Serum Lactate Dehydrogenase (LDH) in Pneumocystis carinii Pneumonia, Tuberculosis, and Bacterial Pneumonia

Serum Lactate Dehydrogenase (LDH) in carinii Pneumonia, Pneumocystisand Bacterial Pneumonia* Tuberculosis, Joseph Quist, MD; and A. Ross Hill, MD An increase in serum lactate dehydrogenase (LDH) activity is commonly taken to support the presumptive

pneumonia (PCP), diagnosis of Pneumocystis carinii may also be increased in other although the LDHandlevel of extrapulmonary lung infections itsin a varietyvalue in patients with disorders. To assess diagnostic fever, lung infiltrates, and a high prevalence of HIV infection, we compared LDH levels in 42 hospitalized tuberculosis patients with PCP, 71 with disseminated bacterial with and 37 with 40 TB, (TB), pulmonary in was level LDH Peak higher (p<0.05) pneumonia. 157 U/L) and disseminated TB patients with PCP (547± (569 ±338 U/L) than in patients with pulmonary TB (258±66 U/L) or bacterial pneumonia (331 ± 139 U/L). However, substantial overlap between groups limited its diagnostic value for individual patients. Expressing LDH

as

its ratio to simultaneous

serum

aminotrans-

ferases (AST or ALT) did not enhance its discrimina¬ tory value. Most patients in each group had abnor¬ malities in other serum enzymes (AST, ALT, alkaline

TTuman immunodeficiency virus (HlV)-induced im-¦¦-*¦ to secondary in¬ munodeficiency typicallyofleads which the fections involving Pneumocystis lungs, carinii pneumonia (PCP), bacterial pneumonia, and [TB], fungi) granulomatous infections (tuberculosis are the foremost examples. Definitive diagnosis of these infections, which may entail bronchoscopy or culture results, is often not feasible at presen¬ delayed tation. Hence there is considerable interest in nonin¬ vasive aids to initial presumptive diagnosis and empiric antimicrobial therapy. PCP has been the main focus of attention, because it is the most common opportunis¬ tic pneumonia complicating AIDS and because inva¬ sive methods are often required for diagnosis. The serum lactate dehydrogenase (LDH) activity is increased in more than 90% of AIDS-related cases of PCP,1"4 but it can also be increased in other pulmo¬ and numerous extrapulmonary diseases.67 In nary1,5'6 recent years, we have noted a disconcerting tendency for physicians to rely on the LDH level to discriminate PCP from other lung infections, even to the point of measuring LDH without considering other serum en*From the SUNY Health Science Center and Kings County Hos¬ pital Center, Brooklyn, NY.

Manuscript received October 25,1994; revision accepted February 27, 1995. Reprint requests: Dr. Hill, 450 ClarksonAve, Box 19, Brooklyn, NY

making an iso¬ 7-glutamyltransferase), phosphatase, uncommon level LDH lated elevation of (21% of PCP has a LDH Serum cases). high sensitivity for PCP (100% in this series) but must be interpreted with caution given its lack of specificity. (CHEST 1995; 108:415-18)

ALT=alanine aminotransferase; AST=aspartate ami¬

LDH=lacGGT=Y-glutamyltransferase; PCP=Pneumocystis carinii pneumo¬ dehydrogenase; TB=tuberculosis

notransferase; tate

nia;

Key words: bacterial pneumonia; enzyme tests; HIV infec¬ tion; lactate dehydrogenase; Pneumocystis carinii pneumo¬ nia; tuberculosis

losis)

(pulmonary tuberculosis, miliary tubercu¬

zyme levels that increase concomitantly in nonpulmonary disorders. To reassess its diagnostic utility in the infiltrates, we per¬ setting of a febrile illness withoflung formed a retrospective study LDH in the three most common HIV-associated lung infections in our com¬ munity: PCP, bacterial pneumonia, and TB. Methods of patients hospitalized for PCP, focal samples were drawn from records bacterial and TB, pulmonary consultations pneumonia and from a computerized listing of of pulmonary Convenience

cases diagnoses for 1991 to 1993. Consecutive hospital discharge there were meeting the inclusion criteria were enteredweuntil studied a previ¬ 40 in each group. Additionally, approximately of patients with disseminated TB.8 ously described cohort Patients were included if their medical record contained at least two values for LDH during the acute illness as well as simultaneous values for aspartate aminotransferase (AST) and alanine ami¬ notransferase (ALT). Patients were excluded if they carried a diag¬ nosis associated with raised serum LDH level, including erythrocyte disorders, malignancy, liver disease, shock, rhabdomyolysis, and renal failure. We report the highest LDH value obtained during the first week of hospitalization, as well as the ratios of LDH to the si¬ multaneous AST and ALT. Most patients also had determinations of alkaline phosphatase and 7-glutamyltransferase (GGT) per¬ formed within 3 days of the LDH. The diagnosis of PCP was confirmed bybronchoscopy in all cases. Pulmonary TB was confirmed by culture of Mycobacterium tuber¬ culosis from respiratory secretions. Bacterial pneumonia was diag¬ nosed when the patient presented with fever and focal lung consolidation and responded to treatment with an antibiotic(s) other

CHEST /108 / 2 / AUGUST, 1995

415

Table

Group* PCP DTB PTB BACT

42

71 40 37

Age>

Male,

39±9 36±10 37±11 43±14

71 82 83 65

1.Demographic and Clinical Data HIV

Infection, * 100

>73 >40 >41

T LDH, % (>250 U/L)

Tldh,

4 Non-LDH

AST+ALT, %

Normal,* %

100 93 53 73

21 10 28 22

21 1 25 26

With Normal

Enzymes

DTB=disseminated TB; PTB=pulmonary TB; BACT=bacterial pneumonia. of HIV status from medical records may be incomplete. *AST, ALT, alkaline phosphatase, and GGT all within normal range.

*

* Ascertainment

than trimethoprim/sulfamethoxazole; a bacterial etiology was con¬ firmed by blood culture in 14 of 37 patients (38%; Streptococcus

pneumoniae in 12, Haemophilus influenzae in 1).

Staphylococcus Patients were considered to have HIV disease if they (1) had a confirmed positive serologic test for HIV, (2) met the 1987 Centers for Disease Control and Prevention (CDC) case surveillance def¬ inition for AIDS, or (3) had a risk factor for HIV infection together with a CD4 count <400 cells microliter and a CD4/CD8 in

1,

aureus

ratio per <1.0. All data are presented as the mean±SD. Intergroup differences for each enzyme variable were assessed by one-way analysis of

variance followed by the

Scheffe procedure (SPSS). The relation¬ ship of LDH to the aminotransferases was assessed by analysis of covariance, using AST and ALT as multiple covariates; the adjusted LDH means were compared by the Scheffe procedure.

Results Lactate dehydrogenase level was increased in 100% of patients with PCP, but it was also increased in most patients in each of the other groups (Table 1, Fig 1). The mean values were nearly identical in patients with PCP and disseminated TB, both groups showing higher levels than those with bacterial pneumonia or

TB (Table 2). pulmonary The chest radiographs of patients with disseminated TB showed a miliary pattern in 54%, focal lung lesion(s) in 14%, and clear lungs in 32% at presenta¬ tion (intrathoracic lymphadenopathy was visible in 9 of 23 with clear lungs). There were no significant differ¬ ences in LDH levels at the time of the radiographs among these subgroups (mean LDH=559, 490, and 507 respectively; p=0.71). Among all patients combined, LDH showed inde¬ linear correlations with AST and ALT (r=0.66 pendent and 0.38, respectively; p<0.01). The aminotransferase levels together accounted for a substantial portion of the variability in LDH (1^=0.44; multiple regression, p<0.0001), due largely to its correlation with AST. The mean LDH values adjusted for AST and ALT (analy¬ sis of covariance) remained higher in patients with PCP (579 U/L) and disseminated TB (507 U/L) than in pa¬ tients with bacterial pneumonia (344 U/L) or pulmo¬ nary TB (326 U/L) (p<0.05). Thus the high LDH val¬ ues in disseminated TB were not explained solely by injury to tissues that also release aminotransferases proportionately, eg, liver necrosis. 416

Since the elevation of serum LDH level in patients with PCP is thought to occur independently from other commonly measured enzymes, we hypothesized that the ratio of LDH to AST or ALT would improve dis¬ crimination of PCP from other causes of increased LDH. Both ratios tended to be higher in patients with PCP than in the other groups (Table 2), but the con¬ siderable overlap made them unreliable for diagnosis of PCP in individual patients (Fig 2). Most patients, regardless of group, exhibited mild to moderate increases of at least one enzyme other than LDH (AST, ALT, alkaline phosphatase, GGT; Table 1, Fig 3). In only 21% of patients with PCP was the peak LDH level accompanied by normal aminotransferase levels. Levels of GGT and alkaline phosphatase were both higher in patients with disseminated TB than in the other three groups (data not shown), probably re¬ flecting granulomatous lesions of liver and other

extrapulmonary sites.

Discussion Our main finding is that serum LDH activity is in¬ creased in most patients requiring hospitalization for all four conditions studied. Prior reports have sug¬ gested a diagnostic role for LDH in PCP but included

forms of pneumoni¬ relatively few patientsWewithhaveother found LDH levels be

tis for

comparison.14

to

increased in patients with infections that sometimes mimick PCP (or vice versa) and that frequently enter its differential diagnosis. Thus, our results confirm the of the serum LDH level for PCP, but high sensitivity its that suggest specificity in this clinical setting is lim¬ ited. Pneumocystis carinii pneumonia is considered to produce an isolated elevation of serum LDH level, the putative source,3 although lung parenchyma beingexamined studies have not simultaneous values of prior other enzymes. Lactate dehydrogenase is a ubiquitous enzyme, and serum levels increase in a wide variety of diseases. Some, such as hepatic, hematologic, and neoplastic disorders, occur frequently in the setting of AIDS. Isolated elevation of LDH level proved to be uncommon in our patients with PCP, possibly because background disorders such as chronic viral hepatitis or Clinical Investigations

LDH

1750

LDH/AST

35-i

1500 H

30-

1250 H

25

u/l iooo

H 20 H

750

H

A

500

*

I

t

/A

I

10-

250

IK* ..2 DTB

BACT

PCP

PTB

Figure 1. Peak serum LD H level for individual patients in the

H

four

groups. Horizontal line denotes the upper limit of nor¬ diagnostic mal range (250 U/L). DTB=disseminatedTB; TB;

PTB=pulmonary

BACT=bacterial pneumonia.

i

liver often coexist and contribute to enzyme ab¬ fatty normalities. Clinicians are familiar with mild elevations of serum LDH levels in cases of non-PCP pneumonia. In bac¬ terial pneumonia the injured lung might be the source, but the concomitant abnormalities in "liver enzymes" suggest that alternative mechanisms may often play a role, such as the hepatic dysfunction associated with bacterial sepsis9 and/or other coexisting disorders. To our knowledge, LDH in TB has not received emphasis in the literature. Tissue necrosis, a charac¬ teristic feature of tuberculous granulomas, provides a ready explanation for elevated LDH values. Necrosis was observed in most tissue samples from disseminated

DTB

BACT

.,.

PCP

PTB

Figure 2. Ratio of peak LDH level to simultaneous AST in indi¬ vidual patients. Horizontal lines indicate mean values.

cases8 and was no doubt usually present in pulmonary

well, as evidenced by radiographic cavities in third of patients. Frank necrosis of lung (or other organ) parenchyma may not be required to raise the serum LDH level, however/ as suggested by the ex¬ amples of PCP and pulmonary alveolar proteinosis,5 in which lung architecture is often preserved. Patients with localized pulmonary TB had normal or increased LDH levels, never exceeding 400 mildly U/L. Patients with disseminated TB often showed striking elevations of LDH, exceeding 500 U/L in 41%. The higher levels in disseminated TB might reflect a greater total-body burden of tuberculous lesions, cases as a

Table 2.Serum Enzyme Activities in Units per Liter (Mean±SD)* PCP (n=42) DTB (n=71) PTB (n=40) BACT (n=37)

LDH

AST

ALT

LDH/AST

LDH/ALT

547±157 569±338 258±66 331 ±139

65±34 118±117 45±33 76±85

44±41 65±64

10.4±5.6 6.8±4.0 7.9±4.2 8.4±7.1

21.2±16.3 13.3±13.8 11.7±10.4 15.8±18.1

35±22 47±44

* DTB=disseminated TB; PTB=pulmonary TB; BACT=bacterial pneumonia. Normal ranges: LDH 80-250, AST 0-40, ALT 0-40. Statistical differences (ANOVA, Scheffe procedure, p<0.05):

LDH: PCP, DTB>PTB, BACT. AST: DTB>PCP, PTB. ALT: DTB>PTB. LDH/AST: PCP>DTB. LDH/ALT: PCP>PTB.

CHEST / 108 / 2 / AUGUST, 1995

417

value in individual patients. While its positive predic¬ tive accuracy would improve if one took twice the up¬ per limit of normal (500 U/L) as the diagnostic threshold, this would greatly reduce its sensitivity (Fig 1), especially for cases that are not full-blown radioA prospective study is needed to deter¬ graphically. mine whether knowledge of the serum LDH level a clinician's substantially improves the accuracyourof data caution Meanwhile, presumptive diagnosis. in level alone LDH on the undue reliance against A serum normal a impression. forming diagnostic LDH level may be useful in excluding PCP (at least in cases with definite lung infiltrates), but elevated values remain nonspecific and must be interpreted with due consideration of coexisting diseases and other serum enzyme abnormalities.

AST

550 i 500 450

400

350-j U/L

300-1 250

200 H 150

100

50 0

ACKNOWLEDGMENT: The authors gratefuUy acknowledge the contributions of Drs. Reuben Margolis and Eva Chan to the statis¬

.ar

£

*£

*

A $ 1-

PTB DTB PCP BACT Figure 3. Serum AST level simultaneous with peak LDH level for individual patients in the four diagnostic groups. Horizontal line denotes the upper limit of normal range (40 U/L).

greater access of LDH to the circulation from small of certain extra¬ miliary lesions, a greater propensity bone liver, marrow) to spleen, pulmonary organs (eg, release LDH when involved, or other unidentified factors. LDH values exceeding 1,000 U/L were ob¬

served only in patients with disseminated TB and were a sign of poor prognosis: 6 of 11 died. Such extreme elevations of LDH level probably reflect the wide¬ spread necrotizing lesions of overwhelming miliary disease. In our experience, the initial working diagnosis of acute lung disease in patients with known or suspected HIV infection is guided by clinical observations but rests mainly on the pattern of radiographic abnormal¬ ity. This study does not permit a formal estimate of the specificity or positive predictive accuracy of LDH level in diagnosing PCP, but suggests that LDH, like hypoxemia, is too nonspecific to hold discriminative

418

tical analyses.

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Henry JB, ed. Clinical diagnosis and management by laboratory methods. Philadelphia: WB Saunders, 1991; 250-84 7 Danpure CJ. Lactate dehydrogenase and cell injury. Cell Biochem Function 1984; 2:144-48 8 Hill AR, Premkumar S, Brustein S, et al. Disseminated tubercu¬ losis in the acquired immunodeficiency syndrome era. Am Rev

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Clinical Investigations