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Disseminated histoplasmosis in renal transplant recipients
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 (<3 mo) Painful subcutaneous nodule (
Histopathologic study at autopsy and postmortem cultures Histopathologic study of bone marrow Histopathologic study at autopsy
Histopathologic study of skin biopsy Histopathologic study at autopsy
Histopathologic study of bone marrow Histopathologic study of skin biopsy, eventual positive blood cultures Culture of biopsy of lesion Positive histopathologic study and culture of skin biopsy
The American Journal of Surgery
Disseminated Histoplasmosis
seminated histoplasmosis. Information derived from these reports is summarized.
Comments
Disseminated histoplasmosis occurs in immunosuppressed patients and must be considered in the differential diagnosis of febrile illnesses among renal transplant recipients. The infection occurs as the direct result of immunosuppression. The occurrence of 5 cases among approximately 1,300 renal transplant recipients in Minneapolis, Minnesota, repre-
TABLE II
sents a greatly increased prevalence of the disease in this patient population. Minnesota is a nonendemic area and only one case of disseminated histoplasmosis in a nonimmunosuppressed patient was seen during the 3 year period 1972 to 1975 at the four major teaching hospitals of the University of Minnesota [4]. Clinical features of the five patients reported herein and of the nine previously reported transplant recipients with disseminated histoplasmosis are summarized in Tables I and II. Some of the clinical features of the illness deserve specific comment.
Roentgenologic and Serologic Features, Therapy Given, and Outcome in Five Renal Transplant Recipients (Present Report) and Nine Similar Patients Previously Reported on (Literature Review)
Case No. [Reference]
Aae (vr) & S&x
Chest X-Ray
Fungal Serology
Therapy
Outcome
Present Report I.
AC
61M
II.
RB
49M
Ill.
MS
30M
IV.
AV
49F
V.
LK
41M
Initially normal; subsequently, diffuse interstitial infiltrate with nodule at base of left lung Initially normal; subsequently diffuse interstitial infiltrate Normal
Anticomplementary
Amphotericin
Not done
Initially normal; subsequently bilateral lower lobe infiltrates Normal
Not done
Amphotericin B, 440 mg before death Amphotericin B (minimal total dose) Amphotericin El (2 g)
Yeast phase 1:16
Amphotericin
Not done
B 2,400 mg Infection controlled; graft function maintained; follow-up study 26 mo
B (2 g)
Died before effective therapy could be given Died before effective therapy could be given Infection controlled: graft function maintained; follow-up study 4 mo Infection controlled; graft function maintained; follow-up study 1 mo
Literature Review None
VI.
[51
39M
Pleural effusion, no parenchymal lesions
VII.
t61
10M
Not reported
Negative
VIII.
[ 71
18F
Infiltrate of lower lobe of left lung
Not reported
Amphotericin B (1 day only) None
32M
Miliary infiltrate
Not reported
Amphotericin
B (2 g)
8F
Normal
C.F. 1:32 Histoplasmin
Amphotericin dose)
B (minimal
29M 52M
Not reported Multiple pulmonary
Not reported Not reported
Not reported Amphotericin
IX. X.
XI. XII.
$r;;)mittent
nodules XIII.
XIV.
. [ 7.21
B over
45M
Normal
Negative
Amphotericin
B (2 g)
27F
Normal
Negative
Amphotericin
B (2 g)
voluma 137, May 1979
Died: infection documented due to infected graft Died before effective therapy could be given Death probably due to bacterial infection; had active solitary brain lesion due to H capsdatum at autopsy Infection controlled; graft function maintained Died of fulminant histoplasma meningitis; postmortem cultures of blood and spleen positive Died of histoplasmosis Died of histoplasmosis
Infection controlled: graft function maintained; follow-up study 18 mo at time of report Infection controlled; graft function maintained: follow-up study 12 mo at time of report
689
Davies et al
The mechanism of infection in these patients is uncertain and may not be the same in all cases. Unchecked spread of a primary infection is suggested in patient 12 (Table II), who presented with a pulmonary illness with cough and dyspnea and had multiple pulmonary nodules on the chest roentgenogram. However, most of the remaining patients had no pulmonary symptoms and the chest roentgenogram was within normal limits in eight of the patients at the onset of their illness. In three of these eight patients diffuse interstitial infiltrates developed during the course of their febrile illness; this is more suggestive of hematogenous spread than of inhalational disease. Only two patients lived on a farm (cases V and IX) and there was no history in any patient of an acute illness after an exposure to possibly contaminated soil. These clinical and roentgenologic features suggest endogenous reactivation. The fact that the five cases reported herein occurred in a nonendemic area is additional supportive evidence that endogenous reactivation may occur. Two of our patients had lived and worked in endemic areas prior to moving to Minnesota. The patient in case II had lived in Missouri for 10 years and the patient in case I had worked on farmsin Iowa and southern Illinois. However, there was no proof that either patient had previously been infected with H. caps&turn. A third and final possibility for the mechanism of infection is direct spread of the infection from an infected graft which has been documented on one occasion [5]. The clinical course in our case III was similar to that case but, as discussed herein, no evidence could be generated to support this mechanism of infection for this particular patient. The nonspecific features of the illness should be stressed. There were no specific clinical or laboratory features. Fever was present in 10 cases but absent in 3 of the patients with skin lesions, including the patient in case V. There were usually no symptoms to suggest a primary pulmonary infection. Cytomegalovirus is a common infection among transplant recipients and also can present as a systemic febrile illness without localizing features. In two of our patients (cases I and IV) the diagnosis of cytomegalovirus infection provided an initial explanation for many weeks of spiking fevers. Eventual culture of H. capsulatum from bone marrow (case I) and blood (case IV) finally led to another diagnosis; prompt defervescence followed specific therapy. The other three patients (cases II, III, and V) had no rise in complement fixation titers against cytomegalovirus and baseline titers of 1:16 or less. The relationship of the cytomegalovirus infection to the disseminated histoplasmosis in these two pa690
tients is uncertain. Cytomegalovirus infection has been shown to suppress aspects of cell-mediated immunity in laboratory animals [13,14]. In addition, a striking synergistic effect on mortality has been demonstrated in mice with cytomegalovirus infection when they are inoculated with Candida albicans [15]. The clinical observation that severe cytomegalovirus infections among human renal transplant recipients are frequently terminated by bacterial and/or fungal superinfections has recently been emphasized [16]. Cytomegalovirus infections may have been a specific predisposing factor to the development of disseminated histoplasmosis in cases I and IV. However, it is also possible that the cytomegalovirus infection was clinically insignificant and was important only because it offered a ready explanation for the febrile illness which delayed further investigation. Continued bacteriologic and mycologic surveillance of renal transplant recipients is always necessary during febrile illnesses despite a firm or presumptive diagnosis of cytomegalovirus infection. One of our patients (case V) and four others previously reported on in the literature (cases VII, IX, XIII, and XIV) presented with skin lesions as their primary presenting complaint. The frequency of such a presentation is far greater in this series than in previously reported series of disseminated histoplasmosis in nonimmunosuppressed patients [I 7191, but the significance is uncertain. Skin lesions must be investigated thoroughly in these patients. The diagnosis was based directly on the biopsy of the skin lesion in each of the five cases. Three patients reported on herein (cases I, IV, and V) and three previously reported on in the literature (cases IX, XIII, and XIV) survived the infection. All maintained good function in their grafts despite treatment with amphotericin B. Thus, diagnosis is particularly important since specific therapy is readily available and can be administered without sacrificing the transplanted organ. In our patients the speed with which the diagnosis was made did not correlate with survival. The two patients with a fulminant infection (cases II and III) were diagnosed quickly but died of overwhelming infection. Two other patients (cases I and IV) were diagnosed 10 and 17 weeks after the onset of spiking fevers, but their ability to contain the infection was superior to that of the two patients with fatal illness. The immunosuppressive therapy was the only predisposing factor that could be identified with certainty in the five patients reported on herein. The immunosuppressive therapy being given at the time of the onset of fever (four patients) and skin ulcerations (one patient) is recorded in Table III. The The American Journal of Surgery
Disseminated
patient in case III was also receiving antilymphocyte globulin and the two patients in cases II and IV had received this therapy during the preceding 4 months at the time of their transplant surgery. These last two patients had also been on higher doses of prednisone during the immediate posttransplantation period. The patient in case II had been treated for a recent episode of rejection with higher doses of prednisone. Somewhat surprisingly, four of our five patients had excellent renal function (creatinine level less than 2 mg/lOO ml) when they presented. This is in contrast to the experience with invasive candida and aspergillus infections in renal transplant recipients that are often associated with poor graft function and associated higher doses of immunosuppressive therapy. The patient in case III was the only one among our five patients with significant neutropenia and this developed 2 days after the onset of spiking fevers. It is likely that the neutropenia was secondary to the overwhelming sepsis and not a factor predisposing to infection. The patient in case III also received prophylactic antibiotics during the preoperative period; no other patient had received antibiotics during the month before the onset of fever (cases I, II, and IV) or skin ulcerations (case V). Summary
Five cases of disseminated histoplasmosis complicating renal transplantation are reported. Nine previously reported cases from the literature are reviewed. In this setting disseminated histoplasmosis usually presents as a nonspecific systemic febrile illness that may be fulminant or more subacute. Five of 14 patients presented with skin lesions; only one patient presented with primary pulmonary symptoms of cough and dyspnea. Three of our patients and three others previously reported on survived the infection and maintained good function in the transplanted kidney despite prolonged therapy with amphotericin R. Immunosuppression was the only predisposing factor that could be identified with certainty in the five patients reported on herein. However, in two of the five patients the onset of disseminated histoplasmosis coincided with a well documented cytomegalovirus infection; the viral infection may have been a factor predisposing to infection in these two cases. References 1. Rattazzi LG. Simmons RL, Spanos PK, et al: Successful management of miliary tuberculosis after renal transplantation.
Volume 137, May 1979
TABLE III
Histoplasmosis
immunosuppressive Therapy Being Administered to Five Renal Transplant Recipients When They Presented With Disseminated Histoplasmosis
Age W) Case No.
8 Sex
I. II. Ill. IV. V.
61M 49M 30M 49F 41M
Prednisone (mgjday) 60 25 50 12.5 20
Azathioprine (mgjday) 200 150 200 150
Am J Surg 130: 359,.1975. 2. Oliver WA: Tuberculosis in renal transplant patients. Med J Australia 1: 828, 1976. 3. Smith EJ, Picardi JW, Alexander KV. et al: Histoplasmosis complicating renal transplantation (abstr). Kidney lnt6: 99A, 1974. 4. Davies SF, Khan M. Sarosi GA: Disseminated histoplasmosis in immunologically suppressed patients. Am J Med 64: 94, 1978. 5. Hood AV, lnglis FG, Lowenstein L, et al: Histoplasmosis and thrombocytopenic purpura: transmission by renal homotransplantation. Can Med Assoc J 93: 587, 1965. 6. Park RK, Goltz RW, Carey TB: Unusual cutaneous infections associated with immunosuppressive therapy. Arch Derm 95: 345,1967. 7. Vanek J, Schwarz J: The gamut of histoplasmosis. Am JMed 50: 89, 1971. 8. Oliver0 JJ, Lozano-Mendez J, Ghafary EM, et al: Mitigation of amphotericin B nephrotoxicity by mannitol. Br Afed J 1: 550, 1975. 9. Karalakulasingam R, Arora KK, Adams G, et al: Meningoencephalitis caused by Histoplasma capsulatum. Arch intern Med 136:,217, 1976. 10. Dismukes WE, Royal SA: Disseminated histoplasmosis in compromised hosts (abstr). Program and abstracts: Sixteenth internscience conference on antimicrobial agents and chemotherapy. American Society for Microbiology, 1976. 11. Daman LA, Hashimoto K, Kaplan RJ, et al: Disseminated histoplasmosis iii an immunosuppressed patient. South Med J 70: 355. 1977. 12. King RW, Kraikitpanitch S, Lindeman RD: Subcutaneous nodules caused by Histoplasma capsulatum. Ann htem hkd 86: 586, 1977. 13. Kesley DK, Olsen GA, Overall JC, et al: Alteration of host defense mechanisms by murine cytomegalovirus infection. Infect lmmun 18: 754. 1977. 14. Howard RJ, Miller J, Najarian JS: Cytomegalovirus-induced immune suppression. II. Cell-mediated immunity. Clin Exp lmmunol18: 119, 1974. 15. Hamilton JR, Overall JC. Glasgow LA: Synergistic effect on mortality in mice with murine cytomegalovirus and Pseudomonas aeruginosa, Staphyloccus aureus. or Candida albicans infections. Infect lmmun 14: 982, 1976. 16. Simmons RL, Matas AJ. Rattazzi LC, et al: Clinical characteristics of the lethal qtomegalovirus infection following renal transplantation. Surgery 82: 537, 1977. 17. Smith JW, Utz JP: Progressive disseminated histoplasmosis: a prospective study of 26 patients. Ann intern Med 76: 557, 1972. 18. Reddy P, Gorelick DF, Brasher CA, et al: Progressive disseminated histoplasmosis as seen in adults. Am J h&d 48: 629, 1970. 19. Sarosi GA, Voth DW, Dahl BA, et al: Disseminated histoplasmosis: results of long-term follow-up. A Center for Disease Control Coooerative Mvcoses Study. Ann Intern Med 75: 5 11, 1971. .
691
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 (<3 mo) Painful subcutaneous nodule (
Histopathologic study at autopsy and postmortem cultures Histopathologic study of bone marrow Histopathologic study at autopsy
Histopathologic study of skin biopsy Histopathologic study at autopsy
Histopathologic study of bone marrow Histopathologic study of skin biopsy, eventual positive blood cultures Culture of biopsy of lesion Positive histopathologic study and culture of skin biopsy
The American Journal of Surgery
Disseminated Histoplasmosis
seminated histoplasmosis. Information derived from these reports is summarized.
Comments
Disseminated histoplasmosis occurs in immunosuppressed patients and must be considered in the differential diagnosis of febrile illnesses among renal transplant recipients. The infection occurs as the direct result of immunosuppression. The occurrence of 5 cases among approximately 1,300 renal transplant recipients in Minneapolis, Minnesota, repre-
TABLE II
sents a greatly increased prevalence of the disease in this patient population. Minnesota is a nonendemic area and only one case of disseminated histoplasmosis in a nonimmunosuppressed patient was seen during the 3 year period 1972 to 1975 at the four major teaching hospitals of the University of Minnesota [4]. Clinical features of the five patients reported herein and of the nine previously reported transplant recipients with disseminated histoplasmosis are summarized in Tables I and II. Some of the clinical features of the illness deserve specific comment.
Roentgenologic and Serologic Features, Therapy Given, and Outcome in Five Renal Transplant Recipients (Present Report) and Nine Similar Patients Previously Reported on (Literature Review)
Case No. [Reference]
Aae (vr) & S&x
Chest X-Ray
Fungal Serology
Therapy
Outcome
Present Report I.
AC
61M
II.
RB
49M
Ill.
MS
30M
IV.
AV
49F
V.
LK
41M
Initially normal; subsequently, diffuse interstitial infiltrate with nodule at base of left lung Initially normal; subsequently diffuse interstitial infiltrate Normal
Anticomplementary
Amphotericin
Not done
Initially normal; subsequently bilateral lower lobe infiltrates Normal
Not done
Amphotericin B, 440 mg before death Amphotericin B (minimal total dose) Amphotericin El (2 g)
Yeast phase 1:16
Amphotericin
Not done
B 2,400 mg Infection controlled; graft function maintained; follow-up study 26 mo
B (2 g)
Died before effective therapy could be given Died before effective therapy could be given Infection controlled: graft function maintained; follow-up study 4 mo Infection controlled; graft function maintained; follow-up study 1 mo
Literature Review None
VI.
[51
39M
Pleural effusion, no parenchymal lesions
VII.
t61
10M
Not reported
Negative
VIII.
[ 71
18F
Infiltrate of lower lobe of left lung
Not reported
Amphotericin B (1 day only) None
32M
Miliary infiltrate
Not reported
Amphotericin
B (2 g)
8F
Normal
C.F. 1:32 Histoplasmin
Amphotericin dose)
B (minimal
29M 52M
Not reported Multiple pulmonary
Not reported Not reported
Not reported Amphotericin
IX. X.
XI. XII.
$r;;)mittent
nodules XIII.
XIV.
. [ 7.21
B over
45M
Normal
Negative
Amphotericin
B (2 g)
27F
Normal
Negative
Amphotericin
B (2 g)
voluma 137, May 1979
Died: infection documented due to infected graft Died before effective therapy could be given Death probably due to bacterial infection; had active solitary brain lesion due to H capsdatum at autopsy Infection controlled; graft function maintained Died of fulminant histoplasma meningitis; postmortem cultures of blood and spleen positive Died of histoplasmosis Died of histoplasmosis
Infection controlled: graft function maintained; follow-up study 18 mo at time of report Infection controlled; graft function maintained: follow-up study 12 mo at time of report
689
Davies et al
The mechanism of infection in these patients is uncertain and may not be the same in all cases. Unchecked spread of a primary infection is suggested in patient 12 (Table II), who presented with a pulmonary illness with cough and dyspnea and had multiple pulmonary nodules on the chest roentgenogram. However, most of the remaining patients had no pulmonary symptoms and the chest roentgenogram was within normal limits in eight of the patients at the onset of their illness. In three of these eight patients diffuse interstitial infiltrates developed during the course of their febrile illness; this is more suggestive of hematogenous spread than of inhalational disease. Only two patients lived on a farm (cases V and IX) and there was no history in any patient of an acute illness after an exposure to possibly contaminated soil. These clinical and roentgenologic features suggest endogenous reactivation. The fact that the five cases reported herein occurred in a nonendemic area is additional supportive evidence that endogenous reactivation may occur. Two of our patients had lived and worked in endemic areas prior to moving to Minnesota. The patient in case II had lived in Missouri for 10 years and the patient in case I had worked on farmsin Iowa and southern Illinois. However, there was no proof that either patient had previously been infected with H. caps&turn. A third and final possibility for the mechanism of infection is direct spread of the infection from an infected graft which has been documented on one occasion [5]. The clinical course in our case III was similar to that case but, as discussed herein, no evidence could be generated to support this mechanism of infection for this particular patient. The nonspecific features of the illness should be stressed. There were no specific clinical or laboratory features. Fever was present in 10 cases but absent in 3 of the patients with skin lesions, including the patient in case V. There were usually no symptoms to suggest a primary pulmonary infection. Cytomegalovirus is a common infection among transplant recipients and also can present as a systemic febrile illness without localizing features. In two of our patients (cases I and IV) the diagnosis of cytomegalovirus infection provided an initial explanation for many weeks of spiking fevers. Eventual culture of H. capsulatum from bone marrow (case I) and blood (case IV) finally led to another diagnosis; prompt defervescence followed specific therapy. The other three patients (cases II, III, and V) had no rise in complement fixation titers against cytomegalovirus and baseline titers of 1:16 or less. The relationship of the cytomegalovirus infection to the disseminated histoplasmosis in these two pa690
tients is uncertain. Cytomegalovirus infection has been shown to suppress aspects of cell-mediated immunity in laboratory animals [13,14]. In addition, a striking synergistic effect on mortality has been demonstrated in mice with cytomegalovirus infection when they are inoculated with Candida albicans [15]. The clinical observation that severe cytomegalovirus infections among human renal transplant recipients are frequently terminated by bacterial and/or fungal superinfections has recently been emphasized [16]. Cytomegalovirus infections may have been a specific predisposing factor to the development of disseminated histoplasmosis in cases I and IV. However, it is also possible that the cytomegalovirus infection was clinically insignificant and was important only because it offered a ready explanation for the febrile illness which delayed further investigation. Continued bacteriologic and mycologic surveillance of renal transplant recipients is always necessary during febrile illnesses despite a firm or presumptive diagnosis of cytomegalovirus infection. One of our patients (case V) and four others previously reported on in the literature (cases VII, IX, XIII, and XIV) presented with skin lesions as their primary presenting complaint. The frequency of such a presentation is far greater in this series than in previously reported series of disseminated histoplasmosis in nonimmunosuppressed patients [I 7191, but the significance is uncertain. Skin lesions must be investigated thoroughly in these patients. The diagnosis was based directly on the biopsy of the skin lesion in each of the five cases. Three patients reported on herein (cases I, IV, and V) and three previously reported on in the literature (cases IX, XIII, and XIV) survived the infection. All maintained good function in their grafts despite treatment with amphotericin B. Thus, diagnosis is particularly important since specific therapy is readily available and can be administered without sacrificing the transplanted organ. In our patients the speed with which the diagnosis was made did not correlate with survival. The two patients with a fulminant infection (cases II and III) were diagnosed quickly but died of overwhelming infection. Two other patients (cases I and IV) were diagnosed 10 and 17 weeks after the onset of spiking fevers, but their ability to contain the infection was superior to that of the two patients with fatal illness. The immunosuppressive therapy was the only predisposing factor that could be identified with certainty in the five patients reported on herein. The immunosuppressive therapy being given at the time of the onset of fever (four patients) and skin ulcerations (one patient) is recorded in Table III. The The American Journal of Surgery
Disseminated
patient in case III was also receiving antilymphocyte globulin and the two patients in cases II and IV had received this therapy during the preceding 4 months at the time of their transplant surgery. These last two patients had also been on higher doses of prednisone during the immediate posttransplantation period. The patient in case II had been treated for a recent episode of rejection with higher doses of prednisone. Somewhat surprisingly, four of our five patients had excellent renal function (creatinine level less than 2 mg/lOO ml) when they presented. This is in contrast to the experience with invasive candida and aspergillus infections in renal transplant recipients that are often associated with poor graft function and associated higher doses of immunosuppressive therapy. The patient in case III was the only one among our five patients with significant neutropenia and this developed 2 days after the onset of spiking fevers. It is likely that the neutropenia was secondary to the overwhelming sepsis and not a factor predisposing to infection. The patient in case III also received prophylactic antibiotics during the preoperative period; no other patient had received antibiotics during the month before the onset of fever (cases I, II, and IV) or skin ulcerations (case V). Summary
Five cases of disseminated histoplasmosis complicating renal transplantation are reported. Nine previously reported cases from the literature are reviewed. In this setting disseminated histoplasmosis usually presents as a nonspecific systemic febrile illness that may be fulminant or more subacute. Five of 14 patients presented with skin lesions; only one patient presented with primary pulmonary symptoms of cough and dyspnea. Three of our patients and three others previously reported on survived the infection and maintained good function in the transplanted kidney despite prolonged therapy with amphotericin R. Immunosuppression was the only predisposing factor that could be identified with certainty in the five patients reported on herein. However, in two of the five patients the onset of disseminated histoplasmosis coincided with a well documented cytomegalovirus infection; the viral infection may have been a factor predisposing to infection in these two cases. References 1. Rattazzi LG. Simmons RL, Spanos PK, et al: Successful management of miliary tuberculosis after renal transplantation.
Volume 137, May 1979
TABLE III
Histoplasmosis
immunosuppressive Therapy Being Administered to Five Renal Transplant Recipients When They Presented With Disseminated Histoplasmosis
Age W) Case No.
8 Sex
I. II. Ill. IV. V.
61M 49M 30M 49F 41M
Prednisone (mgjday) 60 25 50 12.5 20
Azathioprine (mgjday) 200 150 200 150
Am J Surg 130: 359,.1975. 2. Oliver WA: Tuberculosis in renal transplant patients. Med J Australia 1: 828, 1976. 3. Smith EJ, Picardi JW, Alexander KV. et al: Histoplasmosis complicating renal transplantation (abstr). Kidney lnt6: 99A, 1974. 4. Davies SF, Khan M. Sarosi GA: Disseminated histoplasmosis in immunologically suppressed patients. Am J Med 64: 94, 1978. 5. Hood AV, lnglis FG, Lowenstein L, et al: Histoplasmosis and thrombocytopenic purpura: transmission by renal homotransplantation. Can Med Assoc J 93: 587, 1965. 6. Park RK, Goltz RW, Carey TB: Unusual cutaneous infections associated with immunosuppressive therapy. Arch Derm 95: 345,1967. 7. Vanek J, Schwarz J: The gamut of histoplasmosis. Am JMed 50: 89, 1971. 8. Oliver0 JJ, Lozano-Mendez J, Ghafary EM, et al: Mitigation of amphotericin B nephrotoxicity by mannitol. Br Afed J 1: 550, 1975. 9. Karalakulasingam R, Arora KK, Adams G, et al: Meningoencephalitis caused by Histoplasma capsulatum. Arch intern Med 136:,217, 1976. 10. Dismukes WE, Royal SA: Disseminated histoplasmosis in compromised hosts (abstr). Program and abstracts: Sixteenth internscience conference on antimicrobial agents and chemotherapy. American Society for Microbiology, 1976. 11. Daman LA, Hashimoto K, Kaplan RJ, et al: Disseminated histoplasmosis iii an immunosuppressed patient. South Med J 70: 355. 1977. 12. King RW, Kraikitpanitch S, Lindeman RD: Subcutaneous nodules caused by Histoplasma capsulatum. Ann htem hkd 86: 586, 1977. 13. Kesley DK, Olsen GA, Overall JC, et al: Alteration of host defense mechanisms by murine cytomegalovirus infection. Infect lmmun 18: 754. 1977. 14. Howard RJ, Miller J, Najarian JS: Cytomegalovirus-induced immune suppression. II. Cell-mediated immunity. Clin Exp lmmunol18: 119, 1974. 15. Hamilton JR, Overall JC. Glasgow LA: Synergistic effect on mortality in mice with murine cytomegalovirus and Pseudomonas aeruginosa, Staphyloccus aureus. or Candida albicans infections. Infect lmmun 14: 982, 1976. 16. Simmons RL, Matas AJ. Rattazzi LC, et al: Clinical characteristics of the lethal qtomegalovirus infection following renal transplantation. Surgery 82: 537, 1977. 17. Smith JW, Utz JP: Progressive disseminated histoplasmosis: a prospective study of 26 patients. Ann intern Med 76: 557, 1972. 18. Reddy P, Gorelick DF, Brasher CA, et al: Progressive disseminated histoplasmosis as seen in adults. Am J h&d 48: 629, 1970. 19. Sarosi GA, Voth DW, Dahl BA, et al: Disseminated histoplasmosis: results of long-term follow-up. A Center for Disease Control Coooerative Mvcoses Study. Ann Intern Med 75: 5 11, 1971. .
691