Scand J Infect Dis 24: 309-315, 1992
Serum Carcinoembryonic Antigen: A Prognostic Marker in HIV-related Pneumocystis ca rinii Pneumonia JEAN-PIERRE BEDOS', CHANTAL HIGNETTE', JEAN-CHRISTOPHE LUCET', BADER KILANI'. ENRIQUE CASALINO', MICHEL WOLFF', SOPHIE MATHERON'. CATHERINE LEPORT' and FRANCOIS VACHON'
Scand J Infect Dis Downloaded from informahealthcare.com by Queen's University on 12/30/14 For personal use only.
From the Departments of 'Infectious and Intensive Cure Medicine and 'Nlrclear Medicine. Hopitul Bichat-Claude Bernard, Paris, France Serum concentrations of carcinoemhryonic antigen (CEA) were measured in 43 consecutive patients with HIV-related Pneumocystis carinii pneumonia (PCP). The subjects were divided into 2 groups according to the severity of the PCP: PaO, in ambient air (AA) 5 50 mmHg on admission ( n = 22, group 1) and PaO, > 50 mmHg ( n = 21, group 2). In addition, 57 HIV patients with either non-PCP pulmonary diseases ( n = 34, group 3) or extrapulmonary disease ( n = 23, group 4) were studied. Mean CEA levels (ng/ml) were 13 f 10 in group I and 4.9 k 5.5 in group 2 ( p < 0.001). The corresponding values in groups 3 and 4 were much lower (2.7 k 1.8 and 2.4 f 1.8, respectively). In group 1, mean initial CEA levels were higher (p < 0.001) in the patients who died ( n = 6; 23.5 & 11) than in the survivors (n = 16; 8.9 f 7), although the initial mean PaO, were identical (39 f 7 and 39 k 8 mmHg, respectively) and the initial mean LDH levels were not significantly different (1544 f 530 and 1200 2 457 IU/l). CEA levels fell during specific anti-PCP therapy associated with corticosteroids hut returned to normal only in the survivors. We conclude that CEA levels are increased in patients with PCP and acute respiratory distress. Among the patients with PaO, levels of 5 50 mmHg before treatment, only high levels of CEA (> 20 nglrnl) were associated with a fatal outcome, regardless of anti-PCP therapy associated with corticosteroids. The prognostic value of initial serum CEA levels suggested by these preliminary data should he taken into account in the prospective search for a specific severity index for patients with HIV-related PCP. Once identified, patients with a poor short-term prognosis could benefit from adapted therapeutic protocols.
J . P. Btdos, M D , Clinique de Riaanimation des Maladie7 Infectieuses, H6pital Bichat-Claude Bernard, 46, Rue Henri-Huchard, 75018 Paris, France
INTRODUCTION More than 60% of HIV-infected patients develop Pneumocystis carinii (PCP) pneumonia ( I ) . The mortality rate in primary episodes of PCP varies from 5 to 20% in the published serics (2-5). The corresponding figure in patients with acute respiratory distress rises to 1540°/0 (6) and to 80-90% in patients requiring respiratory assistance with intubation ( 7 ) , although recent reports have given more encouraging results, with a mortality rate < SOYO (8, 9). I n our intensive care unit specializing in infectious diseases, 67 patients with HIVrelated PCP and an initial PaOz in ambient air (AA) of 5 50 mmHg were admitted 1986-1990. All received specific anti-PCP treatment (generally cotrimoxazole), associated with corticosteroids and continuous positive airway pressure (CPAP) with a face mask. The overall mortality rate was 31Y0, but 80% of those requiring respiratory support with intubation died of respiratory failure. This underlines the need for specific gravity indices in this setting in order to adapt the treatment t o the individual short-term prognosis (treatment iit home, in hospital or in intensive care; adjuvant steroids for the prophylaxis of respiratory failure, with doses and duration of treatment adapted to the risk; new therapeutic approach). Various markers of poor prognosis at diagnosis and before treatment have been
Scand J Infect Dis Downloaded from informahealthcare.com by Queen's University on 12/30/14 For personal use only.
310 J.-P. Be'dos et al.
Scand J Infect Dis 24
forwarded (2, 10-13), including hypoxemia ( 5 50 mmHg in A A o r an alveolar-arterial oxygen gradient > 30 mmHg), elevated lactate dehydrogenase levels > 300 IUll, serum albumin (< 35 gll), and polynucleosis in the broncho-alveolar lavage (BAL) fluid > 5-10% in the absence of associated bacterial lung infection. Unfortunately, none of these factors, although they are correlated, shows a sufficiently high positive predictive value to predict unfavourable outcome in a given patient. Carcinoembryonic antigen (CEA) is a glycoprotein belonging to the class of oncofetal antigens. It is synthesized by fetal tissues of endodermic origin (14), particularly the lung, liver, pancreas and intestines (15). In the adult, C E A is used as a serum tumor marker (16), although it is known to give false-positive results in patients with inflammatory lung diseases (17), and levels can be high in bacterial pneumonia (18). The aims of this study were to detect a possible initial increase in CEA levels in patients with HIV-related PCP and to determine whether the initial serum C E A value prior to treatment was related to the mortality, particularly in patients with severe PCP in terms of PaO, in A A (550 mmHg). We also followed the variations in serum CEA levels during anti-PCP therapy. MATERIALS AND METHODS Parient population 100 consecutive HIV-infected patients seen at the HBpital Bichat-Claude Bernard were included in the study. Primary PCP was the only active disease in 43 patients. There were 37 males and 6 females. The risk factors for HIV infection were homosexuality ( n = 21). bisexuality ( n = 6 ) , intravenous drug abuse ( n = 14) and blood product transfusion ( n = 2). HIV infection was diagnosed on the basis of tests for specific antibodies. 22 patients (mean age f SD: 38 f 10 years) had a PaO, in AA of 5 50 mmHg at diagnosis of PCP (group I ) ; the remaining 21 PCP patients (mean age 34 t 7 years) had PaO, values > 50 mmHg in the same conditions of measurement (group 2). All the group 1 patients were treated with cotrimoxazole associated with a 9-day course of adjuvant steroids (methylprednisolone intravenously (iv), 240 mg. 120 mg and 60 mg for 3 days each). Group 2 patients received cotrimoxazole alone. Seven group 1 patients were intubated and ventilated either immediately or after failure of CPAP; the remaining 15 patients received continuous CPAP for a mean period of 4.8 f 3.7 days. Group 2 patients received nasal oxygen therapy. Survivors were defined by the resolution of the acute respiratory distress in terms of clinical signs, blood gases and discharge from the intensive care unit; non-survivors were patients who died of acute respiratory failure. Group 3 consisted of 34 HIV-infected patients with pulmonary diseases other than PCP of varying seriousness (bacterial pneumonia, n = 18; acute respiratory distress syndrome secondary to septic shock of bacterial origin, n = 5; Kaposi's sarcoma, n = 3; pulmonary lymphoma, n = 3; disseminated toxoplasmosis, n = 2; pulmonary tuberculosis, n = 1; cytomegalovirus pneumonia, n = 1; cotrimoxazole immuno-allergic pneumonia, n = 1). Group 4 consisted of 23 HIV-infected patients with extra-pulmonary diseases (cerebral toxoplasmosis, n = 11; lymphoma, n = 4; non-obstructive cardiomyopathy, n = 4; E. coli meningitis, n = 1 ; pyelonephritis, n = I ; tuberculous meningitis, n = 1; Streptococcus pneumoniae pericarditis, n = 1).
Diagnostic approach PCP was diagnosed by the direct identification of P. carinii with Gomori-Grocott staining in the BAL fluid obtained during fiberoptic bronchoscopy, or by the detection of typical cysts in tracheal secretions obtained by the induced sputum technique (3 patients). All the patients with PCP (groups 1 and 2) were evaluated on admission according to the same criteria, comprising simplified acute physiologic score (SAPS) in case of admission to the ICU, time between the presenting symptoms of PCP (cough, fever, dyspnea) and the diagnosis, smoking habits (number of pack years), weight loss, history of chronic lung disease or bowel disease, serum albumin level, total white cell and CD4+ lymphocyte counts, arterial blood gases in AA, LDH level, and serum CEA level. In group 1, arterial blood gases under 100% oxygen through a face mask were determined on admission, LDH and CEA were also determined on days 7 and 14. In group 2, LDH and CEA blood levels were determined only at the admission time. CEA was determined in group 3 before starting specific therapy and in group 4 during therapy. Post-mortem examination of the 6 patients who died included histological examination of the lungs.
Serum carcinoenihryonic antigerz 31 1
Scand J Infect Dis 24
Table I . Base-line characteristics of the 43 PCP putrents according to the PaO, at adniission Group 1 ( n
=
22)
Scand J Infect Dis Downloaded from informahealthcare.com by Queen's University on 12/30/14 For personal use only.
Time since onset of pulmonary symptoms (days) 17k I 1 Weight loss (kg) -7.8k5.8 Smoking (pack years) Ilk13 Albumin (g/l) 2.5.6k6.9 Totnl lymphocytes (/kl) 76Xt612 CD4+ lymphocytes (/PI) 86k102 LDH (IUII) 1298+492 39f7 Arterial PO1 in room air (inmHg)
Group 2 ( n = 21) 17kll
-7.4+5 1758 27.1k6.3 994k772
78*96 952 f 414" 62 k 8''
" p < 0.05, " p < 0.001
CEA determination CEA was assayed in serum by mcans of a solid-phase sandwich-type immunoradiometric method (IRMA. Kit ELISA 2 C E A . CIS Bioindustries) The usual values for normal subjects (blood donors) in our laboratory is 5 5 ng/ml (18a).
Serirrii
Srullsrics All clinical and laboratory data are given as mcan f standard deviation. Data were analysed using Student's f-test or the Mann-Whitney U-tcst and Spearman's rank correlation. The threshold of significance was set at p < 0.05.
~ i g I. . Mean C E A serum levels
in groups 1 4 .
CEA (ng/ml)
25
15
10
5 0
Gr 1
Gr 2
Gr 3
Gr 4
11-22 pts
n=21 pts
n 9 4 pts
n=23 pts
312 J.-P. Bidos et al.
Scand J Infect Dis 24
Table 11. Clinical and laboratory data for patients with severe PCP (PaO, 5 50 mmHg A A ) according to outcome. SAPS
=
simplified acute physiologic score
Scand J Infect Dis Downloaded from informahealthcare.com by Queen's University on 12/30/14 For personal use only.
Survivors ( n = 16) 37+8 Age (years) 9213 Smoking (pack years) Time since onset of pulmonary symptoms (days) 1 6 i l l -7.9f6 Weight loss (kg) 8+4 SAPS 28.4k3.9 Albumin (g/l) Total lymphocytes (/PI) 866f648 1062 112 CD4+ lymphocytes (/PI) Arterial PO, in room air (mmHg) 39i8 2S3+ 114 Arterial POz 100%,FiOz LDH (IU/I) 12002457 CEA (ngiml) 8.9f6
Non survivors (n = 6) 41 2 14 15f14 18211 -7.5f3 llf4 21.4k8.5 505f447 29f25 3927 194273 1544k530 23.5211"
" p= 0.008
RESULTS 37 of the 43 patients with primary PCP survived. The 6 deaths occurred among group 1 patients and were due to respiratory failure in spite of ventilation. The mortality rate was 14% overall, 27% in the patients with acute respiratory distress and 80% in the patients requiring intubation. The base-line characteristics of the 43 patients according to the PaO, cut-off are given in Table I. As shown in Fig. 1, the mean C E A serum level was significantly higher in group 1 than in group 2 (13 i 10 vs 4.9 S 5.7 ng/ml;p < 0.001); the corresponding values in groups 3 and 4 were low (2.7 S 1.8 and 2.4 t 1.8 ng/ml, respectively). The mean C E A serum level was significantly higher in the patients with PCP than in those with other pulmonary diseases (group 1 and 2: 8.8 4 9, group 3: 2.7 f 1.8; p < 0.001). When the various clinical and biological parameters were compared between patients with severe PCP (group 1) who died and those who survived, only C E A was significantly different (23.5 +_ 11 vs 8.9 S 6; p < 0.008) (Table 11). C E A levels differed significantly throughout treatment in group 1 patients, LDH levels also at day 7 (Table 111). Regardless of the baseline value, C E A levels progressively decreased towards normal during treatment, particularly in the survivors. The mean CEA serum level remained higher at day 7 (p = 0.054) and significantly so at day 14 (p = 0.03). The mean C E A serum level at the time of death in the 6 group 1 patients was 11.2 k Table 111. Serum L D H and CEA levels during treatmentfor severe PCP according to outcome Day of study
Survivors ( n = 16)
Non survivors ( n = 6)
P
LDH (lU/l)
DO D7 D14
1200+457 775 2203 9322366
1544f 530 1194k568 908t425
NS 0.008 NS
CEA (ng/ml)
DO D7 D14
8.926 1027.6 7.4k5
23.5k11 18k7 15.728.4
0.0028 0.054 0.03
ScanJ J lntect Dis 24
Serum carcinoernbryonic uritigen
Scand J Infect Dis Downloaded from informahealthcare.com by Queen's University on 12/30/14 For personal use only.
5.5 ng/ml, with a mean time since diagnosis of23 f 7 days. Postmortem pulmonary histology in thcse patients showed edematous and diffuse collagen fibrosis in every case, florid PCP in 4. numerous cytomegalovirus inclusion bodies in 2, disseminated cryptococcosis in 1 and pulmonary aspergillosis in 1. C E A would not appear to be a marker of irreversible pulmonary fibrosis, since its level fell as the fibrosis developed. With regard to the changes in LDH levels, the fall in the mean level between day 0 and day 7 was significant for the group 1 survivors (1200 k 457 vs 755 k 203 IUA; p = 0.0028), but not for the 6 patients who died. There was no correlation between CEA levels in group 1 (PaO, A A 5 mmHg) and other parameters (SAPS, LDH, PaO,, total and CD4+ lymphocytes, albumin). DISCUSSION The risk of death increases in patients with HIV-related PCP according to the degree of hypoxemia in room air on admission. With a PaO? of 70 mmHg, the risk is about 15%, and increases to 4(b50% with a PaO, of 5 50 mmHg (6). Recent randomized studies (19-21) have shown the beneficial effect of early corticosteroid therapy (starting 2 4 7 2 h after initiating anti-PCP treatment) on the progression of patients with moderate o r severe PCP towards acute respiratory failure and death. In the studies by Bozette et al. (20) and Gagnon et al. (21). the mortality rate among patients with severe PCP remained high (20 and 25%, respectively), despite the administration of adjuvant steroids within 72 h. These findings show the importance of identifying PCP patients with a high risk of death despite appropriate specific therapy and adjuvant steroids. This would permit more aggressive management at an early stage, particularly with regard to steroid treatment (higher doses, longer duration, different daily dosage schedule) and the administration of drugs to counteract the deleterious effects of cytokines and other mediators on the lung tissue (22). Indeed. even high-dose "salvage" steroid regimens appear unable to prevent the death of these patients in the terminal phase (20). High C E A levels have been reported in the context of pneumonia due to various infective agents (18), but not P. carinii. In our study. the mean C E A serum level was higher in thc patients with PCP than in HIV-infected patients with other pulmonary or extrapulmonary diseases. This increase would appear to be specific for PCP, particularly in the more severe forms. i.e. group 1, and was associated with an increase in LDH levels and a fall in PaO, which were significantly greater than in the PCP patients without acute respiratory distress (group 2). The other clinical and biological parameters were not significantly different. Although smoking can lead to a rise in C E A levels, there was no correlation here between the number of pack years and C E A levels; in addition, all the smokers in this study had stopped at least 3 weeks prior to admission. We found no evidence of chronic lung disease or liver. colon o r pancreatic illness which could have accounted for an increase in CEA levels. Analysis of the initial predictive factors in the group of patients with severe PCP gave interesting results. Only the initial C E A serum level was associated with a fatal outcome. The following parameters showed no difference between the subgroups of patients who survived and those who died (Table 11): time between onset of symptoms and diagnosis, weight loss, SAPS, hypoalbuminemia, total and CD4+ lymphocyte counts, LDH increase, PaO, in room air, pulmonary shunt in terms of PaO, (FiO, 100%). The mortality rate among patients with an initial C E A serum level > 20 ng/ml was 80%. In contrast, 88% of the patients with C E A levels of 5 20 ng/ml survived. Only 2 patients with C E A levels > 20 ngirnl survived. In one case, PCP was the presenting illness of AIDS: the initial PaO, was 31 mmHg in room air and the initial C E A level was 24.6 ng/ml. This patient was in a very good overall condition and underwent 10 days of continuous CPAP with a face mask (+ 6 to + 12 cm HzO), with an FiOz of 60%. Chest X-rays showed the presence of bullous lung de-
3 13
Scand J Infect Dis Downloaded from informahealthcare.com by Queen's University on 12/30/14 For personal use only.
314 J.-P. Be'dos et al.
Scand J Infect Dis 24
struction, with a voluminous compressive bulla which required surgical treatment. Histological examination of pulmonary tissue obtained during surgery showed a large number of P. carinii cysts, together with edematous and diffuse collagen fibrosis. It is interesting to note the progression of C E A serum levels during treatment: 16.2 nglml at day 14,5.3nglml at day 33 (surgery) and 1.9 ng/ml at day 45, with a concomitant PaO, in room air of 75 mmHg. PCP was also the presenting illness of AIDS in the second patient. The initial PaO, in room air was 56 mmHg and the CEA serum level was 25.2 ng/ml. The patient was a smoker (2 pack years) and had no liver, intestinal or pancreatic illness. At day 14 of treatment the PaO, in room air was 112 mmHg and the C E A level 20.1 ng/ml. The patient is currently undergoing tests to detect a suspected neoplastic disease, as the C E A remained high although the outcome of the PCP was favorable. The reasons for the initial increase in C E A levels during severe PCP are not clear. The histology of PCP usually consists of an accumulation of a foamy intraalveolar exudate, with an interstitial mononuclear cell infiltrate (24). P. carinii binds to type-I pneumocytes, probably for its nutrition and growth (25). The damage to the type-I pneumocyte is followed by the denudation of the basement membrane (26). Hypertrophic changes of alveolar type-I1 pneumocytes are a host reparative response to alveolar injury by P. carinii (diffuse alveolar damage) (27). The increase in C E A levels might reflect this alveolar damage, with dedifferentiation of pulmonary alveolar cells (particularly type-I1 pneumocytes) and the reappearance of oncofetal proteins such as CEA. High serum levels of CEA could reflect a high parasitic inoculum and/or particularly high virulence leading to extensive changes in alveolar epithelial cells. Indeed, immunostaining of airway cells with anti-CEA antibodies has been described in areas of regenerating airway epithelium (17). The passage of C E A into the serum could result from the increased permeability of the alveolo-capillar membrane observed in PCP (26). The initial elevation of C E A serum levels would appear to reflect the active phase of conflict between the parasite and the alveolar epithelium. The decrease observed during treatment would reflect the efficacy of specific anti-PCP treatment, regardless of the secondary progression towards pulmonary fibrosis consecutive to the initial deleterious injury. Despite the fall in C E A during treatment, a high level at day 14 was associated with a poor vital prognosis. Similarly, as reported by other authors (S), a high LDH level at day 7 was also a factor indicating a poor prognosis. In conclusion, we have found that C E A serum levels change during severe PCP. C E A appears to be a marker of the initial conflict between the parasite and alveolar epithelial cells. Among our patients with a PaO, of 5 SO mmHg at A A before treatment, only a high serum level of C E A (> 20 ng/ml) was associated with a fatal outcome, despite specific treatment and associated steroid therapy. Assays of initial C E A levels are relatively easy to obtain and should be integrated into prospective studies to identify a specific gravity index for patients with HIV-related PCP. This will enable new therapeutic protocol to be developed and applied at an early stage for patients with a particularly poor short-term prognosis. REFERENCES Glatt AE, Chirgwin K , Landesman SH. Treatment of infections associated with human immunodeficiency virus. N Engl J Med 318: 439448, 1988. Brenner M, Ognibene FP, Lack EE, Simmons JT. Suffredini AF, Lane MC, Fauci AS, Parillo JE, Shelhamer JH, Masur H. Prognostic factors and life expectancy of patients with acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia. Am Rev Respir Dis 136: 1199-1206, 1987. Gazzard BG. Pneurnocystis carinii pneumonia and its treatment in patients with AIDS. J Antimicrob Chemother 23, Suppl A: 67-75, 1989.
Scand J Infect Dis Downloaded from informahealthcare.com by Queen's University on 12/30/14 For personal use only.
Scand J Infect Dis 24
Serum curcinoemhryonic antigen 315
4. Miller RF. Mitchell D M . Management of respiratory failure in patients with the acquired immune deficiency syndrome and Pneumocystis carinii pneumonia. Thorax 45: 14G146, 1990. 5 , Wachter R M , Luce J M , Turner J, Volderbing P. Hopewell PC. Intensive care of patients with the acquired immunodeficiency syndrome: outcome and changing patterns of utilization. Am Rev Respir Dis 134: 891-896, 1986. 6. The National Institutes of Health-University of California Expert Panel for Corticosteroids as Adjunctive Therapy for Pneumocystis Pneumonia. Consensus statement on the use of corticosteroids as adjunctive therapy for Pneumocystis carinii pneumonia in the immunodeficiency syndrome. N Engl J Med 323: 150S1504, 1990. 7. Luce JM, Wachter R M . Hopewell PC. Intensive care of patients with the acquired immunodeficiency syndrome: time for a reassessment? Am Rev Kcspir Dis 137: 1261-1263, 1988. 8. El-Sadr W, Simberkoff MS. Survival and prognostic factors in severe Pneumocystis carinii pneumonia requiring mechanical ventilation. Am Rev Respir Dis 137: 1264-1267, 1988. 9. Efferen LS, Nadarajad D , Palat DS. Survival following mechanical ventilation for Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome: a different perspective. Am J Med 87: 401-404, 1989. 10. Kales CP. Murren J R , Torres R A , Crocco J A , Early predictors of in-hospital mortality for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Arch Intern Med 147: 1413-1417. 1987. 11. Garay SM, Greene J. Prognostic indicators in the initial presentation of Pneumocystis carinii pneumonia. Chest 95: 769-772, 1989. 12. Zaman MK, White D A . Serum lactate dehydrogenase levels and Pneumocystis carinii pneumonia: diagnostic and prognostic significance. Am Rcv Respir Dis 137: 79C800, 1985. 13. Mason G R , Hashimoto CH. Dickman PS. Foutty LF, Cobb CJ. Prognostic implications of bronchoalveolar lavage neutrophilia in patients with Pneumocystis carinii pneumonia and AIDS. Am Rev Respir Dis 139: 1336-1442, 1989. 14. Pascal R R , Mesa-Tejada R , Bennett SJ. Garces A , Fenoglio CM. Carcinoembryonic antigen. Arch Pathol Lab Med 101: 568-571, 1977. IS. Pusztaszeri G , Mach JP. Carcinoembryonic antigen (CEA) in non-digestive cancerous and normal tissues. Immunochemistry 10: 197-204, 1973. 16. National Institutes of Health Consensus Development Conference Statement. Carcinoembryonic antigen: its role as a marker in the management of cancer. Cancer Res 41: 2017-2018, 1981. 17. Biyoudi-Vouenze R , Tazi A , Hance AJ. Chastre J. Basset F, Soler P. Abnormal epithelial cells recovered by bronchoalveolar lavage: are they malignant? Am Rev Respir Dis 142: 686-690. 1990. 18. Weber T H , Kerttula Y . Carcinoembryonic antigen ( C E A ) in blood in cases of pneumonia. Scand J Infect Dis 18: 547-S50. 1986. 18a. Kupchik H Z . Zurawski VR. Hurrell JGR. Zamchek N, Black PH. Monoclonal antibodies to carcinoembryonic antigen produced by somatic cell fusion. Cancer Res 43: 3857-3864. 1981. 19. Montaner JSG, Lawson LM. Levitt N. Bclzberg A. Schechter MT. Ruedy J. Corticosteroids prevent carly deterioration in patients with moderately severe Pneumocystis carinii pncurnonia and the acquired immunodeficiency syndrome (AIDS). Ann Intern Med I13: 14-20, 1990. 20. Bozette SA, Sattler F R , Chiu J , Wu AW, Gluckstein D . Kemper C , Bartok A , Niosi J , Abramson I . Coffman J , Hughlett C. Loya R. Cassens B. Akil B. Meng TC, Boylen T, Nielsen D , Richman DD. Tilles J G , Leedon J. McCutchan J A and the California Collaborative Trcatrnent Group. A controlled trial of early adjunctivc treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 323: 1451-1457, 1990. 21. Gagnon S , Boota AM, Fischl M A . Baier H , Kirksey O W , La Voie L. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a double-blind, placebo-controlled trial. N Engl J Med 323: 14441450, 1990. 22. Said SI. Foda HD. Pharmacologic modulation of lung injury. Am Rev Respir Dis 139: 1553-1564. 1989. 23. Stockley R A , Shaw J , Whitfield A G W . Whitehead TP, Clarke C A , Burnett D. Effect of cigarette smoking. pulmonary inflammation, and lung disease on concentrations of carcinoembryonic antigen in serum and secretions. Thorax 41: 17-24. 1986. 24. Weber W, Askin F. Dehner L. Lung biopsy in Pneumocystis carinii pneumonia. Am J Clin Pathol 67: 11-19. 1577. 25. Henshaw N G , Carson J L , Collier AM. Ultrastructural observations in Pneumocystis carinii attachment to rat lung. J Infect Dis 151: 181-186, 1Y85. 26 Yoneda K, Walzer P D . Mechanism of pulmonary alveolar injury in experimental Pneumocystis carinii pneumonia in the rat. Br J Exp Pathol 62: 139-346, 1981. 27. Yoneda K, Walzer PD. Interaction of Pneumocystis carinii with host lungs: an ultrastructural study. Infect lmmun 29: 928. 1980.
Serum Carcinoembryonic Antigen: A Prognostic Marker in HIV-related Pneumocystis ca rinii Pneumonia JEAN-PIERRE BEDOS', CHANTAL HIGNETTE', JEAN-CHRISTOPHE LUCET', BADER KILANI'. ENRIQUE CASALINO', MICHEL WOLFF', SOPHIE MATHERON'. CATHERINE LEPORT' and FRANCOIS VACHON'
Scand J Infect Dis Downloaded from informahealthcare.com by Queen's University on 12/30/14 For personal use only.
From the Departments of 'Infectious and Intensive Cure Medicine and 'Nlrclear Medicine. Hopitul Bichat-Claude Bernard, Paris, France Serum concentrations of carcinoemhryonic antigen (CEA) were measured in 43 consecutive patients with HIV-related Pneumocystis carinii pneumonia (PCP). The subjects were divided into 2 groups according to the severity of the PCP: PaO, in ambient air (AA) 5 50 mmHg on admission ( n = 22, group 1) and PaO, > 50 mmHg ( n = 21, group 2). In addition, 57 HIV patients with either non-PCP pulmonary diseases ( n = 34, group 3) or extrapulmonary disease ( n = 23, group 4) were studied. Mean CEA levels (ng/ml) were 13 f 10 in group I and 4.9 k 5.5 in group 2 ( p < 0.001). The corresponding values in groups 3 and 4 were much lower (2.7 k 1.8 and 2.4 f 1.8, respectively). In group 1, mean initial CEA levels were higher (p < 0.001) in the patients who died ( n = 6; 23.5 & 11) than in the survivors (n = 16; 8.9 f 7), although the initial mean PaO, were identical (39 f 7 and 39 k 8 mmHg, respectively) and the initial mean LDH levels were not significantly different (1544 f 530 and 1200 2 457 IU/l). CEA levels fell during specific anti-PCP therapy associated with corticosteroids hut returned to normal only in the survivors. We conclude that CEA levels are increased in patients with PCP and acute respiratory distress. Among the patients with PaO, levels of 5 50 mmHg before treatment, only high levels of CEA (> 20 nglrnl) were associated with a fatal outcome, regardless of anti-PCP therapy associated with corticosteroids. The prognostic value of initial serum CEA levels suggested by these preliminary data should he taken into account in the prospective search for a specific severity index for patients with HIV-related PCP. Once identified, patients with a poor short-term prognosis could benefit from adapted therapeutic protocols.
J . P. Btdos, M D , Clinique de Riaanimation des Maladie7 Infectieuses, H6pital Bichat-Claude Bernard, 46, Rue Henri-Huchard, 75018 Paris, France
INTRODUCTION More than 60% of HIV-infected patients develop Pneumocystis carinii (PCP) pneumonia ( I ) . The mortality rate in primary episodes of PCP varies from 5 to 20% in the published serics (2-5). The corresponding figure in patients with acute respiratory distress rises to 1540°/0 (6) and to 80-90% in patients requiring respiratory assistance with intubation ( 7 ) , although recent reports have given more encouraging results, with a mortality rate < SOYO (8, 9). I n our intensive care unit specializing in infectious diseases, 67 patients with HIVrelated PCP and an initial PaOz in ambient air (AA) of 5 50 mmHg were admitted 1986-1990. All received specific anti-PCP treatment (generally cotrimoxazole), associated with corticosteroids and continuous positive airway pressure (CPAP) with a face mask. The overall mortality rate was 31Y0, but 80% of those requiring respiratory support with intubation died of respiratory failure. This underlines the need for specific gravity indices in this setting in order to adapt the treatment t o the individual short-term prognosis (treatment iit home, in hospital or in intensive care; adjuvant steroids for the prophylaxis of respiratory failure, with doses and duration of treatment adapted to the risk; new therapeutic approach). Various markers of poor prognosis at diagnosis and before treatment have been
Scand J Infect Dis Downloaded from informahealthcare.com by Queen's University on 12/30/14 For personal use only.
310 J.-P. Be'dos et al.
Scand J Infect Dis 24
forwarded (2, 10-13), including hypoxemia ( 5 50 mmHg in A A o r an alveolar-arterial oxygen gradient > 30 mmHg), elevated lactate dehydrogenase levels > 300 IUll, serum albumin (< 35 gll), and polynucleosis in the broncho-alveolar lavage (BAL) fluid > 5-10% in the absence of associated bacterial lung infection. Unfortunately, none of these factors, although they are correlated, shows a sufficiently high positive predictive value to predict unfavourable outcome in a given patient. Carcinoembryonic antigen (CEA) is a glycoprotein belonging to the class of oncofetal antigens. It is synthesized by fetal tissues of endodermic origin (14), particularly the lung, liver, pancreas and intestines (15). In the adult, C E A is used as a serum tumor marker (16), although it is known to give false-positive results in patients with inflammatory lung diseases (17), and levels can be high in bacterial pneumonia (18). The aims of this study were to detect a possible initial increase in CEA levels in patients with HIV-related PCP and to determine whether the initial serum C E A value prior to treatment was related to the mortality, particularly in patients with severe PCP in terms of PaO, in A A (550 mmHg). We also followed the variations in serum CEA levels during anti-PCP therapy. MATERIALS AND METHODS Parient population 100 consecutive HIV-infected patients seen at the HBpital Bichat-Claude Bernard were included in the study. Primary PCP was the only active disease in 43 patients. There were 37 males and 6 females. The risk factors for HIV infection were homosexuality ( n = 21). bisexuality ( n = 6 ) , intravenous drug abuse ( n = 14) and blood product transfusion ( n = 2). HIV infection was diagnosed on the basis of tests for specific antibodies. 22 patients (mean age f SD: 38 f 10 years) had a PaO, in AA of 5 50 mmHg at diagnosis of PCP (group I ) ; the remaining 21 PCP patients (mean age 34 t 7 years) had PaO, values > 50 mmHg in the same conditions of measurement (group 2). All the group 1 patients were treated with cotrimoxazole associated with a 9-day course of adjuvant steroids (methylprednisolone intravenously (iv), 240 mg. 120 mg and 60 mg for 3 days each). Group 2 patients received cotrimoxazole alone. Seven group 1 patients were intubated and ventilated either immediately or after failure of CPAP; the remaining 15 patients received continuous CPAP for a mean period of 4.8 f 3.7 days. Group 2 patients received nasal oxygen therapy. Survivors were defined by the resolution of the acute respiratory distress in terms of clinical signs, blood gases and discharge from the intensive care unit; non-survivors were patients who died of acute respiratory failure. Group 3 consisted of 34 HIV-infected patients with pulmonary diseases other than PCP of varying seriousness (bacterial pneumonia, n = 18; acute respiratory distress syndrome secondary to septic shock of bacterial origin, n = 5; Kaposi's sarcoma, n = 3; pulmonary lymphoma, n = 3; disseminated toxoplasmosis, n = 2; pulmonary tuberculosis, n = 1; cytomegalovirus pneumonia, n = 1; cotrimoxazole immuno-allergic pneumonia, n = 1). Group 4 consisted of 23 HIV-infected patients with extra-pulmonary diseases (cerebral toxoplasmosis, n = 11; lymphoma, n = 4; non-obstructive cardiomyopathy, n = 4; E. coli meningitis, n = 1 ; pyelonephritis, n = I ; tuberculous meningitis, n = 1; Streptococcus pneumoniae pericarditis, n = 1).
Diagnostic approach PCP was diagnosed by the direct identification of P. carinii with Gomori-Grocott staining in the BAL fluid obtained during fiberoptic bronchoscopy, or by the detection of typical cysts in tracheal secretions obtained by the induced sputum technique (3 patients). All the patients with PCP (groups 1 and 2) were evaluated on admission according to the same criteria, comprising simplified acute physiologic score (SAPS) in case of admission to the ICU, time between the presenting symptoms of PCP (cough, fever, dyspnea) and the diagnosis, smoking habits (number of pack years), weight loss, history of chronic lung disease or bowel disease, serum albumin level, total white cell and CD4+ lymphocyte counts, arterial blood gases in AA, LDH level, and serum CEA level. In group 1, arterial blood gases under 100% oxygen through a face mask were determined on admission, LDH and CEA were also determined on days 7 and 14. In group 2, LDH and CEA blood levels were determined only at the admission time. CEA was determined in group 3 before starting specific therapy and in group 4 during therapy. Post-mortem examination of the 6 patients who died included histological examination of the lungs.
Serum carcinoenihryonic antigerz 31 1
Scand J Infect Dis 24
Table I . Base-line characteristics of the 43 PCP putrents according to the PaO, at adniission Group 1 ( n
=
22)
Scand J Infect Dis Downloaded from informahealthcare.com by Queen's University on 12/30/14 For personal use only.
Time since onset of pulmonary symptoms (days) 17k I 1 Weight loss (kg) -7.8k5.8 Smoking (pack years) Ilk13 Albumin (g/l) 2.5.6k6.9 Totnl lymphocytes (/kl) 76Xt612 CD4+ lymphocytes (/PI) 86k102 LDH (IUII) 1298+492 39f7 Arterial PO1 in room air (inmHg)
Group 2 ( n = 21) 17kll
-7.4+5 1758 27.1k6.3 994k772
78*96 952 f 414" 62 k 8''
" p < 0.05, " p < 0.001
CEA determination CEA was assayed in serum by mcans of a solid-phase sandwich-type immunoradiometric method (IRMA. Kit ELISA 2 C E A . CIS Bioindustries) The usual values for normal subjects (blood donors) in our laboratory is 5 5 ng/ml (18a).
Serirrii
Srullsrics All clinical and laboratory data are given as mcan f standard deviation. Data were analysed using Student's f-test or the Mann-Whitney U-tcst and Spearman's rank correlation. The threshold of significance was set at p < 0.05.
~ i g I. . Mean C E A serum levels
in groups 1 4 .
CEA (ng/ml)
25
15
10
5 0
Gr 1
Gr 2
Gr 3
Gr 4
11-22 pts
n=21 pts
n 9 4 pts
n=23 pts
312 J.-P. Bidos et al.
Scand J Infect Dis 24
Table 11. Clinical and laboratory data for patients with severe PCP (PaO, 5 50 mmHg A A ) according to outcome. SAPS
=
simplified acute physiologic score
Scand J Infect Dis Downloaded from informahealthcare.com by Queen's University on 12/30/14 For personal use only.
Survivors ( n = 16) 37+8 Age (years) 9213 Smoking (pack years) Time since onset of pulmonary symptoms (days) 1 6 i l l -7.9f6 Weight loss (kg) 8+4 SAPS 28.4k3.9 Albumin (g/l) Total lymphocytes (/PI) 866f648 1062 112 CD4+ lymphocytes (/PI) Arterial PO, in room air (mmHg) 39i8 2S3+ 114 Arterial POz 100%,FiOz LDH (IU/I) 12002457 CEA (ngiml) 8.9f6
Non survivors (n = 6) 41 2 14 15f14 18211 -7.5f3 llf4 21.4k8.5 505f447 29f25 3927 194273 1544k530 23.5211"
" p= 0.008
RESULTS 37 of the 43 patients with primary PCP survived. The 6 deaths occurred among group 1 patients and were due to respiratory failure in spite of ventilation. The mortality rate was 14% overall, 27% in the patients with acute respiratory distress and 80% in the patients requiring intubation. The base-line characteristics of the 43 patients according to the PaO, cut-off are given in Table I. As shown in Fig. 1, the mean C E A serum level was significantly higher in group 1 than in group 2 (13 i 10 vs 4.9 S 5.7 ng/ml;p < 0.001); the corresponding values in groups 3 and 4 were low (2.7 S 1.8 and 2.4 t 1.8 ng/ml, respectively). The mean C E A serum level was significantly higher in the patients with PCP than in those with other pulmonary diseases (group 1 and 2: 8.8 4 9, group 3: 2.7 f 1.8; p < 0.001). When the various clinical and biological parameters were compared between patients with severe PCP (group 1) who died and those who survived, only C E A was significantly different (23.5 +_ 11 vs 8.9 S 6; p < 0.008) (Table 11). C E A levels differed significantly throughout treatment in group 1 patients, LDH levels also at day 7 (Table 111). Regardless of the baseline value, C E A levels progressively decreased towards normal during treatment, particularly in the survivors. The mean CEA serum level remained higher at day 7 (p = 0.054) and significantly so at day 14 (p = 0.03). The mean C E A serum level at the time of death in the 6 group 1 patients was 11.2 k Table 111. Serum L D H and CEA levels during treatmentfor severe PCP according to outcome Day of study
Survivors ( n = 16)
Non survivors ( n = 6)
P
LDH (lU/l)
DO D7 D14
1200+457 775 2203 9322366
1544f 530 1194k568 908t425
NS 0.008 NS
CEA (ng/ml)
DO D7 D14
8.926 1027.6 7.4k5
23.5k11 18k7 15.728.4
0.0028 0.054 0.03
ScanJ J lntect Dis 24
Serum carcinoernbryonic uritigen
Scand J Infect Dis Downloaded from informahealthcare.com by Queen's University on 12/30/14 For personal use only.
5.5 ng/ml, with a mean time since diagnosis of23 f 7 days. Postmortem pulmonary histology in thcse patients showed edematous and diffuse collagen fibrosis in every case, florid PCP in 4. numerous cytomegalovirus inclusion bodies in 2, disseminated cryptococcosis in 1 and pulmonary aspergillosis in 1. C E A would not appear to be a marker of irreversible pulmonary fibrosis, since its level fell as the fibrosis developed. With regard to the changes in LDH levels, the fall in the mean level between day 0 and day 7 was significant for the group 1 survivors (1200 k 457 vs 755 k 203 IUA; p = 0.0028), but not for the 6 patients who died. There was no correlation between CEA levels in group 1 (PaO, A A 5 mmHg) and other parameters (SAPS, LDH, PaO,, total and CD4+ lymphocytes, albumin). DISCUSSION The risk of death increases in patients with HIV-related PCP according to the degree of hypoxemia in room air on admission. With a PaO? of 70 mmHg, the risk is about 15%, and increases to 4(b50% with a PaO, of 5 50 mmHg (6). Recent randomized studies (19-21) have shown the beneficial effect of early corticosteroid therapy (starting 2 4 7 2 h after initiating anti-PCP treatment) on the progression of patients with moderate o r severe PCP towards acute respiratory failure and death. In the studies by Bozette et al. (20) and Gagnon et al. (21). the mortality rate among patients with severe PCP remained high (20 and 25%, respectively), despite the administration of adjuvant steroids within 72 h. These findings show the importance of identifying PCP patients with a high risk of death despite appropriate specific therapy and adjuvant steroids. This would permit more aggressive management at an early stage, particularly with regard to steroid treatment (higher doses, longer duration, different daily dosage schedule) and the administration of drugs to counteract the deleterious effects of cytokines and other mediators on the lung tissue (22). Indeed. even high-dose "salvage" steroid regimens appear unable to prevent the death of these patients in the terminal phase (20). High C E A levels have been reported in the context of pneumonia due to various infective agents (18), but not P. carinii. In our study. the mean C E A serum level was higher in thc patients with PCP than in HIV-infected patients with other pulmonary or extrapulmonary diseases. This increase would appear to be specific for PCP, particularly in the more severe forms. i.e. group 1, and was associated with an increase in LDH levels and a fall in PaO, which were significantly greater than in the PCP patients without acute respiratory distress (group 2). The other clinical and biological parameters were not significantly different. Although smoking can lead to a rise in C E A levels, there was no correlation here between the number of pack years and C E A levels; in addition, all the smokers in this study had stopped at least 3 weeks prior to admission. We found no evidence of chronic lung disease or liver. colon o r pancreatic illness which could have accounted for an increase in CEA levels. Analysis of the initial predictive factors in the group of patients with severe PCP gave interesting results. Only the initial C E A serum level was associated with a fatal outcome. The following parameters showed no difference between the subgroups of patients who survived and those who died (Table 11): time between onset of symptoms and diagnosis, weight loss, SAPS, hypoalbuminemia, total and CD4+ lymphocyte counts, LDH increase, PaO, in room air, pulmonary shunt in terms of PaO, (FiO, 100%). The mortality rate among patients with an initial C E A serum level > 20 ng/ml was 80%. In contrast, 88% of the patients with C E A levels of 5 20 ng/ml survived. Only 2 patients with C E A levels > 20 ngirnl survived. In one case, PCP was the presenting illness of AIDS: the initial PaO, was 31 mmHg in room air and the initial C E A level was 24.6 ng/ml. This patient was in a very good overall condition and underwent 10 days of continuous CPAP with a face mask (+ 6 to + 12 cm HzO), with an FiOz of 60%. Chest X-rays showed the presence of bullous lung de-
3 13
Scand J Infect Dis Downloaded from informahealthcare.com by Queen's University on 12/30/14 For personal use only.
314 J.-P. Be'dos et al.
Scand J Infect Dis 24
struction, with a voluminous compressive bulla which required surgical treatment. Histological examination of pulmonary tissue obtained during surgery showed a large number of P. carinii cysts, together with edematous and diffuse collagen fibrosis. It is interesting to note the progression of C E A serum levels during treatment: 16.2 nglml at day 14,5.3nglml at day 33 (surgery) and 1.9 ng/ml at day 45, with a concomitant PaO, in room air of 75 mmHg. PCP was also the presenting illness of AIDS in the second patient. The initial PaO, in room air was 56 mmHg and the CEA serum level was 25.2 ng/ml. The patient was a smoker (2 pack years) and had no liver, intestinal or pancreatic illness. At day 14 of treatment the PaO, in room air was 112 mmHg and the C E A level 20.1 ng/ml. The patient is currently undergoing tests to detect a suspected neoplastic disease, as the C E A remained high although the outcome of the PCP was favorable. The reasons for the initial increase in C E A levels during severe PCP are not clear. The histology of PCP usually consists of an accumulation of a foamy intraalveolar exudate, with an interstitial mononuclear cell infiltrate (24). P. carinii binds to type-I pneumocytes, probably for its nutrition and growth (25). The damage to the type-I pneumocyte is followed by the denudation of the basement membrane (26). Hypertrophic changes of alveolar type-I1 pneumocytes are a host reparative response to alveolar injury by P. carinii (diffuse alveolar damage) (27). The increase in C E A levels might reflect this alveolar damage, with dedifferentiation of pulmonary alveolar cells (particularly type-I1 pneumocytes) and the reappearance of oncofetal proteins such as CEA. High serum levels of CEA could reflect a high parasitic inoculum and/or particularly high virulence leading to extensive changes in alveolar epithelial cells. Indeed, immunostaining of airway cells with anti-CEA antibodies has been described in areas of regenerating airway epithelium (17). The passage of C E A into the serum could result from the increased permeability of the alveolo-capillar membrane observed in PCP (26). The initial elevation of C E A serum levels would appear to reflect the active phase of conflict between the parasite and the alveolar epithelium. The decrease observed during treatment would reflect the efficacy of specific anti-PCP treatment, regardless of the secondary progression towards pulmonary fibrosis consecutive to the initial deleterious injury. Despite the fall in C E A during treatment, a high level at day 14 was associated with a poor vital prognosis. Similarly, as reported by other authors (S), a high LDH level at day 7 was also a factor indicating a poor prognosis. In conclusion, we have found that C E A serum levels change during severe PCP. C E A appears to be a marker of the initial conflict between the parasite and alveolar epithelial cells. Among our patients with a PaO, of 5 SO mmHg at A A before treatment, only a high serum level of C E A (> 20 ng/ml) was associated with a fatal outcome, despite specific treatment and associated steroid therapy. Assays of initial C E A levels are relatively easy to obtain and should be integrated into prospective studies to identify a specific gravity index for patients with HIV-related PCP. This will enable new therapeutic protocol to be developed and applied at an early stage for patients with a particularly poor short-term prognosis. REFERENCES Glatt AE, Chirgwin K , Landesman SH. Treatment of infections associated with human immunodeficiency virus. N Engl J Med 318: 439448, 1988. Brenner M, Ognibene FP, Lack EE, Simmons JT. Suffredini AF, Lane MC, Fauci AS, Parillo JE, Shelhamer JH, Masur H. Prognostic factors and life expectancy of patients with acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia. Am Rev Respir Dis 136: 1199-1206, 1987. Gazzard BG. Pneurnocystis carinii pneumonia and its treatment in patients with AIDS. J Antimicrob Chemother 23, Suppl A: 67-75, 1989.
Scand J Infect Dis Downloaded from informahealthcare.com by Queen's University on 12/30/14 For personal use only.
Scand J Infect Dis 24
Serum curcinoemhryonic antigen 315
4. Miller RF. Mitchell D M . Management of respiratory failure in patients with the acquired immune deficiency syndrome and Pneumocystis carinii pneumonia. Thorax 45: 14G146, 1990. 5 , Wachter R M , Luce J M , Turner J, Volderbing P. Hopewell PC. Intensive care of patients with the acquired immunodeficiency syndrome: outcome and changing patterns of utilization. Am Rev Respir Dis 134: 891-896, 1986. 6. The National Institutes of Health-University of California Expert Panel for Corticosteroids as Adjunctive Therapy for Pneumocystis Pneumonia. Consensus statement on the use of corticosteroids as adjunctive therapy for Pneumocystis carinii pneumonia in the immunodeficiency syndrome. N Engl J Med 323: 150S1504, 1990. 7. Luce JM, Wachter R M . Hopewell PC. Intensive care of patients with the acquired immunodeficiency syndrome: time for a reassessment? Am Rev Kcspir Dis 137: 1261-1263, 1988. 8. El-Sadr W, Simberkoff MS. Survival and prognostic factors in severe Pneumocystis carinii pneumonia requiring mechanical ventilation. Am Rev Respir Dis 137: 1264-1267, 1988. 9. Efferen LS, Nadarajad D , Palat DS. Survival following mechanical ventilation for Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome: a different perspective. Am J Med 87: 401-404, 1989. 10. Kales CP. Murren J R , Torres R A , Crocco J A , Early predictors of in-hospital mortality for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Arch Intern Med 147: 1413-1417. 1987. 11. Garay SM, Greene J. Prognostic indicators in the initial presentation of Pneumocystis carinii pneumonia. Chest 95: 769-772, 1989. 12. Zaman MK, White D A . Serum lactate dehydrogenase levels and Pneumocystis carinii pneumonia: diagnostic and prognostic significance. Am Rcv Respir Dis 137: 79C800, 1985. 13. Mason G R , Hashimoto CH. Dickman PS. Foutty LF, Cobb CJ. Prognostic implications of bronchoalveolar lavage neutrophilia in patients with Pneumocystis carinii pneumonia and AIDS. Am Rev Respir Dis 139: 1336-1442, 1989. 14. Pascal R R , Mesa-Tejada R , Bennett SJ. Garces A , Fenoglio CM. Carcinoembryonic antigen. Arch Pathol Lab Med 101: 568-571, 1977. IS. Pusztaszeri G , Mach JP. Carcinoembryonic antigen (CEA) in non-digestive cancerous and normal tissues. Immunochemistry 10: 197-204, 1973. 16. National Institutes of Health Consensus Development Conference Statement. Carcinoembryonic antigen: its role as a marker in the management of cancer. Cancer Res 41: 2017-2018, 1981. 17. Biyoudi-Vouenze R , Tazi A , Hance AJ. Chastre J. Basset F, Soler P. Abnormal epithelial cells recovered by bronchoalveolar lavage: are they malignant? Am Rev Respir Dis 142: 686-690. 1990. 18. Weber T H , Kerttula Y . Carcinoembryonic antigen ( C E A ) in blood in cases of pneumonia. Scand J Infect Dis 18: 547-S50. 1986. 18a. Kupchik H Z . Zurawski VR. Hurrell JGR. Zamchek N, Black PH. Monoclonal antibodies to carcinoembryonic antigen produced by somatic cell fusion. Cancer Res 43: 3857-3864. 1981. 19. Montaner JSG, Lawson LM. Levitt N. Bclzberg A. Schechter MT. Ruedy J. Corticosteroids prevent carly deterioration in patients with moderately severe Pneumocystis carinii pncurnonia and the acquired immunodeficiency syndrome (AIDS). Ann Intern Med I13: 14-20, 1990. 20. Bozette SA, Sattler F R , Chiu J , Wu AW, Gluckstein D . Kemper C , Bartok A , Niosi J , Abramson I . Coffman J , Hughlett C. Loya R. Cassens B. Akil B. Meng TC, Boylen T, Nielsen D , Richman DD. Tilles J G , Leedon J. McCutchan J A and the California Collaborative Trcatrnent Group. A controlled trial of early adjunctivc treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 323: 1451-1457, 1990. 21. Gagnon S , Boota AM, Fischl M A . Baier H , Kirksey O W , La Voie L. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a double-blind, placebo-controlled trial. N Engl J Med 323: 14441450, 1990. 22. Said SI. Foda HD. Pharmacologic modulation of lung injury. Am Rev Respir Dis 139: 1553-1564. 1989. 23. Stockley R A , Shaw J , Whitfield A G W . Whitehead TP, Clarke C A , Burnett D. Effect of cigarette smoking. pulmonary inflammation, and lung disease on concentrations of carcinoembryonic antigen in serum and secretions. Thorax 41: 17-24. 1986. 24. Weber W, Askin F. Dehner L. Lung biopsy in Pneumocystis carinii pneumonia. Am J Clin Pathol 67: 11-19. 1577. 25. Henshaw N G , Carson J L , Collier AM. Ultrastructural observations in Pneumocystis carinii attachment to rat lung. J Infect Dis 151: 181-186, 1Y85. 26 Yoneda K, Walzer P D . Mechanism of pulmonary alveolar injury in experimental Pneumocystis carinii pneumonia in the rat. Br J Exp Pathol 62: 139-346, 1981. 27. Yoneda K, Walzer PD. Interaction of Pneumocystis carinii with host lungs: an ultrastructural study. Infect lmmun 29: 928. 1980.
