410
fraction of the oral dose escaping the first-pass hepatic extraction and therefore entering the peripheral circula-
LEGIONNAIRES’ DISEASE IN RENAL-TRANSPLANT RECIPIENTS
same for doses of 10 mg, 20 mg, and 40 mg. Our study, in which propranolol blood-levels measured by conventional fluorometry and gas-liquid chromatography have been compared, strongly supports the
tion is the
questioning by Chidsey et al.25 and Gomeni et al. 16 of the significance of the oral-threshold concept for drugs undergoing first-pass effect. We might possibly be criticised for using a pharmacological, rather than a physiological, method to assess beta-blockade. The physiological stimuli customarily used to assess beta-blockade are tilt and exercise tachycardia ; however, there is evidence that neither of these stimuli acts only through beta-adrenoreceptors, and alterations in vagal tone probably explain why even very large doses of propranolol block only 35-95% of the maximum heart-rate response to exercise.27 Inhibition of exercise-induced tachycardia is undoubtedly useful in assessing beta-blockade in angina; but its relevance is less certain for some other disorders, such as hypertension, and the therapeutic response in these conditions is usually assessed with the patient at rest. Moreover, the suppression by beta-blockade of the tachycardia associated with motor-car driving is much more closely related to the suppression of tachycardia induced by isoprenaline than by exercise.28 In this study the use of isoprenaline enables the action of propranolol on cardiac, vascular, and renal receptors to be assessed. Moreover, the modification by propranolol of the- isoprenaline response relates well to its action on basal heart-rate, P.R.A., and arterial pressure. It might be argued that the falls in basal heart-rate and arterial pressure that we have observed after propranolol are due to placebo effect or are exaggerated by anxiety in the control study. However, for each -subject we have defined these basal values from both the control isoprenaline infusion and from a subsequent study done after the 5 mg propranolol study, when anxiety would have been minimised. Furthermore, the striking reduction of responsiveness to isoprenaline and the pronounced falls in basal P.R.A. provide parallel confirmatory evidence for beta-blockade. Although we show clear evidence of beta-blockade with a very low dose of propranolol, we are unable, at this preliminary stage, to define fully the clinical relevance of our findings. However, these data suggest that lower doses than are commonly used might be effective in therapy of ischsemic heart-disease and/or hypertension. Certainly both basal heart-rate and P.R.A. and their
responsiveness to isoprenaline are strikingly diminished at this dose, and this effect was associated with a slight fall of arterial pressure. Moreover, if these findings are confirmed in patients with hypertension, the low-dose effects of propranolol may yield clues to the various mechanisms by which this agent lowers blood-pressure. R. D. was in receipt of the Berkeley fellowship and a Wellcome research travel grant. We thank Pamela Peters, R.N., and Patricia Sullivan, R.N., for their help. We are grateful to Henry L. Le Mein, Jr, of Ayerst Laboratories for arranging the fluorometric propranolol determinations.
Requests for reprints should be addressed to R. D., Cobbold Laboratories, Middlesex Hospital Medical School, London WIN 8AA.
BARBARA D. KIRBY BONNIE V. BOCK WILLIAM L. GEORGE PAUL H. EDELSTEIN MILTON L. OWENS KIM M. SNYDER CHARLES E. HALEY CAROLE M. HATAYAMA RICHARD D. MEYER ROBERT P. LEWIS SYDNEY M. FINEGOLD
Infectious Disease Section, Research and Medical Services, Renal Transplant Section, Surgical Service, Pathology Service, Wadsworth Veterans Administration Hospital, Los Angeles Departments of Medicine and Surgery, University of California, Los Angeles, California Field Services Division, Bureau of Epidemiology, Center for Disease Control, Department of Health, Education and Welfare, Atlanta, Georgia California Department of Health, Berkeley, California
Legionnaires’ disease is reported in five renal-transplant recipients. All had febrile respiratory illnesses with pulmonary infiltrates and one died. The diagnosis was made on clinical features and by indirect fluorescent antibody titres. Symptoms started after maximum immunosuppressive therSummary
apy.
Introduction LEGIONNAIRES’ disease (L.D.) is a systemic illness, presumably airborne, and is manifested primarily by pneumonia.1,2 There have been sporadic cases in both
DR DAVIES AND OTHERS: REFERENCES 1. 2.
B. N.
Pritchard, C., Gillam, P. M. S. Br. med. J. 1969, i, 7. Gibson, D., Sowton, E. Prog. cardiovasc. Dis. 1969, 12, 16.
Pritchard, B. N. C. Drugs, 1974, 7, 55. Hadden, D. R., Montgomery, D. A. D., Shanks, R. G., Weaver, J. A. Lancet, 1968, ii, 852. 5. Turner, P., Granville-Grossman, K. L., Smart, J. V. ibid. 1965, ii, 1316. 6. Widero, T. E., Vigander, T. Br. med. J. 1974, ii, 699. 7. Leonetti, G., et al. Clin. Sci. mol. Med. 1975, 48, 491. 8. Pine, M., Favrot, L., Smith, S., McDonald, K., Chidsey, C. A. Circulation, 1975, 52, 887. 9. Frishman, W., Smithen, C., Killip, T. Am. J. Cardiol. 1974, 33, 1937 10. Shand, D. G., Nuckolls, E. M., Oates, J. Clin. Pharmac. Ther. 1970, 11, 3. 4.
112.
Paterson, J. W., Conolly, M. E., Dollery, C. T., Hayes, A., Cooper, R. Pharmac. clinica, 1970, 2, 127. 12. Evans, G., Shand, D. G. Clin. Pharmac. Ther. 1973, 14, 487. 13. Shand, D. G. N. Engl. J. Med. 1975, 293, 280. 14. Chidsey, C. A., Morselli, P., Bianchetti, G., Morganti, A., Leonetti, G., Zanchetti, A. Circulation, 1975,52,313. 15. DiSalle, E., Baker, K. M., Bareggi, S. R., Watkins, W. D., Chidsey, C. A., Frigerio, A., Morselli, P. J. Chromatog. 1973, 84, 347. 16. Gomeni, R., Bianchetti, G., Sega, R., Morselli, P. L. J. Pharmacokin. Biopharmac. 1977, 5, 183. 17. Davies, R., Slater, J. D. H. Lancet, 1976, ii, 594. 18. Davies, R., Slater, J. D. H., Rudolf, M., Geddes, D. M. Clin. Endocr. 1977, 11.
6, 345. Sealey, J. E , Laragh, J. H. Semin. nucl. Med. 1975, 5, 183. George, C. F., Fenyvesi, T., Dollery, C. T. in Biological Effects of Drugs in Relation to their Plasma Concentration. (edited by D. S. Davis and B. N. C. Prichard). Maryland, 1973. 21. Alderman, A. F., Davis, R. O., Crowley, J. J. Circulation, 1975, 51, 964. 19. 20.
22. Nies, A. S., Shand, D. G. ibid. 1975, 52, 6. 23. Shand, D. G. Postgrad. med. J. 1976, 52 (suppl. 4), 22. 24. Michelakis, A. M., McAllister, R. G. J. clin. Endocr. 1972, 34, 386. 25. Chidsey, C. A., Pine, M., Favrot, L., Smith, S., Leonetti, G., Morselli, P., Zanchetti, A. Postgrad. med. J. 1976, 52 (suppl. 4), 26. 26. Cleaveland, C. R., Shand, D. G. Clin. Pharmac. Ther. 1972, 13, 181. 27. Epstein, S. E., Robinson, B. F., Kahler, R. L., Braunwald, E. J. clin. Invest. 28.
1965, 44, 1945. Taylor, S. H., Meeran, M. K. Br. med. J. 1973, iv, 257.
411
America and Europe, and several epidemics of
disease with a significant mortality rate.2-6 incubation period of 2-10 days, the patient usually has fever, malaise, myalgia, and headache.1,2 Within a week a consolidated pneumonia develops although some patients may have only an interstitial infiltrate.2,3The causative agent is a small, pleomorphic gram-negative bacillus which requires special media and conditions for growth.’-9 It has been isolated from pleural fluid and lung tissue.3 Diagnosis is usually made on a fourfold rise in the indirect fluorescent antibody (LF.A.) titre in serum, or on a single titre of 1/128 or more.9 Cultured organisms often stain with gram stain, but those found in bodyfluids or in histological sections cannot usually be stained by standard techniques. The Dieterle silverimpregnation stain and direct fluorescent antibody (D.F.A.) techniques have been useful for detecting the organism in lung tissue. 10, 11 The Center for Disease Control (C.D.C.) has given preliminary reports of L.D. in several patients with impaired host defences.12,13 We report five other instances
respiratory After
patient gradually improved and was well when last seen January,1978. The
severe
an
in
Case 2 man received a renal transplant on Aug. 20, treated with 200 mg azathioprine and 50 mg prednisone per day. He had diarrhoea for 4 days from Aug. 25. On Sept. 1 he had hxmoptysis and myalgia. His temperature was 38.0°C, pulse 100/min, and respiratory rate 20/min. Rales, rhonchi, wheezes, and dullness to percussion were present at his right lung base. Bilateral lower lobe infiltrates were seen on chest X-ray. The W.B.C. was 13 100/µl (94% neutrophils), serum creatinine 0.9mg/dl, Pa02 82 mm Hg on room air. Gram stain of a T.T.A. revealed rare gram-negative bacilli. The patient did not respond to carbenicillin, 20 g per day, and gentamicin, 4.5 mg/kg per day, which were given from Sept. 2. Ampicillin, 6 g per day, was substituted from Sept. 5, when Haniophilus influenzce was grown on culture. The dose of’
A
49-year-old
1977, and
was
immunosuppressives was reduced. On Sept. 4, his temperature was 39.1°C and bronchoscopy was non-diagnostic. The next day the infiltrates were more extensive (fig. 1). An open lung biopsy showed a consolidated pneumonia of the right lower lobe. Histological examination showed interstitial and acute bronchopneumonia (fig. 2).
in renal-transplant recipients. The new Wadsworth Veterans Administration Hospital building opened in March, 1977. Nine patients
received allogeneic renal homotransplants between March and November; five had febrile respiratory illnesses and abnormal chest X-rays. When the diagnosis was not apparent from transtracheal aspiration and thoracentesis or on clinical grounds, bronchoscopy and open lung biopsy were carried out. Serum i.F.A. titres for L.D. were determined in the four patients without pneumonia; these titres were negative or insignificant.
Case-reports Case1 man had received a renal transplant on he was given 150 mg of azathioprine and 60. April 13, 1977, of prednisone per day. Methylprednisolone, 1 g per day, mg was given on May 6-8 for graft rejection. On May 13, he had headache, nasal congestion, dry cough, and a temperature of 38.9°C; the next day he had pleuritic pain and chills. His tem-
After
a
40-year-old
39-4°C, pulse 110/min; dullness to percussion, perature increased tactile fremitus, and rales were present at the base was
of the left lung. Chest X-ray showed a perihilar infiltrate which progressed over the next 3 days. The white blood-cell count was 5600/µl. A few gram-negative bacilli were seen in a transtracheal aspirate (T.T.A.), but aerobic, anaerobic, and fungal cultures were negative. A few bacilli were also seen in bronchial washings stained by Gomori methenamine silver. Co-trimoxazole (600 mg trimethoprim and 3 - 0 g sulphamethoxazole) per day was begun on May 16 for 6 days, followed by sulphadiazine 4 g per day for 5 days. Azathioprine was discontinued and prednisone was reduced to 20 mg per day. Open lung biopsy on May 17 revealed an acute bronchopneumonia and interstitial fibrosis. No Pneumocystis carinii or viral inclusion bodies were seen. Gram stain and acid-fast stains were negative, as were all cultures for bacteria. Benzylpenicillin, 6 million units per day, was given for 10 days. Cytomegalovirus (c.M.v.) was grown; c.M.v. titres were 1/128 on May 31 and 1/256 on Aug. 15. He became afebrile a week after the open lung biopsy, and the infiltrate cleared after a month. A very small section of lung stained by Dieterle and D.F.A. stains at the C.D.C. was negative for L.D. bacillus. I.F.A. titres for L.D. in the patient’s serum were 1/64 on May 16, 1/256 on May 27, 1/128 on June 11, and 1/32 on Aug. 17.
1--Case 2: posterior-anterior chest lower-lobe infiltrates.
Fig.
X-ray, Sept. 5; bilateral
Fig. 2--Case 2: histopathological section (x2000) of biopsy, right lower lobe.
open
lung
’
412 Gram stain, Ziehl-Neelsen, and Gomori methenamine silver stains were negative, as were aerobic and anaerobic bacterial, fungal, and viral cultures. Later, the C.D.C. reported that the D.F.A. stain was negative for the L.D. bacillus. There was no growth on Mueller-Hinton agar supplemented with 1% haemoglobin and 1% ’IsoVitaleX’ (BBL)-a medium enrichment for fastidious microorganisms which contains vitamin
B,2, L-glutamine, adenine, guanine HCI, p-aminobenzoic acid, diphosphopyridine nucleotide, co-carboxylase, ferric nitrate, thiamine HC1, cysteine HC1, L-cystine, dextrose-incubated in air. On Sept. 14, I.F.A. titre for L.D. of serum drawn on Sept. 6 was positive in a dilution of 1/128, and 2 g of erythromycin per day was substituted for the ampicillin. The patient became afebrile after 5 days but received additional corticosteroids for mild graft rejection; the infiltrate resolved after 10 days. He received 3 weeks of erythromycin. Repeat I.F.A. titres on Sept. 15 and 30, and Oct. 15, were 1/512, 1/256, and 1/256 respectively. Renal function remained normal. On Oct. 13, he had a low-grade fever and a left upper-lobe infiltrate. There was no growth from a T.T.A. specimen. Cultures of a percutaneous and a second open lung biopsy specimen on Oct. 27 gave a moderate growth of Staphylococcus aureus. The Gomori methenamine silver stain was negative. Oxacillin 9 g per day was started, and erythromycin 2.0g per day was reinstituted. The patient became afebrile and continued to improve; he was discharged from the hospital on ’
Nov. 29.
Case 3 A
43-year-old
man
had
a
temperature of 384°C
on
Sept.
27, a week after unsuccessful treatment with methylprednisolone, 1 g per day, for rejection of his second renal transplant. He had herpetic lesions on the oral mucosa. Frontal headache, cough, malaise, diarrhoea, and a rapid rise of temperature to 41.1°C developed on Sept. 30. A turbid left pleural effusion showed 10 000 white cells/µl (89% neutrophils). All cultures and stains were negative. The next day his peripheral w.B.c. was 1200/µl and a hazy left upper-lobe infiltrate was noted. Bronchoscopy and open lung biopsy were done. Histological examination showed acute interstitial pneumonitis and bronchopneumonia. All standard stains and cultures were negative, as was a culture on supplemented Mueller-Hinton agar. The infiltrate extended to involve the entire left lung on Oct. 8. He was started on oxacillin, penicillin, and amikacin. Intubation and assisted ventilation were required for severe hypoxia. His temperature rose to 42.2°C, and he died on Oct. 9. At necropsy, lobar pneumonia was present in the left upper and lower lobes, and the right lower lobe. The left lung weighed 1540 g, the right 790 g. The alveoli were distended and filled with necrotic debris, neutrophils, fibrin strands, and erythrocytes. Subsequently, the C.D.C. reported that the D.F.A., and the Dieterle stain on lung tissue revealed many L.D. bacilli. An I.F.A. titre of serum drawn on Sept. 14 was nonreactive, but on Oct. 4, the titre was 1/128.
Case 4 A 57-year-old man received a renal transplant on Sept. 6, but poor function necessitated hxmodialysis. Methylprednisolone, 1 g per day, was given from Sept. 22 to 24. On Sept. 30, he had pleuritic pain, dyspnoea, malaise, and hxmoptysis. His temperature was 39-2°C and pulse 104/min. X-rays showed left upper-lobe and lingular infiltrates. W.B.C. was 8600/µl. Neutrophils and monocytes, but no bacteria, were seen on gram stain of a T.T.A. Erythromycin was given for 24 hours, but was then discontinued and amikacin, 5 mg per kg after each dialysis, and cephazolin, 500 mg per day, were substituted when gentamicin-resistant Klebsiella pneumonia was cultured. The dose of immunosuppressive agents was reduced. The patient’s sputum became purulent. He had hypotension and required respiratory support for several days. A smear
made from a 350 ml pleural effusion contained neutrophils and a few gram-negative rods. He responded to antibiotic therapy after 1 week, although the infiltrate resolved slowly. Cephazolin and amikacin were discontinued after 6 weeks. A transplant nephrectomy was performed on Nov. 25 because of rejection. A considerable rise in serum-alkaline-phosphatase (to 2068 LU.) appeared during October and persisted for 2 months. An I.F.A. titre on serum for L.D. drawn on Sept. 30 was 1/32; on Nov. 9 it was > 1/1024. Erythromvcin was then given.
Case 5 A 50-year-old man had a temperature of 389°C on Oct. 19, 6 days after a renal transplant. A diagnosis of rejection was made because of the presence of lymphocytes in the urine, deterioration in renal function, and a pleural effusion. This responded transiently to 1 g per day of methylprednisolone. The pleural effusion cleared and he became afebrile. On Oct. 26, oral prednisone, 40 mg per day, was begun. The patient had a nonproductive cough on Oct. 29. 2 days later his temperature was 40.0°C and a right lower-lobe infiltrate was seen on X-ray. Prednisone was reduced to 10 mg per day and haemodialysis was begun. On Nov. 2 right basilar rates were present. Culture of a T.T.A. did not grow any pathogens. 2 days later, 2 g/day of erythromycin was started. The chest X-ray cleared gradually but the patient remained febrile until
lymphocytic
after transplant nephrectomy was done when respiratory signs and symptoms had resolved by the middle of November. I.F.A. on Nov. 5, 1/128 on Nov. 9, and titres for L.D. were
fraction of the oral dose escaping the first-pass hepatic extraction and therefore entering the peripheral circula-
LEGIONNAIRES’ DISEASE IN RENAL-TRANSPLANT RECIPIENTS
same for doses of 10 mg, 20 mg, and 40 mg. Our study, in which propranolol blood-levels measured by conventional fluorometry and gas-liquid chromatography have been compared, strongly supports the
tion is the
questioning by Chidsey et al.25 and Gomeni et al. 16 of the significance of the oral-threshold concept for drugs undergoing first-pass effect. We might possibly be criticised for using a pharmacological, rather than a physiological, method to assess beta-blockade. The physiological stimuli customarily used to assess beta-blockade are tilt and exercise tachycardia ; however, there is evidence that neither of these stimuli acts only through beta-adrenoreceptors, and alterations in vagal tone probably explain why even very large doses of propranolol block only 35-95% of the maximum heart-rate response to exercise.27 Inhibition of exercise-induced tachycardia is undoubtedly useful in assessing beta-blockade in angina; but its relevance is less certain for some other disorders, such as hypertension, and the therapeutic response in these conditions is usually assessed with the patient at rest. Moreover, the suppression by beta-blockade of the tachycardia associated with motor-car driving is much more closely related to the suppression of tachycardia induced by isoprenaline than by exercise.28 In this study the use of isoprenaline enables the action of propranolol on cardiac, vascular, and renal receptors to be assessed. Moreover, the modification by propranolol of the- isoprenaline response relates well to its action on basal heart-rate, P.R.A., and arterial pressure. It might be argued that the falls in basal heart-rate and arterial pressure that we have observed after propranolol are due to placebo effect or are exaggerated by anxiety in the control study. However, for each -subject we have defined these basal values from both the control isoprenaline infusion and from a subsequent study done after the 5 mg propranolol study, when anxiety would have been minimised. Furthermore, the striking reduction of responsiveness to isoprenaline and the pronounced falls in basal P.R.A. provide parallel confirmatory evidence for beta-blockade. Although we show clear evidence of beta-blockade with a very low dose of propranolol, we are unable, at this preliminary stage, to define fully the clinical relevance of our findings. However, these data suggest that lower doses than are commonly used might be effective in therapy of ischsemic heart-disease and/or hypertension. Certainly both basal heart-rate and P.R.A. and their
responsiveness to isoprenaline are strikingly diminished at this dose, and this effect was associated with a slight fall of arterial pressure. Moreover, if these findings are confirmed in patients with hypertension, the low-dose effects of propranolol may yield clues to the various mechanisms by which this agent lowers blood-pressure. R. D. was in receipt of the Berkeley fellowship and a Wellcome research travel grant. We thank Pamela Peters, R.N., and Patricia Sullivan, R.N., for their help. We are grateful to Henry L. Le Mein, Jr, of Ayerst Laboratories for arranging the fluorometric propranolol determinations.
Requests for reprints should be addressed to R. D., Cobbold Laboratories, Middlesex Hospital Medical School, London WIN 8AA.
BARBARA D. KIRBY BONNIE V. BOCK WILLIAM L. GEORGE PAUL H. EDELSTEIN MILTON L. OWENS KIM M. SNYDER CHARLES E. HALEY CAROLE M. HATAYAMA RICHARD D. MEYER ROBERT P. LEWIS SYDNEY M. FINEGOLD
Infectious Disease Section, Research and Medical Services, Renal Transplant Section, Surgical Service, Pathology Service, Wadsworth Veterans Administration Hospital, Los Angeles Departments of Medicine and Surgery, University of California, Los Angeles, California Field Services Division, Bureau of Epidemiology, Center for Disease Control, Department of Health, Education and Welfare, Atlanta, Georgia California Department of Health, Berkeley, California
Legionnaires’ disease is reported in five renal-transplant recipients. All had febrile respiratory illnesses with pulmonary infiltrates and one died. The diagnosis was made on clinical features and by indirect fluorescent antibody titres. Symptoms started after maximum immunosuppressive therSummary
apy.
Introduction LEGIONNAIRES’ disease (L.D.) is a systemic illness, presumably airborne, and is manifested primarily by pneumonia.1,2 There have been sporadic cases in both
DR DAVIES AND OTHERS: REFERENCES 1. 2.
B. N.
Pritchard, C., Gillam, P. M. S. Br. med. J. 1969, i, 7. Gibson, D., Sowton, E. Prog. cardiovasc. Dis. 1969, 12, 16.
Pritchard, B. N. C. Drugs, 1974, 7, 55. Hadden, D. R., Montgomery, D. A. D., Shanks, R. G., Weaver, J. A. Lancet, 1968, ii, 852. 5. Turner, P., Granville-Grossman, K. L., Smart, J. V. ibid. 1965, ii, 1316. 6. Widero, T. E., Vigander, T. Br. med. J. 1974, ii, 699. 7. Leonetti, G., et al. Clin. Sci. mol. Med. 1975, 48, 491. 8. Pine, M., Favrot, L., Smith, S., McDonald, K., Chidsey, C. A. Circulation, 1975, 52, 887. 9. Frishman, W., Smithen, C., Killip, T. Am. J. Cardiol. 1974, 33, 1937 10. Shand, D. G., Nuckolls, E. M., Oates, J. Clin. Pharmac. Ther. 1970, 11, 3. 4.
112.
Paterson, J. W., Conolly, M. E., Dollery, C. T., Hayes, A., Cooper, R. Pharmac. clinica, 1970, 2, 127. 12. Evans, G., Shand, D. G. Clin. Pharmac. Ther. 1973, 14, 487. 13. Shand, D. G. N. Engl. J. Med. 1975, 293, 280. 14. Chidsey, C. A., Morselli, P., Bianchetti, G., Morganti, A., Leonetti, G., Zanchetti, A. Circulation, 1975,52,313. 15. DiSalle, E., Baker, K. M., Bareggi, S. R., Watkins, W. D., Chidsey, C. A., Frigerio, A., Morselli, P. J. Chromatog. 1973, 84, 347. 16. Gomeni, R., Bianchetti, G., Sega, R., Morselli, P. L. J. Pharmacokin. Biopharmac. 1977, 5, 183. 17. Davies, R., Slater, J. D. H. Lancet, 1976, ii, 594. 18. Davies, R., Slater, J. D. H., Rudolf, M., Geddes, D. M. Clin. Endocr. 1977, 11.
6, 345. Sealey, J. E , Laragh, J. H. Semin. nucl. Med. 1975, 5, 183. George, C. F., Fenyvesi, T., Dollery, C. T. in Biological Effects of Drugs in Relation to their Plasma Concentration. (edited by D. S. Davis and B. N. C. Prichard). Maryland, 1973. 21. Alderman, A. F., Davis, R. O., Crowley, J. J. Circulation, 1975, 51, 964. 19. 20.
22. Nies, A. S., Shand, D. G. ibid. 1975, 52, 6. 23. Shand, D. G. Postgrad. med. J. 1976, 52 (suppl. 4), 22. 24. Michelakis, A. M., McAllister, R. G. J. clin. Endocr. 1972, 34, 386. 25. Chidsey, C. A., Pine, M., Favrot, L., Smith, S., Leonetti, G., Morselli, P., Zanchetti, A. Postgrad. med. J. 1976, 52 (suppl. 4), 26. 26. Cleaveland, C. R., Shand, D. G. Clin. Pharmac. Ther. 1972, 13, 181. 27. Epstein, S. E., Robinson, B. F., Kahler, R. L., Braunwald, E. J. clin. Invest. 28.
1965, 44, 1945. Taylor, S. H., Meeran, M. K. Br. med. J. 1973, iv, 257.
411
America and Europe, and several epidemics of
disease with a significant mortality rate.2-6 incubation period of 2-10 days, the patient usually has fever, malaise, myalgia, and headache.1,2 Within a week a consolidated pneumonia develops although some patients may have only an interstitial infiltrate.2,3The causative agent is a small, pleomorphic gram-negative bacillus which requires special media and conditions for growth.’-9 It has been isolated from pleural fluid and lung tissue.3 Diagnosis is usually made on a fourfold rise in the indirect fluorescent antibody (LF.A.) titre in serum, or on a single titre of 1/128 or more.9 Cultured organisms often stain with gram stain, but those found in bodyfluids or in histological sections cannot usually be stained by standard techniques. The Dieterle silverimpregnation stain and direct fluorescent antibody (D.F.A.) techniques have been useful for detecting the organism in lung tissue. 10, 11 The Center for Disease Control (C.D.C.) has given preliminary reports of L.D. in several patients with impaired host defences.12,13 We report five other instances
respiratory After
patient gradually improved and was well when last seen January,1978. The
severe
an
in
Case 2 man received a renal transplant on Aug. 20, treated with 200 mg azathioprine and 50 mg prednisone per day. He had diarrhoea for 4 days from Aug. 25. On Sept. 1 he had hxmoptysis and myalgia. His temperature was 38.0°C, pulse 100/min, and respiratory rate 20/min. Rales, rhonchi, wheezes, and dullness to percussion were present at his right lung base. Bilateral lower lobe infiltrates were seen on chest X-ray. The W.B.C. was 13 100/µl (94% neutrophils), serum creatinine 0.9mg/dl, Pa02 82 mm Hg on room air. Gram stain of a T.T.A. revealed rare gram-negative bacilli. The patient did not respond to carbenicillin, 20 g per day, and gentamicin, 4.5 mg/kg per day, which were given from Sept. 2. Ampicillin, 6 g per day, was substituted from Sept. 5, when Haniophilus influenzce was grown on culture. The dose of’
A
49-year-old
1977, and
was
immunosuppressives was reduced. On Sept. 4, his temperature was 39.1°C and bronchoscopy was non-diagnostic. The next day the infiltrates were more extensive (fig. 1). An open lung biopsy showed a consolidated pneumonia of the right lower lobe. Histological examination showed interstitial and acute bronchopneumonia (fig. 2).
in renal-transplant recipients. The new Wadsworth Veterans Administration Hospital building opened in March, 1977. Nine patients
received allogeneic renal homotransplants between March and November; five had febrile respiratory illnesses and abnormal chest X-rays. When the diagnosis was not apparent from transtracheal aspiration and thoracentesis or on clinical grounds, bronchoscopy and open lung biopsy were carried out. Serum i.F.A. titres for L.D. were determined in the four patients without pneumonia; these titres were negative or insignificant.
Case-reports Case1 man had received a renal transplant on he was given 150 mg of azathioprine and 60. April 13, 1977, of prednisone per day. Methylprednisolone, 1 g per day, mg was given on May 6-8 for graft rejection. On May 13, he had headache, nasal congestion, dry cough, and a temperature of 38.9°C; the next day he had pleuritic pain and chills. His tem-
After
a
40-year-old
39-4°C, pulse 110/min; dullness to percussion, perature increased tactile fremitus, and rales were present at the base was
of the left lung. Chest X-ray showed a perihilar infiltrate which progressed over the next 3 days. The white blood-cell count was 5600/µl. A few gram-negative bacilli were seen in a transtracheal aspirate (T.T.A.), but aerobic, anaerobic, and fungal cultures were negative. A few bacilli were also seen in bronchial washings stained by Gomori methenamine silver. Co-trimoxazole (600 mg trimethoprim and 3 - 0 g sulphamethoxazole) per day was begun on May 16 for 6 days, followed by sulphadiazine 4 g per day for 5 days. Azathioprine was discontinued and prednisone was reduced to 20 mg per day. Open lung biopsy on May 17 revealed an acute bronchopneumonia and interstitial fibrosis. No Pneumocystis carinii or viral inclusion bodies were seen. Gram stain and acid-fast stains were negative, as were all cultures for bacteria. Benzylpenicillin, 6 million units per day, was given for 10 days. Cytomegalovirus (c.M.v.) was grown; c.M.v. titres were 1/128 on May 31 and 1/256 on Aug. 15. He became afebrile a week after the open lung biopsy, and the infiltrate cleared after a month. A very small section of lung stained by Dieterle and D.F.A. stains at the C.D.C. was negative for L.D. bacillus. I.F.A. titres for L.D. in the patient’s serum were 1/64 on May 16, 1/256 on May 27, 1/128 on June 11, and 1/32 on Aug. 17.
1--Case 2: posterior-anterior chest lower-lobe infiltrates.
Fig.
X-ray, Sept. 5; bilateral
Fig. 2--Case 2: histopathological section (x2000) of biopsy, right lower lobe.
open
lung
’
412 Gram stain, Ziehl-Neelsen, and Gomori methenamine silver stains were negative, as were aerobic and anaerobic bacterial, fungal, and viral cultures. Later, the C.D.C. reported that the D.F.A. stain was negative for the L.D. bacillus. There was no growth on Mueller-Hinton agar supplemented with 1% haemoglobin and 1% ’IsoVitaleX’ (BBL)-a medium enrichment for fastidious microorganisms which contains vitamin
B,2, L-glutamine, adenine, guanine HCI, p-aminobenzoic acid, diphosphopyridine nucleotide, co-carboxylase, ferric nitrate, thiamine HC1, cysteine HC1, L-cystine, dextrose-incubated in air. On Sept. 14, I.F.A. titre for L.D. of serum drawn on Sept. 6 was positive in a dilution of 1/128, and 2 g of erythromycin per day was substituted for the ampicillin. The patient became afebrile after 5 days but received additional corticosteroids for mild graft rejection; the infiltrate resolved after 10 days. He received 3 weeks of erythromycin. Repeat I.F.A. titres on Sept. 15 and 30, and Oct. 15, were 1/512, 1/256, and 1/256 respectively. Renal function remained normal. On Oct. 13, he had a low-grade fever and a left upper-lobe infiltrate. There was no growth from a T.T.A. specimen. Cultures of a percutaneous and a second open lung biopsy specimen on Oct. 27 gave a moderate growth of Staphylococcus aureus. The Gomori methenamine silver stain was negative. Oxacillin 9 g per day was started, and erythromycin 2.0g per day was reinstituted. The patient became afebrile and continued to improve; he was discharged from the hospital on ’
Nov. 29.
Case 3 A
43-year-old
man
had
a
temperature of 384°C
on
Sept.
27, a week after unsuccessful treatment with methylprednisolone, 1 g per day, for rejection of his second renal transplant. He had herpetic lesions on the oral mucosa. Frontal headache, cough, malaise, diarrhoea, and a rapid rise of temperature to 41.1°C developed on Sept. 30. A turbid left pleural effusion showed 10 000 white cells/µl (89% neutrophils). All cultures and stains were negative. The next day his peripheral w.B.c. was 1200/µl and a hazy left upper-lobe infiltrate was noted. Bronchoscopy and open lung biopsy were done. Histological examination showed acute interstitial pneumonitis and bronchopneumonia. All standard stains and cultures were negative, as was a culture on supplemented Mueller-Hinton agar. The infiltrate extended to involve the entire left lung on Oct. 8. He was started on oxacillin, penicillin, and amikacin. Intubation and assisted ventilation were required for severe hypoxia. His temperature rose to 42.2°C, and he died on Oct. 9. At necropsy, lobar pneumonia was present in the left upper and lower lobes, and the right lower lobe. The left lung weighed 1540 g, the right 790 g. The alveoli were distended and filled with necrotic debris, neutrophils, fibrin strands, and erythrocytes. Subsequently, the C.D.C. reported that the D.F.A., and the Dieterle stain on lung tissue revealed many L.D. bacilli. An I.F.A. titre of serum drawn on Sept. 14 was nonreactive, but on Oct. 4, the titre was 1/128.
Case 4 A 57-year-old man received a renal transplant on Sept. 6, but poor function necessitated hxmodialysis. Methylprednisolone, 1 g per day, was given from Sept. 22 to 24. On Sept. 30, he had pleuritic pain, dyspnoea, malaise, and hxmoptysis. His temperature was 39-2°C and pulse 104/min. X-rays showed left upper-lobe and lingular infiltrates. W.B.C. was 8600/µl. Neutrophils and monocytes, but no bacteria, were seen on gram stain of a T.T.A. Erythromycin was given for 24 hours, but was then discontinued and amikacin, 5 mg per kg after each dialysis, and cephazolin, 500 mg per day, were substituted when gentamicin-resistant Klebsiella pneumonia was cultured. The dose of immunosuppressive agents was reduced. The patient’s sputum became purulent. He had hypotension and required respiratory support for several days. A smear
made from a 350 ml pleural effusion contained neutrophils and a few gram-negative rods. He responded to antibiotic therapy after 1 week, although the infiltrate resolved slowly. Cephazolin and amikacin were discontinued after 6 weeks. A transplant nephrectomy was performed on Nov. 25 because of rejection. A considerable rise in serum-alkaline-phosphatase (to 2068 LU.) appeared during October and persisted for 2 months. An I.F.A. titre on serum for L.D. drawn on Sept. 30 was 1/32; on Nov. 9 it was > 1/1024. Erythromvcin was then given.
Case 5 A 50-year-old man had a temperature of 389°C on Oct. 19, 6 days after a renal transplant. A diagnosis of rejection was made because of the presence of lymphocytes in the urine, deterioration in renal function, and a pleural effusion. This responded transiently to 1 g per day of methylprednisolone. The pleural effusion cleared and he became afebrile. On Oct. 26, oral prednisone, 40 mg per day, was begun. The patient had a nonproductive cough on Oct. 29. 2 days later his temperature was 40.0°C and a right lower-lobe infiltrate was seen on X-ray. Prednisone was reduced to 10 mg per day and haemodialysis was begun. On Nov. 2 right basilar rates were present. Culture of a T.T.A. did not grow any pathogens. 2 days later, 2 g/day of erythromycin was started. The chest X-ray cleared gradually but the patient remained febrile until
lymphocytic
after transplant nephrectomy was done when respiratory signs and symptoms had resolved by the middle of November. I.F.A. on Nov. 5, 1/128 on Nov. 9, and titres for L.D. were
