Fungal Infections in Renal Transplant Recipients RICHARD J. HOWARD, M.D., PH.D.,* RICHARD L. SIMMONS, M.D., F.A.C.S., JOHN S. NAJARIAN, M.D., F.A.C.S.
Infection continues to be a major source of morbidity and the major source of mortality in renal transplant recipients who are susceptible to opportunistic infections. We recently reviewed all renal transplant recipients who had fungi cultured during a three year period. C. albicans and T. glabrata were cultured most frequently. Deep fungal infections occurred in many patients and were frequently observed late in the course of bacterial and viral infections. Ten patients had fungemia, and primary fungal pneumonia occurred in eight patients. Three patients had fungal infection of the central nervous system. Three of eight patients with fungal pneumonia and eight of ten patients with fungemia died as a result of their fungus infections. These patients frequently had poor renal function and were receiving high steroid doses or hsd recently been treated for kidney rejection. One patient with fungal pneumonia and six patients with fungemia had the fungus cultured from a superficial site. Several patients developed fungal infections late in the course of viral or bacterial infections. Amphotericin-B and 5-fluorocytosine remain the mainstays of antifungal therapy. INFECTION CONTINUES TO BE A MAJOR source
of morbidity and mortality in renal transplant recipients and in other immunosuppressed patients.5'10'1215'17,18,22,27 The most common causes of serious illness and
death in transplant patients are bacterial infectionsespecially Staphylococci and the Gram-negative enteric bacteria.1'823 Viral infections,92225 and protozoal infection-Pneumocystis carinii -also can cause lethal infections in immunosuppressed patients.23 Fungal infections, too, cause disease and death in transplant recipients. 3,5-7,11,15-17,19,23 There is a relatively high incidence of primary fungal pneumonia and meningitis, and several reports suggest that urinary tract or mucosal surface infections can serve as sources for deep infections.17 In addition, the high incidence of fungal infections has been blamed on the "indiscriminate use of antibiotics" in these patients. No one has correlated the incidence and severity of deep fungal infections with the incidence of fungal contamination of * Recipient of Research Career Development Award No., AI K04-167. Reprint requests: Dr. Richard J. Howard, Box 435 Mayo, University of Minnesota Health Sciences Center, Minneapolis, Minnesota 55455. Submitted for publication: December 12, 1977.
From the Department of Surgery, University of Minnesota Health Sciences Center, Minneapolis, Minnesota
superficial sites. Some of the reports are derived from transplant centers where antimicrobial agents are given to all patients. To ascertain a truer incidence of fungal contamination of the urine and of superficial sites (mouth, throat, nasopharynx), we examined all fungal cultures from our renal transplant recipients for a three year period. We also reviewed patients with deep fungal infections to determine whether predisposing causes and modes of clinical evidence were present. Almost all transplant recipients at this center have received antimicrobial prophylaxis. Patients and Methods The subjects of this report are all transplant recipients who had fungus detected by culture during a three year period from January 1, 1974 to December 31, 1976 (544 patients were transplanted prior to 1974 and 356 patients were transplanted after 1974). Approximately 60% of the recipients were male, 60% received kidneys from cadaver donors, and 35% had renal failure caused by juvenile onset, insulin dependent, diabetes mellitus. A combined bilateral nephrectomy and splenectomy procedure usually preceded each transplant. Standard posttransplant immunosuppressive therapy was usedantilymphoblast globulin (30 mg/kg for 14 days), maintenance azathioprine (1.5-2.5 mg/kg/day), and maintenance prednisone (0.25-0.33 mg/kg/day).24 Rejection episodes were treated by increasing the prednisone dosage to 2 mg/kg/day and tapering it gradually to 0.5 mg/kg/day one month later. Azathioprine dosage is never increased. For antimicrobial prophylaxis our transplant patients receive dicloxacillin for 21 days. They also swish and swallow 100,000 units of nystatin four times a day for one month, and nearly all patients receive sulfasoxazole (1 g four times a day) indefinitely. Before transplantation routine culture mediums of the throat, sputum, and urine (or bladder irrigation) are prepared for bacteria, fungi, and viruses. These
0003-4932/78/1100/0598 $00.90 © J. B. Lippincott Company
598
VOl. 188 . NO. S
599
INFECTIONS IN TRANSPLANT RECIPIENTS TABLE 1. Fungi Cultured from Superficial Sites in 181 Transplant Recipients
Fungi
Urine
Throat
Sputum
Stool
Mouth
Vagina
Nasopharynx
Shunt & IV
Candida albicans other species Torulopis
64 2
80 2
36 2
30 1
6
4
1
2
21
5
2
6
glabrata
2
Crytococcus
neoformans
I
Aspergillus niger
I
tests are repeated whenever a patient returns to the
hospital. If the patient is febrile, cultures of the blood, nose, throat, sputum, and urine are repeatedly taken. Transtracheal aspiration has been an inefficient means of diagnosing pulmonary infections, and has caused local neck infections in these immunosuppressed patients. Instead, we perform bronchoscopy,2 promptly. We seldom use a lung biopsy for the diagnosis of pulmonary infiltrates. Specimens for fungal isolation are plated on inhibitory mold media, brain-heart infusion agar, and mycobiotic agar (Gibco Diagnostics, Madison, Wisc.) and incubated in air at 300 for 30 days. Some fungi (Histoplasma capsulatum) can take up to 25 days to grow. Results
Superficial Sites Four species of fungi were cultured from eight superficial sites in 181 transplant recipients (Table 1). Of these 181 patients, only 18 (10%) developed a deep fungal infection or fungemia with an organism that had been previously cultured from a superficial site. In these patients the fungal contamination of the urine, or epithelial, or mucosal surface may have served as a focus for fungal infection of a deeper site. Six of the eight patients with fungemia caused by Candida albicans had the yeast previously cultured from superficial sites (five from the urine and one from the throat). One patient who had pneumonia due to Candida albicans also had the fungus in the urine and throat. The one patient with Cryptococcus neoformans cultured from the urine, also had it in his cerebrospinal fluid. The patient with Torulopsis glabrata cultured from the peritoneal fluid, previously had it in the urine-a bladder leak, that communicated with the peritoneal cavity, developed after transplantation. Ten of the 12 patients with contamination of wound infections also had the fungi cultured from the urine (nine patients) or sputum (one patient). Only two wound infections were
contaminated with, or infected by, fungi which had not been previously cultured from a superficial site. Only six patients with involvement of a superficial site were treated with antifungal agents. Two of these had infection of the mouth (thrush) with Candida albicans and were treated successfully with nystatin mouth washes. The four others received nystatin suppositories for vaginitis caused by Candida albicans. Deep Sites Wounds. Twelve patients had fungi cultured from wounds (Table 2). Eleven of the 12 wound infections were contaminated with C. albicans. Torulopsis glabrata as cultured from one wound. None of these infections was a primary infection because bacteria were also cultured. In several instances the fungus was only cultured after the wound had been opened, drained, and treated with antibiotics. None of these patients was treated with antifungal agents, because the fungus was considered to be a wound contaminant. In no instance was it associated with local or distant tissue invasion. There were eight TABLE 2. Fungi Cultured from Deep Sites in Transplant Recipients
Fungi Candida albicans Torulopsi glabrata Aspergillus fumigatus niger
Central Perito- Nervous Kidney Wound nium System Graft Lung Blood 11
2
1
1
2
5
8
1
flaves Cryptococcus neoformans Histoplasma capsulatum Coccidiodes immitis
2
1 1
1
2
2
600
HOWARD, SIMMONS AND NAJARIAN
combined fungal and bacterial infections around transplanted kidneys and all were treated by nephrectomy. Although all of these patients died, three of them had recovered from their deep wound infection. Peritonium. Three patients had yeasts cultured from the peritoneal cavity. All three also had concomitant bacterial peritonitis within two months of transplantation. All three were receiving more than 0.5 mg/kg/day of prednisone, and two had serum creatinine levels greater than 2.1 mg/dl. One patient with diabetes mellitus underwent total gastrectomy because of hemorrhagic gastritis. She developed Candida and bacterial peritonitis caused by a leak from the esophogojejunostomy. Candida had been cultured from the throat and probably found its way into the peritoneal cavity from swallowed saliva. She died of bacterial peritonitis. Although Candida had been cultured from the peritoneal cavity during exploration for the leak from the esophogojejunostomy, none was found at postmortem examination, ten days after treatment with amphotericin B was begun. The second patient, a 40-year-old diabetic woman, developed a bladder leak into the peritoneal cavity two months after receiving a transplant from a cadaver donor. The bladder was reclosed. The peritoneal fluid contained Torulopsis glabrata (T. glabrata had been repeatedly cultured from the urine) and Serratia marcescens. She was treated with amphotericin-B and tobramycin. She still has normal renal function 48 months later. The third patient, a 20-year-old diabetic man, had primary peritonitis caused by Salmonella five days posttransplant. He was treated with gentamycin and had a laparotomy seven days later. Salmonella and Candida albicans were cultured from the peritoneum. He died 15 days after laparotomy. An autopsy revealed disseminated candidiases, without Salmonella. Cenitral nervous siystem. Three patients had fungal infections of the central nervous system. Two adult patients had meningitis caused by Cryptococcus neoformans 6-17 months posttransplant. Cryptococcus was not cultured from any other site. One patient had renal failure secondary to diabetes mellitus and the other had polycystic renal disease. Both had fever (38 and 38.50) and mild headache. The white blood cell counts were 5,800 and 7,000 per mm3. They were on maintenance doses of immunosuppression. In both cases the diagnosis was made after the immediate examination of the spinal fluid with an India ink preparation. Both patients recovered with systemic amphotericin-B and 5-fluorocytosine treatment, without intrathecal therapy. Another patient had renal failure caused by Fabry's disease, and received a cadaver renal allograft. Five weeks after transplantation he became febrile (400).
Ann. Surg. a November 1978
Over the course of two weeks he became obtunded; he died five months after transplantation. Diagnostic tests, including repeated spinal taps and brain biopsies gave no cause for his decline. He never responded to either antibacterial or antifungal treatment. Autopsy findings included Coccidioides immitis that involved the brain, lungs, and kidney. Kidney graft. Two patients had Candida albicans cultured from their transplanted kidneys. One, a diabetic, had C. albicans cultured from a lymphocele three months before laparotomy for a suspected abscess was performed. Instead, bacterial peritonitis was found so a transplant nephrectomy was performed. Candidta albicans was cultured from the kidney specimen. The patient died four days later of bacterial peritonitis. In the other patient, Candida albicans was cultured from the kidney after transplant nephrectomy for chronic rejection. She recovered without further treatment and is now on maintenance hemodialysis. Lung. Eight patients (age range 17-52 years) had primary fungal pneumonia (Table 3). One-half of the infections were recognized four to seven months after transplantation. Pneumonia occurred from 27 to 72 months posttransplant in the other four. One patient had a normal temperature, and the other seven had fevers between 38.5 and 39.5°. The eight patients had white blood cell counts of between 3,550 and 19,000 per mm3; only two had white blood cell counts above 10,000 per mm3. Five of the patients had poor graft function with serum creatinine levels greater than 2.1 mg/dl. Although seven of them had been treated for at least one rejection episode, only one patient was receiving more than 25 mg/kg/day at the time he developed fungal pneumonia. Four of the patients had recently been treated for rejection episodes. Four patients had fungal pneumonia caused by Candida albicans, two had pneumonia caused by Histoplasma capsulatum, and two had Aspergillus cultured from the lung (one of these also had Cryptococcus). Two patients also had bacteria isolated from the lung and were treated with antibiotics, in addition to antifungal agents. Three patients died as a direct consequence of persistent fungal pneumonia. One patient (No. 4, Table 3) with pulmonary histoplasmosis (he also had Histoplasma capsulatum cultured from the blood) was found to have it in the liver as well. Two additional patients have died subsequently, one (No. 3, Table 3) died one year after successful treatment for pneumonia caused by Histoplasma capsulatum, but the autopsy results revealed disseminated Herpesvirus hominis. The other patient (No. 1, Table 3) died of liver failure after a second kidney transplant. Three patients are cur-
Vol. 188 * No. S
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INFECTIONS IN TRANSPLANT RECIPIENTS CIS
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Infection continues to be a major source of morbidity and the major source of mortality in renal transplant recipients who are susceptible to opportunistic infections. We recently reviewed all renal transplant recipients who had fungi cultured during a three year period. C. albicans and T. glabrata were cultured most frequently. Deep fungal infections occurred in many patients and were frequently observed late in the course of bacterial and viral infections. Ten patients had fungemia, and primary fungal pneumonia occurred in eight patients. Three patients had fungal infection of the central nervous system. Three of eight patients with fungal pneumonia and eight of ten patients with fungemia died as a result of their fungus infections. These patients frequently had poor renal function and were receiving high steroid doses or hsd recently been treated for kidney rejection. One patient with fungal pneumonia and six patients with fungemia had the fungus cultured from a superficial site. Several patients developed fungal infections late in the course of viral or bacterial infections. Amphotericin-B and 5-fluorocytosine remain the mainstays of antifungal therapy. INFECTION CONTINUES TO BE A MAJOR source
of morbidity and mortality in renal transplant recipients and in other immunosuppressed patients.5'10'1215'17,18,22,27 The most common causes of serious illness and
death in transplant patients are bacterial infectionsespecially Staphylococci and the Gram-negative enteric bacteria.1'823 Viral infections,92225 and protozoal infection-Pneumocystis carinii -also can cause lethal infections in immunosuppressed patients.23 Fungal infections, too, cause disease and death in transplant recipients. 3,5-7,11,15-17,19,23 There is a relatively high incidence of primary fungal pneumonia and meningitis, and several reports suggest that urinary tract or mucosal surface infections can serve as sources for deep infections.17 In addition, the high incidence of fungal infections has been blamed on the "indiscriminate use of antibiotics" in these patients. No one has correlated the incidence and severity of deep fungal infections with the incidence of fungal contamination of * Recipient of Research Career Development Award No., AI K04-167. Reprint requests: Dr. Richard J. Howard, Box 435 Mayo, University of Minnesota Health Sciences Center, Minneapolis, Minnesota 55455. Submitted for publication: December 12, 1977.
From the Department of Surgery, University of Minnesota Health Sciences Center, Minneapolis, Minnesota
superficial sites. Some of the reports are derived from transplant centers where antimicrobial agents are given to all patients. To ascertain a truer incidence of fungal contamination of the urine and of superficial sites (mouth, throat, nasopharynx), we examined all fungal cultures from our renal transplant recipients for a three year period. We also reviewed patients with deep fungal infections to determine whether predisposing causes and modes of clinical evidence were present. Almost all transplant recipients at this center have received antimicrobial prophylaxis. Patients and Methods The subjects of this report are all transplant recipients who had fungus detected by culture during a three year period from January 1, 1974 to December 31, 1976 (544 patients were transplanted prior to 1974 and 356 patients were transplanted after 1974). Approximately 60% of the recipients were male, 60% received kidneys from cadaver donors, and 35% had renal failure caused by juvenile onset, insulin dependent, diabetes mellitus. A combined bilateral nephrectomy and splenectomy procedure usually preceded each transplant. Standard posttransplant immunosuppressive therapy was usedantilymphoblast globulin (30 mg/kg for 14 days), maintenance azathioprine (1.5-2.5 mg/kg/day), and maintenance prednisone (0.25-0.33 mg/kg/day).24 Rejection episodes were treated by increasing the prednisone dosage to 2 mg/kg/day and tapering it gradually to 0.5 mg/kg/day one month later. Azathioprine dosage is never increased. For antimicrobial prophylaxis our transplant patients receive dicloxacillin for 21 days. They also swish and swallow 100,000 units of nystatin four times a day for one month, and nearly all patients receive sulfasoxazole (1 g four times a day) indefinitely. Before transplantation routine culture mediums of the throat, sputum, and urine (or bladder irrigation) are prepared for bacteria, fungi, and viruses. These
0003-4932/78/1100/0598 $00.90 © J. B. Lippincott Company
598
VOl. 188 . NO. S
599
INFECTIONS IN TRANSPLANT RECIPIENTS TABLE 1. Fungi Cultured from Superficial Sites in 181 Transplant Recipients
Fungi
Urine
Throat
Sputum
Stool
Mouth
Vagina
Nasopharynx
Shunt & IV
Candida albicans other species Torulopis
64 2
80 2
36 2
30 1
6
4
1
2
21
5
2
6
glabrata
2
Crytococcus
neoformans
I
Aspergillus niger
I
tests are repeated whenever a patient returns to the
hospital. If the patient is febrile, cultures of the blood, nose, throat, sputum, and urine are repeatedly taken. Transtracheal aspiration has been an inefficient means of diagnosing pulmonary infections, and has caused local neck infections in these immunosuppressed patients. Instead, we perform bronchoscopy,2 promptly. We seldom use a lung biopsy for the diagnosis of pulmonary infiltrates. Specimens for fungal isolation are plated on inhibitory mold media, brain-heart infusion agar, and mycobiotic agar (Gibco Diagnostics, Madison, Wisc.) and incubated in air at 300 for 30 days. Some fungi (Histoplasma capsulatum) can take up to 25 days to grow. Results
Superficial Sites Four species of fungi were cultured from eight superficial sites in 181 transplant recipients (Table 1). Of these 181 patients, only 18 (10%) developed a deep fungal infection or fungemia with an organism that had been previously cultured from a superficial site. In these patients the fungal contamination of the urine, or epithelial, or mucosal surface may have served as a focus for fungal infection of a deeper site. Six of the eight patients with fungemia caused by Candida albicans had the yeast previously cultured from superficial sites (five from the urine and one from the throat). One patient who had pneumonia due to Candida albicans also had the fungus in the urine and throat. The one patient with Cryptococcus neoformans cultured from the urine, also had it in his cerebrospinal fluid. The patient with Torulopsis glabrata cultured from the peritoneal fluid, previously had it in the urine-a bladder leak, that communicated with the peritoneal cavity, developed after transplantation. Ten of the 12 patients with contamination of wound infections also had the fungi cultured from the urine (nine patients) or sputum (one patient). Only two wound infections were
contaminated with, or infected by, fungi which had not been previously cultured from a superficial site. Only six patients with involvement of a superficial site were treated with antifungal agents. Two of these had infection of the mouth (thrush) with Candida albicans and were treated successfully with nystatin mouth washes. The four others received nystatin suppositories for vaginitis caused by Candida albicans. Deep Sites Wounds. Twelve patients had fungi cultured from wounds (Table 2). Eleven of the 12 wound infections were contaminated with C. albicans. Torulopsis glabrata as cultured from one wound. None of these infections was a primary infection because bacteria were also cultured. In several instances the fungus was only cultured after the wound had been opened, drained, and treated with antibiotics. None of these patients was treated with antifungal agents, because the fungus was considered to be a wound contaminant. In no instance was it associated with local or distant tissue invasion. There were eight TABLE 2. Fungi Cultured from Deep Sites in Transplant Recipients
Fungi Candida albicans Torulopsi glabrata Aspergillus fumigatus niger
Central Perito- Nervous Kidney Wound nium System Graft Lung Blood 11
2
1
1
2
5
8
1
flaves Cryptococcus neoformans Histoplasma capsulatum Coccidiodes immitis
2
1 1
1
2
2
600
HOWARD, SIMMONS AND NAJARIAN
combined fungal and bacterial infections around transplanted kidneys and all were treated by nephrectomy. Although all of these patients died, three of them had recovered from their deep wound infection. Peritonium. Three patients had yeasts cultured from the peritoneal cavity. All three also had concomitant bacterial peritonitis within two months of transplantation. All three were receiving more than 0.5 mg/kg/day of prednisone, and two had serum creatinine levels greater than 2.1 mg/dl. One patient with diabetes mellitus underwent total gastrectomy because of hemorrhagic gastritis. She developed Candida and bacterial peritonitis caused by a leak from the esophogojejunostomy. Candida had been cultured from the throat and probably found its way into the peritoneal cavity from swallowed saliva. She died of bacterial peritonitis. Although Candida had been cultured from the peritoneal cavity during exploration for the leak from the esophogojejunostomy, none was found at postmortem examination, ten days after treatment with amphotericin B was begun. The second patient, a 40-year-old diabetic woman, developed a bladder leak into the peritoneal cavity two months after receiving a transplant from a cadaver donor. The bladder was reclosed. The peritoneal fluid contained Torulopsis glabrata (T. glabrata had been repeatedly cultured from the urine) and Serratia marcescens. She was treated with amphotericin-B and tobramycin. She still has normal renal function 48 months later. The third patient, a 20-year-old diabetic man, had primary peritonitis caused by Salmonella five days posttransplant. He was treated with gentamycin and had a laparotomy seven days later. Salmonella and Candida albicans were cultured from the peritoneum. He died 15 days after laparotomy. An autopsy revealed disseminated candidiases, without Salmonella. Cenitral nervous siystem. Three patients had fungal infections of the central nervous system. Two adult patients had meningitis caused by Cryptococcus neoformans 6-17 months posttransplant. Cryptococcus was not cultured from any other site. One patient had renal failure secondary to diabetes mellitus and the other had polycystic renal disease. Both had fever (38 and 38.50) and mild headache. The white blood cell counts were 5,800 and 7,000 per mm3. They were on maintenance doses of immunosuppression. In both cases the diagnosis was made after the immediate examination of the spinal fluid with an India ink preparation. Both patients recovered with systemic amphotericin-B and 5-fluorocytosine treatment, without intrathecal therapy. Another patient had renal failure caused by Fabry's disease, and received a cadaver renal allograft. Five weeks after transplantation he became febrile (400).
Ann. Surg. a November 1978
Over the course of two weeks he became obtunded; he died five months after transplantation. Diagnostic tests, including repeated spinal taps and brain biopsies gave no cause for his decline. He never responded to either antibacterial or antifungal treatment. Autopsy findings included Coccidioides immitis that involved the brain, lungs, and kidney. Kidney graft. Two patients had Candida albicans cultured from their transplanted kidneys. One, a diabetic, had C. albicans cultured from a lymphocele three months before laparotomy for a suspected abscess was performed. Instead, bacterial peritonitis was found so a transplant nephrectomy was performed. Candidta albicans was cultured from the kidney specimen. The patient died four days later of bacterial peritonitis. In the other patient, Candida albicans was cultured from the kidney after transplant nephrectomy for chronic rejection. She recovered without further treatment and is now on maintenance hemodialysis. Lung. Eight patients (age range 17-52 years) had primary fungal pneumonia (Table 3). One-half of the infections were recognized four to seven months after transplantation. Pneumonia occurred from 27 to 72 months posttransplant in the other four. One patient had a normal temperature, and the other seven had fevers between 38.5 and 39.5°. The eight patients had white blood cell counts of between 3,550 and 19,000 per mm3; only two had white blood cell counts above 10,000 per mm3. Five of the patients had poor graft function with serum creatinine levels greater than 2.1 mg/dl. Although seven of them had been treated for at least one rejection episode, only one patient was receiving more than 25 mg/kg/day at the time he developed fungal pneumonia. Four of the patients had recently been treated for rejection episodes. Four patients had fungal pneumonia caused by Candida albicans, two had pneumonia caused by Histoplasma capsulatum, and two had Aspergillus cultured from the lung (one of these also had Cryptococcus). Two patients also had bacteria isolated from the lung and were treated with antibiotics, in addition to antifungal agents. Three patients died as a direct consequence of persistent fungal pneumonia. One patient (No. 4, Table 3) with pulmonary histoplasmosis (he also had Histoplasma capsulatum cultured from the blood) was found to have it in the liver as well. Two additional patients have died subsequently, one (No. 3, Table 3) died one year after successful treatment for pneumonia caused by Histoplasma capsulatum, but the autopsy results revealed disseminated Herpesvirus hominis. The other patient (No. 1, Table 3) died of liver failure after a second kidney transplant. Three patients are cur-
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