Oral infection in immunosuppressed renal transplant patients Martin
A’. Greenberg,
ALBERT
EINSTEIN
UNIVERSITY
D.D.S.,#
MEDICAL
OF PENNSYLVANIA
and Gary Cohen, B.S.,*# Philadelphia,
CENTER, SCHOOL
NORTHERN OF DENTAL
Pa.
DIVISION MEDICINE
The most common cause of death in patients taking immunosuppressive (IS) drugs is infection. Many of the microorganisms which infect these IS patients may be found in the mouth, but the mouth has not been investigated as a potential source of lethal infection. In view of this, we studied twenty-seven IS patients taking Imuran and prednisone for 6 to 61 weeks and eighteen normal controls. The patients were followed monthly, and the incidence of oral and systemic complications was recorded. There were no deaths due to infection during the lo-month study period. Oral infection OCcurred as frequently as pneumonia or urinary tract infection. Systemic factors which were related to the development of dental infection were lymphocyte count and length of time on immunosuppressive drug therapy.
T
he most frequent complication in the immunosuppressed (IS) patient is infection.l+ A majority of these infections are caused by microorganisms which are of little or no pathologic significance in the normal person but which often cause fatal infection in the patient with an impaired immunologic response. A majority of the microorganisms which have been shown to cause fatal complications in the immunosuppressed patient may be found in the oral cavity. Periodontal disease, pulpal infection, and oral ulcers may cause the spread of these oral microorganisms into the bloodstream, or aspiration may cause them to spread to the respiratory tract. Yet in none of the studies of infection in immunosuppressed patients was the oral microbial flora considered to be a potential source of infection; nor was oral disease considered as a potential threat to the outcome of treatment. This study was supported in part by Biomedical Research Support Einstein Medical Center. Northern Division. *Associate Professor of Oral Medicine, University of Pennsylvania; Services, Albert Einstein Medical Center, Northern Division. **Senior Student.
Grant Director
5505,
Albert
of Dental
879
880
Greenberg
alld Cohen
The most widely studied group of IS patients are patients taking azathioprine and prednisone to prevent graft rejection after renal transplantation. Azathioprine is known to impair both cellular and humoral immunity.l Tapia and coworker@ studied sixteen patients who died after renal transplantation. Sixty-nine per cent of the deaths were caused by infection, The most frequent cause of death was gram-negative bacteria, such as Klebsiella, Pseudomoncls crerugiqaosa,and Bacteroides. Other deaths were caused by Ca,ndida al&curls and cytomegalovirus. These microorganisms may be isolated from the mouth. Tapia suspected that the gastrointestinal tract was a primary source of entry of bacteria, but obvious portals of entry through chronic oral diseasewere never considered. In another study, Anderson and associates5found gram-negative bacteria the most frequent cause of posttransplant septicemia. Candida albicans also caused death in this study. In only 40 per cent of the caseswas the primary site of infection identified, and Anderson stated : “The high mortality in patients with an unidentified portal of entry is of particular concern.” The mouth as a potential source of infection was not considered. Eickhoff23 studied 224 renal transplant recipients and found infectious complications in 80 per cent. The infectious organisms in his study included bacteria such as Pseudomonas and Klebsiella, fungi such as ‘Candida nlbicans and Aspergillus, and viruses such as herpes viruses. Bach and colleagues7studied fifty-one renal transplant patients and found fungal infection with Aspergillus, Candida, Cryptococcus, phycomycetes, and Nocardia as the most common cause of death. Rifkind and associates” found Candida to be the most prevalent infectious organism. In other studies by Lopez and co-workers” and Stevens,1° viral infections were prevalent in renal transplant patients. In one study,g 87 per cent of sixty-one patients developed viral infections. The viruses involved were herpes simplex virus, cytomegalovirus, and varicella-zoster virus. Herpes simplex virus and cytomegalovirus are carried in the mouths of asymptomatic carriers.ll’ I2 Patients who are immunosuppressed by causes other than transplantation have also been studied. For example, patients with renal failure have impairment of both humoral and cellular immunity,13, I4 and these patients have an increased risk of infecti0n.l” There is considerable evidence to show that patients treated with corticosteroids have an increased susceptibility to both fungal and nocardial infections.16,I7 This increased susceptibility is thought to be due to decreased migration and impaired phagocytic function of leukocytes and macr0phages.l” There are isolated case reports of severe oral infection in patients taking steroids,l” but the incidence of this problem is unknown. Other types of cytoxic agents, such as cyclophosphamide, 6-mercaptopurine, 5-fluorouracil, and methotrexate, also cause increased incidence of infection, most frequently fungal infection .*“j 21 These infections are thought to be caused by either leukopenia’l or immunosuppression.** MATERIALS AND METHODS A lo-month pilot study of oral infection in kidney transplant patients taking immunosuppressive drugs was undertaken. This study had the following objec-
Volume 43 Number 6
Oral infection in renal transplant patients
881
tives : (1) To determine whether the oral flora is a source of systemic infection in IS patients. (2) To identify oral and systemic factors which predispose IS patients to systemic infections with oral microorganisms. (3) To determine the level of oral diseasein IS patients. During an initial pilot investigation, twenty-seven renal transplant patients taking azathioprine and prednisone and eighteen normal control patients matched for age and sex were studied ; all were outpatients at Albert Einstein Medical Center, Northern Division, in Philadelphia. The following procedures were performed on each patient : History. A history of diseasesor medications which could affect the immune system were obtained from each patient, as well as a history of recent antibiotic therapy. Control patients with a positive history of any of the above were eliminated from the study. Dose of IS drugs and length of time on IS therapy were recorded for each transplant patient. GeneraZ laboratory tests. Total and differential white blood counts, as well as serum IgG, IgA, and IgM, determinations using the technique of immunodiffusion in agar gel, were carried out. Control patients in whom the laboratory tests showed any abnormalities were eliminated from the study. Oral studies. Each patient was examined for the presence of oral mucosal ulcers, dental abscesses,candidiasis, or fusospirochetal infection. A Panorex radiograph was taken to detect periapical radiolucencies. The following indices of periodontal diseasewere obtained : LGe’s gingival index, Ramf jord’s periodontal index, L6e’s plaque index, and Ramfjord’s calculus index. Microbiologic studies were performed to determine the patients who were carriers of organisms which had been previously shown to be of particular danger in IS patients. Swabs were taken of the buccal mucosa, tongue, and gingival sulcus for isolation of the following organisms : Bacteria. Swabs taken from the patient’s oral cavity were immediately inoculated into thioglycollate broth for isolation of Klebsiella, Pseudomonas aeruginosa, Proteus vulgaris, and Bacteroides fragilis. The same swabs were used to streak blood agar culture plates and desoxycholate plates for gram-negative bacteria. For Bacteriodes isolation, anaerobic plates were streaked with special anaerobic equipment using anaerobic conditions. The tubes and plates were incubated at 37 degrees for 24 to 48 hours, and the organisms growing on the plates were identified by standard cultural and biochemical techniques.25 Fungi. The following fungi were specially sought in oral cavity specimens : Candida albica.ns, Aspergillus, Cryptococcus, and Mucormycosis. Standard fungal mycologic proceduresZ5were used with Sabaraud’s agar and blood agar plates. Microscopic and cultural examination procedures25 were used to identify these organisms. Nocardia. Oral cavity specimens were incubated on blood agar plates for up to 10 days to determine the presence of Nocardia, which were identified by both microscopic and morphologic assay.25 Viruses. Oral cavity specimens were examined specifically for the presence of herpes simplex and cytomegalovirus. For this, the virology
882
Greenberg
and Cohen
Table
I. Mean blood values Transplant
(27patients)
White blood cells Neutrophils Lymphocytes kG kM kA *Significant
Oral June,
9,086 1,432 1,173 156 118 132
Surg. 1977
Control(l8patients~ mm.3* mm.3* mm.3* mg.% mg.% mg.%
5,423 3,032 1,904 1,274 227 168
mm.3 mm.3 mm.3 mg.% mg.% mg.%
at 0.01 level.
II. Systemic complications in twenty-seven transplant patients, lo-month follow-up Table
Rejection of transplant Urinary tract infection Pneumonia Viral hepatitis Generalized herpes simplex Skin abscess Total complications *One
4* iA3 E. co/i; I Candida) I t Is
death.
facilities of the diagnostic microbiology laboratory and described techniques were used.2” Specifically, specimens were incubated on three tissue culture cell systems (Hep-2, WI-38, Rh MK cells) for a period of up to 10 days at 37 degrees in culture tubes or plates. Those cultures showing evidence of cytopathogenicity were examined by serologic techniques to determine whether a virus was present. Studies on transplant patients were repeated whenever these patients visited the outpatient clinic. This ranged from once a month to once every 3 months. Control patients were seen only once to obtain base line data on the Einstein population. RESULTS
Twenty-seven IS transplant patients and eighteen control patients were studied initially. The mean age of the transplant patients was 31, while the mean age of the control group was 32. The transplant patients were taking azathioprine and prednisone for a period ranging from 6 weeks to 51/, years. The mean length of time the patients were taking these drugs was 30 months. The mean dose of azathioprine was 118 mg. per day, and the mean dose of prednisone was 19 mg. per day. Table I showsthe mean blood values for transplant versus control patients. The mean total white blood count is significantly higher for the IS transplant patients than for the controls (9,086 mm.” for transplant patients versus 5,423 mm.3 for controls). Using the analysis of covariance, this difference is significant at the 0.01 level. The increase in total white blood cells in the transplant group is due to an increase in neutrophils (7,432 mm.3 for the transplant group versus 3,032 mm.3 for the controls). This difference is also significant at the 0.01 level. The level of lymphocytes is lower for the transplant group (1,173 mm.3 versus 1,904 mm.3). These findings are consistent with those of other investigators, such as McAlack,24
Oral infection Table III. Oral complications follow-up
in twenty-seven
in renal transplmt
patients
transplant
10 month
Acute abscess Oral ulcers Chronic abscess Candidiasis Total
patients,
803
4 : I To
Table IV. Microbiology Results* Organism Transplant (27parients) Klebsiella 3 Pseudomonas 12 Candida Herpes simplex virus 2 Cytomegalovirus 1 *Organism isolated from at least one person.
Control(l8patients) I I : 0
who studied patients taking IS drugs at similar doses. They found a large compensatory increase in neutrophils in patients with suppressed lymphocytes. The levels of all three immunoglobulin classeswere lower in transplant patients than in the control group. Table II demonstrates that in the lo-month pilot study, no casesof bacterial or fungal septicemia or generalized bacterial infection occurred. There were no deaths from infection. There were only four bacterial infections outside the mouth -one on the skin of the foot and three E. coli urinary tract infections. There were also one Candida urinary tract infection, three casesof viral pneumonia, one case of generalized mucocutaneous herpes simplex infection, and one case of viral hepatitis B. Table III summarizes the oral complications which occurred in the twentyseven renal transplant patients during the initial lo-month study period. Four acute dental abscessesoccurred. The predominant organism in all infections was alpha streptococcus. The infections all responded to local surgical therapy and antibiotics. No patient developed signs of systemic involvement as a result of the infection. Clinical candidiasis was present in one patient, and oral ulcers were present in three. In two other patients periapical radiolucencies around nonvital teeth were detected on Panorex radiographs. Both patients refused treatment, and to date neither has developed an acute infection or clinical signs and symptoms of septicemia. Table IV shows the results of the microbiology studies on transplant and control patients. Organisms not listed were not isolated from any individuals. Note that 59 per cent of the transplant patients were carriers of Candida species, although only one had clinical signs of candidiasis. DISCUSSION Recent advances in medicine have confronted the dentist with new clinical problems. The technique of kidney transplantation is almost routine in many
884
Greenberg
and Cohen
Ord Surg. .rorle,
1977
large medical centers, and patients are now able to live relatively normal lives without having to spend hours each week on a hemodialysis machine. However, they must continually take IS drugs to prevent rejection of the renal graft. Studies have shown that these patients have an increased susceptibility to infection. The organisms which cause the majority of these infections can be found as part of the oral flora, but the incidence of severe infection caused by oral bacteria or oral infection is not known. The risk of routine restorative dental procedures or oral surgery has also not been studied. In an attempt to begin to learn about this probelm in a systemized way, the study described here was carried out. In the patients evaluated, there were no cases of septicemia or other generalized bacterial or fungal infection. The two deaths that occurred were not from infection but from thrombosis due to acute rejection and an automobile accident. Four acute dental abscesses developed during the course of the study, but they all remained localized. It should be noted that dental infection occurred as frequently as pneumonia or urinary tract infections. An attempt was made to distinguish patients who developed acute dental infections from those who did not. Two systemic factors studied appeared to influence whether a susceptible patient developed a dental abscess ; these were (1) lymphocyte count and (2) length of time the patient had been on IS drug therapy. The four patients who developed acute abscesses all had lymphocyte counts below 400 mm.3 This contrasts sharply with the group mean of 1,173 mm.3 Two patients with chronic periapical radiolucencies who did not develop acute abscesses had lymphocyte levels of 2,100 mm.3 and 3,100 mm.3, respectively. There were five patients in the study who had been taking IS drugs for more than 5 years. The four patients who developed acute infections were in this category. This preliminary report suggests that lymphocyte count and length of time on IS drug therapy may influence the predisposition of IS patients to acute dental infection. Dentists practicing in hospitals where renal transplantation is carried out should arrange for prospective transplant patients to have a preoperative dental evaluation. This is rarely difficult since dialysis patients often have to wait a considerable period of time before a suitable donor is located. This cooperative routine will permit obviously diseased teeth to be removed or treated and periodontal disease to be treated before IS drug therapy is instituted, thus lowering the risk of infection to the patients. The authors wish to thank Drs. H. Friedman and E. Hampton of the Department biology and Drs. J. Rosenbaum and Raja, Department of Renology, Albert Einstein Center, Northern Division.
of MicroMedical
REFERENCES
1. Anderson, R. J., et al. : Infectious Risk Factors in the Immunosuppressed Host, Am. J. Med. 54: 453-459, 1973. 2. Rodriguez, V., and Bodey, 0. P. : Bacterial Infections in Immunosuppressed Patients: Diagnosis and Management, Transplant. Proc. 5: 1249-1254, 1973. 3. Ninth Report of the Human Renal Transplant Registry, J. A. M. A. 220: 253-260, 1972. 4. Eickhoff, T. C., et al.: Current Problems and Approaches to Diagnosis of Infection in Renal Transplant Recipients, Transplant. Proc. 4: 693-697, 1972. 5. Anderson, R. J., et al.: Septicemia in Renal Transplant Recipients, Arch. Surg. 106: 692-694, 1973.
Oral infection
in rend
transplaant
patients
885
6. Tapia, H. R., et al.: Causes of Death After Renal Transplantation, Arch. Intern. Med. 131: 204-210, 1973. 7. Bach, M. C., et al.: Influence of Rejection Therapy on Fungal and Nocardial Infections in Renal Transplant Recipients, Lancet 1: 180-184, 1973. 8. Rifkind, D., Marchioro, T. L., Sehneck, S. A., and Hill, R. B.: Systemic Fungal Infections Complicating Renal Transplantation and Immunosuppressive therapy, Am. J. Med. 43: 28-38, 1967. 9. Lopez, C., et al.: Role of Virus Infections in Immunosuppressed Renal Transplant Patients, Transplant. Proc. 5: 803-808, 1973. 10. Stevens, D. A.: Immunosuppression and Virus Infection, Transplant. Proc. 5: 1259-1262, -,,“n 11. Greenberg, M. S., Brightman, V. J., and Ship, I. I.: Clinical and Laboratory Differential of Recurrent Intraoral Herpes Simplex Infections Following Fever, J. Dent. Res. 48: 385391, 1969. 12. Henson, D., et al.: Cytomegalovirus Infections During Acute Childhood Leukemia, J. Infect. Dis. 126: 467-481, 1972. 13. Wilson, W. E., Kirkpatrick, C. H., and Talmage, D. W.: Suppression of Immunologic Resnonsiveness in Uremia. Ann. Intern. Med. 62: 1-14. 1965. 14. Newberry, W. M., and S’anford, J. P.: Defective Cellular Immunity in Renal Failure, J. Clin. Invest. 50: 1262-1271, 1971. 15. Montgomerie, J. Z., Kalmanson, G. M., and Guze, L. B.: Renal Failure and Infection, Medicine (Baltimore) 47: l-32, 1968. 16. Neu, H. C., et al.: Neerotizing Nocardial Pneumonitis! Ann. Intern. Med. 66: 274.284, 1967. 17. Frenkel, J. K.: Role of Corticosteroids as Predisposing Factors in Fungal Diseases, Lab. Invest. 11: 1192-1208, 1962. 18. Moeschlin, S., Zuruczogiu, W., and Crabbie, J.: Studies on the Effect of Cortisone and ACTH on Phagocytosis ‘of Leukocytes and Maerophages, Acta. Haematol. 9: 277-288, 1953. 19. Moskow, B. S., Crekelau, G. F., and Wheaton, E. A.: Severe Oral Infection Associated With Prolonged Steroid Therapy, ORAL SURG. 34: 590-602; 1972. 20. Keye, J. D., et al. : Fungal Diseases in a General Hospital: Study of 88 Cases, Am. J. Clin. Pathol. 26: 1235-1253, 1956. 21. Craig, J. M., and Farber! 8.: Development of Disseminated Visceral Mycosis During Therapy for Acute Leukemia, Am. J. Pathol. 29: 601, 1953. 22. Santos, G. W., Owens, A. H., and Sensenbrenner, L. L.: Effects of Selected Cytotoxic Agents on Antibody Formation in Man, Ann. N. Y. Acad. Sci. 114: 404-423, 1964. 23. Eickhoff, T. C. : Infectious Complications in Renal Transplant Recipients, Transplant. Proc. 5: 1233-1268, 1973. 24. McAlaek, R.: Personal Communication, 1976. 25. Lennette, E. H. (editor) : Manual of Clinical Microbiology, ed. 2, Washington, D.C., 1974, American Society for Microbiology. Reprint requests to: Dr. Martin 8. Greenberg Department of Oral Medicine University of Pennsylvania School 4001 Spruce St. Philadelphia, Pa. 19104
of Dental
Medicine
A’. Greenberg,
ALBERT
EINSTEIN
UNIVERSITY
D.D.S.,#
MEDICAL
OF PENNSYLVANIA
and Gary Cohen, B.S.,*# Philadelphia,
CENTER, SCHOOL
NORTHERN OF DENTAL
Pa.
DIVISION MEDICINE
The most common cause of death in patients taking immunosuppressive (IS) drugs is infection. Many of the microorganisms which infect these IS patients may be found in the mouth, but the mouth has not been investigated as a potential source of lethal infection. In view of this, we studied twenty-seven IS patients taking Imuran and prednisone for 6 to 61 weeks and eighteen normal controls. The patients were followed monthly, and the incidence of oral and systemic complications was recorded. There were no deaths due to infection during the lo-month study period. Oral infection OCcurred as frequently as pneumonia or urinary tract infection. Systemic factors which were related to the development of dental infection were lymphocyte count and length of time on immunosuppressive drug therapy.
T
he most frequent complication in the immunosuppressed (IS) patient is infection.l+ A majority of these infections are caused by microorganisms which are of little or no pathologic significance in the normal person but which often cause fatal infection in the patient with an impaired immunologic response. A majority of the microorganisms which have been shown to cause fatal complications in the immunosuppressed patient may be found in the oral cavity. Periodontal disease, pulpal infection, and oral ulcers may cause the spread of these oral microorganisms into the bloodstream, or aspiration may cause them to spread to the respiratory tract. Yet in none of the studies of infection in immunosuppressed patients was the oral microbial flora considered to be a potential source of infection; nor was oral disease considered as a potential threat to the outcome of treatment. This study was supported in part by Biomedical Research Support Einstein Medical Center. Northern Division. *Associate Professor of Oral Medicine, University of Pennsylvania; Services, Albert Einstein Medical Center, Northern Division. **Senior Student.
Grant Director
5505,
Albert
of Dental
879
880
Greenberg
alld Cohen
The most widely studied group of IS patients are patients taking azathioprine and prednisone to prevent graft rejection after renal transplantation. Azathioprine is known to impair both cellular and humoral immunity.l Tapia and coworker@ studied sixteen patients who died after renal transplantation. Sixty-nine per cent of the deaths were caused by infection, The most frequent cause of death was gram-negative bacteria, such as Klebsiella, Pseudomoncls crerugiqaosa,and Bacteroides. Other deaths were caused by Ca,ndida al&curls and cytomegalovirus. These microorganisms may be isolated from the mouth. Tapia suspected that the gastrointestinal tract was a primary source of entry of bacteria, but obvious portals of entry through chronic oral diseasewere never considered. In another study, Anderson and associates5found gram-negative bacteria the most frequent cause of posttransplant septicemia. Candida albicans also caused death in this study. In only 40 per cent of the caseswas the primary site of infection identified, and Anderson stated : “The high mortality in patients with an unidentified portal of entry is of particular concern.” The mouth as a potential source of infection was not considered. Eickhoff23 studied 224 renal transplant recipients and found infectious complications in 80 per cent. The infectious organisms in his study included bacteria such as Pseudomonas and Klebsiella, fungi such as ‘Candida nlbicans and Aspergillus, and viruses such as herpes viruses. Bach and colleagues7studied fifty-one renal transplant patients and found fungal infection with Aspergillus, Candida, Cryptococcus, phycomycetes, and Nocardia as the most common cause of death. Rifkind and associates” found Candida to be the most prevalent infectious organism. In other studies by Lopez and co-workers” and Stevens,1° viral infections were prevalent in renal transplant patients. In one study,g 87 per cent of sixty-one patients developed viral infections. The viruses involved were herpes simplex virus, cytomegalovirus, and varicella-zoster virus. Herpes simplex virus and cytomegalovirus are carried in the mouths of asymptomatic carriers.ll’ I2 Patients who are immunosuppressed by causes other than transplantation have also been studied. For example, patients with renal failure have impairment of both humoral and cellular immunity,13, I4 and these patients have an increased risk of infecti0n.l” There is considerable evidence to show that patients treated with corticosteroids have an increased susceptibility to both fungal and nocardial infections.16,I7 This increased susceptibility is thought to be due to decreased migration and impaired phagocytic function of leukocytes and macr0phages.l” There are isolated case reports of severe oral infection in patients taking steroids,l” but the incidence of this problem is unknown. Other types of cytoxic agents, such as cyclophosphamide, 6-mercaptopurine, 5-fluorouracil, and methotrexate, also cause increased incidence of infection, most frequently fungal infection .*“j 21 These infections are thought to be caused by either leukopenia’l or immunosuppression.** MATERIALS AND METHODS A lo-month pilot study of oral infection in kidney transplant patients taking immunosuppressive drugs was undertaken. This study had the following objec-
Volume 43 Number 6
Oral infection in renal transplant patients
881
tives : (1) To determine whether the oral flora is a source of systemic infection in IS patients. (2) To identify oral and systemic factors which predispose IS patients to systemic infections with oral microorganisms. (3) To determine the level of oral diseasein IS patients. During an initial pilot investigation, twenty-seven renal transplant patients taking azathioprine and prednisone and eighteen normal control patients matched for age and sex were studied ; all were outpatients at Albert Einstein Medical Center, Northern Division, in Philadelphia. The following procedures were performed on each patient : History. A history of diseasesor medications which could affect the immune system were obtained from each patient, as well as a history of recent antibiotic therapy. Control patients with a positive history of any of the above were eliminated from the study. Dose of IS drugs and length of time on IS therapy were recorded for each transplant patient. GeneraZ laboratory tests. Total and differential white blood counts, as well as serum IgG, IgA, and IgM, determinations using the technique of immunodiffusion in agar gel, were carried out. Control patients in whom the laboratory tests showed any abnormalities were eliminated from the study. Oral studies. Each patient was examined for the presence of oral mucosal ulcers, dental abscesses,candidiasis, or fusospirochetal infection. A Panorex radiograph was taken to detect periapical radiolucencies. The following indices of periodontal diseasewere obtained : LGe’s gingival index, Ramf jord’s periodontal index, L6e’s plaque index, and Ramfjord’s calculus index. Microbiologic studies were performed to determine the patients who were carriers of organisms which had been previously shown to be of particular danger in IS patients. Swabs were taken of the buccal mucosa, tongue, and gingival sulcus for isolation of the following organisms : Bacteria. Swabs taken from the patient’s oral cavity were immediately inoculated into thioglycollate broth for isolation of Klebsiella, Pseudomonas aeruginosa, Proteus vulgaris, and Bacteroides fragilis. The same swabs were used to streak blood agar culture plates and desoxycholate plates for gram-negative bacteria. For Bacteriodes isolation, anaerobic plates were streaked with special anaerobic equipment using anaerobic conditions. The tubes and plates were incubated at 37 degrees for 24 to 48 hours, and the organisms growing on the plates were identified by standard cultural and biochemical techniques.25 Fungi. The following fungi were specially sought in oral cavity specimens : Candida albica.ns, Aspergillus, Cryptococcus, and Mucormycosis. Standard fungal mycologic proceduresZ5were used with Sabaraud’s agar and blood agar plates. Microscopic and cultural examination procedures25 were used to identify these organisms. Nocardia. Oral cavity specimens were incubated on blood agar plates for up to 10 days to determine the presence of Nocardia, which were identified by both microscopic and morphologic assay.25 Viruses. Oral cavity specimens were examined specifically for the presence of herpes simplex and cytomegalovirus. For this, the virology
882
Greenberg
and Cohen
Table
I. Mean blood values Transplant
(27patients)
White blood cells Neutrophils Lymphocytes kG kM kA *Significant
Oral June,
9,086 1,432 1,173 156 118 132
Surg. 1977
Control(l8patients~ mm.3* mm.3* mm.3* mg.% mg.% mg.%
5,423 3,032 1,904 1,274 227 168
mm.3 mm.3 mm.3 mg.% mg.% mg.%
at 0.01 level.
II. Systemic complications in twenty-seven transplant patients, lo-month follow-up Table
Rejection of transplant Urinary tract infection Pneumonia Viral hepatitis Generalized herpes simplex Skin abscess Total complications *One
4* iA3 E. co/i; I Candida) I t Is
death.
facilities of the diagnostic microbiology laboratory and described techniques were used.2” Specifically, specimens were incubated on three tissue culture cell systems (Hep-2, WI-38, Rh MK cells) for a period of up to 10 days at 37 degrees in culture tubes or plates. Those cultures showing evidence of cytopathogenicity were examined by serologic techniques to determine whether a virus was present. Studies on transplant patients were repeated whenever these patients visited the outpatient clinic. This ranged from once a month to once every 3 months. Control patients were seen only once to obtain base line data on the Einstein population. RESULTS
Twenty-seven IS transplant patients and eighteen control patients were studied initially. The mean age of the transplant patients was 31, while the mean age of the control group was 32. The transplant patients were taking azathioprine and prednisone for a period ranging from 6 weeks to 51/, years. The mean length of time the patients were taking these drugs was 30 months. The mean dose of azathioprine was 118 mg. per day, and the mean dose of prednisone was 19 mg. per day. Table I showsthe mean blood values for transplant versus control patients. The mean total white blood count is significantly higher for the IS transplant patients than for the controls (9,086 mm.” for transplant patients versus 5,423 mm.3 for controls). Using the analysis of covariance, this difference is significant at the 0.01 level. The increase in total white blood cells in the transplant group is due to an increase in neutrophils (7,432 mm.3 for the transplant group versus 3,032 mm.3 for the controls). This difference is also significant at the 0.01 level. The level of lymphocytes is lower for the transplant group (1,173 mm.3 versus 1,904 mm.3). These findings are consistent with those of other investigators, such as McAlack,24
Oral infection Table III. Oral complications follow-up
in twenty-seven
in renal transplmt
patients
transplant
10 month
Acute abscess Oral ulcers Chronic abscess Candidiasis Total
patients,
803
4 : I To
Table IV. Microbiology Results* Organism Transplant (27parients) Klebsiella 3 Pseudomonas 12 Candida Herpes simplex virus 2 Cytomegalovirus 1 *Organism isolated from at least one person.
Control(l8patients) I I : 0
who studied patients taking IS drugs at similar doses. They found a large compensatory increase in neutrophils in patients with suppressed lymphocytes. The levels of all three immunoglobulin classeswere lower in transplant patients than in the control group. Table II demonstrates that in the lo-month pilot study, no casesof bacterial or fungal septicemia or generalized bacterial infection occurred. There were no deaths from infection. There were only four bacterial infections outside the mouth -one on the skin of the foot and three E. coli urinary tract infections. There were also one Candida urinary tract infection, three casesof viral pneumonia, one case of generalized mucocutaneous herpes simplex infection, and one case of viral hepatitis B. Table III summarizes the oral complications which occurred in the twentyseven renal transplant patients during the initial lo-month study period. Four acute dental abscessesoccurred. The predominant organism in all infections was alpha streptococcus. The infections all responded to local surgical therapy and antibiotics. No patient developed signs of systemic involvement as a result of the infection. Clinical candidiasis was present in one patient, and oral ulcers were present in three. In two other patients periapical radiolucencies around nonvital teeth were detected on Panorex radiographs. Both patients refused treatment, and to date neither has developed an acute infection or clinical signs and symptoms of septicemia. Table IV shows the results of the microbiology studies on transplant and control patients. Organisms not listed were not isolated from any individuals. Note that 59 per cent of the transplant patients were carriers of Candida species, although only one had clinical signs of candidiasis. DISCUSSION Recent advances in medicine have confronted the dentist with new clinical problems. The technique of kidney transplantation is almost routine in many
884
Greenberg
and Cohen
Ord Surg. .rorle,
1977
large medical centers, and patients are now able to live relatively normal lives without having to spend hours each week on a hemodialysis machine. However, they must continually take IS drugs to prevent rejection of the renal graft. Studies have shown that these patients have an increased susceptibility to infection. The organisms which cause the majority of these infections can be found as part of the oral flora, but the incidence of severe infection caused by oral bacteria or oral infection is not known. The risk of routine restorative dental procedures or oral surgery has also not been studied. In an attempt to begin to learn about this probelm in a systemized way, the study described here was carried out. In the patients evaluated, there were no cases of septicemia or other generalized bacterial or fungal infection. The two deaths that occurred were not from infection but from thrombosis due to acute rejection and an automobile accident. Four acute dental abscesses developed during the course of the study, but they all remained localized. It should be noted that dental infection occurred as frequently as pneumonia or urinary tract infections. An attempt was made to distinguish patients who developed acute dental infections from those who did not. Two systemic factors studied appeared to influence whether a susceptible patient developed a dental abscess ; these were (1) lymphocyte count and (2) length of time the patient had been on IS drug therapy. The four patients who developed acute abscesses all had lymphocyte counts below 400 mm.3 This contrasts sharply with the group mean of 1,173 mm.3 Two patients with chronic periapical radiolucencies who did not develop acute abscesses had lymphocyte levels of 2,100 mm.3 and 3,100 mm.3, respectively. There were five patients in the study who had been taking IS drugs for more than 5 years. The four patients who developed acute infections were in this category. This preliminary report suggests that lymphocyte count and length of time on IS drug therapy may influence the predisposition of IS patients to acute dental infection. Dentists practicing in hospitals where renal transplantation is carried out should arrange for prospective transplant patients to have a preoperative dental evaluation. This is rarely difficult since dialysis patients often have to wait a considerable period of time before a suitable donor is located. This cooperative routine will permit obviously diseased teeth to be removed or treated and periodontal disease to be treated before IS drug therapy is instituted, thus lowering the risk of infection to the patients. The authors wish to thank Drs. H. Friedman and E. Hampton of the Department biology and Drs. J. Rosenbaum and Raja, Department of Renology, Albert Einstein Center, Northern Division.
of MicroMedical
REFERENCES
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