:16 also are compatible with chronic pulmonary histoplasmosis. Lowell and Shuford79 found that over 70% of 179 patients with chronic pulmonary histoplasmosis had CF titers of 1:8 or more to either yeast-phase or histoplasmin antigens.79 Only one of the 92 patients they studied with chronic ob¬ structive lung disease or tuberculosis (diseases that are clinically similar to chronic histoplasmosis) had a positive histoplasmin CF reaction, while ten of the 92 patients had CF titers of 1:8 or more to the yeast antigen.79 A positive histoplasmin skin test induces elevated histo¬ plasmin CF titers in 12% to 27% of persons.80 Because crossreaction exists between the serologie responses to H capsulatum and dermatitidis, positive CF reactions to these organisms may result from infection with either one.2,10,26,80 False-negative CF reactions may occur with any form of infection, but are most frequent in immunosuppressed patients with disseminated disease.81 Thus, a positive CF reaction never definitely establishes the diagnosis of histo¬ plasmosis, and a negative CF reaction never definitely excludes the diagnosis. The demonstration of precipitating antibodies to H capsulatum by ID or CIE is valuable in the diagnosis of histoplasmosis.82"84 Sensitivity of these qualitative tests appears to be slightly less than that of CF.20 They do have the advantage of being quicker and simpler than the CF test, and together ID and CIE have been proposed as screening tests for histoplasmosis.86 Two precipitin bands are significant: the h band (closer to the serum well) and the m band (closer to the antigen well). The m band appears early after infection, but persists after recovery, and thus is not specific for active infection. Furthermore, it also may appear following a histoplasmin skin test.20 The presence of a discrete h band is highly specific for active histoplasmosis. Unfortunately the h band is not often present, even with active infection.20 The histoplasmin LA test is rapid and simple, but is not recommended because false-positive reactions are common and it yields false-negative results in about 50% of cases.86,86 This test is no longer commercially available. An RIA using histoplasmin and yeast antigens has been developed that is more sensitive than the CF test.87 Al¬ though the titers of antibody to histoplasmin in healthy individuals are higher with RIA than with CF, the total incidence of false-positive results is similar for both.87 We currently interpret RIA titers less than 1:16 to both histo¬ plasmin and yeast antigens as indicating that a diagnosis of active pulmonary histoplasmosis is very unlikely. False-

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negative results have occurred with disseminated disease.87 The value of RIA is increased when ID is simultaneously performed. Results of both tests can be available within 24 hours, and may be helpful in the management of some acute clinical situations. The presence of an h band

on

ID is

highly specific for active histoplasmosis, while the absence of significant RIA titers makes the diagnosis very unlikely. These tests should be supplemented by serial CF tests, and by vigorous attempts to isolate the organism. The Figure is 40:108).

reproduced with permission

from

Mycopathologia (1970;

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