Disseminated Histoplasmosis in Renal Transplant Recipients
Scott F. Davies, MD,’ Minneapolis, George A. Sarosi, MD, FACP,’
Minnesota
Minneapolis,
Phillip K. Peterson, MD,’ Minneapolis, Mohammed Khan, MD,’ Minneapolis,
Minnesota
Richard J. Howard, MD,t Minneapolis,
Minnesota
Richard L. Simmons, MD,f Minneapolis, John S. Najarian, MD,7 Minneapolis,
Minnesota
Minnesota
Minnesota
Minnesota
The protection of a transplanted kidney from rejection depends on the suppression of cell-mediated immunity which is responsible for graft rejection. This part of the immune system, however, is vital in host defense against intracellular pathogens, including mycobacteria and certain fungi. Initial predictions that tuberculosis would be a common infection in the setting of renal transplatitation were not fulfilled, although the continuing occurrence of sporadic cases serves to maintain vigilance [1,2]. Similarly, the potential for infection with the intracellular pathogenic fungus Histoplasma capsulatum was also a source of concern during the early experience with transplantation, especially in endemic areas [J]. However, as a large experience with transplantation in these areas accumulated, it became evident that histoplasmosis was only rarely a clinical problem. Despite this reassuring experience, systemic infection with H. capsulatum does occur in the setting of renal transplantation. The same constant vigilance afforded to tuberculosis is also necessary with respect to histoplasmosis. Five cases of disseminated histoplasmosis occurred in a 4 year period among transplant recipients in Minneapolis, Minnesota. The purpose of this report is to examine the clinical features of disseminated histoplasmosis in these patients and in the nine previously reported renal transplant patients with disseminated histoplasmosis in an attempt to increase awareness of this potentially treatable opportunistic infection. Based on our experience, disseminated histoplasmosis is a particularly important infection among From the Departments of Internal Medicine’ and Surgery’. University of Minnesota: and Medical Services. Veterans Administration Hcscital and ’ Hennepin County Medical Center, ‘Minneapolis, Minnesota. Reprint requests should be addressed to George A. Sarosi. MD, Department of Medicine (111). Veterans Hospital, 54th Street and 46th Avenue South, Minneapolis, Minnesota 55417.
666
renal transplant recipients for several reasons. First, it presents in a nonspecific manner which can delay diagnosis greatly. Second, disseminated histoplasmosis may mimic or occur simultaneously with cytomegalovirus infection which is a frequent concomitant of renal transplantation. Finally, unlike other invasive fungal infections in this setting, disseminated histoplasmosis often occurs in patients with good graft function and the prospect of years of productive life. Case Reports Casr I. This 61 year old man (AC) received a renal transplant (cadaver donor) for renal failure secondary to polycystic kidney disease in October 1974. He had been semiretired since 1963 due to residua from a ruptured cerebral aneurysm. The posttransplant course was complicated by the onset of high spiking fevers. The chest roentgenogram was initially negative for abnormalities and the patient had no pulmonary symptoms. He spent several months in the hospital undergoing evaluation and received an empiric course of gentamycin and cefazolin without response. The spiking fever was eventually attributed to cytomegalovirus infection because the virus was cultured from the urine and there was a rise in complement fixing serologic titer from 1:16 to 1:128. Because the fever continued over many weeks, a more aggressive diagnostic investigation was undertaken. This included a bone marrow examination which revealed noncaseating granulomas. Organisms were not seen despite special stains for acid-fast organisms and for fungi. A repeated chest roentgenogram 2 months after the onset of fever revealed a diffuse interstitial infiltrate with a nodular component at the base of the left lung. The patient was treated with isoniazid, ethambutol, and pyridoxine but the fever did not abate. Finally, in April 1974 cultures submitted 8 weeks earlier were reported positive for H.capsulatum in bone marrow, urine, and sputum. The patient responded well to a total dose of 2.4 g of amphotericin B given three times weekly The American
Journal of Surgwy
Disseminated
on an outpatient basis over a 6 month period. The fever disappeared within the first 2 weeks of therapy. Follow-up study 24 months after the last amphotericin B treatment revealed normal renal function (creatinine 0.9 mg/lOO ml). The patient was clinically well in April 1978 on continued immunosuppressive therapy including prednisone, 15 mg every other day, and azathioprine, 200 mg daily. Comment: This patient had a benign clinical course despite hectic spiking fevers over a 17 week period prior to diagnosis. For 2 months the fever was attributed to the documented cytomegalovirus infection; for another 2 months he was treated as having probable tuberculosis. The diagnosis of disseminated histoplasmosis led to specific therapy with amphotericin B and a prompt response. Case II. The patient was a 49 year old man (RB) who received a kidney transplant (living related donor) for renal failure secondary to chronic glomerulonephritis in April 1970. He had several subsequent hospitalizations for treatment of acute rejection. One such admission, in September 1975, was associated with an episode of pneumonia. Nontypable Hemophilus influenza was recovered from bronchial washings and the patient responded to therapy ampicillin. He returned to the hospital with spiking fevers and myalgias in January 1976. He had no pulmonary symptoms and the chest roentgenographam showed normal findings. The complement fixation titer for cytomegalovirus was 1:8. The fever persisted and within 2 weeks diffuse interstitial infiltrates developed on chest roentgenography. There was no response to broad spectrum antibiotics and he followed a fulminant septic course with complications of gastrointestinal bleeding and progressive jaundice. He died within 5 weeks of the onset of fever despite early diagnosis (yeast grown from the blood were identified as H. capsdatum within 3 weeks of the onset of fever). He did not survive long enough to receive an adequate course of amphotericin B (total dose 440 mg) and autopsy showed widespread involvement with H. capsulatum, most prominent in the liver and the lung. Comment: This patient had an accelerated course despite relative good health prior to admission. Although he had had a recent episode of rejection, the creatinine level at the time of admission was 1.9 mg/lOO ml. Case 111. This patient was a 31 year old diabetic man (MS) with renal failure who received an unsuccessful cadaver transplant in October 1975. After rejection and nephrectomy all immunosuppressive therapy was stopped and chronic dialysis was continued. In September 1976 he received a second kidney, also from a cadaver. He was afebrile at the time of admission for transplantation. The transplanted kidney never functioned. Two weeks after surgery daily spiking fevers began and the patient’s condition rapidly deteriorated. The chest roentgenogram gave normal results and bacterial cultures of the blood were negative. Nephrectomy was performed 1 week later and yeast organisms were seen on histopathologic sections of the removed kidney. Blood cultures from 6 separate days Volume 137, May 1979
Histoplasmosis
grew H. capsdatum, and the organisms were also seen on the peripheral blood smear. The patient died 11 days after the onset of fever after receiving only 3 days of therapy with amphotericin B. Autopsy showed massive involvement of the liver, lungs, and adrenals with H. capsulatum. Comment: In this case there were fungi on microscopic examination of the surgically removed rejected kidney and histoplasmosis was later proved by culture from this same specimen. Therefore, there was initial speculation that this patient Tight have acquired histoplasmosis from the transplanted kidney, as occurred in a well documented case reported by Hood et al [5]. The time course of the illness was certainly similar with a fulminant course immediately after transplantation and death within 1 month of surgery. However, the donor of this patient’s kidney, as opposed to the donor in Hood et al’s report, died an accidental death without any acute medical illness. The donor was from a nonendemic area of northern Minnesota. His second kidney was transplanted into a 51 year old man who died 6 weeks post transplantation of bacterial sepsis at another center. Review of the autopsy material on the second recipient including fungal stains on all tissues revealed no evidence of histoplasmosis. For these reasons it is not considered likely that histoplasmosis was transmitted to this patient by the transplanted kidney. Case IV. This patient was a 48 year old woman (AV) who received a renal transplant (cadaver donor) in November 1976 for renal failure secondary to polycystic kidney disease. Function in the transplanted kidney was excellent. Four months after transplantation she presented with early morning fevers and chills. She also complained of myalgias. She had no pulmonary symptoms. The initial chest roentgenogram was entirely within normal limits, but bilateral interstitial infiltrates developed within 2 weeks. The only laboratory abnormality was a moderate elevation of the serum glutamic oxaloacetic transaminase (50 IU) and alkaline phosphatase (190 IU). A diagnosis of cytomegalovirus infection was based on a febrile illness with bilateral pulmonary infiltrates, an elevation in complement fixation titer from 1:64 to 1:512, and a positive sputum culture for the virus. A pattern of daily fever spikes to 39°C continued over the next several weeks but cultures of blood drawn during the initial hospitalization for suspected cytomegalovirus infection eventually grew H. capsulatum. The patient was started on amphotericin B and promptly defervesced. She was treated with a total dose of 2 g of a three times a week outpatient schedule. She retained excellent function in the graft throughout her therapy and was clinically well in April 1978,6 months after her last dose of amphotericin B. Current medications include prednisone, 20 mglday, and azathioprine, 125 mglday. Comment: This patient had 10 weeks of spiking fevers without clinical deterioration. She was considered to have cytomegalovirus infection until multiple blood cultures grew H. plasma capsulatum. Clinical response to amphotericin B was prompt and the infection was controlled without sacrificing function of the graft. 667
Davies et al
Case V. This 41 year old man (LK) received a renal transplant (cadaver donor) in March 1967 for renal failure due to polycystic kidney disease. Function in the graft remained excellent over many years and the patient was able to work full time as a farmer. The patient did raise chickens on his farm. In May 1977 he presented with a 2 year history of swelling of all his fingers and an 8 month history of multiple ulcerations on both of his hands. Examination revealed diffuse swelling of all the fingers on both hands. The swelling was most marked periarticularly and along the tendon sheaths; there was no synovitis in any of the joints. There were six ulcerations on the volar surfaces of his hands, the largest of which was 3 by 4 cm. These were located on the left thumb and third finger and the right thumb and index finger. Roentgenograms of the hands showed soft tissue swelling without bone or joint abnormality. Histopathologic examination of a biopsy of one of the ulcers revealed organisms consistent with H. capsulatum, and this was confirmed by culture of the biopsy specimen. The skin lesions healed completely with specific therapy (a total course of 2 g of amphotericin B given three times
TABLE I
weekly with a maximal dose of 40 mg). The excellent function of the long-standing graft was maintained throughout the therapy and the patient was well in April 1978,3 months after his last dose of amphotericin B. Comment: The patient presented with skin disease as his only clinical manifestation of disseminated histoplasmosis. The chest roentgenogram was normal and there was no sign of other involvement. It was possible to treat the histoplasmosis effectively without compromising his very successful engrafted kidney. Patients
and Methods
From January 1,1974 to January 1,1978, five patients with disseminated histoplasmosis were seen among renal transplant recipients at the University of Minnesota (four patients) and the Hennepin County Medical Center (one patient). In all patients H. capsdatum was cultured from an extrapulmonary site. (Clinical data from three of these patients [cases I, II, and III] was included in table form in a previous publication [4].) Review of the English literature revealed nine other reported cases of renal transplantation complicated by dis-
Clinical Features of Five Renal Transplant Recipients With Disseminated Histoplasmosis (Present Report) and Nine Similar Patients Previously Reported (Literature Review)
Interval Post Transplantation Case No. [Reference]
Age (yr) & Sex
at Onset of Symptoms
Presenting Symptoms (Duration of Symptoms Before Diagnosis)
Method of Diagnosis
Present Report I. II. Ill. IV.
AC RB MS AV
61M 49M 30M 49F
2 mo 56 mo 2 wk 4mo
V.
LK
41M
122 mo
Fever, dry cough (17 wk) Fever, myalgias (4 wk) Fever (2 wk) Fever, night sweats, chills (10 wk) Ulcerating lesions on both hands (8 mo)
Cultures Cultures Cultures Cultures
of of of of
bone marrow blood blood blood
Histopathologic study and culture of skin biopsy
Literature Review VI.
151
39M
12 days
VII.
t’31
10M
8mo
VIII.
171
18F
12 mo
IX.
[al
32M
41 mo
X.
[91
8F
8mo
XI. XII.
illI
[lOI
29M 52M
2mo 6mo
XIII.
I121
45M
11 mo
XIV.
[I21
27F
6mo
608
Fever, leukocytosis (death within 1 wk) Painful erythematous rash, fever (8 wk) Fever, leukocytosis, increasing renal failure (symptoms not due to histoplasmosis) Cellulitis, skin ulceration, fever (< 1 mo) Hepatosplenomegaly; fever (died within 3 wk of onset of fever) Not reported Fever, cough, dyspnea, indurated erythematous lesions on arms (
Scott F. Davies, MD,’ Minneapolis, George A. Sarosi, MD, FACP,’
Minnesota
Minneapolis,
Phillip K. Peterson, MD,’ Minneapolis, Mohammed Khan, MD,’ Minneapolis,
Minnesota
Richard J. Howard, MD,t Minneapolis,
Minnesota
Richard L. Simmons, MD,f Minneapolis, John S. Najarian, MD,7 Minneapolis,
Minnesota
Minnesota
Minnesota
Minnesota
The protection of a transplanted kidney from rejection depends on the suppression of cell-mediated immunity which is responsible for graft rejection. This part of the immune system, however, is vital in host defense against intracellular pathogens, including mycobacteria and certain fungi. Initial predictions that tuberculosis would be a common infection in the setting of renal transplatitation were not fulfilled, although the continuing occurrence of sporadic cases serves to maintain vigilance [1,2]. Similarly, the potential for infection with the intracellular pathogenic fungus Histoplasma capsulatum was also a source of concern during the early experience with transplantation, especially in endemic areas [J]. However, as a large experience with transplantation in these areas accumulated, it became evident that histoplasmosis was only rarely a clinical problem. Despite this reassuring experience, systemic infection with H. capsulatum does occur in the setting of renal transplantation. The same constant vigilance afforded to tuberculosis is also necessary with respect to histoplasmosis. Five cases of disseminated histoplasmosis occurred in a 4 year period among transplant recipients in Minneapolis, Minnesota. The purpose of this report is to examine the clinical features of disseminated histoplasmosis in these patients and in the nine previously reported renal transplant patients with disseminated histoplasmosis in an attempt to increase awareness of this potentially treatable opportunistic infection. Based on our experience, disseminated histoplasmosis is a particularly important infection among From the Departments of Internal Medicine’ and Surgery’. University of Minnesota: and Medical Services. Veterans Administration Hcscital and ’ Hennepin County Medical Center, ‘Minneapolis, Minnesota. Reprint requests should be addressed to George A. Sarosi. MD, Department of Medicine (111). Veterans Hospital, 54th Street and 46th Avenue South, Minneapolis, Minnesota 55417.
666
renal transplant recipients for several reasons. First, it presents in a nonspecific manner which can delay diagnosis greatly. Second, disseminated histoplasmosis may mimic or occur simultaneously with cytomegalovirus infection which is a frequent concomitant of renal transplantation. Finally, unlike other invasive fungal infections in this setting, disseminated histoplasmosis often occurs in patients with good graft function and the prospect of years of productive life. Case Reports Casr I. This 61 year old man (AC) received a renal transplant (cadaver donor) for renal failure secondary to polycystic kidney disease in October 1974. He had been semiretired since 1963 due to residua from a ruptured cerebral aneurysm. The posttransplant course was complicated by the onset of high spiking fevers. The chest roentgenogram was initially negative for abnormalities and the patient had no pulmonary symptoms. He spent several months in the hospital undergoing evaluation and received an empiric course of gentamycin and cefazolin without response. The spiking fever was eventually attributed to cytomegalovirus infection because the virus was cultured from the urine and there was a rise in complement fixing serologic titer from 1:16 to 1:128. Because the fever continued over many weeks, a more aggressive diagnostic investigation was undertaken. This included a bone marrow examination which revealed noncaseating granulomas. Organisms were not seen despite special stains for acid-fast organisms and for fungi. A repeated chest roentgenogram 2 months after the onset of fever revealed a diffuse interstitial infiltrate with a nodular component at the base of the left lung. The patient was treated with isoniazid, ethambutol, and pyridoxine but the fever did not abate. Finally, in April 1974 cultures submitted 8 weeks earlier were reported positive for H.capsulatum in bone marrow, urine, and sputum. The patient responded well to a total dose of 2.4 g of amphotericin B given three times weekly The American
Journal of Surgwy
Disseminated
on an outpatient basis over a 6 month period. The fever disappeared within the first 2 weeks of therapy. Follow-up study 24 months after the last amphotericin B treatment revealed normal renal function (creatinine 0.9 mg/lOO ml). The patient was clinically well in April 1978 on continued immunosuppressive therapy including prednisone, 15 mg every other day, and azathioprine, 200 mg daily. Comment: This patient had a benign clinical course despite hectic spiking fevers over a 17 week period prior to diagnosis. For 2 months the fever was attributed to the documented cytomegalovirus infection; for another 2 months he was treated as having probable tuberculosis. The diagnosis of disseminated histoplasmosis led to specific therapy with amphotericin B and a prompt response. Case II. The patient was a 49 year old man (RB) who received a kidney transplant (living related donor) for renal failure secondary to chronic glomerulonephritis in April 1970. He had several subsequent hospitalizations for treatment of acute rejection. One such admission, in September 1975, was associated with an episode of pneumonia. Nontypable Hemophilus influenza was recovered from bronchial washings and the patient responded to therapy ampicillin. He returned to the hospital with spiking fevers and myalgias in January 1976. He had no pulmonary symptoms and the chest roentgenographam showed normal findings. The complement fixation titer for cytomegalovirus was 1:8. The fever persisted and within 2 weeks diffuse interstitial infiltrates developed on chest roentgenography. There was no response to broad spectrum antibiotics and he followed a fulminant septic course with complications of gastrointestinal bleeding and progressive jaundice. He died within 5 weeks of the onset of fever despite early diagnosis (yeast grown from the blood were identified as H. capsdatum within 3 weeks of the onset of fever). He did not survive long enough to receive an adequate course of amphotericin B (total dose 440 mg) and autopsy showed widespread involvement with H. capsulatum, most prominent in the liver and the lung. Comment: This patient had an accelerated course despite relative good health prior to admission. Although he had had a recent episode of rejection, the creatinine level at the time of admission was 1.9 mg/lOO ml. Case 111. This patient was a 31 year old diabetic man (MS) with renal failure who received an unsuccessful cadaver transplant in October 1975. After rejection and nephrectomy all immunosuppressive therapy was stopped and chronic dialysis was continued. In September 1976 he received a second kidney, also from a cadaver. He was afebrile at the time of admission for transplantation. The transplanted kidney never functioned. Two weeks after surgery daily spiking fevers began and the patient’s condition rapidly deteriorated. The chest roentgenogram gave normal results and bacterial cultures of the blood were negative. Nephrectomy was performed 1 week later and yeast organisms were seen on histopathologic sections of the removed kidney. Blood cultures from 6 separate days Volume 137, May 1979
Histoplasmosis
grew H. capsdatum, and the organisms were also seen on the peripheral blood smear. The patient died 11 days after the onset of fever after receiving only 3 days of therapy with amphotericin B. Autopsy showed massive involvement of the liver, lungs, and adrenals with H. capsulatum. Comment: In this case there were fungi on microscopic examination of the surgically removed rejected kidney and histoplasmosis was later proved by culture from this same specimen. Therefore, there was initial speculation that this patient Tight have acquired histoplasmosis from the transplanted kidney, as occurred in a well documented case reported by Hood et al [5]. The time course of the illness was certainly similar with a fulminant course immediately after transplantation and death within 1 month of surgery. However, the donor of this patient’s kidney, as opposed to the donor in Hood et al’s report, died an accidental death without any acute medical illness. The donor was from a nonendemic area of northern Minnesota. His second kidney was transplanted into a 51 year old man who died 6 weeks post transplantation of bacterial sepsis at another center. Review of the autopsy material on the second recipient including fungal stains on all tissues revealed no evidence of histoplasmosis. For these reasons it is not considered likely that histoplasmosis was transmitted to this patient by the transplanted kidney. Case IV. This patient was a 48 year old woman (AV) who received a renal transplant (cadaver donor) in November 1976 for renal failure secondary to polycystic kidney disease. Function in the transplanted kidney was excellent. Four months after transplantation she presented with early morning fevers and chills. She also complained of myalgias. She had no pulmonary symptoms. The initial chest roentgenogram was entirely within normal limits, but bilateral interstitial infiltrates developed within 2 weeks. The only laboratory abnormality was a moderate elevation of the serum glutamic oxaloacetic transaminase (50 IU) and alkaline phosphatase (190 IU). A diagnosis of cytomegalovirus infection was based on a febrile illness with bilateral pulmonary infiltrates, an elevation in complement fixation titer from 1:64 to 1:512, and a positive sputum culture for the virus. A pattern of daily fever spikes to 39°C continued over the next several weeks but cultures of blood drawn during the initial hospitalization for suspected cytomegalovirus infection eventually grew H. capsulatum. The patient was started on amphotericin B and promptly defervesced. She was treated with a total dose of 2 g of a three times a week outpatient schedule. She retained excellent function in the graft throughout her therapy and was clinically well in April 1978,6 months after her last dose of amphotericin B. Current medications include prednisone, 20 mglday, and azathioprine, 125 mglday. Comment: This patient had 10 weeks of spiking fevers without clinical deterioration. She was considered to have cytomegalovirus infection until multiple blood cultures grew H. plasma capsulatum. Clinical response to amphotericin B was prompt and the infection was controlled without sacrificing function of the graft. 667
Davies et al
Case V. This 41 year old man (LK) received a renal transplant (cadaver donor) in March 1967 for renal failure due to polycystic kidney disease. Function in the graft remained excellent over many years and the patient was able to work full time as a farmer. The patient did raise chickens on his farm. In May 1977 he presented with a 2 year history of swelling of all his fingers and an 8 month history of multiple ulcerations on both of his hands. Examination revealed diffuse swelling of all the fingers on both hands. The swelling was most marked periarticularly and along the tendon sheaths; there was no synovitis in any of the joints. There were six ulcerations on the volar surfaces of his hands, the largest of which was 3 by 4 cm. These were located on the left thumb and third finger and the right thumb and index finger. Roentgenograms of the hands showed soft tissue swelling without bone or joint abnormality. Histopathologic examination of a biopsy of one of the ulcers revealed organisms consistent with H. capsulatum, and this was confirmed by culture of the biopsy specimen. The skin lesions healed completely with specific therapy (a total course of 2 g of amphotericin B given three times
TABLE I
weekly with a maximal dose of 40 mg). The excellent function of the long-standing graft was maintained throughout the therapy and the patient was well in April 1978,3 months after his last dose of amphotericin B. Comment: The patient presented with skin disease as his only clinical manifestation of disseminated histoplasmosis. The chest roentgenogram was normal and there was no sign of other involvement. It was possible to treat the histoplasmosis effectively without compromising his very successful engrafted kidney. Patients
and Methods
From January 1,1974 to January 1,1978, five patients with disseminated histoplasmosis were seen among renal transplant recipients at the University of Minnesota (four patients) and the Hennepin County Medical Center (one patient). In all patients H. capsdatum was cultured from an extrapulmonary site. (Clinical data from three of these patients [cases I, II, and III] was included in table form in a previous publication [4].) Review of the English literature revealed nine other reported cases of renal transplantation complicated by dis-
Clinical Features of Five Renal Transplant Recipients With Disseminated Histoplasmosis (Present Report) and Nine Similar Patients Previously Reported (Literature Review)
Interval Post Transplantation Case No. [Reference]
Age (yr) & Sex
at Onset of Symptoms
Presenting Symptoms (Duration of Symptoms Before Diagnosis)
Method of Diagnosis
Present Report I. II. Ill. IV.
AC RB MS AV
61M 49M 30M 49F
2 mo 56 mo 2 wk 4mo
V.
LK
41M
122 mo
Fever, dry cough (17 wk) Fever, myalgias (4 wk) Fever (2 wk) Fever, night sweats, chills (10 wk) Ulcerating lesions on both hands (8 mo)
Cultures Cultures Cultures Cultures
of of of of
bone marrow blood blood blood
Histopathologic study and culture of skin biopsy
Literature Review VI.
151
39M
12 days
VII.
t’31
10M
8mo
VIII.
171
18F
12 mo
IX.
[al
32M
41 mo
X.
[91
8F
8mo
XI. XII.
illI
[lOI
29M 52M
2mo 6mo
XIII.
I121
45M
11 mo
XIV.
[I21
27F
6mo
608
Fever, leukocytosis (death within 1 wk) Painful erythematous rash, fever (8 wk) Fever, leukocytosis, increasing renal failure (symptoms not due to histoplasmosis) Cellulitis, skin ulceration, fever (< 1 mo) Hepatosplenomegaly; fever (died within 3 wk of onset of fever) Not reported Fever, cough, dyspnea, indurated erythematous lesions on arms (
