Candida Study 2009

7/31/2019 Candida Study 2009

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ARTICLE

Mucosal Candida infection and colonisation as well as associated

risk factors in solid organ transplant recipients

L. Antoniewicz & D. Relijc & C. Poitschek& E. Presterl &

A. Geusau

Received: 18 October 2008 /Accepted: 14 March 2009# Springer-Verlag 2009

Abstract More detailed information on Candida colonisa-

tion and infection of the mucous membranes in organ

transplant recipients (OTR) is of particular interest. There-

fore, this issue was prospectively evaluated in 400 different

OTR in different posttransplantation periods as well as in

405 healthy age- and sex-matched controls. In addition,

possible risk factors and the clinical condition in the OTR

were evaluated. Independent of the transplanted organ there

is a statistically significant decrease in the number of

positive culture results, of symptomatic candidiasis and an

increase of isolated non-albicans Candida species

corresponding to length of the posttransplantation period.

No significant differences could be observed in the OTR in

association with different immunosuppressive regimen;

however, higher dosages of corticosteroids and tacrolimus

correlated with symptomatic candidiasis. As Candida spp.

may also cause systemic infection and dissemination,

additional knowledge about cofactors and associated strains

may have an impact on therapeutic decisions.

Introduction

Organ transplant recipients (OTR) are susceptible to infec-

tions, particularly to fungal infections, generally occurring

within the first 6 months after transplantation [1, 2]. The skin

and the mucous membranes may either be primarily affected

and/or indicative for generalized infection, thus taking

central position in the diagnosis and recognition of infections

in organ transplant recipients. Superficial infections may also

be restricted to the skin and mucous membranes in OTR.

The most common fungal infection of the mucous mem-

branes is thrush, highly prevalent during the first three

posttransplant months, gradually tapering off in the subse-

quent months of the first posttransplant year [3]. The most

common pathogen reported is C. albicans, but also non-

albicans Candida species have been described, among them

C. tropicalis, C. krusei, C. glabrata, and C. parapsilosis [4].

Candida is a true opportunist occurring on the surface of

mucous membranes as saprophytes and generally without

pathogenic potency. However, in the scenario of immuno-

suppression, colonisation with Candida spp. may cause not

only infection of the mucous membranes but may be

indicative for invasive disease and dissemination [5].

Epidemiological data on colonisation of the mucous

membranes due to Candida spp. and the respective clinical

manifestations in the different organ transplant patient

groups are rare. This study was designed to evaluate the

prevalence, the clinical signs and symptoms, and the

species spectrum of Candida colonisation in OTR as well

as to determine the associated risk factors and the relevance

of particular immunosuppressive regimens and the different

posttransplant periods.

Eur J Clin Microbiol Infect Dis

DOI 10.1007/s10096-009-0730-8

L. Antoniewicz : C. Poitschek: A. Geusau (*)

Department of Dermatology Division of Immunology,

Allergy and Infectious Diseases (DIAID),

Medical University of Vienna,

Waehringer Grtel 1820 ,

1090 Vienna, Austria

e-mail: [email protected]

D. Relijc

Department of Dermatology, Division of Specific Dermatology

and Environmental Dermatology, Medical University of Vienna,

Vienna Waehringer Grtel 1820,


E. Presterl

Department of Medicine I, Division of Infectious Diseases

and Tropical Medicine, Medical University of Vienna,

Vienna Waehringer Grtel 1820,



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Patients and methods

Data/strain collection and study population

Four hundred organ transplant recipients (kidney transplant

recipients [KTR], and similarly, heart [HTR], lung [LuTR], and

liver [LTR]), who had been transplanted at the organ transplant

unit of the Medical University of Vienna, were included

prospectively in the study between May 2005 and April 2007

(24 months). With regard to their posttransplantation period,

the patients were classified into three groups: (1) patients

within the first 6 months after transplantation, (2) in the period

between 6 and 18 months after transplantation, and (3) patients

in the period more than 18 months after transplantation.

The patients were evaluated according to an established

protocol. The data included: sex and age, age at the time of

transplantation, type of transplanted organ, as well as type and

daily dosage of immunosuppressive (IS) therapy. In addition,

it was evaluated whether the patients had had a rejection of

their organ or cytomegalovirus infection within the preceding

6 weeks of evaluation, whether they had neutropenia, an in-

situ central or peripheral intravenous catheter at the time of

evaluation, any bacterial infection, antibiotic therapy or a

surgical procedure within the preceding 3 weeks. Diabetes

mellitus, parenteral nutrition and whether and what type of

dentures the patient was wearing was also recorded.

Symptomatic oropharyngeal candidiasis was diagnosed

on the basis of the following criteria: xerostomia, burning

sensation of the oral mucous membranes, clinical signs of

erythematous or pseudomembranous, or hyperplastic can-

didal infection, dysphagia or cheilitis angularis. Symptom-

atic genital candidiasis was considered when burning

sensations, redness, thrush of the vaginal mucosa or the

glans penis and/or genital discharge were present.

Oral and genital swabs for microscopic and cultural

detection of Candida spp. were taken from every OTR

patient. Mouth and vaginal/penile specimens were exam-

ined microscopically using potassium hydroxide prepara-

tion (KOH) and were cultured in Sabouraud broth with

bacitracin (Merck, Darmstadt, Germany). Fungal cultures

were incubated at 37C for one week and evaluated daily. A

positive culture subsequently was transferred onto a rice agar

plate and a Sabouraud dextrose agar plate in parallel and

incubated for 2472 h at 30C. The presence of chlamydo-

spores microscopically indicated Candida albicans; further

species identification was performed by API system

(bioMerieux, LEtoile, France).

Furthermore, four clinical groups in the OTR were

distinguished:

1. Negative patients without clinical and microbiological

evidence for oropharyngeal/genital Candida infection

or colonisation

2. Colonised patients, i.e. asymptomatic patients with

positive cultures and negative smears

3. Facultative symptomatic patients characterized by the

fact that they were asymptomatic with smears yielding

hyphal elements, pseudohyphae and/or blastoconidia

chlamydospores representing a pathogenic form of

Candida with or without positive culture results

4. True infection was diagnosed when the patient was

symptomatic with a positive smear and culture result.

Asymptomatic patients with negative cultures but

positive smears were counted as facultative symptom-

atic. Patients exhibiting clinical symptoms with positive

cultures but negative smears or negative cultures but

positive smears were also regarded as symptomatic

patients.

Controls

Four hundred five healthy age- and sex-matched controlswere recruited at the Vienna General Hospital, either from

the ophthalmology or casualty ward, where they had been

either in- or outpatients seen on routine basis (e.g. routine

check after emergency) or for a presurgical visit (e.g.

cataract surgery). Subjects with the following conditions

were excluded: symptoms on the oral or genital mucosa,

intake or topical application of antifungals or antibiotics,

acute infections of skin or infectious diseases (e.g. hepatitis,

influenca), autoimmune diseases, immunosuppression ei-

ther induced or due to congenital or acquired immunode-

ficiency syndrome (HIV/AIDS). In each of the subjects two

body sites were sampled for culture (from the oral andvaginal mucosa/glans penis).

The study has been approved by the local ethical

committee of the Medical University of Vienna. An

informed consent was signed by patients and controls prior

to inclusion into the study.

Statistical analysis

Statistical analyses were done using SPSS 15.0 software for

Windows (SPSS Inc., Chicago, IL, USA). Categorical

variables were compared by Qui-square analysis or Fishers

exact test and quantitative variables by Mann-Whitney U-test. Binary logistic regression (method: enter) was used to

define associated risk factors for symptomatic infection and

colonisation and for non-albicans Candida isolation.

Results are presented in odd ratios with 95% confidence

intervals. Data was checked for colinearity. All p values are

two tailed and were considered statistically significant at


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of dentures, which were all coded as dummy variables.

Three statistical analyses were performed to analyse for

significant risk factors: positive versus negative culture

results, symptomatic versus asymptomatic patients and

Candida albicans versus non-Candida albicans spp. The

low number of symptomatic patients infected with non-

Candida albicans spp. did not allow the evaluation of all

risk factors in regression analysis [6].

Results

Demographic data study patients and controls

Of the 400 OTR, 151 (37.8%) were KTR, 116 (29.0%)

HTR, 91 (22.8%) LuTR and 42 patients (10.5%) were LTR

(Table 1). Most of the study participants were between 40

and 79 years old. Mean age of the OTR was 56 years (55.9

in NTR, 58.2 in HTR, 52.1 in LuTR, 58.4 in LTR) (median

58, range 59.1) and 56.7 years in the controls (median 57.1,

range 66). Mean age at transplantation was 50.8 years;

mean time after transplantation was 5.2 years (NTR 5.4;

HTR 7.0, LuTR 2.5, LTR 5.2) (median 3.8, range 26.7). Of

the patients, 256 were male and 144 female, which

corresponds to a male to female ratio of 1:1.8; there was

about a same sex distribution among the controls (259 males,

146 females). Thirty-nine of the patients (28 KTR, 7 LuTR,

and 4 HTR) had been re-transplanted at a mean time of

9.1 years after their first procedure. The distribution with

regard to the posttransplantation period was as follows: 87

OTR were in the early posttransplantation period

(


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Genital symptoms were present in 35 (9%) patients,

characterized by burning/stinging sensations (63%), genital

discharge (16%), redness (symptomatic 9%, asymptomatic

5%), and coverings on the vaginal mucosa or the surface of

the glans penis (symptomatic 2%, asymptomatic 5%). In 19

of the symptomatic patients culture and smear were negative,

and they were excluded from the group of symptomatic

genital candidiasis. Nine of the 35 patients exhibited two,

and 26 of the 35 patients, one of the listed symptoms.

The distribution of mucosal Candida manifestations

according to the four defined clinical groups (negative,

colonised, facultative symptomatic, symptomatic) in the

different OTR and posttransplantation periods in compari-

son to the healthy controls is shown in Table 1 and Fig. 1a,

b. In OTR, the number of patients with positive cultures

(with and without symptoms) is dependent on the post-

transplantation period, i.e. there was a decreased number of

positive culture results with the lengths of the posttrans-

plantation period which applied both for the oral and

genital site and was statistically significant. In the first 6

months after transplantation, Candida spp. could be

isolated in 70% of the OTR from the oral site and in 31%

from the genital area, which is significantly more frequent

compared to OTR in the late posttransplantation period

(oral: 18 months: 70%/54%, p=0.03; genital:

18 months: 31%/12%, p =0.001). This

remained statistically significant in the regression analysis,

indicating a two-fold risk for a positive culture from the

oral mucosa, and three-fold from the genital area for

patients in the early period compared to long term OTR

(Tables 2 and 3).

There was no significant difference with regard to

positive cultures when the late posttransplantation period

(>18 months after transplantation) was compared to the

controls who had colonisation in 54% (n=142) on the oral

and in 12% (n=59) on the genital mucosa, respectively

(oral: OTR/Co 54% vs 51%, p = n.s.; genital: OTR/Co 12%

vs 15%, p = n.s.). However, 6070% of those with positive

cultures in the group of OTR were symptomatic or

facultative symptomatic. When the OTR were analysed all

together and compared to the controls, they had signifi-

cantly more frequent positive culture results from the oral,

but not from the genital site (oral: OTR/Co: 60%/51%, p=

0.014; genital: OTR/Co: 18%/15%, p = n.s.). The effect

was more pronounced in the early posttransplantation

period and statistically significant for both sites when this

posttransplantation period was analysed and compared to

the results in the controls (oral:


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However, with length of the posttransplantation period, there

was an increasing percentage of these strains which was

significant, in particular when the long-term transplant

patients were compared (oral mucosap = n.s.; genital mucosa

p=0.005) (Fig. 2, see Tables 2 and 3) and for the genital

site (OTR vs Co oral: 11% vs 11%, p = n.s.; genital: 53%

vs Co: 29%, p=0.022). C. albicans was the predominant

cause for symptomatic infections. However, the proportion

Fig. 1 Candida infection or

colonisation with regard to the

four defined clinical groups

(negative, colonised, facultative

symptomatic, symptomatic) and

the risk factors posttransplanta-

tion period, transplanted organs

and daily dosage of steroids and

tacrolimus in comparison to

healthy controls



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Table2

Thedistributionofage,se

x,posttransplantationperiod,thetypeofO

TRandtheriskfactors

Riskfactors

Positivecultures(vsnegativeculture)

Symptomatic(vscolonised+

fak.sympt.)

Non-albicans(vsC.albicans)

Oralmucosa

Genitalarea

Oralmucosa

Genitalarea

Oralmucosa

Genitalarea

Positive

Negative

Positive

Negative

Sympt.

Colon.

Sym

pt.

Colon.

Non-a.

Albicans

Non-a.

Albicans

Age(y)

2039

28

15

9

34

7

23

3

10

1

27

1

8

65.10%

34.90%

20.90%

79.10%

23.30%

76.70%

23.10%

76.90%

3.60%

96.40%

11.10%

88.90%

4059

106

79

39

146

36

78

7

42

13

93

15

24

57.30%

42.70%

21.10%

78.90%

31.60%

68.40%

14.30%

85.70%

12.30%

87.70%

38.50%

61.50%

6079

104

67

24

147

42

77

6

29

9

95

9

15

60.80%

39.20%

14.00%

86.00%

35.30%

64.70%

17.10%

82.90%

8.70%

91.30%

37.50%

62.50%

Sex

Male

139

117

33

223

53

107

4

42

11

128

9

24

54.30%

45.70%

12.90%

87.10%

33.10%

66.90%

8.70%

91.30%

7.90%

92.10%

27.30%

72.70%

Female

100

44

39

105

33

71

12

39

13

87

16

23

69.40%

30.60%

27.10%

72.90%

31.70%

68.30%

23.50%

76.50%

13.00%

87.00%

41.00%

59.00%

PostTxperiod

18

m

142

120

32

230

46

115

10

38

17

125

17

15

54.20%

45.80%

12.20%

87.80%

28.60%

71.40%

20.80%

79.20%

12.00%

88.00%

53.10%

46.90%

Trans-plantedorgan

KTR

93

58

27

124

33

68

6

29

9

84

10

17

61.60%

38.40%

17.90%

82.10%

32.70%

67.30%

17.10%

82.90%

9.70%

90.30%

37.00%

63.00%

HTR

59

57

17

99

25

46

6

20

6

53

7

10

50.90%

49.10%

14.70%

85.30%

35.20%

64.80%

23.10%

76.90%

10.20%

89.80%

41.20%

58.80%

LuTR

59

32

21

70

21

41

4

24

5

54

6

15

64.80%

35.20%

23.10%

76.90%

33.90%

66.10%

14.30%

85.70%

8.50%

91.50%

28.60%

71.40%

LTR

28

14

7

35

7

23

0

8

4

24

2

5

66.70%

33.30%

16.70%

83.30%

23.30%

76.70%

0.00%

100.00%

14.30%

85.70%

28.60%

71.40%

Diabetesmellitus

None

196

138

54

280

71

145

12

61

21

175

18

36

58.70%

41.30%

16.20%

83.80%

32.90%

67.10%

16.40%

83.60%

10.70%

89.30%

33.30%

66.70%

Yes

43

23

18

48

15

33

4

20

3

40

7

11

65.20%

34.80%

27.30%

72.70%

31.30%

68.80%

16.70%

83.30%

7.00%

93.00%

38.90%

61.10%



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of non-albicans strains compared to C. albicans strains

isolated from symptomatic and colonised patients increased

in long-term transplant patients. This is true in particular for

the genital area where non-albicans strains comprised over

50% of the positive cultures (Table 4).

Associated factors for colonisation and symptomatic

candidiasis in OTR

Types of immunosuppressive therapy Most of the patients

had a combined immunosuppressive (IS) regime, usually a

triple combination therapy containing corticosteroids plus a

calcineurin inhibitor, i.e. cyclosporine (CSA) or tacrolimus

(TAC), plus an antiproliferative drug, i.e. mycophenolat-

mofetil (MMF) or azathioprin (Aza), or a regimen containing

an mTOR antagonist (Fig. 3a). The regimen (mono-, double-

or triple-drug combination therapy) and the dosages of the

various drugs were dependent on the type of organ trans-

planted and significantly different in the different organ

recipients (p


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mucosa were marginally nonsignificant (positive cultures:

10 mg/d: 60% vs 83%; p = ns). A non

significant trend towards more frequent oral candidiasis in

patients with high Tacrolimus dosages could be observed

(symptomatic: 10 mg/d: 25% vs 53%; p = n.s.).

A similar trend was observed for CSA; however, this was

not statistically significant (symptomatic, oral mucosa:

250 mg/d: 23% vs 44%; p = n.s.).

For corticosteroids, symptomatic oral candidiasis is more

frequent in the >10 mg daily dosage population (5 mg/d

vs >10 mg/d: 29% vs 54%; p =0.004). This applies also for

patients with a positive culture from the genital area

(5 mg/d vs >10 mg/d: 13% vs 38%; p


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Table4

DistributionofCandidastrainsinOTR,thethreeposttransplantation

periodsandincontrols

Cultureresults

Organtransplantrecipients(OTR)

Controls

18m

All

Colonised

Symptomatic

Colonis

ed

Symptomatic

Colonised

Symptomatic

Colonised

Symp

tomatic

n

%

n

%

n

%

n

%

n

%

n

%

n

%

n

%

n

%

Oralmucosa

C.albicans

34

97.1%

25

96.2%

22

8

8.0%

9

90.0%

93

88.6%

32

86.5%

149

90.3%

66

90.4%

184

88.9%

C.glabrata

1

2.9%

0

0.0%

2

8

.0%

0

0.0%

7

6.6%

3

8.1%

10

6.1%

3

4.1%

10

4.8%

C.parapsilosis

0

0.0%

1

3.8%

1

4

.0%

0

0.0%

3

2.8%

0

0.0%

4

2.4%

1

1.4%

3

1.4%

C.

tropicalis

0

0.0%

0

0.0%

0

0

.0%

0

0.0%

0

0.0%

2

5.4%

0

0.0%

2

2.7%

4

1.9%

C.

krusei

0

0.0%

0

0.0%

0

0

.0%

1

10.0%

0

0.0%

0

0.0%

0

0.0%

1

1.4%

3

1.4%

C.

lusitaniae

0

0.0%

0

0.0%

0

0

.0%

0

0.0%

1

1.0%

0

0.0%

1

0.6%

0

0.0%

1

0.5%

C.

dubliniensis

0

0.0%

0

0.0%

0

0

.0%

0

0.0%

0

0.0%

0

0.0%

0

0.0%

0

0.0%

2

1.0%

C.norvegensis

0

0.0%

0

0.0%

0

0

.0%

0

0.0%

1

1.0%

0

0.0%

1

0.6%

0

0.0%

0

0.0%

Genitalarea

C.albicans

20

83.3%

3

100.0%

6

6

0.0%

3

100.0%

13

48.1%

2

40.0%

39

63.9%

8

72.7%

42

71.2%

C.glabrata

3

12.5%

0

0.0%

4

4

0.0%

0

0.0%

6

22.2%

2

40.0%

13

21.3%

2

18.2%

8

13.6%

C.parapsilosis

1

4.2%

0

0.0%

0

0

.0%

0

0.0%

4

14.8%

1

20.0%

5

8.2%

1

9.1%

5

8.5%

C.

tropicalis

0

0.0%

0

0.0%

0

0

.0%

0

0.0%

0

0.0%

0

0.0%

0

0.0%

0

0.0%

1

1.7%

C.

krusei

0

0.0%

0

0.0%

0

0

.0%

0

0.0%

3

11.1%

0

0.0%

3

4.9%

0

0.0%

1

1.7%

C.

lusitaniae

0

0.0%

0

0.0%

0

0

.0%

0

0.0%

1

3.7%

0

0.0%

1

1.6%

0

0.0%

0

0.0%

C.

dubliniensis

0

0.0%

0

0.0%

0

0

.0%

0

0.0%

0

0.0%

0

0.0%

0

0.0%

0

0.0%

1

1.7%

C.norvegensis

0

0.0%

0

0.0%

0

0

.0%

0

0.0%

0

0.0%

0

0.0%

0

0.0%

0

0.0%

1

1.7%

Oralmucosa

C.albicans

34

97.1%

25

96.2%

22

8

8.0%

9

90.0%

93

88.6%

32

86.5%

149

90.3%

66

90.4%

184

88.9%

non-albicans

1

2.9%

1

3.8%

3

1

2.0%

1

10.0%

12

11.4%

5

13.5%

16

9.7%

7

9.6%

23

11.1%

Genitalarea

C.albicans

20

83.3%

3

100.0%

6

6

0.0%

3

100.0%

13

48.1%

2

40.0%

39

63.9%

8

72.7%

42

71.2%

non-albicans

4

16.7%

0

0.0%

4

4

0.0%

0

0.0%

14

51.9%

3

60.0%

22

36.1%

3

27.3%

17

28.8%



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nutrition and in situ peripheral venous devices were present

in a small number of patients (n =9) only. The same applied

to preceding CMV infection (n=12) and neutropenia (n=

14). A central venous catheter in the OTR (n=24) was

significantly associated with oral candidiasis (42% with

versus 20% without, p=0.02), but was excluded from theanalysis in order to prevent a bias in the logistic regression

model because all those patients were in the first post-

transplantation period. Bacterial infection (n =54) was

always associated with antibiotic intake and could therefore

not be analyzed separately. Our evaluation of associated

factors therefore concentrated on antibiotic intake (therapy

and prophylaxis, n=147), diabetes mellitus (n=66), and, for

the oral mucosa, wearing of dentures (n=199) (Table 2).

The distribution/percentage of patients with diabetes

mellitus in the different transplant groups and posttrans-

plantation periods was similar. When analyzed in the

regression analysis, genital colonisation with Candida spp.in OTR was significantly associated with diabetes mellitus

(p =0.006) with an overall more than two-fold increased

risk compared to patients without diabetes mellitus (Tables 3

and 4). Antibiotic therapy consisted of prophylactic intake

as well as high-dose treatment for relevant bacterial

infections. In the analysis, we used the factor antibiotic

treatment as one risk factor regardless of the type of

regimen or the dosage (therapeutic or prophylactic). We

evaluated all OTR together, as there was an equal

distribution of these subgroups in each of the OTR groups

and posttransplantation periods (data not shown). Antibiotic

intake had an impact on symptomatic oropharyngeal

candidiasis (39% with versus 28% without) and genital

colonisation (26% with versus 13% without), but for both

conditions regression analysis and qui-square analysisshowed no significance (Table 3). Patients wearing dentures

had an almost two-fold higher risk for being colonised at

the oral mucosa than those without (66% versus 53%, p=

0.01) (Tables 2 and 3).

Discussion

Fungal infections in OTR are a significant cause of

morbidity and mortality. The most common fungal infec-

tion in OTR is candidiasis. Like intensive care-unit patientsand HIV-infected individuals with CD4 depletion, iatro-

genic immunosuppressed transplant patients are more likely

to develop candidiasis of the mucous membranes and

comprise, compared to the normal population, higher rates

of colonisation [79]. Apart from that, recent epidemiolog-

ical data suggest the emergence of non-albicans Candida

species and resistant Candida species as well as fungi other

than Candida in these patients [10]. Within the frame of our

prospective study we were able to investigate a substantial

Fig. 2 Distribution of C. albi-

cans and non-C. albicans spe-

cies in the three

posttransplantation periods in

comparison to healthy controls

Fig. 3 Distribution of immuno-

suppressive therapy combina-

tions in all OTR (a) and in the

different transplanted organs (b).

(1xIS: one immunosuppressant;

2xIS: two immunosuppressants;

cortisone + 1xIS: cortisone plus

one immunosuppressant)



11/13

number of transplant patients who had received different

organs including hearts, kidneys, lungs and livers and who

were in different time periods after transplantation. We also

evaluated the spectrum of Candida species isolated in our

population. In addition, we had precise information about

their IS-regimes and possible risk factors. For the first time,

genital swabs were evaluated concomitantly from such a

big sample size. The comparison with a representative

control group gives us reliable information about factors

associated with transplantation. Thus far, this is the largest

prospective study in transplant patients with regard to

Candida colonisation and mucosal Candida infection [5,

11, 12].

Candida spp. are saprophytes on mucous membranes

without pathogenetic potency for humans under normal

conditions. Therefore, isolation of Candida spp. in culture

is not necessarily an indication for infection [13]. A

correlation has to be made between clinical characteristics

of candidiasis and mycological tests such as direct

investigation and cultures. Colonisation of mucous mem-

branes is common in the normal population and, according

to literature, amounts to 1.969% on oral mucosa and for

15% (for men) and 20% (for women) in the genital area/

mucosa [1418]. Colonisation increases with age [1416].

The colonisation rate in our control group corresponds with

the published data; 51% of healthy subjects had a positive

culture for Candida spp. and 15% from genital swabs, with

a higher rate in women (20%) than in male controls (11%),

which is also in accordance to literature [17, 19].

The relevance of the isolation of Candida spp. from oral

or genital mucosa has to be judged in connection with

clinical symptoms and the proof of hyphae on direct

examination, which is a pathogenetic form of yeasts [18,

20]. In our population of transplant patients, direct

examination of a fresh sample was positive for pseudohy-

phae or pseudomycelia in 44% from oral mucosa and in

14% from the genital area/mucosa of the patients. Taking

into account the different symptom groups we had defined,

the proof of fungi in the wet mount preparation was

indicative for symptomatic candidiasis or facultative symp-

tomatic patients. Of those with positive cultures from the

oral mucosa site who met the criteria of symptomatic

candidiasis, 72% had concomitant positive smear results.

From the genital site, it was 81%. The sensitivity of a wet

mount preparation for the diagnosis of symptomatic

candidiasis is therefore comparable to what is reported in

literature [21]. Due to the fact that C. glabrata lacks the

ability of producing pseudohyphae, there could have been a

bias with reg ard to the ide ntification of facultative

symptomatic patients by wet mount preparation in our

analysis. However, C. glabrata comprised only 9% of all

isolated strains in OTR, and even less in the colonized

patients, of whom a minimal proportion could therefore

have been missed to be counted as facultative symptomatic.

Fig. 4 Box plots of daily im-

munosuppressive therapies (in

mg/d) in the three different

posttransplantation periods



12/13

There are only a few pro- or retrospective studies on

candidal colonisation or infection in transplant patients;

only two of them deal with genital candidasis [5, 12]. In a

small sample of renal transplant patients, Glec and

coworkers found symptomatic oral candidiasis in 26% of

the patients [11]. This percentage corresponds to the rate of

patients with symptomatic oropharyngeal candidiasis in our

transplant population and to the rate observed in the

subgroups of the kidney and heart transplant recipients,

namely, 22%. In comparison, 17% of the liver- and 23% of

the lung-transplant recipients had oropharyngeal candidia-

sis. Liver transplant patients had the lowest prevalence

compared to the other OTR, but the difference was not

statistically significant. This is in contrast to what is known

for invasive candidiasis, which affects liver transplant

recipients more significantly, indicating an association of

this condition with a particular organ transplanted, i.e. the

particular associated surgical procedure. Apart from that,

invasion occurs more likely in rejection periods, which

require higher dosages of IS-therapy, and mainly in the

early posttransplantation period [2, 22, 23].

Because of our classification of four different clinical

groups a comparison of our results to published data on the

prevalence of asymptomatic Candida colonisation of the

oral mucosa in transplant patients is difficult. However, we

can summarize the number of our asymptomatic OTR who

are culture-positive, i.e. colonised, and those who fulfil

the criteria of facultative symptomatic patients, i.e. who

have positive cultures and/or smears but lack clinical

symptoms. These numbers set in contrast with the preva-

lence of colonisation reported in literature show that our

data are within the same range. In a report of Baidee and

coworkers, 35% of 120 kidney transplant patients and 78%

of 50 liver transplant patients had oral colonisation with

Candida spp. in the early posttransplantation period (the

first 6 months), indicating a significant difference for these

two transplant groups [5]. In our study population analysed

for the same posttransplantation period, 37% of the kidney

transplant and 60% of liver transplant patients were

colonised orally. However, the difference was not statisti-

cally significant, which most likely is due to the small

sample size of liver transplant patients in this period.

Kurnatowska and co-workers stated a genital colonisation

rate of 25% in a small sample of 32 kidney transplant

patients; for comparison, it was 23% in our population [12].

The observed age-effect in the controls, i.e. the increase of

colonisation with age, could not be observed in the

transplant population and was more or less overruled by

other more relevant factors.

Altogether, 245 Candida strains could be isolated from

the oral cavity and 72 isolates from the genital area of the

400 transplant patients. Similarly, in the controls, 213

isolates were found orally and 59 genitally. In the OTR, the

early posttransplantation period was clearly associated with

a significantly higher numbers of positive cultures from the

oral and genital site compared to patients in the late

posttransplantation period or to controls. This applied for

all types of OTR. Six controls and six OTR had double

colonisation on the oral site, primarily with C. albicans and

C. glabrata. Sixty-two of the patients were culture-positive

concomitantly on the oral and genital sites, a condition

mainly observed in the early period after transplantation.

However, this effect was without statistical significance

when the different posttransplantation periods were com-

pared. A significant difference in the concordance of

cultures was found between the early and late posttrans-

plantation period with significantly more discordant cul-

tures in the late phase.

Recent literature reports an increase of non-albicans

strains and the emergence of resistant strains in certain risk

groups, particularly in patients who are immunosuppressed

or require recurrent systemic antifungal therapy [8, 2426].

In our study population, when all patients were analysed

together, there was no proportional difference with regard

to C. albicans and non-albicans Candida species isolated

from patients and controls from both sites. However, when

the different posttransplantation periods were analysed

separately, there was a statistically significant increase of

non-albicans Candida species with time after transplanta-

tion (after 18 months) in comparison to the early post-

transplantation period (the first 6 months) in the genital and

oral sites. When the early period was compared to the

control group, this increase was only significant for the

genital site.

A possible explanation could be that most of the patients

receive systemic antifungal therapy within their posttrans-

plant lives [1, 27, 28], but we have no explanation for this

distribution in the control group.

From the various known risk factors for oropharyngeal

and genital candidiasis and colonisation [1, 2, 4, 22, 23,

2931], there was a trend of increasing symptomatic

oropharyngeal candidiasis and genital colonisation in the

patients with antibiotic intake or antibiotic prophylaxis in

the preceding 3 weeks; however, in the multivariable

analysis this effect was not statistically significant. Patients

wearing dentures had a nearby two-fold increased risk for

having a positive culture result on the oral site. Genital

colonisation was more than two-fold increased in patients

with diabetes mellitus compared to those without; this was

true for all patient groups and all posttransplantation

periods. All other risk factors, i.e. CMV infection or

neutropenia, were not evaluated due to small numbers.

Another relevant factor turned out to be gender; female

organ transplant recipients had a three-fold risk for a

positive culture result from a genital swab and a almost

two-fold risk for oral swab.



13/13

Immunosuppressive drug-combinations and dosages

differ significantly in the different types of transplanted

organs and posttransplantation phases. Higher dosages of

CsA, tacrolimus and steroids were administrated in the first

6 months after transplantation, and liver transplant recipi-

ents have significantly more often a mono or dual therapy.

A direct association between positive cultures and immu-

nosuppressive therapy could therefore only be observed for

higher dosages of tacrolimus and corticosteroids.

With this prospective study we were able to get additional

information about candidal colonisation and infection of the

mucous membranes in a large group of different transplant

patients with particular focus on immunusppressive regimens

and different periods in the posttransplantation phase.

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