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Nocardial Infections in Bone Marrow Transplant Recipients Carlos Choucifio, Stacey A. Goodman, John P. Greer, Richard S. Stein, Steven N. Wolff, and J. Stephen Dummer

From the Department of Medicine, Divisions of Infectious Diseases, Hematology, and Oncology, and the Department of Surgery, Vanderbilt University School of Medicine,. and The Nashville Veterans Administration Hospital, Nashville, Tennessee

Infections caused by Nocardia species have been infrequently described in bone marrow transplant (BMT) recipients. We reviewed six cases of nocardiosis occurring in our population of BMT recipients and the four cases previously reported in the literature. The rate of nocardial infection at our institution was 0.2% (1 of 554) among autologous BMT recipients and 1.7% (5 of 302) among allogeneic BMT recipients (odds ratio, 9.3 [95% confidence interval, 1.1 —80.1]; P = .046). All 10 patients had received immunosuppressive medications, and all but one allogeneic BMT recipient had acute or chronic graft-vs.-host disease (GVHD). Four patients had extensive exposure to soil or dust before nocardiosis developed. Seventy percent of the patients died, but death was less often due to progressive nocardial infection than to complications of GVHD and associated invasive infection with Aspergillus species. Three patients had nocardiosis despite receiving prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMZ) on an intermittent basis two or three times a week. These data show that nocardial infection is an important if infrequent complication of bone marrow transplantation and is associated with a high rate of invasive fungal infection. TMP-SMZ prophylaxis given intermittently does not reliably protect against infection. Nocardia species are aerobic actinomycetes that are widely distributed in nature and often found in decaying organic matter and natural soil. Nocardia may cause disease in patients with normal immunity but more often causes opportunistic infections in patients whose immune systems are compromised by lymphoreticular neoplasms, AIDS, autoimmune disorders, and immunosuppression associated with transplantation. The risk of nocardial disease in solid organ transplant recipients is well recognized, but only four cases of nocardial infection after bone marrow transplantation have been reported [1-4]. Over the past 14 years, we have diagnosed nocardial infections in six bone marrow transplant (BMT) recipients at our institution. In this report, we describe and comment on these six cases and the four cases previously reported in the literature.

Materials and Methods We identified all Nocardia species isolated from patients who underwent bone marrow transplantation at our institution between 1 January 1980 and December 1994. Isolates of Nocardia were identified by standard biochemical tests. Isolates from four of our six cases (cases 1, 2, 4, and 6) were sent to the laboratory of Dr. Richard Wallace, Jr., at the University of Texas Health Sciences Center at Tyler, where species determi-

Received 16 January 1996; revised 31 May 1996. Reprints or correspondence: Dr. J. Stephen Dummer, 911 Oxford House, 1313 21st Avenue South, Vanderbilt University School of Medicine, Nashville, Tennessee 37232. Clinical Infectious Diseases 1996; 23:1012-9

© 1996 by The University of Chicago. All rights reserved. 1058-4838/96/2305-0011$02.00

nation and sensitivity testing were done. Demographic, clinical, laboratory, and radiological data were obtained from each patient's records. Autopsy reports were also reviewed. A search of the English-language literature via MEDLINE was conducted for other cases reported between 1966 and 1995. The proportion of allogeneic and autologous transplant patients in whom nocardiosis developed was compared by calculating an odds ratio and 95% confidence intervals. Significance testing was done with Fisher's exact test. Case Reports Case 1

A 48-year-old farmer underwent allogeneic bone marrow transplantation for treatment of the chronic phase of chronic myelogenous leukemia (CML); the Philadelphia chromosome was present in his marrow cells. His posttransplantation course was complicated by acute respiratory distress syndrome and mastoiditis. Acute and chronic graft-vs.-host disease (GVHD) also developed, which required continued treatment with oral corticosteroids. One and one-half years after transplantation, the patient was admitted to the hospital because of a 4-week history of a progressively severe parietal headache and blurred vision. The patient's medications included cyclosporine (240 mg three times a week), methylprednisolone (24 mg every other day), and trimethoprim-sulfamethoxazole (TMP-SMZ; two doublestrength tablets twice a week). He was afebrile. Neurological examination revealed only slow mentation and mild proximal myopathy due to steroid use. His WBC count was 7,000/mm 3 (88% neutrophils). A CT of the head showed an abscess cavity in the left temporal lobe that was enhanced with intravenous

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contrast medium. Culture of a stereotactic aspirate of the abscess yielded Nocardia nova. The patient was treated with intravenous cefotaxime (2 g every 6 hours), amikacin (360 mg every 12 hours), and oral sulfisoxazole (1.5 g four times daily). After 3 weeks, ceftriaxone (2 g every 12 hours) was substituted for cefotaxime because of a superior in vitro MIC (4 ,ug/mL vs. 32 ,ug/mL, respectively), and the sulfisoxazole dosage was increased to 2 g four times a day because of serum levels of 53 mg/dL. The patient's condition became more stable over 2 weeks and then gradually improved. Therapy with intravenous amikacin was discontinued after 1 month, as was intravenous ceftriaxone therapy after 3 months. Fourteen months later, CTs of the brain showed resolution of the abscess, and sulfisoxazole therapy was stopped. The patient has remained well during a 3-year follow-up.

to be a toxic reaction to his chemotherapy). He received therapy with a 2-week tapering course of prednisone (starting at 40 mg twice a day) and two double-strength tablets of TMP-SMZ twice a week for 2 weeks. When a urine culture yielded cytomegalovirus, he also received ganciclovir therapy for 2 weeks. Four months after transplantation, the patient was admitted to the hospital because of fever (temperature to 103°F), pleuritic chest pain, and a productive cough. Physical examination revealed rales and changes consistent with consolidation in both upper lung fields. A chest radiograph showed infiltrates in the right middle lung and left suprahilar area. His WBC count was 8,500/mm 3 (79% neutrophils). Therapy with erythromycin and cefotaxime was administered empirically. During bronchoscopy, white friable endobronchial lesions were seen throughout the airways of the right lung. Cultures of bronchoscopy specimens yielded both Blastomyces dermatitidis and Nocardia ast-

Case 2

eroides.

A 23-year-old college student underwent matched unrelated bone mone transplantation for treatment of a relapse of acute myelomonocytic leukemia. His course was complicated by grade III GVHD of the skin and gastrointestinal tract that was treated with antithymocyte globulin and oral methylprednisolone. Inhaled pentamidine was administered monthly as prophylaxis for pneumocystis pneumonia. Thirteen months after transplantation, he had a flare of GVHD of the skin accompanied by a new onset of cough and dyspnea without fever. His WBC count was 9,400/mm 3 (85% neutrophils). Radiographs and a CT showed patchy peripheral infiltrates. The lung disease was ascribed either to bronchiolitis obliterans or to bacterial infection, and he received treatment with oral corticosteroids, cyclosporine, and erythromycin. The skin rash decreased, but the cough and shortness of breath persisted; he was admitted to the hospital. Daily medications at this time included methylprednisolone (20 mg) and cyclosporine (50 mg). A transbronchial biopsy was nondiagnostic, but bronchial cultures yielded N. nova. Treatment with sulfisoxazole (1 g four times daily) and imipenem (500 mg every 8 hours) was initiated, and a repeat course of antithymocyte globulin was given for treatment of presumed bronchiolitis obliterans. The patient's radiographically evident infiltrates decreased, but his respiratory status worsened. Twenty-one days later, an open lung biopsy confirmed the clinical diagnosis of bronchiolitis obliterans. Nocardia was not detected in the biopsy samples. The patient's respiratory status continued to deteriorate, and he died 2 weeks later. Case 3

A 37-year-old man who was a part-time farmer and construction worker underwent autologous bone marrow transplantation for treatment of large transformed cell lymphoma. His posttransplantation course was complicated by bacteremia due to Klebsiella pneumoniae and mild alveolitis (which was thought

A CT of the brain was unremarkable, but an MRI showed increased signals in the left caudate nucleus and right internal capsule. The blastomyces infection was treated with amphotericin (total dose, 2 g) followed by ketoconazole (200 mg twice a day) for 6 months. The nocardial infection was treated with minocycline (200 mg twice a day) for 6 months. The patient has remained free of recurrent blastomycosis or nocardiosis during a 5-year follow-up.

Case 4 A 39-year-old man underwent allogeneic bone marrow transplantation for treatment of CML. A short course of corticosteroids was administered as treatment of an allergic skin reaction to TMP-SMZ, and monthly treatments with inhaled pentamidine were substituted for prophylaxis for pneumocystis pneumonia. Seven weeks after transplantation, a new rash occurred. Findings of skin biopsy were suggestive of acute GVHD, and therapy with oral corticosteroids was reinstituted. Four months after transplantation, the patient had a cough and right-sided pleuritic chest pain that continued for 2 weeks. A chest radiograph showed a masslike infiltrate in the right costophrenic angle. Culture of a sputum sample yielded K. pneumoniae. This infection was treated with intravenous cefotaxime for 4 days and oral ofloxacin for 2 weeks, and the patient's condition improved. Four weeks later, his cough and chest pain recurred. Medications at this time included cyclosporine (100 mg daily) and methylprednisolone (24 mg every other day). At the time of admission, a chest radiograph showed a pleural-based mass in the right costophrenic angle. A CT of the brain revealed an area of low attenuation in the right cerebellum, and an MRI of the head demonstrated multiple enhancing lesions in the cerebellum, thalamus, and right temporal and left frontal cortex. His WBC count was 2,800/mm 3 (69% neutrophils). N. asteroides was isolated from a sputum sample, and intravenous

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antibiotics (imipenem and amikacin) were administered for 4.5 weeks followed by oral clarithromycin (500 mg twice a day). During a follow-up 3 weeks later, an MRI of the brain revealed that all of the brain lesions except the cerebellar lesion had resolved. Two months later, the patient was readmitted to the hospital because of fever, epistaxis, and lethargy. A chest radiograph showed a new infiltrate in the right lower lobe. A CT showed resolution of all brain lesions. Blood cultures yielded Pseudomonas aeruginosa and Cognebacterium jeikeium. Antibiotic therapy was administered, and the patient's condition stabilized. However, a few days later, he had severe grade IV GVHD of the skin with extensive exfoliation that led to multiorgan failure and death. Case 5

A 49-year-old man underwent allogeneic bone marrow transplantation for treatment of the chronic phase of CML. His posttransplantation course was complicated by bacteremia associated with an intravenous catheter and grade II acute GVHD that evolved into chronic GVHD (for which continuous corticosteroid therapy was required). Nine months after transplantation, the patient had fever (temperature to 101.5°C) with back and upper abdominal pain. At the time of admission, his daily medications included methylprednisolone (40 mg), cyclosporine (100 mg), and fluconazole (200 mg). Physical examination revealed markedly decreased breath sounds and dullness over the left lung field. His WBC count was 8,300/mm 3 (86% neutrophils), and liver function tests demonstrated findings consistent with cholestatis. A CT of the chest showed a pleural-based nodule in the right lung and a collapse of the left upper and lower lobes with a soft-tissue mass inferior to the collapsed left lower lobe. A CT of the brain was unremarkable. N. asteroides was isolated from the sputum. Treatment with imipenem (500 mg every 6 hours) and TMPSMZ (300 mg/1,500 mg every 6 hours) was started. Fluconazole therapy was continued. A drainage tube was placed in the left pleural cavity, and the patient subsequently underwent decortication for treatment of his empyema. Examination of stains of tissue specimens obtained during the procedure showed organisms typical of Nocardia, but cultures of these specimens remained negative. A follow-up CT of the brain revealed multiple low-density areas. A few days after decortication, the patient's clinical condition rapidly declined with respiratory failure, and the patient died. Shortly before death, Aspergillus fumigatus was isolated from an endotracheal aspirate. At autopsy, disseminated aspergillosis involving the lungs and brain was found, but Nocardia was not identified. Case 6 A 32-year-old farmer underwent allogeneic bone marrow transplantation for treatment of CML. His posttransplantation

CID 1996;23 (November)

course was complicated by grade II acute GVHD of the skin that evolved into chronic GVHD (for which continuous corticosteroid therapy was required). Six months after transplantation, the patient had headache and oral ulcers as well as rising values for tests of liver function. A CT of the brain was unremarkable, and the abnormalities resolved with an increase in his daily steroid dose. Ten months after transplantation, the patient used a bulldozer to clear fallen trees and brush from his property. Two weeks later, he had dyspnea and dry cough that progressively worsened over 2 days up until admission to the hospital. The patient's temperature was 99.2°F, and he was in moderate respiratory distress. A chest radiograph showed a new nodular infiltrate in the right lower lobe. His WBC count was 3,300/mm 3 (90% neutrophils). Daily medications at the time of admission included methylprednisolone (28 mg), cyclosporine (150 mg), and itraconazole (200 mg). The patient underwent bronchoscopy. N. nova was isolated from both bronchoalveolar lavage fluid and expectorated sputum. Gram staining of one sputum sample demonstrated Nocardia organisms. No other pathogens were isolated. Therapy with intravenous ceftriaxone (2 g/d) and oral sulfisoxazole (1.5 g four times daily) was begun. Ceftriaxone therapy was discontinued after 2 weeks, and the patient was discharged in improved condition; medications at the time of discharge were oral sulfisoxazole and itraconazole. One month later, he had worsening cough, shortness of breath, and low-grade fever of 3 days' duration. At the time of admission, his WBC count was 4,400/mm 3 (86% neutrophils), and a chest radiograph showed new nodular lesions in both lungs. Examination of stains of tissue biopsy specimens obtained during bronchoscopy revealed a beaded, filamentous gram-positive rod, but cultures of tissue specimens and other samples remained negative. Despite broad-spectrum antibacterial therapy (including imipenem and intravenous TMP-SMZ), the patient's condition deteriorated, and he died of sepsis and respiratory failure. At autopsy, no residual nocardiosis was detected, but pulmonary aspergillosis with dissemination to the CNS was found. Results The demographic characteristics, clinical courses, and outcomes of the patients are summarized in tables 1 and 2. The age of the patients ranged from 13 to 49 years; eight patients were males, and two were females. Three of our patients (cases 1, 3, and 6) and one additional patient (case 9), who resided in rural Venezuela, had a significant exposure to soil and dust. Three patients (cases 1, 3, and 6) were farmers, and one patient (case 3) was also employed as a part-time construction worker. One patient (case 6) had operated a bulldozer 2 weeks earlier on his farm. The patient's underlying diseases were CML in 5 cases, acute myelogenous leukemia in 3 cases, non-Hodgkin's

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Table 1. Demographics and prior clinical courses of 10 BMT recipients with nocardial infections.

Underlying disease



Time (mo) BMT type, HLA matches to diagnosis

Prior clinical course, Immunosuppressive PCP prophylaxis, medication, dosage duration (d) dosage

Case no. [reference]

Age (y)/ sex

1 [PR]

48/M

Part-time farming

CML

Allogeneic, 5 of 6

18

Pneumonitis, 16; mastoiditis, 75; GVHD, 230

2 [PR]

23/M

None

AML

Allogeneic MUD, 6 of 6

14.5

3 [PR]

37/M

NHL

Autologous

4

4 [PR]

39/M

Farming and construction None

CML

Allogeneic, 6 of 6

5.5

Acute GVHD, 15; chronic GVHD, 110; BO, 450 Alveolitis, 64; CMV viruria, 80 Acute GHVD, 47; chronic GVHD, 120

5 [PR]

49/M

None

CML

Allogeneic, 5 of 6

9

6 [PR]

32/M

Farming, bulldozer use

CML

Allogeneic, 6 of 6

10

7 [1]

29/M

NA

AML

2

8 [2]

17/F

None

9 [3]

13/M

Residence in rural area

Allogeneic, 6 of 6 Allogeneic, AML 6 of 6 Aplastic anemia Allogeneic, 6 of 6

10 [4]

48/F

None

CML

Soil exposure



Allogeneic, 6 of 6

7 2.5

3

MTP, 24 mg q.o.d.; Cysp, 240 mg three times a week MTP, 20 mg q.d.; Cysp, 50 mg q.d.

TMP-SMZ, two double-strength tablets twice a week Pentamidine

Prd for 2 w

None

MTP, 24 mg q.o.d.; Pentamidine Cysp, 100 mg q.d. Acute GVHD, 29; MTP, 40 mg q.d.; Pentamidine chronic GVHD, 120 Cysp, 100 mg q.d. MTP, 28 mg q.d.; Pentamidine Acute GVHD, 25; chronic GVHD, 100 Cysp, 150 mg q.d. Mucositis; Procarbazine; CPP; N4 thrombocytopenia ATG Acute GVHD, 30; MTP; Cysp NA CMV pneumonitis Acute GVHD, 39; MTP; Cysp TMP-SMZ, one chronic GVHD; BO double-strength tablet three times a week Chronic GVHD; MTP; Cysp TMP-SMZ, two CMV syndrome double-strength tablets twice a week

NOTE. AML = acute myelogenous leukemia; ATG = antithymocyte globulin; BMT = bone marrow transplant; BO = bronchiolitis obliterans; CML = chronic myelogenous leukemia; CMV = cytomegalovirus; CPP = cyclophosphamide; Cysp = cyclosporine; GVHD = graft-vs.-host disease; HLA human leukocyte antigen; MTP = methylprednisolone; MUD = matched unrelated donor; NA = not available; NHL = non-Hodgkin's lymphoma; PCP = Pneumocystis carinii pneumonia; PR = present report; Prd = prednisone; q.o.d. = every other day; TMP-SMZ = trimethoprim-sulfanethoxazole.

lymphoma in 1 case, and aplastic anemia in 1 case. Eight patients received allogeneic BMTs from relatives, six with six of six human leukocyte antigen matches and two with five of six human leukocyte antigen matches. One patient's BMT was from a matched unrelated donor, and one patient received an autologous BMT. In the interval studied, the overall rate of nocardiosis among our population of BMT recipients was 0.7% (6 of 856). The rate was 0.2% (1 of 554) among recipients of autologous BMTs, 1.6% (4 of 252) among recipients of allogeneic BMTs from relatives, and 2.0% (1 of 50) among recipients of BMTs from unrelated donors. The rate of nocardiosis among recipients of allogeneic BMTs, whether- from related or unrelated donors, was significantly higher than the rate among recipients of autologous BMTs (OR, 9.3 [95% CI, 1.1-80.1]; P = .046). The interval from transplantation to the diagnosis of nocardiosis ranged from 2 to 18 months. Eight patients had GVHD; two of these patients also had bronchiolitis obliterans. None

of our patients were neutropenic. One patient (case 8) had a WBC count of 5,700/mm 3 , but the absolute neutrophil count was not reported. Five of our patients received cyclosporine and methylprednisolone as prophylaxis or treatment for GVHD. One patient (case 3), an autologous BMT recipient, received a short course of prednisone before the isolation of Nocardia. In cases 8-10, therapy with methylprednisolone and cyclosporine was given, but the doses were not reported. One patient (case 7) received treatment with procarbazine, cyclophosphamide, and antithymocyte globulin. TMP-SMZ was used as prophylaxis for Pneumocystis carinii pneumonia in three patients. The doses varied from two doublestrength capsules twice a week to one double-strength capsule three times a week. Therapy with inhaled pentamidine was given to four patients. Information was not available for two patients, and one patient did not receive prophylaxis. The most common presenting symptoms were fever (5 patients), cough (4 patients), pleuritic chest pain (2 patients), and abdominal or back pain (2 patients). Headache, toe swelling,

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Table 2. Clinical presentations and outcomes of 10 BMT recipients with nocardial infections. Chest roentgenogram finding(s)

Case no. [reference]

Symptom(s) at presentation

1 [PR]

Parietal headache, blurred vision

Normal

2 [PR]

Dry cough, SOB

3 [PR]

4 [PR]

5 [PR]

Imaging finding(s) (procedure)

Neutrophil count (/mm 3 )

Isolate(s) (source)

Treatment

Enhancing lesion (head CT)

6,160

Nocardia nova (brain)

Peripheral infiltrates

Peripheral infiltrates (chest CT)

7,990

N. nova (BAL fluid)

Fever, purulent sputum, pleuritic chest pain

Bilateral infiltrates

Normal (head CT)

6,715

Nocardia asteroides/ Blastomyces dermatitidis

Ceftriaxone, sulfisoxazole, amikacin Sulfisoxazole, imipenem, amikacin Cefotaxime, minocycline, amphotericin B

Fever, chronic cough, abdominal pain Fever, back and abdominal pain

Pleural-based mass

Dry cough, SOB

7 [1]

Fever

Multiple CNS lesions (head MRI)

1,932

Pleural-based mass, effusion

Multiple CNS lesions (head CT)

7,138

N. asteroides and Aspergillus

Nodules and cavitation Nodules and cavitation

NA

2,970

N. nova (sputum)

NA

NA

Nocardia otitidiscaviarum

N. asteroides

(sputum)

Imipenem, amikacin, clarithromycin TMP-SMZ, imipenem, amphotericin B Sulfisoxazole, ceftriaxone TMP-SMZ, minocycline

(BAL fluid, blood, skin) 8 [2]

9 [3] 10 [4]

Alive

Death, autopsy denied

Alive

(sputum/BAL fluid)

(sputum) 6 [PR]

Outcome or autopsy findings

Subcutaneous nodules

NA

Toe swelling

NA

Normal (chest CT)

Fever, pleuritic chest pain, SOB

Right lung infiltrate

Pleural-based cavitation (chest CT)

Normal (chest and head CT)

NA (WBC count, 5,700/mm 3 ) NA NA

N. asteroides

(forearm) N. asteroides (toe) N. asteroides (lung

biopsy specimen)

TMP-SMZ, minocycline TMP-SMZ, minocycline Imipenem

Death, autopsy denied

Disseminated aspergillosis Disseminated aspergillosis Disseminated aspergillus and nocardial infections and CMV in the lungs Death, autopsy denied

Alive Disseminated CMV infection and Nocardia in the lungs

NOTE. BAL = bronchoalveolar lavage; BMT = bone marrow transplant; CMV = cytomegalovirus; NA = not available; PR = present report; SOB = shortness of breath; TMP-SMZ = trimethoprim-sulfamethoxazole.

and subcutaneous nodules were noted as presenting symptoms in one patient each. Findings on chest radiographs for seven of eight patients for whom they were reported were abnormal. Three patients had pulmonary infiltrates (bilateral in two cases). Pleural-based masses and cavitating nodules were seen in two patients each; one patient had a pleural effusion. Findings of CNS evaluations by CT or MRI of three of five patients were abnormal. A single enhancing lesion was seen on one patient's image, and multiple lesions were seen on the images of the other two. Four patients underwent chest CT; the results for two patients were abnormal. One patient had a pleural-based cavitation, and the other had peripheral infiltrates. The Nocardia species isolated were identified as N asteroides in 6 cases, N nova in 3 cases, and Nocardia otitidiscaviarum in 1 case. The source of the isolates was the lung in 6 cases, the skin or soft tissue in 3 cases, and the brain in 1 case. Cultures of specimens from several sites, including blood, from one patient were positive. Four of the 10 patients had an invasive fungal infection diagnosed either at the time that nocardial infection was diagnosed or soon thereafter. These fungal infec-

tions included aspergillosis in three cases and B. dermatitidis infection in one case. Two instances of aspergillus infection were not recognized until death. Seven of the 10 patients died during follow-up. Permission for an autopsy was denied in three cases. Two patients had disseminated aspergillosis, and one had disseminated nocardiosis and aspergillosis along with cytomegalovirus involvement of the lungs; the third patient had disseminated cytomegalovirus infection, and Nocardia was isolated from the lungs after death. Residual nocardial infection was not found in two of our patients who underwent autopsies or in one patient (case 2) who underwent an open lung biopsy before death that showed only bronchiolitis obliterans. Discussion

Nocardia species are aerobic actinomycetes that are considered saprophytic; they are found in the soil and are primarily responsible for the decomposition of organic plant material. The N asteroides complex, which in the past was often consid-

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Nocardia and Bone Marrow Transplantation

ered a single species, includes N. asteroides sensu stricto, Nocardia farcinica, and N. nova. Other species of medical importance include Nocardia brasiliensis, N. otitidiscaviarum, and Nocardia transvalensis [5]. N. asteroides appears to be geographically widespread and is the most common isolate from clinical specimens. Most cases of N. brasiliensis infections have originated in the southern United States [6]. The incidence of new cases of nocardiosis in North America has been estimated to be between 500 and 1,000 per year [7]; this figure is derived from a survey of infectious diseases specialists that was reported in 1976. Some investigators believe that this figure is an underestimate of the annual incidence of the disease in the 1990s because of the growth in the number of immunocompromised patients since 1980 [8, 9]. Data from recent surveys in the United States are not available. One French laboratory estimated the annual incidence of nocardial infection in France from 1987 to 1990 to be about three to five cases per million population [10], which is similar to the earlier estimate in America. By contrast, a State Health Laboratory in Queensland, Australia (population of