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Candida krusei infectious arthritis
Candida krusei Infectious Arthritis A Rare Complication of Neutropenia
VINH Q. NGUYEN, M.D. ROBERT L. PENN, M.D. Shreveport,
Louisiana
Candida krusei infections are increasing in neutropenic patients. This is the first report of a case of C. krusei arthritis in a neutropenic leukemic patient. The organism colonized the patient’s respiratory tract and most likely seeded the right knee by hematogenous spread. Knee swelling and tenderness were minimal. Joint fluid Gram stain and fungal smears did not show the organism despite positive results on cultures. With therapy, the joint fluid converted from neutrophilic predominance to lymphocytic predominance. Despite sterilization of knee fluid, clinical relapse occurred after therapy with 256 mg of systemic amphotericin B; the infection was cured after a total dose of 456 mg. Infectious arthritis due to Candida species is uncommon [l-3]. Arthritis caused by Candida krusei is extremely rare; to our knowledge, the only previously reported case occurred in a heroin addict who was otherwise normal [4]. We describe herein the pathogenesis, clinical characteristics, and response to therapy of arthritis caused by C. krusei in a neutropenic patient with leukemia. Since systemic infections due to C. krusei are increasing in neutropenic patients with lymphoma or leukemia [5,6], it is likely that clinicians will encounter future cases of Candida arthritis due to this organism.
MATERIALS AND METHODS The clinical mycology laboratory used two different commercial kits to speciate yeast: Uni-Yeast-Tek Plate (Flow Laboratory, Inc., McLean, Virginia) and Vitek Yeast Biochemical Card (Vitek System, McDonnell Douglas Health Systems Company, Hatelwood, Missouri). Isolates were identified as C. krusei by the absence of germ tube production, the fermentation and assimilation of only glucose, production of characteristic hyphae and blastospores, and weak or absent urease activity [7].
CASE REPORT
From the Department of Medicine, Section of infectious Diseases, Louisiana State University School of Medicine, Shreveport, and Veterans Administration Hospital, Shreveport, Louisiana. This work was supported by the Veterans Administration. Requests for reprints should be addressed to Dr. Robert L. Penn, Infectious Diseases Section, Department of Medicine, Veterans Administration Medical Center, 510 East Stoner Avenue, Shreveport, Louisiana 7 1130. Manuscript submitted January 6, 1987, and accepted April 2, 1987.
A 41-year-old white man was admitted to the Shreveport Veterans Administration Medical Center on July 15, 1986, for daunorubicin and cytarabine therapy of acute myelogenous leukemia in relapse. The patient became neutropenic following chemotherapy and was placed in a private room without prophylactic antibiotic or antifungal therapy. History and findings on physical examination were unremarkable except for a chronic “smoker’s” cough productive of clear sputum and the presence of a long-standing Hickman catheter. Chest roentgehogram did not show an infiltrate. Surveillance sputum and urine cultures were done every two to three days while the patient was neutropenic and afebrile. All five sputum cultures grew C. krusei. One of six urine cultures also grew C. krusei on the 10th hospital day. Blood cultures were negative for fungi, but one grew a coagulasenegative staphylococcal strain.
November
1987
The American
Journal
of Medicine
Volume
83
963
CANDIDA
krusei
TABLE I
ARTHRITIS-NGUYEN
Characteristics
Date 8/5/86 8/8/86 g/2/86
INFECTIOUS
of Synoviai
FungalSmear Not done No organisms No organisms
AND
Fluid during Therapy
Gram-StainSmear No organisms No organisms No organisms
seen seen
PENN
seen seen seen
Culture C. krusei C. krusei Sterile
for C. krusel Arthritis Leukocytes/mm3 (percent neutrophils/ percent lymphocytes)
Quantity not sufficient 2,800 (98/2) 2,950 (8/92)
The patient remained neutropenic (less than 100/mm3) and &febrile until the 16th hospital day when he had a temperature of 103OF. At that time, he had mild, generai-
Sputum continued to grow C. krusei, but the urine was negative. One of two blood cultures again grew a coaguiase-negative staphyiococcai strain. Fever persisted on the 21st hospital day (August 5,
1986). The right knee was minimally tender and contained a small effusion. Arthrocentesis obtained 1.0 ml of serous fluid that was sufficient only for microbiologic studies. The
results of this and subsequent synoviai fluid analysis are shown in Table I. day (August
8, 1986), the patient
became afebriie as the peripheral neutrophii count increased to 400/mm3. His right knee was less tender but the effusion enlarged; repeated arthrocentesis obtained 10.0 ml of serous fluid (Table I). Intravenous amphotericin B therapy was started on the 27th hospital day (August 11, 1986) after the second knee fluid culture grew C. krusei. The peripheral
neutrophil
count
rose above
1,000/mm3;
tenderness and effusion of the knee disappeared, and the patient was discharged on the 29th hospital day (August 13, 1986) to receive amphotericin B 40 mg intravenously three times weekly as an outpatient. After a &muiative dose of 256 mg of systemic amphotericin B, our patient refused further therapy because his knee was better and he was having nausea with the infusions. By seven days after the cessation of amphotericiri B, swelling and tenderness of the right knee returned. Arthrocentesis was repeated on September 2, 1986 (Table I). The
patient was encouraged to restart amphotericin B therapy. Three months later, after a cumulative dose of 456 mg of amphotericin B, he was admitted for relapse of the ieukemia. During this hospitalization, he had no knee conipiaints and there was no clinical evidence of arthritis. COMMENTS
[141.
C. krus&, an infrequent pathogen in humans, has been implicated in endocarditis [8], ocular infection [9], and intra-abdominal abscess [lo]. Arthritis due to C. krusei is extremely rare. The only previous report of C. krusei arthritis occurred as a complication of heroin addiction [4]. To our knowledge, this is the first reported case of
964
November
1987
The
American Journal of Medicine
Quantity 365 Quantity
not sufficient not sufficient
Protein (g/W Quantity 13.6 Quantity
not sufficient not sufficient
arthritis due to C. krusei in a neutropenic subject with leukemia. The pathogenesis of candidal arthritis is not completely understood, but infection is thought to result from hematogenous dissemination in 89 percent of the cases [2]. Our patient had colonization of the respiratory tract with C. krusei as evidenced by the persistent isolation of this organism in the sputum. On one occasion, the organism was also isolated from the urine. Thus, it was likely that transient fungemia occurred and seeded the knee joint. Merz et al [6] studied 868 neutropenic patients undergoing chemotherapy for hematologic malignancies or bone marrow transplantation and found that 108 (12.4 percent) were colonized with C. krusei. C. krusei fungemia developed in 10 of these colonized patients. Six of these 10 were receiving systemic antifungal therapy with amphotericin B or miconazole at the time of fungemia. Since C. krusei fungemia in neutropenic patients is increasing in frequency [5,6], it is likely that future cases of arthritis caused by this organism will be encountered. The clinical manifestations observed in our patient were similar to those of other Candida joint infections. Physical examination of the knee initially revealed only minimal tenderness, warmth, and swelling, perhaps because of our patient’s neutropenia. However, candidal arthritis in patients without neutropenia may have a very indolent presentation, and mild symptoms may persist for many months prior to diagnosis [2,11,12]. The knee has been involved in approximately 80 percent of the reported cases of arthritis due to other Candida species [l-3]. It should be noted that careful examination of the knee fluid Gram stain on two separate occasions failed to reveal any typical Candida blastospores despite positive cultures. This is not unexpected since Candida is seen on smears in less than 20 percent of the culture-positive joint fluids examined [l-3,13]. This is much lower than th8 65 percent smear-positive rate obseived in bacterial arthritis
ized myaigias and arthraigias including both knees, but results of complete physical examination wdre unremarkable. Empiric intravenous therapy with ticarciiiin/ciavuianic acid and amikacin was started after cultures were repeated.
On the 24th hospital
Glucose (Wdi)
Cell counts from our patient’s joint fluids are summarized in Table I. Within three weeks of treatment, the joint effusion converted from neutrophilic predominance (2,800 leukocytes/mm3, 98 percent neutrophils) to one with lymphocytic predominance (2,950 leukocytes/mm3, 92 percent lymphocytes). There is limited information on
Volume
83
CANDIDA
krusei
INFECTIOUS
ARTHRITIS-NGUYEN
AND
PENN
joint fluid cell counts in previous reports of candidal arthritis [2,3]. In a patient with Candida tropicalis isolated from the olecranon bursa, Murray et al [I] observed that after administration of 511 mg of intravenous amphotericin B over four weeks the bursal fluid cell counts had evolved from 1 i ,000 leukocytes/mm3 with 92 percent neutrophils to 3,778 leukocytes/mm3 with 54 percent neutrophils. In contrast, Mandel et al [13] reported the persistence of a predominantly neutrophilic effusion despite sterilization of the knee joint fluid after two weeks of treatment with amphotericin B. Optimal therapy for C. krusei arthritis is not known. Experience with joint infections caused by other Candida species is limited [ l-3,12,13], but intravenous amphoter-
We thank Dr. Stephen A. Klotz for reviewing the manuscript, Lydgia Jackson for isolating the organism, and Denise Dorsey for assistance with the manuscript.
Murray HW, Fialk MA, Roberts RB: Candida arthritis: a manifestation of disseminated candidiasis. Am J Med 1976; 60: 587-595. Bayer AS, Guze LB: Fungal arthritis. I. Candida arthritis: diagnostic and prognostic implications and therapeutic considerations. Semin Arthritis Rheum 1978; 8: 142-150. Fainstein V, Gilmore C, Hopfer RL, Maksymiuk A, Bodey GP: Septic arthritis due to Candida species in patients with cancer: report of five cases and review of the literature. Rev Infect Dis 1982; 4: 78-85. Carcassi A, Saletti M, Boschi S: Artrite acuta da Candida: lsolamento di Candida krusei in un eroinomane. Minerva Med 1982; 73: 2905-2909. Horn R, Wong B , Kiehn TE, Armstrong D: Fungemia in a cancer hospital: changing frequency, earlier onset, and results of therapy. Rev Infect Dis 1985; 7: 646-655. Merz WG, Karp JE, Schron D, Sara1 R: Increased incidence of fungemia caused by Candida krusei. J Clin Microbial 1986; 24: 581-584. Cooper BH, Silva-Hutner M: Yeasts of medical importance. In: Lennette EH, Balows A, Hausler WJ Jr, Shadomy HJ, eds. Manual of clinical microbiology, 4th ed. Washington: American Society for Microbiology, 1985; 527. Rubinstein E, Noriega ER, Simberkoff MS, Holzman R, Rahal JJ Jr: Fungal endocarditis: analysis of 24 cases and re-
view of the literature. Medicine (Baltimore) 1975; 54: 331-344. Segal E, Roman0 A, Eylan E, Stein R: Experimental and clinical studies of 5fluorocytosine activity in candida ocular infections. I. In vitro activity of .5-fluorocytosine on Candida species isolated from ocular infections. Chemotherapy 1975; 21: 358-366. Gordon RA, Simmons BP, Appelbaum PC, Aber RC: Intraabdominal abscess and fungemia caused by Candida krusei (letter). Arch Intern Med 1980; 140:1239-1240. Glauser MP, Gerster JC, Delacretaz F: Chronic candida arthritis in leukemic patients, Rev Infect Dis 1982; 4: 1071. Katzenstein D: Isolated candida arthritis: report of a case and definition of a distinct clinical syndrome. Arthritis Rheum 1985: 28: 1421-1424. .. Mandel DR, Segal AM, Wysenbeek AJ, Calabrese LH: Two unusual’ strains of candida arthritis. Am J Med Sci 1984; 288: 25-27: Goldenberg DL, Cohen AS: Acute infectious arthritis: a review of patients with nongonococcal joint infections (with emphasis on therapy and prognosis). Am .I Med 1976; 60: 369-377. * Lindstrom FD, Lindholm T: Candida albicans arthritis treated with flucytosine (letter). Ann Intern Med 1973; 79: 131.
8.
November
icin B has been most successful. Sterilization of the infected joint has occurred after as little as 158 mg of systemic amphotericin B [I 31, but relapse is possible and therapy may have to be reinstituted [ 151. Negative joint fluid culture occurred in our patient after 256 mg of systemic amphotericin B despite the persistence of joint effusion and clinical relapse. Cure was eventually achieved after a total dose of 456 mg of systemic amphotericin B. ACKNOWLEDGMENT
9.
10.
11.
12.
13.
14.
15.
1987
The American
Journal
of Medicine
Volume
83
965
VINH Q. NGUYEN, M.D. ROBERT L. PENN, M.D. Shreveport,
Louisiana
Candida krusei infections are increasing in neutropenic patients. This is the first report of a case of C. krusei arthritis in a neutropenic leukemic patient. The organism colonized the patient’s respiratory tract and most likely seeded the right knee by hematogenous spread. Knee swelling and tenderness were minimal. Joint fluid Gram stain and fungal smears did not show the organism despite positive results on cultures. With therapy, the joint fluid converted from neutrophilic predominance to lymphocytic predominance. Despite sterilization of knee fluid, clinical relapse occurred after therapy with 256 mg of systemic amphotericin B; the infection was cured after a total dose of 456 mg. Infectious arthritis due to Candida species is uncommon [l-3]. Arthritis caused by Candida krusei is extremely rare; to our knowledge, the only previously reported case occurred in a heroin addict who was otherwise normal [4]. We describe herein the pathogenesis, clinical characteristics, and response to therapy of arthritis caused by C. krusei in a neutropenic patient with leukemia. Since systemic infections due to C. krusei are increasing in neutropenic patients with lymphoma or leukemia [5,6], it is likely that clinicians will encounter future cases of Candida arthritis due to this organism.
MATERIALS AND METHODS The clinical mycology laboratory used two different commercial kits to speciate yeast: Uni-Yeast-Tek Plate (Flow Laboratory, Inc., McLean, Virginia) and Vitek Yeast Biochemical Card (Vitek System, McDonnell Douglas Health Systems Company, Hatelwood, Missouri). Isolates were identified as C. krusei by the absence of germ tube production, the fermentation and assimilation of only glucose, production of characteristic hyphae and blastospores, and weak or absent urease activity [7].
CASE REPORT
From the Department of Medicine, Section of infectious Diseases, Louisiana State University School of Medicine, Shreveport, and Veterans Administration Hospital, Shreveport, Louisiana. This work was supported by the Veterans Administration. Requests for reprints should be addressed to Dr. Robert L. Penn, Infectious Diseases Section, Department of Medicine, Veterans Administration Medical Center, 510 East Stoner Avenue, Shreveport, Louisiana 7 1130. Manuscript submitted January 6, 1987, and accepted April 2, 1987.
A 41-year-old white man was admitted to the Shreveport Veterans Administration Medical Center on July 15, 1986, for daunorubicin and cytarabine therapy of acute myelogenous leukemia in relapse. The patient became neutropenic following chemotherapy and was placed in a private room without prophylactic antibiotic or antifungal therapy. History and findings on physical examination were unremarkable except for a chronic “smoker’s” cough productive of clear sputum and the presence of a long-standing Hickman catheter. Chest roentgehogram did not show an infiltrate. Surveillance sputum and urine cultures were done every two to three days while the patient was neutropenic and afebrile. All five sputum cultures grew C. krusei. One of six urine cultures also grew C. krusei on the 10th hospital day. Blood cultures were negative for fungi, but one grew a coagulasenegative staphylococcal strain.
November
1987
The American
Journal
of Medicine
Volume
83
963
CANDIDA
krusei
TABLE I
ARTHRITIS-NGUYEN
Characteristics
Date 8/5/86 8/8/86 g/2/86
INFECTIOUS
of Synoviai
FungalSmear Not done No organisms No organisms
AND
Fluid during Therapy
Gram-StainSmear No organisms No organisms No organisms
seen seen
PENN
seen seen seen
Culture C. krusei C. krusei Sterile
for C. krusel Arthritis Leukocytes/mm3 (percent neutrophils/ percent lymphocytes)
Quantity not sufficient 2,800 (98/2) 2,950 (8/92)
The patient remained neutropenic (less than 100/mm3) and &febrile until the 16th hospital day when he had a temperature of 103OF. At that time, he had mild, generai-
Sputum continued to grow C. krusei, but the urine was negative. One of two blood cultures again grew a coaguiase-negative staphyiococcai strain. Fever persisted on the 21st hospital day (August 5,
1986). The right knee was minimally tender and contained a small effusion. Arthrocentesis obtained 1.0 ml of serous fluid that was sufficient only for microbiologic studies. The
results of this and subsequent synoviai fluid analysis are shown in Table I. day (August
8, 1986), the patient
became afebriie as the peripheral neutrophii count increased to 400/mm3. His right knee was less tender but the effusion enlarged; repeated arthrocentesis obtained 10.0 ml of serous fluid (Table I). Intravenous amphotericin B therapy was started on the 27th hospital day (August 11, 1986) after the second knee fluid culture grew C. krusei. The peripheral
neutrophil
count
rose above
1,000/mm3;
tenderness and effusion of the knee disappeared, and the patient was discharged on the 29th hospital day (August 13, 1986) to receive amphotericin B 40 mg intravenously three times weekly as an outpatient. After a &muiative dose of 256 mg of systemic amphotericin B, our patient refused further therapy because his knee was better and he was having nausea with the infusions. By seven days after the cessation of amphotericiri B, swelling and tenderness of the right knee returned. Arthrocentesis was repeated on September 2, 1986 (Table I). The
patient was encouraged to restart amphotericin B therapy. Three months later, after a cumulative dose of 456 mg of amphotericin B, he was admitted for relapse of the ieukemia. During this hospitalization, he had no knee conipiaints and there was no clinical evidence of arthritis. COMMENTS
[141.
C. krus&, an infrequent pathogen in humans, has been implicated in endocarditis [8], ocular infection [9], and intra-abdominal abscess [lo]. Arthritis due to C. krusei is extremely rare. The only previous report of C. krusei arthritis occurred as a complication of heroin addiction [4]. To our knowledge, this is the first reported case of
964
November
1987
The
American Journal of Medicine
Quantity 365 Quantity
not sufficient not sufficient
Protein (g/W Quantity 13.6 Quantity
not sufficient not sufficient
arthritis due to C. krusei in a neutropenic subject with leukemia. The pathogenesis of candidal arthritis is not completely understood, but infection is thought to result from hematogenous dissemination in 89 percent of the cases [2]. Our patient had colonization of the respiratory tract with C. krusei as evidenced by the persistent isolation of this organism in the sputum. On one occasion, the organism was also isolated from the urine. Thus, it was likely that transient fungemia occurred and seeded the knee joint. Merz et al [6] studied 868 neutropenic patients undergoing chemotherapy for hematologic malignancies or bone marrow transplantation and found that 108 (12.4 percent) were colonized with C. krusei. C. krusei fungemia developed in 10 of these colonized patients. Six of these 10 were receiving systemic antifungal therapy with amphotericin B or miconazole at the time of fungemia. Since C. krusei fungemia in neutropenic patients is increasing in frequency [5,6], it is likely that future cases of arthritis caused by this organism will be encountered. The clinical manifestations observed in our patient were similar to those of other Candida joint infections. Physical examination of the knee initially revealed only minimal tenderness, warmth, and swelling, perhaps because of our patient’s neutropenia. However, candidal arthritis in patients without neutropenia may have a very indolent presentation, and mild symptoms may persist for many months prior to diagnosis [2,11,12]. The knee has been involved in approximately 80 percent of the reported cases of arthritis due to other Candida species [l-3]. It should be noted that careful examination of the knee fluid Gram stain on two separate occasions failed to reveal any typical Candida blastospores despite positive cultures. This is not unexpected since Candida is seen on smears in less than 20 percent of the culture-positive joint fluids examined [l-3,13]. This is much lower than th8 65 percent smear-positive rate obseived in bacterial arthritis
ized myaigias and arthraigias including both knees, but results of complete physical examination wdre unremarkable. Empiric intravenous therapy with ticarciiiin/ciavuianic acid and amikacin was started after cultures were repeated.
On the 24th hospital
Glucose (Wdi)
Cell counts from our patient’s joint fluids are summarized in Table I. Within three weeks of treatment, the joint effusion converted from neutrophilic predominance (2,800 leukocytes/mm3, 98 percent neutrophils) to one with lymphocytic predominance (2,950 leukocytes/mm3, 92 percent lymphocytes). There is limited information on
Volume
83
CANDIDA
krusei
INFECTIOUS
ARTHRITIS-NGUYEN
AND
PENN
joint fluid cell counts in previous reports of candidal arthritis [2,3]. In a patient with Candida tropicalis isolated from the olecranon bursa, Murray et al [I] observed that after administration of 511 mg of intravenous amphotericin B over four weeks the bursal fluid cell counts had evolved from 1 i ,000 leukocytes/mm3 with 92 percent neutrophils to 3,778 leukocytes/mm3 with 54 percent neutrophils. In contrast, Mandel et al [13] reported the persistence of a predominantly neutrophilic effusion despite sterilization of the knee joint fluid after two weeks of treatment with amphotericin B. Optimal therapy for C. krusei arthritis is not known. Experience with joint infections caused by other Candida species is limited [ l-3,12,13], but intravenous amphoter-
We thank Dr. Stephen A. Klotz for reviewing the manuscript, Lydgia Jackson for isolating the organism, and Denise Dorsey for assistance with the manuscript.
Murray HW, Fialk MA, Roberts RB: Candida arthritis: a manifestation of disseminated candidiasis. Am J Med 1976; 60: 587-595. Bayer AS, Guze LB: Fungal arthritis. I. Candida arthritis: diagnostic and prognostic implications and therapeutic considerations. Semin Arthritis Rheum 1978; 8: 142-150. Fainstein V, Gilmore C, Hopfer RL, Maksymiuk A, Bodey GP: Septic arthritis due to Candida species in patients with cancer: report of five cases and review of the literature. Rev Infect Dis 1982; 4: 78-85. Carcassi A, Saletti M, Boschi S: Artrite acuta da Candida: lsolamento di Candida krusei in un eroinomane. Minerva Med 1982; 73: 2905-2909. Horn R, Wong B , Kiehn TE, Armstrong D: Fungemia in a cancer hospital: changing frequency, earlier onset, and results of therapy. Rev Infect Dis 1985; 7: 646-655. Merz WG, Karp JE, Schron D, Sara1 R: Increased incidence of fungemia caused by Candida krusei. J Clin Microbial 1986; 24: 581-584. Cooper BH, Silva-Hutner M: Yeasts of medical importance. In: Lennette EH, Balows A, Hausler WJ Jr, Shadomy HJ, eds. Manual of clinical microbiology, 4th ed. Washington: American Society for Microbiology, 1985; 527. Rubinstein E, Noriega ER, Simberkoff MS, Holzman R, Rahal JJ Jr: Fungal endocarditis: analysis of 24 cases and re-
view of the literature. Medicine (Baltimore) 1975; 54: 331-344. Segal E, Roman0 A, Eylan E, Stein R: Experimental and clinical studies of 5fluorocytosine activity in candida ocular infections. I. In vitro activity of .5-fluorocytosine on Candida species isolated from ocular infections. Chemotherapy 1975; 21: 358-366. Gordon RA, Simmons BP, Appelbaum PC, Aber RC: Intraabdominal abscess and fungemia caused by Candida krusei (letter). Arch Intern Med 1980; 140:1239-1240. Glauser MP, Gerster JC, Delacretaz F: Chronic candida arthritis in leukemic patients, Rev Infect Dis 1982; 4: 1071. Katzenstein D: Isolated candida arthritis: report of a case and definition of a distinct clinical syndrome. Arthritis Rheum 1985: 28: 1421-1424. .. Mandel DR, Segal AM, Wysenbeek AJ, Calabrese LH: Two unusual’ strains of candida arthritis. Am J Med Sci 1984; 288: 25-27: Goldenberg DL, Cohen AS: Acute infectious arthritis: a review of patients with nongonococcal joint infections (with emphasis on therapy and prognosis). Am .I Med 1976; 60: 369-377. * Lindstrom FD, Lindholm T: Candida albicans arthritis treated with flucytosine (letter). Ann Intern Med 1973; 79: 131.
8.
November
icin B has been most successful. Sterilization of the infected joint has occurred after as little as 158 mg of systemic amphotericin B [I 31, but relapse is possible and therapy may have to be reinstituted [ 151. Negative joint fluid culture occurred in our patient after 256 mg of systemic amphotericin B despite the persistence of joint effusion and clinical relapse. Cure was eventually achieved after a total dose of 456 mg of systemic amphotericin B. ACKNOWLEDGMENT
9.
10.
11.
12.
13.
14.
15.
1987
The American
Journal
of Medicine
Volume
83
965