Nosocomial Legionnaires' disease

Nosocomial Legionnaires’ Disease

Occurrence in Recipients of Bone Marrow Transplants

JOHN W. KUGLER, M.D.

JAM& 0. ARMITAGE, M.D.

CHARLES M. HELMS, M.D., Ph.D.

LYNELL W. KLASSEN, M.D.

NANCY E. GOEKEN, Ph.D.

GERALD 6. AHMANN, M.D., Ph.D.

ROGER D. GINGRICH, M.D., Ph.D.

WILLIAM JOHNSON, Ph.D.

MARY J. R. GILCHRIST, Ph.D.

lowa City, lowa

From the Department of internal Medicine and Microbiology, University of Iowa College of Med- icine, and the University Hygienic Laboratory, Iowa City, Iowa. Requests for reprints should be ad- dressed to Dr. John W. Kugler, Department of In- ternal Medicine, University of Iowa Hospitars, Iowa City, Iowa 52242. Manuscript accepted May 12, 1982.

Nosocomial pneumonia caused by Legionella pneumophila serogroup 1 occurred in five patients afler bone marrow transplantatton for hematologic malignancies. Two patients died as a result of the infection despite treatment with erythromycin. Serologic screening revealed no other cases of Legionnaires’ disease in 40 consecutive reciptents of bone marrow transplants, giving a frequency of infection of 13 percent. These five cases represent 23 percent of the pneumonia occurring in this group of patients. Patients undergokg bone marrow transplantation are highly susceptible to infectious complications. Legionnaires’ disease must now be added to the list of pathogens infecting this group of patients. Erythromyctn is not generally a part of standard empiric antibiotic regimens in februe neutropenic patients, but appears to be a reasonable addftion when pneumonia does not respond to conventional, empirk treatment. Even with appropriate therapy, Legionnaires’ dtsease remains a highly lethal infectton in immunocompromised hosts.

Legionnaires’ disease was first described in association with an out- break of pneumonia at an American Legion convention in Philadelphia, Pennsylvania, in 1976 [ 11. The causative agent, a fastidious gram- negative bacterium, was first isolated by McDade and associates [2] and subsequently named Legionella pneumophila [3]. In retrospect, this organism was identified as a pathogen as long ago as 1947

[41. lmmunocompromised patients have a markedly increased risk of

infectious complications, including Legionnaires’ disease [5-g]. Among immunocompromised hosts, the recipients of renal transplants appear to be particularly susceptible to Legionella infection, especially in the hospital setting [8-lo]. Nosocomial L. pneumophila infection after cardiac transplantation has also been reported [ 111. Patients undergoing bone marrow transplantation are extremely prone to infectious complications [ 121. To our knowledge, however, Legion- naires’ disease has not been previously described in recipients of bone marrow transplants. We report herein five cases of nosocomial Le- gionnaires’ disease complicating bone marrow transplantation. The occurrence of Legionnaires’ disease in this group of patients adds another to the list of those immunocompromised hosts at risk for this potentially lethal infection.

CASE REPORTS

Patient 1. In July 1981, a 23-yearalcl man with acute lymphoblastic leukemia in early third relapse underwent preparative cytoreductive therapy for bone marrow transplantation with 5 mg/kg of cytarabine on pretransplant Days 7 and 2 and 90 mg/kg of cyclophosphamide on pretransplant Day 5. On the

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NOSOCOMIAL LEGIONNAIRES’ DISEASE-KUGLER ET AL

day of transplantation (Day 0), he received 900 rads of total body irradiation at 8 rads per minute. The donor was his fa- ther, in whom mixed lymphocyte culture gave nonreactive results but with whom there was a mismatch for one of the HLA-A antigens. Prophylactic trimethoprim-sulfamethoxazole was administered from pretransplant Day 7 through pretransplant Day 2. Methotrexate was given at dosages of 15 mg/m* on post-transplant Day 1 and, subsequently, 10 mg/m* on post-transplant Days 3, 6, and 11 and then weekly except for post-transplant Day 18. On post-transplant Day 4, the patient had right eye periorbital erythema and swelling but remained afebrile. On post-transplant Day 7, he had a fever of 39.4’C. Results of a chest x-ray were normal. After a thorough examination and after blood, urine, and stool culture specimens had been obtained, the patient received cefazolin 2 g every six hours and 120 mg of tobramycin initially followed by 100 mg every eight hours. On post-transplant Day 9, because of persistent fevers, 5 g of carbenicillin every four hours was added. On post-transplant Day 10, right anterior pleuritic chest pain developed. Results of chest examination were normal, and a chest x-ray was again unremarkable. Amphotericin B was begun the same day. On post-transplant Day 12, the right chest pain became persistent, and the patient became tachypneic and dyspneic. Chest examination results remained normal, but a chest x-ray showed a small right middle lobe alveolar infiltrate. Relative bradycardia was noted with heart rates of 90 beats per minute and concurrent temperatures greater than 39.5’C. Intrave- nous administration of 500 mg of erythromycin every six hours was begun. On post-transplant Day 13, a nonproductive cough developed, along with intermittent episodes of marked confusion and short-term memory loss. The white blood cell count at this time was 0.2 X log/liter. The serum sodium level was 129 meq/liter. A work-up for inappropriate secretion of antidiuretic hormone gave negative results. The serum creatinine level increased from 0.8 to 1.4 mg/dl. By post- transplant Day 14, defervescence occurred, and his condition clinically stabilized. The cough gradually became more productive with small amounts of hemoptysis. By post- transplant Day 15, the mental status changes had cleared and the serum sodium and creatinine levels had returned to their previous normal baseline values. All antibiotics were subsequently discontinued except for erythromycin. On radio- graphic study, the pneumonia was seen to progress to consolidation of the right middle lobe by post-transplant Day 18 (Figure 1). The pneumonia gradually resolved clinically by post-transplant Day 40, although there was some minimal residual scarring visible radiographically. The patient received a 24day course of 500 mg of erythromycin orally four times a day and is currently beyond post-transplant Day 265 without any recurrence of the Legionnaires’ disease and with excellent graft function.

A smear of sputum obtained on post-transplant Day 12 contained 25 fluorescent rods per oil-immersion field visible by direct fluorescent antibody staining for L. pneumophila serogroup 1. The organism was subsequently isolated on charcoal-yeast extract agar after inoculation with spleen homogenates from guinea pigs that had received intraperi- toneal injection of the patient’s sputum. Acute and convalescent indirect fluorescent antibody titers against heat-killed

L. pneumophila serogroup 1 were less than 1:32 and 1:512, respectively, with the convalescent serum drawn three weeks after the onset of the infection and run in parallel with the acute specimen. Acute and convalescent antibody titers against mycoplasmal, protozoal, fungal, and viral pathogens did not rise. Patient 2. Also in July 1981, a 15-year-old man with acute lymphoblastic leukemia in third complete remission underwent cytoreductive therapy for bone marrow transplantation identical to that reported in Patient 1. His donor was an HLA-identical sibling. He also received the same prophylactic trimethoprim-sulfamethoxazole and methotrexate regimens as reported in Patient 1. On post-transplant Day 9, he became febrile to 39.5’C. Results of a chest x-ray were normal. Physical examination was remarkable only for the finding of several pustulo-vesicular lesions on his face. After a Tzanck smear gave negative results and after culture samples of these lesions and of blood and urine were obtained, he began receiving 2 g of cefazolin every six hours and 145 mg of tobramycin initially followed by 120 mg every eight hours. Within 48 hours, the patient had defervescence and remained afebrile. A blood culture specimen grew Staphylococcus aureus that was sensitive to the antibiotics the patient was receiving. He continued to do well clinically and remained afebrile until post-transplant Day 15 when he began com- plaining of left shoulder pain. On post-transplant Day 16, he became febrile to 39.2’C. The left shoulder pain persisted and was associated with left pleuritic chest pain without cough or sputum production. Chest examination gave normal findings, but the chest x-ray showed a localized infiltrate in the left lower lobe seen only in the lateral projection (Figure 2). Blood and urine specimens were recultured. He received 500 mg of erythromycin every six hours in addition to the other antibiotic regimen. Within 24 hours, he had defervescence and subsequently remained afebrile. On post-transplant Day 17, fine rales were heard over the left base with localized egophony. The white blood cell count at this time was 0.5 X log/liter. His entire chemistry profile at this time was within normal limits. By post-transplant Day 20 his chest was again clear on physical examination, and the left lower lobe infiltrate was seen as resolving on radiologic study. By post-transplant Day 24, his white blood cell count was 3.3 X log/liter with 1.6 X log/liter neutrophils. Blood cultures were sterile at this time, and administration of cefazolin and tobramycin was discontinued. Erythromycin, 500 mg intravenously four times a day, was continued for a 16day course and was then discontinued. The patient was discharged on post-transplant Day 35 and was seen daily as an outpatient. All positive microbiologic and serologic results at the time the pneumonitis had developed were negative.

He was readmitted on post-transplant Day 45 after several days of progressive malaise, weakness, anorexia, and IOW- grade fever. On post-transplant Day 46, the patient became febrile to 39.9OC, had episodes of chills and sweating, and a nonproductive cough without other respiratory symptoms. Repeated attempts to obtain sputum were unsuccessful. Results of chest examination were normal, and the chest x-ray was unremarkable. Cultures of blood and urine specimens were again sterile. Other laboratory studies were remarkable for a white blood cell count of 1.3 X log/liter with

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of the right middle lobe.

0.5 X log/liter neutrophils. Liver function results showed new abrupt abnormal elevations: serum glutamic-oxaloacetic transaminase of 290 IMiter (normal 7.5 to 40), serum glutamic-pyruvic transaminase of 226 Ill/liter (normal < 35), lactate dehydrogenase of 924 Ill/liter (normal 100 to 225), and gamma-glutamyl transpeptidase 977 IMiter (normal 10 to 85). He began receiving 500 mg of erythromycin every 6 hours. Within 24 hours, he had defervescence and subsequently remained afebrile. By post-transplant Day 48 he was much improved clinically. The chest was clear on physical examination, and the chest x-ray was still unremarkable. He was discharged on post-transplant Day 50 entirely asymptomatic and completed a full Plday course of erythromycin. He is currently beyond post-transplant Day 258 and is asymptomatic. His liver function results have returned to normal. His white blood cell count is currently 4.5 X log/liter with 2.9 X log/liter neutrophils.

In this case, sputum specimens were not obtainable. Acute and convalescent indirect fluorescent antibody titers against L. pneumophila serogroup 1, however, were less than I:32 and 1512, respectively, with the convalescent serum drawn four weeks after the onset of pneumonitis and run in parallel with the acute specimen. Acute and convalescent antibody titers for all other mycoplasmal, protozoal, fungal, and viral pathogens did not rise. Patient 3. In August 1981, a 27-year-old man with a dysmyelopoietic syndrome and increasing marrow cellularity underwent cytoreductive therapy for bone marrow transplantation identical to that reported in Patient 1. His donor was an HLA-identical, mixed lymphocyte culture-nonreactive sibling. He also received the same trimethoprim-sulfamethoxazole and methotrexate prophylaxis regimens as described in Patient 1. His bone marrow sample on post-transplant Day 14 Showed evidence of early engraftment of the new marrow, followed by good peripheral recovery beginning on post- transplant Day 20. A maculopapular graft-versus-host rash developed on post-transplant Day 29 and quickly progressed

Figure 2. Lateral chest radiogram Day 2 of illness in Patient 2 showing a very localized infiltrate silhouetting a portion of the left hemidiaphragm.

to clinical stage 3 by post-transplant Day 32. On post-transplant Day 33, he had evidence of hepatic graft-versus-host disease that subsequently progressed to clinical stage 3 and later stage 4 on post-transplant Days 45 and 65, respectively. The graft-versus-host disease was managed with methylprednisolone and azathioprine. He remained afebrile throughout the post-transplantation period, until post-transplant Day 61 when his temperature spiked to 38.6%. Chest x-ray findings were normal, and a thorough examination revealed no identifiable source of infection except for a small abscess in the right thigh from which Staph. aureus had been cultured on post-transplant Day 5 1. This was continuing to resolve with 2 g of cefazolin intravenously every six hours, to which the organism showed in vitro sensitivity. Since the patient’s white blood cell count at this time was 4.3 X log/liter with 3.4 X log/liter neutrophils, additional antibiotics were withheld pending initial culture results. On the following day, he complained of right posterior chest pain associated with a slight hacking nonproductive cough. Both chest examination and chest x-ray results were again normal. These symptoms persisted, and on the following day (post-transplant Day 63), chest examination showed decreased breath sounds at the right base and a chest x-ray showed a small right lower lobe infiltrate. Tobramycin, 100 mg initially followed by 80 mg every eight hours, and carbenicillin, 5 g every four hours, were subsequently added to the antibiotic regimen. On post-transplant Day 65, the patient’s cough became productive of some blood-tinged sputum, and he complained of a headache associated with the cough. A chest x-ray showed progression of the right lower lobe infiltrate along with a new right pleural effusion. Sputum gram stain gave negative results. His white blood cell and neutrophil counts remained stable. However, his platelet count, which had initially re- covered to a maximal level of 142 X log/liter on post- transplant Day 45, had slowly decreased to 26 X 10g/liter. A lumbar puncture was not attempted in view of the throm- bocytopenia. The patient was intermittently lethargic. He also



began receiving 1 g of erythromycin intravenously every six hours and amphotericin. A sputum sample on post-transplant Day 66 contained more than 25 fluorescent rods per oil- immersion field visible by direct fluorescent antibody staining for L. pneumophila serogroup 1. The organism was subsequently grown on charcoal-yeast extract agar directly from the sputum specimen. All other stool, urine, blood, throat, nasopharynx, and routine sputum cultures were ultimately sterile. Amphotericin was discontinued. By post-transplant Day 69, his pulmonary infiltrate had involved the entire right lung and he had an increasingly large right pleural effusion. The patient’s pulmonary and neurologic status continued to deteriorate and he died on post-transplant Day 70. Autopsy was not permitted. All acute serologic studies for mycoplasmal, protozoal, fungal, and viral pathogens gave negative results. Indirect fluorescent antibody titers for L. pneumophila had not risen by the time of his death. Patient 4. In October 1981, a lo-year-old girl with acute nonlymphoblastic leukemia in early fourth relapse underwent cytoreductive therapy for bone marrow transplantation identical to that reported in Patient 1. Her donor was an HLA-identical, mixed lymphocyte culture-nonreactive unre- lated 33-year-old woman. She also received trimethoprim- sulfamethoxazole and prophylaxis similar to that described

Figure 3. Chest radiogram on Day 3 of illness in Patient 4 showing a well-circumscribed nodular lesion in the medial aspect of the anterior segment of the rlghf upper lobe.

in Patient 1. Her bone marrow specimen demonstrated def- inite evidence of early engraftment on post-transplant Day 14 with no evidence of any residual leukemia. On post- transplant Day 19 a rash developed on her palms, soles, and

neck that was clinically consistent with graft-versus-host disease, although the lesions were never biopsied for con- firmation. She was treated with methylprednisolone with complete resolution of the rash by post-transplant Day 24. Sh.e initially became febrile on post-transplant Day 8 with spiking to 38.8OC. Therapeutic doses of cefazolin and tobramycin were begun, and carbenicillin was subsequently administered after a thorough examination and culture work-up. No focus of infection or organism was ever identified, and a chest x-ray was normal. By post-transplant Day 12, she had defervescence and remained afebrile until post-transplant Day 24 when she again had an upward trend in her temperature curves; her temperature spiked to 38.8% on post-transplant Day 25. She was receiving three antibiotics at this time and was entirely asymptomatic. On post-transplant Day 26, she complained of right shoulder and axillary pain associated with motion of the right shoulder girdle but also present with deep inspiration. Results of both chest examination and chest x-ray were normal. The shoulder/ axillary pain was still present the following day but seemed

Figure 4. Chest radiograms on Day 5 of illness in Patient 4 showing progression of the previous nodular lesion to a wedge-shaped consolidation extending to

m the pleural surface.

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Figure 5. Chest radiograms on Day 7 of illness in Patient 4 showing further progression to an infiltrate pattern involving all three segments of the right upper lobe along with a small right pleural effusion.

Figure 6. Portable chest radiogram on Day 10 of illness showing further progression of the infiltrates to involvement of the entire right lung field.

to decrease as the day went on. By post-transplant Day 28 her white blood cell count had increased to 0.8 X log/liter which was hoped to be evidence of early peripheral recovery. Her temperature had further increased to 39.5% and she continued to complain of right shoulder pain. She otherwise remained asymptomatic, and her chest remained clear on examination. A repeat chest x-ray, however, revealed a new well-circumscribed nodular lesion in the right upper lobe (Figure 3) that was localized to the medial aspect of the anterior segment on tomography. Her platelet count at this time was 46 X log/liter. Because of the location of the lesion, percutaneous needle aspiration was believed to be too risky. Thoracotomy was also considered but was decided against. Amphotericin was started. On post-transplant Day 30, a few rales were noted over the right upper lobe anteriorly. A chest x-ray demonstrated wedge-shaped consolidation in the anterior segment of the right upper lobe extending to the pleural surface, suggestive of a pulmonary infarct (Figure 4). By post-transplant Day 32, there were a few rales noted at the right base with associated egophony. At this time, the chest x-ray showed an infiltrate involving all three segments of the upper lobe and a new small pleural effusion at the right base (Figure 5). Thoracentesis was performed after platelet transfusion. Pleural fluid was an exudate. No organisms were seen on gram stain, and no fungal elements were identified. Pleural fluid smears, however, showed greater than 25 fluorescent rods per oil-immersion field on direct fluorescent antibody staining for L. pneumophila serogroup 1. The same organism was subsequently grown on charcoal-yeast extract agar directly from the pleural fluid. She immediately began receiving 500 mg of erythromycin intravenously every six hours. By post-transplant Day 35, the infiltrates involved all three lobes of the right lung, and there was an increase in the pleural effusion (Figure 6). Rifampin, 600 mg every day, was added to her regimen. By post-transplant Day 37, the infiltrates also involved the left perihilar region. Her respiratory status continued to deteriorate. A mild degree of biventricular failure developed and responded to medical management. On post-transplant Day 38, she had cardiorespiratory arrest and could not be resuscitated. Permission for autopsy was not obtained. All of the cultures from her blood, urine, stool, and throat specimens were sterile. Sputum culture specimens

were never obtainable. All acute serologic studies for mycoplasmal, protozoal, fungal, and viral pathogens showed no diagnostic change. The acute indirect fluorescent antibody titer for L. pneumophila also had not yet shown any diagnostic change. Patient 5. The patient, a 23-year-old woman with a one- and-a-half-year history of Philadelphia chromosome-positive chronic myelogenous leukemia, was initially admitted to our institution in July 1981. At the time of admission, she demonstrated a “blast crisis” with an M3 French-American-Brttish classification of her bone marrow sample. She was given two cycles of TADPO’ induction therapy and, despite a multitude of complications, had a complete remission. She was then transferred to our bone marrow transplantation unit in early October 1981, and underwent cytoreductive therapy for bone marrow transplantation identical to that previously described, as well as the same prophylactic trimethoprim-sulfamethoxazole and methotrexate regimens, also previously described. Her donor was a younger brother with whom there was a partial mismatch at the HLA-B locus but who was mixed lymphocyte culture-nonreactive. Her bone marrow specimen on post-transplant Day 14 showed evidence of early engraftment followed by peripheral recovery on post-transplant Day 26. She initially became febrile to 38.5’C on post- transplant Day 8 at which time her white blood cell count was 0.5 X log/liter. Physical examination revealed no source of infection. A chest x-ray was clear, and blood, urine, throat, and stool cultures were all subsequently sterile. She began receiving 2 g of cefazolin every six hours and 80 mg of tobramycin every eight hours. Her temperature continued to rise to 40.0% on post-transplant Day 11, and 4 g of carbenicillin every four hours was added to her antibiotic regimen. Results of physical examination remained unremarkable, and she continued to have fevers spiking as high as 40.7’C. Am-

photericin was added on post-transplant Day 13, with grad-

l Daunomycin, 1.5 mg/kg intravenously, on Days 1, 2, and 3; cy- tosine arabinoside, 2 mg/kg intravenously, every two hours for seven days; 64hioguanine, 2 mg/kg orally, every two bows for seven days: prednisone, 1 mg/kg orally, for seven days; vincristine, 1 mg/m2 (maximum 2 mg) intravenously, on Days 1 and 7.



ually increasing doses each day, again without change in her fever pattern. On post-transplant Day 16, rales were noted at the right base on lung examination. She denied any respiratory symptoms, and a chest x-ray was again clear. On post-transplant Day 17, right basilar rales were still present, and she complained of pleuritic chest pain in this same area. A chest x-ray now showed a right lower lobe and right perihilar alveolar infiltrate. She began receiving 1 g of erythromycin intravenously evely six hours. By post-transplant Day 19, her pleuritic chest pain had resolved, and rales were decreased. A minimal hacking cough did develop on post- transplant Day 19, but this never was productive. By post- transplant Day 21, she had defetvescence and remained afebrile. By post-transplant Day 26, her chest x-ray had entirely cleared. Because of her neutropenia, she continued receiving all antibiotics and amphotericin until post-transplant Day 28, after which they were all discontinued. Her white blood cell count at that time was 2.2 X log/liter with a 1.1 X log/liter neutrophil count. However, because of the strong presumption of Legionnaires’ pneumonia, she continued receiving erythromycin for a full 22-day course. All serial blood, stool, and urine culture samples were subsequently sterile. On post-transplant Day 48, she had low-grade fever to 38% along with mononucleosis-like symptoms. A mo- nospot test result was negative. Her symptoms gradually abated, and her temperature returned to normal over the next seven days without any specific treatment. Cytomegalovirus infection was strongly suspected, and cytomegalovirus was eventually isolated from a urine specimen obtained during this period of time. She was discharged to an outpatient status on post-transplant Day 57 and then seen daily until post- transplant Day 73 before returning home.

Because of the evidence of a cytomegalovirus infection and our strong suspicion of Legionnaires’ disease, serial convalescent specimens were drawn for cytomegalovirus and L. pneumophila titers and run in parallel with the acute specimens. The acute cytomegalovirus titer on post-transplant Day 48 was I:8 and a convalescent titer on post- transplant Day 85 was 1:8; when last checked on post- transplant Day 141, it remained at 1:8. The acute indirect fluorescent antibody titer for L. pneumophila serogroup 1 was 1:64 on post-transplant Day 8, but the convalescent titer rose to 1: 1,024 on post-transplant Day 106. All other acute and convalescent titers for mycoplasmal, protozoa& fungal, and viral pathogens have not increased. She is currently beyond post-transplant Day 160 in good health with no evidence of disease. She has excellent graft function and is Philadelphia chromosome-negative.

COMMENTS

Many patients with Legionnaires’ disease have underlying diseases, with irnmunosuppressed or immunocompromised patients accounting for a significant proportion of these cases [5-lo]. Our cases occurred 42,22,78,38, and 104 days after the patients’ admls- sion to our institution and, therefore were nosocomial infections. In December 1981, L. pneumophila serogroup 1 was isolated from the hospital’s hot water

system using semiselective charcoal-yeast extract medium. Epidemiotogic studies and environmental surveillance are underway to evaluate the significance of this finding.

Although not previously described, it is clear that patients receiving bone marrow transplants, like patients receiving renal transplants [8-lo] and cardiac transplants [ 111 are susceptible to nosocomial L. pneumophila infection. Our first patient exhibited many of the typical clinical and laboratory features that are seen in Legionnaires’ disease [ 5-71. In the second and fifth patients, however, the disease was more occult in clinical behavior. Aside from our clinical suspicions in these cases, we were only able to make the diagnosis retrospectively, based on serologic conversion. The second and fourth patients are unusual in that they were only 15 and 10 years old, respectively. Infections caused by L. pneumophila in immunologically intact or immunocompromised children have been infrequently reported [8]. However, one prospective study by An- dersen et al [ 131 showed that, although L. pneumophila was an uncommon cause of acute lower respiratory disease in childhood in their area, there was a significant exposure rate to the organism as evidenced by a 52 percent incidence of seroconversion in these children

[131. The clinical response to erythromycin therapy in

Patients 1, 2, and 5 was prompt. That patients may re- quire more than two weeks of antibiotic therapy to eradicate infection is suggested by the apparent relapse in Patient 2, who initially received only 16 days of therapy. In this respect, patients receiving bone marrow transplants appear to be similar to other immunocompromised hosts with Legionnaires’ disease in whom a course of at least 21 days has been suggested to pre- vent relapse of the infection [5,6,14].

Patients 3 and 4 graphically represent the potentially malignant nature of this illness, particularly in immunocompromised patients. Case-fatality ratios in patients with Legionnaires’ disease treated with erythromycin vary from 8 to 24 percent depending on the presence or absence of immunosuppression. Without erythromycin therapy, these figures range from 25 to 80 percent in nonimmunosuppressed and immunosuppressed patients, respectively [ 51. Patient 3 died of progressive respiratory insufficiency and subsequent cardiovascular collapse; this has been the most common mode of death in these patients. Patient 4 died from a somewhat unexpected fatal cardiorespiratory arrest, which has also been observed in patients with this infection.

A retrospective surveillance of the first 40 patients receiving bone marrow transplants at the University of Iowa showed seroconversion to have occurred in none other than the three reported herein. Patients 3 and 4 died from their pneumonia before seroconversion. All

286 February 1983 The American Journal of Medlclne Volume 74

patients were serologically evaluated using paired serum specimens run in parallel with an indirect fluorescent antibody technique. Polyvalent antigen (sero- groups 1 to 4) and patient serum samples at a dilution of 1:64 were used to screen for seroconversion. Serum samples obtained before transplantation were used as acute specimens in all cases. In those without documented pneumonia, serum samples drawn just before discharge were used as the convalescent specimens. In patients with documented pneumonia, serum samples drawn three to six weeks after the development of pneumonitis were used as the convalescent specimens. In five patients who died of pneumonia of undiagnosed cause, the time interval between the development of pneumonia and death was less than that required for optimal convalescent serum samples to be obtained. In these five, serum samples at the time of their death were utilized. Autopsies in these patients, however, showed no evidence of L. pneumophila infection, and direct fluorescent antibody smears of their sputum for L. pneumophila had given negative results before their death. Antibody titers have generally begun to increase by three weeks, and a diagnostic four-fold rise has occurred in the majority of patients by six weeks. Ap- proximately 10 percent of patients, however, appear to have seronegative results for reasons that are not clear [ 21. It is of interest that our Patient 5 did not have any evidence of seroconversion until 14 weeks after the onset of her illness. This most likely reflects the im- maturity of the immune system of patients receiving bone marrow transplants in the early post-transplantation period. It might be speculated that she acquired her exposure to L. pneumophila after she left the hospital, accounting for the apparent delay in seroconversion. She, however, had no compatible clinical illness during that period of time, and, therefore, this possibility seems quite unlikely.

The frequency of L. pneumophila infection in our patients undergoing bone marrow transplantation was 13 percent. Overall, there have been 22 cases of pneumonia in our patient population, for an overall frequency of 55 percent. The relative frequency of pneumonia caused by L. pneumophila was, therefore, 23 percent-approximately four times that of L. pneumonia infection found among patients with pneumonia in the overall population of Iowa [ 15,161.

NOSOCOMIAL LEGIONNAIRES DISEASE-KUGLER ET AL

High fever, pleuritic chest and/or shoulder pain, and an intermittent nonproductive cough have been early features present in all five of our patients. It is important to note that these findings preceded any radiologic or auscultatory change, in all but the last patient, by one to two days. Three of our five patients have had mental status changes without focal neurologic findings. The radiologic findings have been extremely variable and, as noted in Patient 4, may be misleading. In that patient, erythromycin therapy was delayed for four days, during a trial of amphotericin for a nodular lesion seen on the chest x-ray that was highly suggestive of a fungal infection.

The prognosis of Legionnaires’ disease is dependent upon the patient’s underlying disease and the early institution of appropriate antibiotic therapy. Patients 3 and 4 exemplify the fact that in immunocompromised patients, even with appropriate therapy, this infection carries a high degree of mortality. We can only spec- ulate whether earlier initiation of erythromycin therapy alone or in combination with rifampin would have al- tered the outcome in those two patients.

Physicians caring for patients receiving bone marrow transplants should be aware of the potential for L. pneumophila as an etiologic agent in the clinical setting of pneumonitis that has not responded to conventional empiric antibiotic regimens in severely neutropenic patients. This is particularly true since erythromycin is not generally used in empiric antibiotic combinations in febrile, neutropenic patients. We believe that in cases of pneumonia in these patients, with nondiagnostic sputum gram stains and negative results of culture, when pneumonitis fails to respond to standard empiric therapy, erythromycin is a reasonable antibiotic to add. In patients in whom Legionella pneumonitis is strongly suspected and who have shown response to erythromycin but remained seronegative, we recommend following convalescent titers at periodic intervals for several months in an effort to document delayed seroconversion as the result of an immature immune system.

ACKNOWLEDGMENT

We wish to thank Ms. Nancy Hall and Mr. John Elliot for their technical assistance in the microbiologic and serologic studies that were conducted for this paper.

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14. Gump DW, Frank RO, Winn WC Jr, Foster RS Jr, Broome CV, Cherry WB: Legionnaires’ disease in patients with associated serious disease. Ann Intern Med 1979; 90: 538- 542.

15. Renner ED, Helms CM, Hierholzer WJ Jr, et al: Legionnaires’ disease in pneumonia patients in Iowa. A retrospective seroepidemiologic study, 1972-1977. Ann Intern Med 1979; 90: 603-606.

16. Helms CM, Renner ED, Viner JP, Hierholzer WJ Jr, Johnson W, Hausler WJ Jr: Legionnaires’ disease among pneumonias in Iowa (FY 1972-1978). J Iowa f&d Sot 1981; 71: 335-339.

288 February 1983 The American Journal of Medlclne Volume 74

Documents

Nosocomial Legionnaires' disease