Candida albicans infection in adults with cysic fibrosis

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

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

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

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

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

Candida species in cystic fibrosis: A road less travelled.

Chotirmall SH¹, Greene CM, McElvaney NG.

Author information

• ¹Department of Medicine, Royal College of Surgeons, Ireland. schotirmall@rcsi.ie

Abstract

Candida species are isolated with high frequency from cystic fibrosis patients, yet their definitive role in the disease remains unclear. Previously considered to have minimal inherent virulence owing to their commensal ability, the last decade has heralded an increasing recognition of Candida infection among patients with cystic fibrosis. What has been more recently hypothesized is that the organism possesses virulence factors that play diverse roles at different body sites during varied stages of an infection. Currently, limited data is accessible in the area of cystic fibrosis. This review aims to provide an overview of the role of Candida species in cystic fibrosis as it is currently understood including the common local and systemic infections observed in clinical practice. The uncertain role of airway colonization and insight into emerging fields such as Candida-bacterial interactions are also addressed. Finally, we outline the current understanding of the innate, cellular and humoral immune responses associated with this genus which has been the major focus of work performed to date.

PMID:

21067323

[PubMed - indexed for MEDLINE

Misaligned Atlas and sinus issues

Symptoms and Signs of Atlas Subluxation

Posted on June 30, 2011 by MindBody

Edited Feb 14 2013

Symptoms

Please be aware that the following list is a list of all possible complications and their anatomical and physiological basis and that few people with this condition will have a full hand of symptoms.
However, a proper understanding of anatomy and physiology of the upper cervical area and brainstem should be enough to make it clear that all of the symptoms listed below are predictable given a large enough subluxation.
The joint between the skull and the neck is designed for nodding movements, and it has been documented that the maximum rotation expected on turning well to the left or right is about 3-4 degrees.
The worst case I have seen was a rotatory subluxation of about 25 degrees demonstrated on a CT upper cervical spine. I was dismayed that the radiologist who reported it failed to note the abnormality. I would observe that this probably happened because such subluxations are not regarded as possible within allopathic medicine- and he was not looking for it. I did get the satisfaction of an amended report after conversation with the radiologist involved.
Most symptoms will be intermittent, and at least partially resolve when the patient is fit and active, so there will be great variability between patients. I have had experience with most of these symptoms being relieved in patients I have seen.
Physical and radiological examination will provide clear cut evidence of the existence of the condition.
Mechanical Symptoms

1. Headaches- often involving the base of the skull, and referring to the sides of the head and around the sinuses.
2. Migraines, often with marked agitation and nausea.
3. Neck pains and stiffness and difficulty finding a comfortable position on the pillow at night.
4. Sometimes crackling or grating noises at the base of the skull when turning the head. Often there are associated shoulder pains, especially between the shoulder blades.
5. Jaw joint pains or dysfunction. Clicking jaw.
6. Chest wall pain- due to the distortion of the ribcage
7. Low back pain and/or disc injuries due to abnormal posture.
8. Nerve root irritations at any level.
9. Pains or injuries in one hip, knee or ankle, often repeated injuries to one side of the body.
10. Patients may be told they have one leg shorter than the other.

Symptoms based on nerve and blood vessel compromise.
Vagus nerve: Nausea, heartburn, irritable bowel, constipation, vasovagal (fainting/near fainting) episodes, probably infantile colic. Cough and voice problems
Internal Jugular Vein and venous drainage of the skull via the foramen magnum: tiredness, mental fogginess (often subtle and this may well contribute to the mental fogginess in ADHD, chronic fatigue syndrome, fibromyalgia and depression). References:
http://www.upright-health.com/
http://www.upright-health.com/vertebral-veins.html
http://www.upright-health.com/brain-cooling.html
 
It is of interest that current research into multiple sclerosis has raised the possibility of venous congestion of the brain having a causative role in that condition.
Dizziness- often subtle and hard to describe, and mild incoordination /clumsiness.
Note that these symptoms are likely to be related to disturbed inputs to the Vestibular/proprioceptive (balance) system caused by nerve impingements, and excess tension in some muscles and on some joints. It is likely that the actual atlas subluxation causes some brainstem injury at the time of the injury.
Tingling or burning fingers or toes- usually migratory and intermittent.
Sympathetic Nervous System:
There are multiple reasons to believe that atlas subluxations may cause sympathetic overactivation (stress response): Poor balance itself is a cause of sympathetic overactivation, also the traction on the brain stem caused by the typical head forward posture of most people with the injury activates a stress response, and there may be further impacts on sympathetic ganglia (nerve cell clusters) that lie close to the spine along the whole length of the spine.
Symptoms would include chronic anxiety and impulsiveness, fine tremor, raised heart rate
It is arguable that chronic sympathetic overactivationmay be lead to:
a)gut problems due to chronic diversion of blood flow away from the gut into the muscles which may well be contributory to peptic ulcers, food allergies ( via increased gut permeability)
b) Adrenal gland activation and chronic over production of cortisone as an expected consequence of chronic sympathetic (stress) response. Adrenal fatigue as a downstream consequence of this.
c) unstable attention- as the body is effectively being given a warning to loo for threat in the environment.
It is arguable that chronic sympathetic activation might be contributory to immune suppression, hypertension, diabetes, osteoporosis, disturbed sleep and depression.
Disturbed sleep:
This is a common complication in our experience and may be contributed to by neck discomfort at night, by sympathetic over-activation, or by a number of brain stem effects caused by alteration in balance inputs into the nervous system.. In a number of patients the neck discomfort has triggered tooth grinding which has improved after treatment.

Signs

The physical signs of atlanto- occipital subluxation are straightforward, and the diagnosis can usually be confirmed without investigations.

Posture- the head is carried forwards of the shoulders. ( In healthy posture the centre of the shoulder joint is vertically directly below the ear canals).
The patient may also have a degree of hunch or a sway back.
The patient will have great difficulty straightening up to hold his head in correct position.
The front on view will often clearly indicate the problem. The head may be tilted to one side, and the neck rotated a few degrees or so off straight ahead.
The midline of the trunk may not be vertical.
One shoulder will be higher than the other.
Often the pelvis will visibly be off level as well (Usually high on the side of the low shoulder).
From the back the difference in the level of the shoulders will be more apparent, and one shoulder should be pushed out to the back. The head, shoulders, and hips may be out of alignment (viewed from above).
The neck will almost always be tender just below the ears and behind the jaw. It may be possible to feel that the neck bone is closer to the jaw on one side than the other. Postural issues, muscle spasm, or a “bull neck” can make this sign difficult to identify. However the joint between the atlas and the skull is not one at which rotation naturally occurs (beyond about 3-4 degrees at the extremes of neck rotation) so this sign is always abnormal if found.

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About MindBody

Medical Practitioner. Special interests: application of mindfulness based treatments to counseling, treatment of Adult ADHD, musculoskeletal medicine. The interface between complementary and conventional medicine. Barriers to adoption of new knowledge and paradigms within established institutions.

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