Candida albicans infection in adults with cystic fibrosis
A K Webb Elizabeth Woolnough
J R Soc Med 2006;99(Suppl. 46):13–16
INTRODUCTION
Care provided by cystic fibrosis (CF) centres has improved
pulmonary function and nutrition of patients with CF—the
two main prognostic indicators for survival.1 In common
with other CF centres the median age of the adults
attending the Manchester Adult CF Centre (MACFC) is
now into the fourth decade of life, whereas 30 years ago it
was only into the second decade of life.
This improved survival has brought hope and optimism
to the CF community: however, as respiratory disease has
been moderated but not cured, a host of unusual and
sometimes unexpected complications of the disease have
emerged from Pandora’s box. These complications include
reduced bone mineral density, female urinary incontinence,
severe liver disease, diabetes mellitus, renal stones, cancer
and the emergence of transmissible bacteria resulting in the
need for ruthless segregation. Also, the cost of this
improved survival has only been gained by the patients
having to endure a huge burden of self care requiring
lifelong oral, nebulized and intravenous antibiotics.
Patients with CF are more likely to become infected
with Candida species. The potential risk factors include
inhaled steroids, lifelong antibiotics and diabetes mellitus.
However, the medical consequences are relatively benign
and it is perhaps not surprising that Candida infections are
not rated very highly as a priority by patients with CF when
considered against their many serious medical problems. In
addition, Candida infections are probably undervalued as a
clinical problem by the CF multidisciplinary team (MDT).
The same maxim applies to published research and audit of
the effect of Candida infections upon the CF population. A
Medline search using ‘Candida’ and ‘cystic fibrosis’ as the
search engines identified 20 peer-reviewed publications but
only one dealt specifically with the symptoms and
associations of oral and genital candidiaisis in patients with
CF.
This review proposes to consider the importance of oral
and genital Candida infections to patients with CF and the
management of Candida species sepsis associated with
infected ports.
GENERAL
Candida albicans is a fungus commonly found as a commensal
in the vagina and oropharynx. It consists of single cells
which reproduce by budding. Usually, Candida is a relatively
benign opportunistic infection of the moist areas of the
body. It is especially common in the vagina where it causes
a vulvovaginitis but is also found in the mouth and skin
folds. Candida infections of the oropharynx and genitals are
commonly known to both patients and medical staff as
‘thrush’.
Candida species in certain situations can be transformed
into a devastating pathogen resulting in considerable
morbidity and mortality. Systemic candidiasis carries a
mortality rate of 75%.2 Patients at risk include those
receiving intensive chemotherapy, those who are immune
suppressed such as following organ transplantation and HIVpositive
patients.
Of the many species of Candida, C. albicans causes
approximately 95% of infections and C. glabrata causes 5%
of infections.3 Other rare Candida species causing more
infections are C. parapsilosis and C. krusei.
ORAL CANDIDA
In the general population, oral candidiasis is an infection of
the oral cavity caused usually by C. albicans. Candida albicans
can be isolated from the oral mucosa of 30–40% of healthy
adults as a normal commensal.4 Common risk factors for
infection with C. albicans in the oropharynx include poor
dentition, older patients, diabetes mellitus, use of inhaled
and systemic steroids, smoking, malignancies and frequent
use of antibiotics. Common symptoms of infection with
C. albicans include local discomfort, a dry mouth or altered
taste sensation and dysphagia. Diagnosis is usually
straightforward and can usually be made by direct
observation of white membranous plaques on the buccal
mucosa and soft palate. Presentation may be atypical
presenting as an area of erythematous inflammation and
sometimes as an angular cheilitis with fissuring at the
corners of the mouth. These areas consist of desquamated
epithelial cells and fungal hyphae. Microbiological diagnosis
can be confirmed usually by staining a smear from a swab of
the area or culturing an oral rinse.
Oral C. albicans infections in patients with CF have
received very little attention. Clearly, there are significant
risk factors in CF which include impaired salivary secretion, 13
J O U R N A L O F T H E R O Y A L S O C I E T Y O F M E D I C I N E S u p p l e m e n t N o . 4 6 V o l u m e 9 9 2 0 0 6
Manchester Adult Cystic Fibrosis Centre, Wythenshawe Hospital, Manchester
M23 9LT, UK
Correspondence to: Professor A K Webb
E-mail: the5webbs@hotmail.com
inhaled steroids, diabetes and lifelong antibiotics. Antibiotics
alter the normal flora of the mouth and have a
permissive effect upon the growth of C. albicans. A study by
the Manchester School of Dentistry at MACFC found that
86% (n=43) of adults studied using refined culture
techniques carried C. albicans in their oral cavity (personal
communication). In the normal population, there is a
carrier rate of approximately 40% for C. albicans.4 In the CF
study, on direct questioning, of the adults, 17 (40%) had
complained of a sore mouth, 10 (24%) of thrush on an
average of five times per year, and a hoarse voice in 16
(38%) on an average of four times per year. Diagnosis of
oral Candida can be aided by taking a mouth swill or can be
used when the infection is not responding to treatment and
it is important to obtain fungal sensitivities to the most
effective treatment.
GENITAL CANDIDA
In the normal population, vulvovaginal candidasis affects
75% of women and 40–50% have recurrent episodes.3
Pruritus and vaginal discharge are the main symptoms of a
C. albicans infection. C. albicans accounts for 90% and
C. glabrata for 5% of infections.3 Isolation of Candida from
vaginal swabs is about 50–90%. The degree to which
C. albicans can be regarded as a commensal rather than a
pathogen is unclear. Vaginal discharge may be caused by
pathogens other than C. albicans in younger women and
includes bacteria, Chlamydia, Gonococcus and Trichomonas.
There is an increasing incidence of genital Chlamydia in
young women with CF which if undetected and untreated
can potentially result in permanent infertility. Genital
candidiasis in men may not be symptomatic but can cause a
balanitis and balanoposthitis in the normal population.
There are very few studies in the CF published literature
about genital Candida. Over 10 years ago, Sawyer et al.
reviewed vulvovaginal candidiasis in 55 young women with
CF using a self-administered questionnaire.5 Control
subjects from general practice answered a modified
questionnaire. Thrush was more common in the CF women
(35%) than the controls (13%) and more persistent and
difficult to treat. The use of antibiotics was significantly
associated with symptomatic vaginal candidiasis. Sawyer et
al. commented that ‘health professionals generally trivialize
illnesses and diseases that are common, easily treated and
not life threatening’. A more recent study reviewed genital
Candida in 40 adults with CF (19 male and 21 female).6
Twenty-five patients had experienced symptoms of Candida
but tellingly only six patients had been asked direct
questions by clinic staff. Patients refused to discuss whether
their partners had been symptomatic. It was concluded that
questions about candidiasis and potential for treatment
should be part of the annual review. This would promote
informed discussion, treatment and inclusion of affected
partners.
A recent survey using a questionnaire delivered via one
interviewer, over a 5-week period to 101 consecutive
inpatients and outpatients reviewed the frequency of
symptoms and the medical risks associated with Candida
infections.7 The questionnaire contained 25 items and
patients were asked to report gender, age, diabetic status,
the use of long-term antibiotics, intravenous antibiotics at
the time of the questionnaire, long-term inhaled steroids,
long-term oral steroids, oral contraception, the presence of
urinary incontinence, whether they would like to be asked
about ‘thrush’ in clinic and with whom they would prefer to
discuss the problem. The questionnaire asked about oral and
genital candidiasis, who diagnosed the infection, whether
they had the infection currently, whether the symptoms
distressed them, if the infection was associated with any of
their treatment, if they had had any treatment for the
‘thrush’ and how effective it was, and whether the infection
made the patient reluctant to receive any of their CF
treatment.
One hundred and one (100%) patients completed the
questionnaire. Of the patients 88 (87.1%) were taking longterm
antibiotics, 75 (74.3%), were using an inhaled term
steroid, 29 (28.7%) had CF-related diabetes mellitus, 12
(25.5%) of the women were using oral contraceptives and
36 (76%) were leaking urine. Sixteen (15.8%) were
receiving intravenous antibiotics at the time of the study.
Ninety-three (92.1%) patients had two or more of the
above risk factors. The only significant risk factor associated
with genital Candida infection was the use of long-term
antibiotics (P=0.001).
In total, 71 (70.3%) of the patients (male and female)
had experienced symptoms of either oral or genital Candida
or both together. 18/45 (40%) of the patients who
reported oral candidiasis and 33/50 (66%) of the patients
who reported genital candidiasis found their condition
distressing. Although many patients found the symptoms
upsetting it did not make them reluctant to receive their
treatment.
The diagnosis of oral candidiasis was made by a doctor at
the CF centre in 24/46 (52.2%) cases. Genital candidiasis
was mainly a self diagnosis: 28/50 (56%). General
practitioners diagnosed more cases of genital infection than
doctors at the CF centre.
SYSTEMIC INFECTION WITH C. ALBICANS IN
CYSTIC FIBROSIS
Systemic infection only occurs in patients with CF in two
circumstances. Occasionally it occurs in immune suppressed
14 patients following organ transplantation although the usual
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infecting fungus for this post-transplant group is Aspergillus
fumigatus.8
However, the usual circumstance for systemic infection
with C. albicans in patients with CF is in the presence of a
totally implantable vascular access device (TIVAD)
commonly known as a ‘port’. Septicaemia due to Candida
species is recognized as the most common infecting
organism associated with a TIVAD.9–11 Diagnosis is made
by the typical swinging temperature associated with
septicaemia and positive blood cultures. Blood cultures
should be taken from the port site and a peripheral vein.
Once the diagnosis has been confirmed with a positive
blood culture it is crucial to remove the device. The device
and the line should always be sent for culture. Removal of
the port usually results in significant clinical improvement.
Transplant candidates who have a fungal port infection
should be temporarily removed from the active list. An
echocardiogram can be done but we have not found fungal
endocarditis in our patient group.
Over a 6-year period, 15 adults with CF attending the
Manchester Centre have developed a Candida infection of
their port confirmed by positive blood cultures. Immediate
removal of the port resulted in an excellent clinical
outcome. The Candida species isolated from blood culture
were C. albicans (9), C. parapsilosis (5) and C. glabrata (1).
Potential risk factors in this group for a Candida port
infection included prolonged use of antibiotics, oral steroids
and diabetes mellitus. Treatment was given with amphotericin
and azoles according to anti-fungal sensitivities. It is
clinical practice following full treatment of the fungal
infection for ports to be replaced after 3 months following
at least three negative blood cultures. Transplant candidates
can be returned to active listing 6 weeks after three negative
blood cultures. There are no clinical trials in CF patients to
support these policies and practice may vary between CF
centres. At the MACFC following identification of a fungus
in the initial cultures, patients are commenced on a loading
of fluconazole and maintained on 400 mgms daily for 2
weeks. This initial treatment is commenced on the basis that
the usual port infection is caused by C. albicans. If a
fluconazole-resistant Candida species is isolated a different
anti-fungal is used according to sensitivity patterns and
following consultation with the microbiologists.
DISCUSSION AND CONCLUSIONS
This paper has highlighted studies of Candida infection in
adults undertaken over a 10-year period. It is remarkable
how few papers about this topic have been published. As
Sawyer et al. have highlighted,5 the problem has perhaps
been trivialized as an issue in comparison to the many other
serious medical problems which afflict CF patients. The
study by Sawyer et al. clearly showed that CF women
suffered from symptoms more regularly than healthy
women in their control group. Lyon et al. also included
men in his study and also tried to address the issue of
symptoms in the partners of the CF patients.6
The Manchester study in a larger group of patients
identified the many risk factors that not surprisingly may
make patients with CF more susceptible to symptomatic
candidiasis. These include long-term usage of antibiotics,
inhaled and oral steroids, diabetes mellitus, urinary
incontinence and perhaps oral contraceptives. Although
the only significant identified risk factor found was for longterm
antibiotic usage and genital candidiasis (P=0.001). This
result is similar to the study carried out by Sawyer et al.
who found a significant association with oral antibiotics and
vulvovaginal candidiasis (P=0.05). Perhaps, of concern is
the large numbers of CF men and women in the Manchester
study who were symptomatic with oral and genital
Candida—but only when asked. Furthermore, although
CF doctors were the source of diagnosis for over 50% of
oral infections, a diagnosis of genital candidiasis was usually
a self diagnosis by the patients or by a consultation with
their general practitioner rather than a CF member of staff.
This may be due to different doctor–patient relationships in
the separate health-care settings. Perhaps, because the focus
within the CF unit is on respiratory and gastrointestinal
symptoms, the patient does not consider it the correct
forum for discussion.
Reassuringly, over half the patients want the issue of
candidiasis to be discussed at clinic, and they do not mind
with which health-care professional they discuss the issue of
fungal infection, although some of the female patients
specified they would prefer to talk to female members of
the team regarding genital symptoms. In addition, although
many of the patients found the symptoms of candidiasis
distressing they were not reluctant to receive treatment.
A major criticism of the three quoted studies is that the
symptoms of oral and genital Candida infection were not
supported by comprehensive microbiological specimens
taken from the oropharynx and vagina.
This paper has highlighted a high frequency of
symptomatic oral and genital candidiasis in the adult CF
population. Long-term antibiotic usage was perceived to be
the most significant causal factor for symptomatic oral and
genital candidiasis. It would appear that the level of
symptoms have been underestimated in the CF adults. CF
health-care professionals should have a positive approach to
asking about symptoms associated with oral and genital
candidiasis. The team should also be sensitive to the fact
that some female patients would prefer to discuss genital
candidiasis with a female health-care professional. Patients
should be asked about symptoms related to candidiasis on a
regular basis or at least at every annual review. It is our
clinical practice at the Manchester Centre for patients who 15
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report that they have had thrush with courses of intravenous
antibiotics are given a course of fluconazole during the
course and usually a couple of days after the end of the
course. Patients who have severe liver disease will usually
be treated with a topical anti-fungal agent.
There are many published studies of the benefit and
efficacy of anti-fungals in the treatment of vulvovaginal
candidiasis in the ‘normal’ female population12 but none in
the CF population. This is not surprising as there is no other
comparable group with an inherited disease who receive
lifelong antibiotics, inhaled steroids and a significant number
have diabetes.
Finally, port infections occur most frequently with
C. albicans. When a port becomes infected it should be
removed immediately, and prompt management will
usually result in an excellent clinical outcome.
REFERENCES
1 Mahadeva R, Webb AK, Westerbeek RC, et al. Clinical outcome in
relation to care in centres specialising in cystic fibrosis: cross sectional
study. BMJ 1998;316:1771–5
2 Fraser VJ, Jones M, Dunkel J, et al. Candidaemia in a tertiary care
hospital: epidemiology, risk factors, and predictors of mortality. Clin
Infect Dis 1992;15:414–21
3 Denning D. Fortnightly review: management of genital candidiasis.
BMJ 1995;10:1241–4
4 Akpan A, Morgan R. Oral candidiasis. Postgrad Med J 2002;78:
455–9
5 Sawyer SM, Bowes G, Phelan PD. Vulvovaginal candidiasis in young
women with cystic fibrosis. BMJ 1994;308:1609
6 Lyon A, Gunn E, Bilton D. Is genital Candida infection a significant
problem for adults with cystic fibrosis. J Cyst Fibros 2004;3:S99
7 Woolnough EM, Smith C, Dodd ME, Jones A, Webb AK. Is
candidiasis a problem in adults with cystic fibrosis? A prospective
study. Thorax 2004;59:S78
8 Helmi M, Love RB, Welter D, Cornwell RD, Meyer KC. Aspergillus
infection in lung transplant recipients with cystic fibrosis: risk factors
and outcomes in comparison to other types of transplant recipients.
Chest 2003;123:800–8
9 Bonacorsi S, Munck A, Ovetchkine P, et al. In situ management and
molecular analysis of candidaemia related to totally implanted vascular
access in cystic fibrosis patients. J Infect 1996;93:49–51
10 Horn CK, Conway SP. Candidaemia: risk factors in patients with
cystic fibrosis who have totally implantable venous access systems. J
Infect 1996;26:127–32
11 Munck A, Malbezin S, Bloch J, et al. Follow up of 452 totally
implantable vascular devices in cystic fibrosis patients. Eur Respir J
2004;23:430–4
12 Watson MC, Grimshaw JM, Bond CM, Mollison J, Ludbrook A. Oral
versus intra-vaginal imidazole and triazole anti-fungal treatment of
uncomplicated vulvovaginal candidiasis (thrush). Cochrane Database Syst
Rev 2001;(4):CD002845
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