legionnaires' disease in renal transplant patients

Legionnaires’ Disease in Renal Transplant Patients

Wendy Marshall, MD, Burlington, Vermont

Roger S. Foster, Jr., MD, Burlington, Vermont Washington Winn, MD, Burlington, Vermont

Legionnaires’ disease is a bacterial disease commonly manifested as pneumonia. The bacterium, Legionella pneumophila, has unusual cultural requirements, and it is usually not visible after Gram’s stain of respiratory secretions [I]. For these two reasons, the cause of Legionnaires’ disease was not recognized until early 1977 after the outbreak of cases among persons attending the convention of the American Legion in 1976 [2]. Cases can occur sporadically as well as in epidemics. Although Legionnaires’ disease appears more common in immunosuppressed persons and in transplant patients in particular, it can also occur after other types of surgery and even in an apparently previously healthy person [3-51.

We first suspected, treated and then later confirmed Legionnaires’ disease in several renal transplant patients during the outbreak of this disease in Vermont during the summer of 1977 [5]. From mid- 1977 until August 1980, we have had eight cases of Legionnaires’ disease after 59 renal transplants. We also retrospectively reviewed the records and all pathologic materials on our patients who underwent transplant from 1972 until our first recognition of Legionnaires’ disease in 1977. Retrospectively, we identified six additional cases of the disease after 43 renal transplants. This report compares the clinical course of Legionnaires’ disease in our patients before and after our recognition of the disease in 1977.

Material and Methods In this study, the possibility of Legionnaires’ disease was

entertained in all renal transplant patients with a pulmonary infiltrate. All clinical histories were reviewed and all available pathologic material from lung biopsies and lung

From the Department of Surgery, University of Vermont College of Medicine. Burlington, Vermont.

Requests for reprints should be addressed to Roger S. Foster, Jr.. MD, Department of Surgery, Given Building, University of Vermont College of Medicine, Burlington, Vermont 05405.

Presented in pat? at the 61st Annual Meeting of the New England Surgical Society, Portsmouth, New Hampshire, September 26-28. 1980.

Volume 141, April 1981

tissue from autopsies was stained with specific stains for L. pneumophila. The diagnosis of Legionnaires’ disease was confirmed by one or more of the following criteria in patients with a compatible clinical picture [6-91: (1) A four- fold or greater increase in serum titers to at least a titer of 1:128 with indirect fluorescent antibody against the Phil- adelphia 1 antigen. Serologic studies were performed in the laboratories at the Center for Disease Control (CDC), At- lanta, Georgia, or the Vermont State Health Department, Burlington, Vermont. (2) Direct immunofluorescent antibody stain for L. pneumophila strains 1 through 4 on sputum or lung tissue. (3) Culture of pleural fluid or lung or bronchial secretions, or a combination of these, on a charcoal yeast extract agar plate.

Immunosuppressive therapy routinely consisted of azathioprine and corticosteroids. Eighteen patients with either cadaver donor transplants or single haplotype living related donor transplants were randomized to receive for the first 21 days 15 mg/kg/day of antilymphocyte globulin (ATGAMe, Upjohn). Azathioprine was begun at 2.5 mg/kg and the dosage reduced to 1 to 1.5 mg/kg by 2 weeks after transplantation. Imurane dosage was decreased by half to two thirds for patients with acute renal failure. Azathio- prine was withheld if neutrophil counts were less than 2,000/mm3. During the preoperative period, 500 mg of methylprednisolone was given intravenously. Prednisone (or equivalent doses of methylprednisolone) was given at a total daily dose of approximately 1.2 mg/kg immediately postoperatively. This dose was tapered to 0.5 mg/kg by the 21st postoperative day. Rejection episodes were treated by intravenous pulses of 15 mg/kg of methylprednisolone with usually no more than three pulses per rejection episode or a total of six to eight pulses. Local graft x-irradiation, 150 rads X3, was used if there was not a prompt response to the methylprednisolone pulses. By 3 months after transplantation, maintenance doses of prednisone were usually 0.2 to 0.3 mg/kg. Before 1980, splenectomy was performed only if laporatomy was being performed for other reasons. Ne- phrectomy was performed only for specific indications. Prophylactic antibiotics were not employed between 1972 and 1978. If sepsis was suspected, azathioprine was discontinued and corticosteroid dosage was rapidly tapered.

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Results renal transplants. One additional patient had legionella organisms identified at autopsy; Legion- naires’ disease was not suspected before death and he was not treated with erythromycin. In this patient, acute pancreatitis developed after the loss of a graft to acute rejection. Pancreatitis was complicated by coagulase-positive Staphylococcus aureus sepsis. At death, large numbers of L. pneumophila bacteria were identified in the lungs.

Six cases of Legionnaires’ disease were uncovered in our retrospective study of pneumonias in patients

We identified 14 cases of Legionnaires’ disease after 101 renal transplants in our unit between April 1972 and July 1980. The transplant patients varied in age from 9 to 63 years, and 14 of the patients had juvenile onset diabetes mellitus. There were 66 cadaver transplants and 35 living related transplants in 92 patients (Table I). Since our first recognition of Legionnaires’ disease in 1977, we have diagnosed and successfully treated it in seven patients after 58

TABLE I Profiles of Renal Transplant Patients in Whom Legionnaires’ Disease (LD) Developed

Case

Days From LD Transplant Other Other Graft Primary

Year Age (yr) Cause of to Onset Complicating Infections Function Cause of of LD (L Sex Renal Failure of LD Illnesses identified at 1 Year Death Death

1 1974 44M

2 1976 27 F

3 1976 52F

4 1976 4afvt

5 1977 41M

6 1977 53F 7 1977 38F

8

9

10

11

12

13

14

1976 50M

1976 36M

1978

1979

1979

42M

46F

1980 43F

1980 i8k.f

Chronic glomeruio- nephritis

Chronic pyeionephritis

Chronic giomeruio- nephritis

Chronic giomerulo- nephritis

Chronic giomerulo- nephritis

5

4

380

UGI bleeding, Staph coag vagotomy, +, E. coil, H. gastroduo- influenza, denotomy Candida

Wound infection Staph coag +

. . .

ia Perforated diverticulitis

472

5 10

Malnutrition, alcoholism, pancreatitis, UGI bleeding, perforated ulcer

. . .

. . .

16 . . .

13

111

a

58

. . .

Pancreatitis, hyperglycemia, bleeding disorder

. . .

34

33

UGI bleeding, small bowel fistuia, malnutrition, diabetes meilitus

. . .

. .

. . . Contributory Yes

. . .

Yes

Yes

No

. .

Yes

. . .

Yes Yes

. .

E. coli, Bacter- oldes, Pseudo- monas, Kiebsielia

Staph coag + Yes Contributory Yes

Sciercderma Chronic

giomeruio- nephritis

Congenital obstructive disease

Chronic glomeruio- nephritis


Hypertensive

ii;

Yes

Yes

Yes Yes . . No

. . .

. . .

. . . No . . .

Kiebsielia and Pseudo- monas

Staph coag +

. . . No

Contributory Yes . . .

Yes

Yes

No

No

. . .

. . .

. . .

E. coii, Staph coag .+, Pseudo- monas

Chronic pyeionephrltis

Poiycystic kidney disease


No’ . . . No

t . . . No Four days after transpian- tation pneumonia 2O to unidentified agent

l Transplant lost to rejection before the development of Legionnaires’ disease. t Good graft function at 4 months. Staph coag + = Staphylococcus aureus coaguiase positive; UGI = upper gastrointestinal.

424 The Amarlcan Journal ot Surgary


who underwent transplant before August 1977. These six cases followed 43 renal transplants, and there were six deaths. In some cases, Legionnaires’ disease was associated with other major septic complications (Table I), but in retrospect it appeared to be the major factor in the deaths of three patients and a probable contributing factor in the deaths of three others.

Signs and symptoms: There was frequently a prodromal phase of several days of malaise, myalgia and headaches followed by a sudden acute change with fever of 38.5 to 41°C (100 percent of patients), dyspnea (93 percent), unproductive cough (86 percent), chest pain (36 percent) and scant hemoptysis (29 percent). Pulmonary infiltrates developed in all patients; however, one patient had a prolonged fe- brile prodrome of 13 days before the first appearance of a pulmonary infiltrate. At the time of development of a pulmonary infiltrate, the physical findings gen- erally demonstrated an acutely ill, toxic and dyspneic patient, and half of the patients had a respiratory rate greater than 25 breaths/min. On examination of the chest, there were initially fine inspiratory rales followed by signs of frank consolidation and occa- sional pleural friction rubs. One third of the patients had abdominal tenderness without peritoneal signs. A depressed mental state with agitation and delirium was a common feature but without specific neurologic findings. The extent of confusion and lethargy appeared out of proportion to either the fever or hypoxia.

Radiologic findings: The initial radiographic changes on chest roentgenography varied from a perihilar infiltrate to a nodular or diffuse bronchopneumonia. Most commonly, round opacities that were initially poorly marginated progressed to lobar consolidation or diffuse bronchopneumonia. Total opacifications were seen in two of the fatal cases. Eleven of 14 patients had bilateral involvement. Six patients had small pleural effusions and two had cavitation. Radiographic resolution usually lagged behind clinical recovery in appropriately treated patients [IO]. The sequential roentgenograms of one patient are shown in Figure 1.

Laboratory findings: All patients had leukocytosis with a shift to the left. White blood cell counts ranged from 10,700 to 33,000/mm3 with a mean granulocyte count of 16,900/mm3. Ten patients had mild abnormalities in liver function tests (elevated levels of serum glutamic oxalacetic transaminase, lactic dehydrogenase, alkaline phosphatase and bi- lirubin). Proteinuria was common, and there was an increase in proteinuria in 6 of 14 patients coincident with the development .of pulmonary changes of Le- gionnaires’ disease. Of the 14 patients who had Le- gionnaires’ disease, 10 had associated graft dysfunction. Of the six patients who died, five had graft dysfunction. Changes in allograft function frequently occurred coincident with the development of the prodromal symptoms.

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F/gure 1. A, earty nodular density of Legionnaires’ disease pneumonia develop/~ 10 days after renal transplant. 6, pro- gmsskw ofpnewnon~ 13 days after transplantat~ &sfMe bmad spectrum antibtotlc therapy. C, radiographic appearance 15 days afler transplantation, at the time of open lung biopsy and the lnl- t/at/on of erythromyctn treatment. 0, chest radiograph 2 years later, 1 year after successful retransplantation wtth a cadaver donor kldney.

Arterial blood gases showed hypoxia (60 percent had a partial arterial oxygen pressure less than 60 mm Hg on room air early in their course). Hypocap- nia and respiratory acidosis were also present. The pleural effusions had characteristics of either an exudate or a transudate.

Pathology: Pathologic specimens of the lung ob- tained by biopsy or at autopsy showed severe, con- fluent lobular pneumonia. The alveolar exudate was rich in fibrin, neutrophils, macrophages and some erythrocytes. Septal inflammation and focal necrosis were present but usually not extensive. There was also acute bronchiolitis with epithelial necrosis in- volving the terminal and respiratory bronchioles, but large bronchi were not involved [II ,121.

Response to treatment: After treatment of our first patient with erythromycin, her fever decreased and pulmonary function improved within 24 hours, followed by further slow but progressive recovery. Her graft was lost to rejection and a successful transplant was performed 1 year later. Since then, all seven patients suspected of having Legionnaires’ disease from clinical criteria and treated with erythromycin with or without rifampin have recovered. Rifampin was used in four patients because of either a slow response, the appearance of cavitation on roentgenography or, in one case, an apparent recrudescence of Legionnaires’ disease 1 week after a 14 day course of erythromycin. Erythromycin was

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usually administered for 21 days at a dose of 4 to 6 g each day. After treatment with erythromycin, there was a clinical response within 48 hours and improvement in radiographic and laboratory findings within 4 days. The radiographic improvement lagged behind the clinical improvement. The mean duration of disease from onset to clinical recovery was 15 days.

One patient had two episodes of pneumonia after transplantation during his hospital stay. The two episodes were similar in clinical presentation and in their resolution after treatment with erythromycin; however, only the second episode with an onset 34 days after transplantation was identified as Le- gionnaires’ disease by fluorescent antibody study of transtracheal aspirate and by a subsequent increase in serum antibody titers against L. pneumophila. The first episode of pneumonia began 4 days after transplantation. Both episodes required endotra- cheal intubation and ventilatory support. Both pneumonias responded to treatment with high doses of intravenous erythromycin. After the first episode of pneumonia, there was no serologic titer change to L. pneumophila, the Pittsburgh pneumonia agent or WIGA. No specific organism was identified in the transtracheal aspirate. We remain suspicious that the first episode of pneumonia was due to legionella-like organisms, which we are as yet unable to identify.

Azathioprine was discontinued in all patients at the time of recognition of sepsis, and corticosteroid dosages were reduced. On recovery, immunosuppression was resumed. In five of six erythromycin- treated patients the graft was maintained. One patient’s graft had been removed because of acute rejection before the development of Legionnaires’ disease.

The administration of various combinations of penicillins, aminoglycosides and cephalosporins did not lead to an improvement and was usually followed by rapid further deterioration. Despite the use of broad spectrum antibiotics, antipyretics and cooling blankets, the patients’ temperatures remained elevated, and five of the six patients treated before mid-1977 had progressive hypoxia and died. The mean duration of illness in these patients from the onset of symptoms to death was 9 days.

Comments

The mechanism of the spread of Legionnaires’ disease is unclear [25]. L. pneumophila is a water- associated organism present in moist soil. L. pneumophila has been identified in air conditioning equipment as well as in hospital shower heads. Air conditioners, air handling equipment and water cooling towers have been implicated as means of spreading organisms. It is possible that bacteria from the environment contaminate air handling equipment, which can then generate small particle aerosols that are more highly infectious than large parti- cles.

Legionella pneumophila and similar organ- Whether direct human-to-human spread occurs isms: Legionella pneumophila, the organism that is unclear [24-261. In the Philadelphia outbreak there causes Legionnaires’ disease, was first identified after appeared to be no such spread. Some investigators the Philadelphia epidemic in 1976 [1,2]. L. pneu- believe that because certain hospital personnel such mophila is an aerobic gram-negative bacillus 0.5 to as inhalation therapists have a higher prevalence of 0.7~ by 2 to 4~. If large numbers of bacteria are antibodies than other population groups, the present, Gram’s stain may demonstrate legionellae human-to-human mode of spread cannot be ruled in respiratory secretions [13-151. The legionella are out [24,25]. Large numbers of L. pneumophila are infrequently visualized with the usual saffranin seen on immunofluorescent staining in the tracheal counter stain, but are demonstrated better by car- secretions of patients with Legionnaires’ disease, and

bol-fuchsin stain [13,14]. The bacteria are commonly present in inflammatory cells as well as free in the alveolar space [12]. The macrophages often appear as large phagocytic vacuoles filled with intact and degenerating bacteria.

There appear to be at least six separate serotypes of L. pneumophila [16]. Thus, failure to identify the organisms in suspicious tissue might be because of an additional yet unidentified L. pneumophila se- rotype. In addition, there are other bacteria that are phenotypically similar but genetically distinct from L. pneumophila, such as the “Pittsburgh pneumonia agent” that was isolated from renal transplant patients and the atypical legionella-like organisms that have been designated ALL0 [ 17-191.

Epidemiology: Legionnaires’ disease appears to occur worldwide. In the United States there have been numerous sporadic cases and at least 13 epidemics [4]. The first isolation of L. pneumophila was made from the blood of a patient with pneumonia in 1947, but it was not recognized as an important human pathogen [20,21]. It has been estimated that Legionnaires’ disease accounts for 1 to 4 percent of pneumonias that previously would have been identified simply as “viral-like” pneumonia [22]. Nu- merous reports of Legionnaires’ disease as a nosocomial infection in patients with and without transplants emphasize the possibility of this serious infection being acquired in a hospital [23,24]. It is probable that many of our cases of Legionnaires’ disease in transplant patients were nosocomial because the patients were hospitalized during the usual incubation period of 2 to 10 days [2]. Information on recrudescence of subclinical disease is not yet available; this may occur in the transplant patients who develop fulminant disease shortly after transplantation.

426 The American Journal of Surgery


it is reasonable to postulate that aerosol transmission from infected persons could occur. However, we have cared for large numbers of patients with Legion- naires’ disease at our hospital and have recognized no cases of the disease in staff members as a result of patient care. The prevalence of Legionnaires’ disease antibodies appears low in the healthy population, but certain geographic areas may be hyperendemic [27]. Smokers, heavy drinkers of alcoholic beverages, immunosuppressed patients and patients with chronic illnesses seem to be more prone to develop Legion- naires’ disease [4,5].

Clinical manifestations: There is wide variation in the clinical spectrum of Legionnaires’ disease [2-41. There can be a serologic titer increase without preceding symptoms. There may be flu-like symptoms with few respiratory symptoms and no radio- graphically identifiable pneumonia. Finally, Le- gionnaires’ disease may present as explosive, severe and rapidly progressive pneumonia with multisystem involvement. It is as yet unclear whether the systemic manifestations are due to a bacteremia or to elabo- ration of a toxin or both [28]. While L. pneumophila is most commonly recovered from the lungs, it has also been identified in hilar lymph nodes [29], blood 1301, heart [31] and kidneys [32].

In our transplant patients, Legionnaires’ disease was clearly a multisystem disease that involved the central nervous system, the gastrointestinal tract, the liver and the kidneys. The neurologic manifestations are interesting in that there was a high frequency of abnormal mental states with delirium, disorientation, confusion and hallucinations, but these findings were out of proportion to the remainder of the clinical examination. There were no associated focal neurologic findings. Findings on lumbar puncture and computed tomographic scans have been normal. In the absence of significant numbers of leukocytes in the cerebral spinal fluid, it seems unlikely that there is invasion of the central nervous system by L. pneumophila and more likely that the neurologic changes are secondary to a toxin. Gastrointestinal symptoms were prominent early in the development of Legionnaires’ disease, as were abnormalities in liver function tests. These findings returned to normal as the patients improved with specific treatment. L. pneumophila has not been isolated from the liver or gastrointestinal tract as yet, again raising the possibility that the gastrointestinal signs and symptoms are secondary to a toxin.

Pulmonary infections are a major cause of death in renal transplant patients in many transplantation units. In our unit, Legionnaires’ disease has been a major cause of morbidity and mortality in both he- modialysis and transplant patients. Of 13 patients who died in the first year after transplantation, 3 died from cardiovascular disease. Of the remaining 10 deaths from sepsis, L. pneumophila infection was a contributory factor in 6.

Once we recognized Legionnaires’ disease and its responsiveness to high doses of erythromycin, the mortality and morbidity from Legionnaires’ disease decreased markedly. Immunosuppressive therapy was reduced in all patients on recognition of any septic event, but we were able to reinstitute immunosuppression with maintenance of graft function in five of six patients after they responded to treatment. Bock et al [33], in their five renal transplant patients with Legionnaires’ disease, reduced immunosuppression and administered a variety of antibiotics. One patient died and two patients had rejection of their grafts.

In patients with high fever, polymorphonuclear leukocytosis and consolidating pneumonia accompanied by scant sputum, Legionnaires’ disease or legionnaires’-like pneumonia should be considered. Our current approach to the evaluation of any suspected bacterial pneumonia is to perform transtracheal aspiration. Any pleural effusions are also as- pirated. Specimens are examined by Gram’s stain and direct immunofluorescence for legionella and are cultured for aerobic and anaerobic bacteria. If transtracheal aspiration is unrewarding or if there is not prompt response to antibiotics, we then proceed to bronchoscopy or needle aspiration and finally to open lung biopsy if necessary.

Treatment: The current treatment of Legion- naires’ disease, or suspected Legionnaires’ disease, is erythromycin in a dose of 2 to 6 g/day [34]. Higher doses are used for more serious infections and are initially given intravenously. After response and clinical improvement, oral administration may be started. Erythromycin is given for a minimum of 3 weeks. There is some evidence that rifampin is also effective in Legionnaires’ disease, and we have used it when improvement is slow [34,35].

Summary

Legionnaires’ disease, which is commonly manifested as pneumonia, was only recently recognized to be a bacterial infection. Diagnosis can be difficult because Gram’s stain does not readily stain the bacterium in pulmonary secretions, the organism is not readily cultured, and legionellae is not affected by many commonly used antibiotics. In a retrospective review of all of our transplant patients, we identified 14 cases of Legionnaires’ disease after 101 renal transplants. The patients characteristically had high fever, polymorphonuclear leukocytosis, dyspnea and an unproductive cough accompanied by radiographic changes of consolidating pneumonia. Legionnaires’ disease can be diagnosed by direct immunofluorescent antibody staining, culture on special media or increases in serum titers of legionella antibodies in surviving patients. Since the recognition of Legion- naires’ disease in 1977, we have successfully treated seven renal transplant patients using erythromycin with or without rifampin.

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References Intern Med 1979;90:667-70.

I. Brenner DJ. Steigerwalt AG, f&Dade JE. Classification of the Legionnaires’ disease bacterium. Ann Intern Med 1979; 90:656-e.

2. f&Dade JE, Shepard CC, Fraser DW, et al. Legionnaires’ disease. Isolation of its role in other respiratory disease. N Engl J Med 1977;297:1197-1203.

3. Saravolatz LD, Burch K, Fisher E. et al. The compromised host and Legionnaires’ disease. Ann Intern Med 1979;90:533- 7.

26. Tobin JO, Dummil MS, Beare J, et al. Legionnaires’ disease in a transplant unit: isolation of the causative agent from shower baths. Lancet 1980; July: 118-S.

27. Broome CV, Fraser DW. Epidemiologic aspects of Legionel- losis. Epidemiologic Rev 1979;1:1-16.

28. Wong KJ, Moss C, Hochstein D. et al. “Endotoxicity” of the Legionnaires’ disease bacterium. Ann Intern Med 1979; 90:624-7.

4. Beaty H, Miller AA, Broome CJ. Legionnaires’ disease in Ver- mont, May to October 1977. JAMA 1978;240:127-31.

5. Foster RS, Winn W, Marshall W, et al. Legionnaires’ disease following renat transplantation. Transpiant Proc 1979;li: 93-5.

6. Cherry WB, Plttman B. Harris PP, et al. Legionnaires’ disease bacteria by direct immunofluorescent staining. J Clin Mi- crobiol 1978;8:329-38.

7. Durnrrroff M. Direct in-vitro isolation of the Legionnaires’ disease bacterium in two fatal cases. Ann Intern Med 1979;QO: 694-6.

29. Weisenburger DD, Helms CM, Viner JP, et al. Demonstration of the Legionnaires’ disease bacillus in Hilar lymph nodes. Arch Pathol Lab Med 1979;103:153.

30. Edelstein P, Meyer RD, Finegold SM. Isolation of Legionella pneumophila from blood. Lancet 1979; April: 750-l.

31. White I-U, Felton WW, Sun CN. Extrapulmonary histopathologic manifestations of Legionnaires’ disease. Arch Pathol Lab Med 1980;104:287-9.

32. Dorman SA, Hardin ND, Winn WC. Pyelonephritis associated with Legionella pneumophila. Serogroup IV. Ann Intern Med 1980;93.

8. Atlanta Center for Disease Control. Legionnaires’ disease indirect fluorescent-antibody reagents. Publication 846. Dec. 1977; revised Feb. 1978.

9. Center for Disease Control, Atlanta, Georgia. Legionnaires’ disease: diagnosis and management. Ann Intern Med 1978;88:363-5.

33. Bock BV. Edelstein P, Snyder K, et al. Legionnaires’ disease in renal transplant recipients. Lancet 1978;1:410-3.

34. Thornsberry C, Baker CN. Kirven LA. In vitro activity of anti- microbial agents on the Legionnaires’ disease bacterium. Antimicrob Agents Chemother 1978;13:78-80.

35. Saravolatz LD, Pohlod DQ, Quinn EL. In vitro susceptibility of Legionella pneumophila. Serogroups I-IV. J Infect Dis 1979;140:25.

10. Dietrich PA, Johnson RD, Fairbank JT. The chest radiograph in Legionnaires’ disease. Radiology 1978;127:577-82.

11. Glavin FL. Winn WC, Craiahead JE. Ultrastructure of luna in Discussion

Legionnaires’ disease. Ann Intern Med 1979;90:555-91 12. Winn WC, Glavin FL, Per1 DP. et al. Macroscopic pathology of

the lungs in Legionnaires’ disease. Ann Intern Med 1979; 90:548-5 1.

13. Edelstein PH. Meyer RD. Finegold SM. Laboratory diagnosis of Legionnaires’ disease. Am Rev Respir Dis 1980;121: 317-27.

14. Porschen RK. LD: More on staining and isolation of Legionella pneumonia (letter to the editor). N Engl J Med 1979300: 369-70.

15. Pascule AW, Myerowitz RL, Rinaldo CR, et al. New bacterial agent of pneumonia isolated from renal-transplant recipients. Lancet 1979;2:58-61.

16. Fraser DW. Legionnaires’ disease: four summer’s harvest. Am J Med 1980;68:1-2.

17. Glick TH, Gregg MB, Berman B, et al. Pontiac fever: an epidemic of unknown etiology in a health department. Am J Epidemiol 1978;107:149-60.

18. Hebert G, Moss C. McDougal L, et al. The Rickettsia-like organisms TATLOCK ( 1943) and HEBA (1959): bacteria phenotypically similar to but genetically distinct from Legionella pneumophila and the WIGA bacterium. Ann Intern Med 1980;92:45-52.

19. Cordes LG, Gorman GW, Wilkinson, et al. Atypical Leg- ionella-like organisms: fastidious water-associated bacteria pathogenic for man. Lancet 1979;2:927-30.

20. Jackson EB, Crocket TT, Smacfel JE. Studies on two Rick- ettsia-like agents probably isolated from guinea pigs. Bac- terial Proc 1952; 119.

21. McDade JE, Brenner D, Bozeman F. Legionnaires’ bacterium isolated in 1947. Ann Intern Med 1979;90:659-61.

22. Renner E, Helms C, Hierholzer W, et al. Legionnaires’ disease in pneumonia patients in Iowa: a retrospective seroepidemic study 1972-1977. Ann Intern Med 1979;90:603-6.

23. Haley CE. Nosocomial Legionnaires’ disease: a continuing common-source epidemic at Wadsworth Medical Center. Ann Intern Med 1979;90:583-6.

24. Saravolatz L, Arking L, Wentworth B, et al. Prevalence of antibody to the Legionnaires’ disease bacterium in hospital employees. Ann Intern Med 1979;90:601-3.

25. Miller RP. Cooling towers and evaporative condensers. Ann

Nicholas L. Tilney (Boston, MA): I had the opportunity to review this excellent manuscript and found the authors’ extensive experience with 14 cases of Legionnaires’ disease in 101 recipients of renal transplants completely unen- viable. There have been scattered reports of this infection from other transplant centers, primarily Los Angeles and Oxford. It is interesting, however, that the infection is not more widespread among the extraordinarily fragile and immunosuppressed transplant population. As the authors suggest, pneumonia is a relatively common and very serious complication of transplant patients, usually secondary to the ordinary bacteria that we see in ordinary patients. However, it also can be secondary to obscure organisms, peculiar viruses such as cytomegalovirus, bacteria such as pneumocystis, or opportunistic fungae.

The regional incidence of the condition is also interesting. For instance, in our own experience at the Peter Bent Brigham Hospital with more than 800 transplants, we have never seen a case of Legionnaires’ disease or at least have not recognized it clinically. One of our pathology residents recently reviewed 124 autopsies of 586 transplant recipients who received 663 allografts between 1964 and 1979. Seventy autopsied patients died with a diagnosis of pneumonia. Of these 70, 3 had Legionnella organisms diagnosed either on tissue section or by immunofluorescence. There was no clinical suspicion of the condition. Moreover, none of these patients had Legionnella pneu- mophilia as reported by the Vermont group, but had related strains such as Legionnella Pittsburgh or WIGA. Thus, we have no experience with the condition.

It appears that the organism either can be acquired through a hospital source, as in the Oxford epidemic that arose through a dirty shower bath, or can be spread from human to human. Do the authors have any ideas regarding the peculiar geographic distribution of their epidemic and the mechanism by which their patients were infected? Was there a temporal sequence? Second, did the onset of this

428 The Am&can Journal of Surgery


disease have any relation to steroid pulses, given for acute rejection episodes, or did it have any relation to existing leukopenia? In our experience with pneumonia, especially fungal or that from pneumocystis, many episodes occur after intense immunosuppression and leukopenia.

I am very impressed with the recent decrease in the mortality rate since the organism was identified. However, hearing about this series is a bit like reading a Gothic novel or seeing a horror film, and I hope we never have to hear much more about this condition.

Richard E. Wilson (Boston, MA): We are indebted to the authors for presenting these data to us and educating us a bit more about this interesting disease. I have just one question. Most patients with transplants and immunosuppression do pretty well handling bacterical infections, especially when they are able to increase their white count effectively. The patient you talked about here increased her count to 19,000/mm3. I wonder if it is really appropriate to discontinue immunosuppression and lose the transplant in these patients now that you know how to diagnose and treat this disease?

Sang I. Cho (Boston, MA): I have two questions. First, of these 14 patients with Legionnaires’ disease, how many received antilymphocyte globulin? It is known that infectious complications, particularly viral or fungal infections, are more common in patients treated with antilymphocyte globulin. Second, early diagnosis of pulmonary infection in transplant patients was found to be critical in the management of this complication. What is the time lapse between the onset of pulmonary symptoms and the es- tablishment of diagnosis in patients with Legionnaires’ disease?

Roger S. Foster, Jr. (closing): Before we were able to recognize Legionnaires’ disease, the management of these patients was extremely frustrating. We not only have had to learn the intracacies of a new family of bacteria, but we have had to deal with purple prose in the regional press, such as the following: “For nearly two months this summer, a deadly mist drifted across a hilltop above this lakeside city of 38,000, picking its victims like some highly selective executioner” (Sunday Times Argus, August 24,198O).

We believe and hope that the source of this past summer’s two outbreaks of Legionnaires’ disease at our hospital, and quite probably the outbreaks in previous sum-

mers, has been identified. About 600 feet south of the hospital building is the medical school complex. Le- gionellae were identified in the cooling tower on that building. The cases of Legionnaires’ disease in our hospital this past summer appeared in two clusters. Operation of the cooling tower began in late spring. Shortly after that there was a clustering of Legionnaires’ disease cases, a culture of the tower showed legionellae, and the tower was given the recommended treatment with chlorine. A second culture from the cooling tower at the time of the second clustering of cases showed a reappearance of legionellae in the tower. Obviously, hyperchlorination was not permanently effective and with the occurrence of the second outbreak, the tower was permanently chlorinated. Plans to totally change the system are underway as the chlorine is destroying the system as it is.

In answer to Dr. Tilney’s question about the relation to high doses of steroids: yes, there is a relation to corticosteroids and immunosuppression. About half of our patients in these outbreaks were either renal failure or transplant patients or patients with malignancy or other diseases treated with steroids. There is clearly a relation- ship.

Many of our transplant patients did not develop Le- gionnaires’ disease in the days and weeks after treatment of acute rejection, but some did. The great majority of these patients did not have preceding leukopenia. The data show leukocytosis at the time of the development of pneumonia.

To answer Dr. Wilson’s question, although we tempo- rarily discontinued immunosuppression, we did reinstitute it once we felt the patient’s disease had been controlled. Since 1977, of the six patients who had a functioning transplant at the time of the development of Legionnaires’ disease, we have managed to keep the transplant to this date in five.

Dr. Cho, only one of our patients was treated with antilymphocyte globulin. Surprisingly, in our randomized trial of antithymocyte globulin, the Legionnaires’ disease seemed to spare the antithymocyte globulin patients. I think that this was just happenstance. If Legionnaires’ disease had been more common in the antithymocyte globulin-treated patients, it would have shut down that trial very quickly.

Most of the patients had not had splenectomy, and this did not seem to be a major factor contributing to susceptibility to Legionnaires’ disease in this group of patients.

Volume 141, ApIll 429

legionnaires' disease in renal transplant patients

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