oral Candidiasis in Patients With Diabetes Mellitus: A ... - Diabetes Care

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ral Candidiasis in Patients With Diabetes Mellitus: A Thorough Analysis GARY A. BARTHOLOMEW, DMD, BRAD RODU, DPS, AND DAVID S. BELL, MD

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It has generally been assumed that oral candidiasis occurs with increased frequency in patients with diabetes mellitus. To evaluate this, we compared the frequency and severity of oral Candida colonization in 60 patients with insulin-dependent diabetes mellitus (IDDM) admitted to a low-intensity-care diabetes unit with those in 57 age- and sex-matched controls. Swabs taken from the tongue and buccal mucosa were examined by cytology rather than culture because of the discrimination provided by the former. Cytological smears were classified according to the presence and morphology of the Candida organisms. Overall, a significant difference in Candida species colonization was found between patients with diabetes (75.0%) and controls (35.1%) (P < .005). In the diabetic group, no relationship was found to recent use of antibiotics, total or differential white blood cell count, serum glucose, presence of diabetic retinopathy, or glycosylated hemoglobin values. We conclude that in IDDM there is a predisposition to oral candidiasis and that this predisposition is independent of glucose control. Diabetes Care 10:60712, 1987

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andidiasis is an infection caused by any of several species of the fungus Candida. By culture, Candida is considered normal oral flora at a frequency of 44-55% (1). This observation is supported by well-controlled studies with exfoliative cytology (1,2). Although numerous candidal species can be isolated from the oral cavity, the predominant species affecting hospitalized patients is Candida albicans (3,4). Clinical diagnosis of oral candidiasis relies on the recognition of granular, erosive, and pseudomembranous forms of the infection, with the easily removed curdlike plaques of the latter being the most common (5). However, substantial colonization can exist in the absence of clinical lesions (2). Although cultures have been favored for confirmation of clinical infections, periodic acid-Schiff-stained cytologic smears are also an excellent method; they hold a marked time advantage over and are less costly than cultures (1). In fact, cytology offers a further advantage in facilitating a distinction on morphological grounds between a carrier state and active infection. Because the pseudohyphal phase is considered the invasive phase of the fungus, the diagnosis of mucosal candidiasis relies on the demonstration of these forms, as well as blastospores (6). The high carrier rate of Candida in a normal population emphasizes the advantage of cytology because it has been stated that positive cultures by

themselves are inadequate for the diagnosis of oral candidiasis (7). Groups classically considered at increased risk for candidal infections include cancer patients and those receiving antibiotics and supraphysiologic doses of corticosteroids or other immunosuppressants (5). In addition, candidal infections are believed to be more frequent in people with diabetes (5,810). It has been suggested that the highest rate of colonization occurs in diabetic patients with poor serum glucose control (11), although proof supporting this association is lacking (8,9). The purpose of this study was to define the prevalence of candidal colonization in people with insulin-dependent diabetes mellitus (IDDM) versus controls and to identify factors predisposing to colonization in the diabetic patient. The variables evaluated include absolute white blood cell counts and differentials, glycosylated hemoglobin (GHb) levels, serum glucose, recent antibiotic or immunosuppressant therapy, duration of diabetes, and diabetic retinopathy. MATERIALS AND METHODS

Oral cytology was performed on 60 patients with IDDM on admission to a low-intensity-care diabetes unit and 57 ageand sex-matched controls (from the Oral Diagnosis Clinic,

DIABETES CARE, VOL. 10 NO. 5, SEPTEMBER-OCTOBER 1987

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FIG. 1. Cytological preparations showing negative smear (A, x 100), scattered budding yeast forms (B, X 160), and proliferation of pseudohyphae (C, X 125).

University of Alabama School of Dentistry). Mucosal scrapings were obtained from the buccal mucosa and posterior dorsum of the tongue of each patient with a tongue blade moistened with water. These scrapings were smeared over a glass microscope slide and sprayed with a commercially prepared fixative (Surgipath, Medical Industries, Grays Lake, IL). The slides were coded and submitted to the Oral Pathology Laboratory, where they were stained with periodic acid-Schiff reagent. All slides were examined microscopically for the presence of Candida. Screening was performed at X 100 with verification of yeast and pseudomycelial forms completed at X 450. All evaluations were performed in a blind manner by one of us (B.R.). Microscopic findings were grouped into the following categories in the same manner as previous investigations (1,12,13; Fig. 1): 0: negative, adequate numbers of epithelial cells with no evidence of fungi. + C: noninvasive colonization, scattered collections of yeast forms in association with epithelial cells. + 1: invasive colonization, variable numbers of intertwining pseudomycelial forms. On admission, the following information was obtained from the study group: age, sex, type and duration of diabetes, and reasons for admission. A detailed history was taken with

regard to current and recent (within 1 mo before admission) medications, with particular attention to the use of antibiotics or immunosuppressant therapy. An oral soft tissue examination was performed to rule out clinical candidiasis. Each patient was assessed by an ophthalmologist for the presence of diabetic retinopathy. A white blood cell count and differential, serum glucose (performed by glucose oxidase method), and GHb value (from ion-exchange chromatography, Isolab Fast Hemoglobin method) were also obtained on admission. A complete history and oral examination were obtained from the control group. Controls who were on immunosuppressant drugs or had a history of recent antibiotic use or malignancy were excluded from the study. The prevalence of colonization was compared by x 2 'dis' tribution with the appropriate degrees of freedom. The G TABLE 1 Comparison of negative, noninvasive, and invasive colonization Diabetic (n = 60) Negative (0) Noninvasive ( + C) Invasive ( + 1 )

15 (25.0) 16(26.7) 29 (48.3)

Control (n

::

57)

37 (64.9) 8 (14.0) 12 (21.1)

G = 19.5. x:.eos,2 — 10.6. Values in parentheses are percentages.


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TABLE 2 Factors associated with candidal colonization in diabetic subjects

Negative (0) Noninvasive ( + C) Invasive ( + 1)

Glycosylated hemoglobin (%)

Blood glucose (ing/100 ml)

Duration of diabetes (yr)

Total white blood cells

Segmented leukocytes

Lymphocytes

10.14 10.55 10.96

297.2 238.9 232.1

9.9 10.2 14.8

7078 8219 7853

7062 5134 5658

2141 2467 2378

statistic for a 3 X 2 contingency table was calculated. The variables were classified and compared according to the original categories (0, + C , +1) by calculating a linear discriminant function based on an assumption of normal occurrence within each variable. Antibiotic history and retinopathy were evaluated by calculating the G statistic for a 3 X 2 contingency table.

(G = 23.06). In the group with diabetes, retinopathy did not show any correlation with colonization status (Table 3). DISCUSSION

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uch has been written about candidiasis in the diabetic patient. Most statements made have been in reference to vulvovaginal infections. These observations are primarily supported by RESULTS empirical clinical observations, and there has been a paucity The mean age of the study population was 31.8 yr (range 9— of properly controlled experimental studies. We thought that 76 yr), and the controls had a mean age of 30.1 yr (range the oral mucosa of the IDDM patient is another likely site 9-66 yr). In both the diabetic and control populations, the of candidal colonization and chose to investigate this further. We have used oral cy to logical smears as a simple, repromale-to-female ratio was 3:2. In the study population the primary reasons for admission ducible means of demonstrating a significant increase in were poorly controlled diabetes mellitus (39 of 60), diabetic frequency of candidal colonization in diabetic patients ketoacidosis (13 of 60), surgical treatment of ophthalmologic compared with age- and sex-matched healthy controls. With complications (6 of 60), and acute infection (2 of 60). Other well-defined microscopic criteria, this technique can semicommon secondary problems on admission included hyper- quantitatively illustrate actual candidal colonization. Theretension, peripheral vascular disease, retinopathy, neuropa- fore, we believe the cytological approach is not only valuable for diagnosis but may play an equally important role in dethy, and chronic infections. Differences in the distribution of Candida colonization be- fining more fundamental pathogenetic aspects of the infectween diabetic patients and controls were statistically sig- tion. nificant (P < .005; Table 1). Oral examinations revealed We are aware of the potential pitfalls in comparing a hosno clinical infections in either the study or control groups, pitalized population with an outpatient group. However, we indicating that the colonization was subclinical. In the group attempted to minimize these disadvantages by I) conducting with diabetes, all variables in Table 2, when subjected to a the study in a low-intensity-care unit, 2) cytologically screenlinear discriminant function analysis, resulted in an ex- ing patients on admission, and 3) analyzing numerous potremely high miscalculation rate, indicating that the predic- tentially complicating factors. Several parameters were tive quality of the collective body of variables or any subset evaluated to identify overt factors responsible for this inthereof was poor. Evaluation of variables related to hospital admission, such TABLE 3 as antibiotic therapy, retinopathy, and ketoacidosis, was perAntibiotic treatment, retinopathy, and ketoacidosis in diabetic group formed (Table 3). Many patients with diabetes were on mulAntibiotic tiple drugs treating either acute or long-term cardiovascular history* Ketoacidosist Retinopathyt complications of diabetes. In general, most of these medications also had no significant impact on the study. ComPositive Negative Positive Negative Positive Negative parison of antibiotic history among microscopic categories showed no significance. The two patients with acute infec- Negative 4 14 6 12 6 9 (0) tions had negative and noninvasive cytology results. No paNoninvasive tient in the control group was under therapy. 3 11 2 11 2 14 (+Q The 13 patients in the study group with ketoacidosis were Invasive distributed fairly evenly among the microscopic categories 9 8 20 20 5 24 (+D (negative, 6; noninvasive colonization, 2; and invasive colonization, 5; Table 3). Elimination of this subgroup from the *G = 0.36 (NS). study population in Table 1 resulted in an increased colo- tG = 1.53 (NS). nization rate in patients with diabetes compared with controls tG = 3.81 (NS).

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creased colonization in diabetic patients. Although examination of white blood cell counts revealed no correlation to colonization status, the complex nature of the defense mechanisms against the Candida organism suggests that covert functional defects of polymorphonuclear leukocytes (14-19) or cell-mediated immunity (20,21) may play an important role in this population. The predisposition of the diabetic patient to infection by pathogenic fungal species has been explained in terms of enhancement of yeast growth by elevated tissue fluid glucose levels (22). In addition, a good correlation between salivary glucose and Candida growth has been demonstrated in diabetic patients (23). Thus, a correlation between diabetic control and extent of oral mucosal yeast colonization would be expected. We evaluated serum glucose levels on admission because subsequently these levels were rapidly adjusted for optimal control. GHb levels were evaluated as an index of control over a more extended period of 2-3 mo (24). However, we were unable to correlate diabetic control with frequency of colonization, as other studies have shown (25). In addition, diabetic ketoacidosis was not important in determining colonization patterns (Table 3). The availability of salivary glucose may influence Candida growth during antibiotic administration due to a selective reduction in oral microflora and subsequent decrease in competition for the nutrient (25). Diabetic patients receiving antibiotics might be expected to demonstrate increased candidal colonization. We were unable to establish any correlation, although only 25% of our diabetic patients were in this group (Table 3). Vascular compromise has been related to the frequency and severity of certain infections in patients with diabetes (10). This may be due to an exaggeration of immunologic deficits by proliferative changes in the capillary endothelial basement membrane causing impedance of leukocyte movement and diffusion of necessary nutrients into tissues (18). In addition, it has been shown that diabetic retinopathy is associated with duration and age at onset of diabetes while also indicating the degree of vascular compromise (5). However, we failed to correlate candidal colonization with either the duration of diabetes or the presence of diabetic retinopathy. Despite solid evidence that candidal colonization is more prevalent in patients with IDDM than in age- and sexmatched controls, the factors responsible are largely unknown. Although fragmentary and circumstantial evidence of immunologic and metabolic defects has been found, a broader perspective on this infection remains elusive. ACKNOWLEDGMENTS:

We thank Carl Russell, DMD, for the

statistical analysis. From the University Hospital Dental Clinic (G.A.B), the Department of Pathology (B.R.), and the Division of Endocrinology Metabolism (D.S.B.), University of Alabama Schools of Medicine and Dentistry, Birmingham, Alabama.

Address correspondence and reprint requests to Brad Rodu, DDS, Box 440, University Station, U.A.B., Birmingham, AL 35294.

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