Invasive candidiasis

Invasive candidiasis, also known as systemic candidiasis, candidemia or deep organ candidiasis, is an infection that is caused by the Candida fungus. In some situations, the terms are used interchangeably as most cases of deep-tissue candidiasis coexist or occur as a result of a previous candidemia infection.

Candidiasis versus Invasive Candidiasis

The difference between general candidiasis and invasive candidiasis is that common oral and genital candida infections are regarded as superficial whereas invasive candidiasis, which comprises of both candidemia and deep-organ candidiasis, are far more severe infections.

Another difference is that the more commonly occuring types of candidiasis are localised in areas such as the throat and mouth (oral thrush) or genitals (genital thrush), whereas invasive candidiasis is systemic (i.e. it occurs throughout the body) and may affect the blood, brain, heart, bones, eyes and a number of other body parts. 

While the more common forms of candidiasis can generally be effectively treated with ease, candidiasis that becomes invasive is often life-threating with a mortality rate between 19 and 24%²¹. The mortality percentages, are, however difficult to quantify correctly as those suffering from invasive candidiasis usually have serious underlying health conditions that could contribute to the reported statistics.

Types of invasive candidiasis

There are two main types of invasive Candida infections (candidiasis):

• Candidemia – This is the most common kind of invasive Candida and involves Candida infecting the bloodstream which can affect various body parts.
• Deep-seated tissue candidiasis – also known as deep-tissue(organ) candidiasis. This involves Candida infecting internal organs and is also known as a deep organ infection.

Candidemia

Candida in the bloodstream is the most common kind of invasive candidiasis and is known as candidemia. 

The bloodstream infection is often the result of:

• Major surgery
• Central venous catheters
• Broad-spectrum antibiotics
• IV hyperalimentation – nutrients are administered via a drip

This condition often results in the sufferer undergoing lengthy hospital stays with high doctor and medical costs. The prognosis of this infection is often poor as the available treatment options often fail to yield effective results.  

Who is at risk of developing candidemia?

Healthy individuals very rarely get candidemia. It is commonly found in those who have a current health issue that leads to the suppression of the immune system as this predisposes them to the development of this severe and dangerous infection²².

Candidemia is one of the most common kinds of infection in people undergoing hospitalisation for an intestinal surgery or organ transplant. Seeing as the Candida yeast naturally resides on the surface of the skin in the majority of people, if the skin is punctured in some way, this provides the fungus with a direct entry point into the bloodstream. In the case of patients undergoing a central venous catheter, the risk of this infection developing is heightened. A central venous catheter which is a tube that is inserted into a main blood vessel for it to deliver certain medications, nutrients or chemotherapy directly to the patient may also create a route for the fungus to enter the bloodstream from the skin.

Candidemia may also infect patients who suffer from a weakened immune system that can be due to a number of causes such as ongoing chemotherapy or an organ transplant. Those who have undergone a high dosage of prophylactic broad-spectrum antibiotics in order to rid their body of a certain bacterial antigen are also at risk as this provides Candida with an ideal environment in which to multiply and infect the body. In addition, those who have received mass doses of corticosteroids (often used to treat asthma) are vulnerable to candida infection. Finally, candidemia may occur in those who suffer from severe diabetes or have an HIV infection.

Symptoms of candidemia

Candidemia lacks exclusive or specific symptoms. A few of the symptoms such as chills and fever, as well as general weakness and fatigue are generally associated with the majority of systemic infections.

Candidemia sufferers may also experience the following:

• Skin rashes
• Abdominal pain
• Muscle aches
• Vision changes
• Loss of vision
• Sustained headaches
• Other neurological issues

Diagnosing candidemia

Diagnosing candidemia is often complex due to the lack of exclusive or specific symptoms. It is, however, important that the condition be diagnosed in the initial stages as those who suffer from the infection over a longer period of time can suffer further complications.

The following tests are used in the diagnosis of invasive candidiasis:

Culture tests

• Blood tests can be conducted to detect the presence of Candida overgrowth, however, test results can often take some time. In some cases, the results will be available within a few days, however, it is important to note that Candida can take as long as 30 days to show up. 
• Culture tests can also be done of the infected tissues or bodily fluids. Here a sample is taken to be examined for fungal infection.
• A number of rapid tests can also be performed. These are known as rapid diagnostic tests (RDT) and they are able to detect the antigens associated with candida overgrowth that are present in the blood.

Screening tests

• A CT (computed tomography) scan or an ultrasound can be conducted to detect any abdominal or renal infections.
• An echocardiography (also known as a cardiac echo) can be conducted to create images of the heart. This is used when cardiac involvement in the infection is suspected.

Other tests

• An endoscopy can also be conducted to check for intestinal infections (this will be done by means of a biopsy).

Treatment of candidemia

The treatment of candidemia can be complicated as the infection progresses and begins to infect some of the organs such as the eyes, brain, heart and kidneys. The most common kind of Candida species, Candida albicans were originally linked to the development of candidemia. However, recently Candida parapsilosis and Candida glabrata have been causing more infections, some of which have also been noted to be resistant to a number of the most widely used antifungal medications like the Azole drugs.  

The popular antifungal drugs that are usually used for candidemia treatment are:

• Azoles
• Echinocandin
• Polyenes

The medication chosen will depend on the health and age of the patient and the species of Candida causing the infection.

Deep-seated tissue candidiasis

Deep-seated tissue candidiasis is also known as deep-seated candidiasis and deep-organ candidiasis, the terms will be used interchangeably in the information that follows.

Invasive candidiasis is comprised of both candidemia and deep-seated tissue candidiasis. Deep-seated candidiasis is a result of either hematogenous dissemination (i.e. it is spread by the bloodstream) or the direct inoculation of the Candida species to a sterile site, for example, the peritoneal cavity (the space between the abdominal wall and the adjacent abdominal organs).

This kind of candidiasis also infects those who are predisposed due to an underlying condition. As with all other forms of candidiasis, a compromised immune system is often the leading cause of its development.

Deep-seated tissue candidiasis is something that is increasingly noted in ICUs where patients are severely ill and are therefore predisposed to the condition. The condition is, however, often misdiagnosed and sufferers remain untreated which can result in the progression of this fungal infection. In some cases, the severity of the infection is life-threatening and results in death.

Research shows that in all recorded episodes of deep-seated candidiasis coexist with or are preceded by candidemia. In both types of invasive candidiasis, Candida is an opportunistic pathogen that results in severe infections. Further research is necessary to better understand this condition. At present very few sources describe deep-seated candidiasis in detail, what is known, however, is that it can be present in any organ, sterile tissue or organ space.

Due to the diagnosis being difficult (diagnosis entail biopsies of the infected areas or blood tests), the estimates regarding the prevalence of the infections lack reliability. As a result, deep-seated candidiasis can be a condition that is severely underestimated in ICUs.

Who is at risk of deep-seated tissue candidiasis?

The majority of the cases of deep-seated tissue candidiasis are linked to a co-existing or previous candidemia infection, making the risk profile for a sufferer is very similar to that of candidemia. A prolonged stay in ICU (seven to ten days or more) is the highest risk factors in the development of deep-seated candidiasis which occurs predominantly in those recovering from surgery or another condition in ICU.

Other risk factors include:

• Previous administration of broad-spectrum antibiotics
• Corticosteroid therapy
• Peritonitis (inflammation of the lining between the abdominal wall and the covering of the abdominal organs)
• Abdominal surgery
• Previous Candida infection (colonisation) in multiple sites on the body
• Multiple lumen catheters
• Administration of parenteral nutrition (i.e. feeding a person via an intravenous line)
• Chemotherapy
• Neutropenia (abnormally low white blood cell count – these form a part of the functioning of the immune system in being able to fight off infections)

Infection sites indeep-seated tissue candidiasis

Due to deep-seated tissue candidiasis coexisting with or evolving from candidemia, roughly 80% of candidemia cases arise from the fungi having access to the vascular system (i.e.  the arteries, veins and blood), often due to the use of central venous catheters (the tubes placed into a vein to administer blood, fluid, medication etc.).

The primary source of entry of candidemia in patients who are non-neutropenic (i.e. who have a normal amount of white blood cells) and develop deep-seated tissue candidiasis may be that of an intravenous catheter or infusion fluid being contaminated. However, infection of the peritoneal cavity can also occur after abdominal surgery or trauma.

It is believed that an infected organ is linked to the site that the haematogenous dissemination took place (i.e. the place from which the fungus entered the blood stream and spread) and whether the affected person has adequate bone marrow functioning. The bone marrow is responsible for producing the body’s blood cells. White blood cells are involved in the immune system's ability to protect the body.

Those with a previously normal white blood cell count (i.e. the immune system is not compromised) who develop deep-seated tissue candidiasis after abdominal surgery or IV catheter-induced phlebitis (trauma to the vein), tend to have myocardial (heart), renal, cerebral (brain), ocular (eyes) and pulmonary (lungs) involvement. Infections of spleen and liver are unusual in these cases, although any organ can be contaminated, colonised (inhabited by the fungus without causing infection) or infected by Candida.

Some of the most commonly seen infections in ICUs are briefly described below:

Gastrointestinal tract, spleen, liver and peritoneum

These infection sites can originate from the Candida fungus moving across the bowel wall, this movement is often facilitated by the decreased functional ability of the mucosal barrier which is often the case in patients in the ICU.

Candidemia of the GI (gastrointestinal tract) is often observed in those who have leukaemia (cancer of the blood).  Candida peritonitis (inflammation of the lining between the abdominal wall and the covering of the abdominal organs), is often seen as a result of a bowel perforation from surgery or trauma.

Lungs and trachea

While extremely rare, some people may suffer from fungal pneumonia. This condition is caused by the candida infection being carried by the blood to the lungs (i.e. via haematogenous dissemination). It is often difficult for trachea and lung infection like this to be diagnosed as screening tests such as CT (computerised tomography) scans cannot be conducted in an ICU and require the patient to be moved.

Urinary tract

In as many as 20% of patients in the ICU, Candida has been seen to be isolated in the urinary tract mainly due to bladder catheterisation. Candida infecting the bladder and kidneys is known as Candida pyelonephritis. 

Cardiovascular candidiasis

This kind of infection infects the cardiovascular system. If Candida infects the heart, known as Candida myocarditis. The heart may be compromised by very subtle alterations in the muscle’s function, this makes it difficult to detect Candida in the heart. Candida infecting and causing swelling of the heart valve, known as Candida endocarditis, is a real threat to those who have recently undergone cardiac surgery, specifically when prosthetic valves have been inserted. 

Central nervous system

Candida meningitis has been noted in those who have HIV, neonates (infants) or those who have had neurosurgery (surgery involving the nervous system which includes the brain, nerves and spinal cord). This has a high mortality rate and is often only detected in a post-mortem.

Eyes

If deep-seated candidiasis infects the eyes is can present as endophthalmitis or chorioretinitis (inflammatory conditions of the eye). An ophthalmoscopy will need to be conducted that allows the doctor to take a look into the structures of the eye using an ophthalmoscope which is a viewing device with various lenses and a light attached.

Symptoms of deep-seated tissue candidiasis

The symptoms experienced with deep-seated tissue candidiasis are dependent on the site infected. Thus, each case is different with different symptoms, and the site of infection dictates the physical symptoms.  Some of the symptoms can include:

• Dysphagia – This is a condition that involves drooling, having a hoarse voice, suffering from heartburn, having pain or difficulty swallowing or regurgitating food.
• Mucosal and skin lesions
• Fever
• Renal (kidney) shutdown 
• Brain fog – This is also known brain fatigue and may involve moderate to severe episodes of the affected person suffering from mental confusion which occurs without warning. This often results in a lack of focus, reduced mental ability and poor memory. This symptom is often linked to the treatment of Candida with antifungal medications and is also associated with the lupus-like symptoms. Brain fog is typically linked to Candida albicans and Candida die-off during treatment.

Diagnosing deep-seated tissue candidiasis

It is often difficult for deep-seated candidiasis to be accurately diagnosed. Blood cultures having a low sensitivity, meaning the results are not always able to detect the fungus and are not completely accurate, therefore not all the cases of invasive candidemia are detected.

The issue with deep-seated tissue candidiasis comes in with colonisation (the organism spreads without causing an infection). People are often heavily colonised, particularly when they have been treated with broad-spectrum antibiotics. A candida infection (candidiasis) usually develops secondary to colonisation.

Early diagnosis and accurate treatment are associated with a more positive prognosis. While tests may show the presence of candida, it is difficult to differentiate between colonisation and infection at present. This is due to the fact that a diagnosis is dependent on the lab findings from blood and culture tests. There is currently an urgent need for more specific markers to be developed in order to make a more accurate diagnosis.

Treating deep-seated tissue candidiasis

The treatment for deep-seated tissue candidiasis will require an individualised approach for each case. Therefore, treating the site of infection or the manifestation of the condition will involve antifungal therapy, with the dose and duration tailored according to the type of infection present. These drugs are likely to be administered intravenously or orally and can include brands in one of the following classes of drugs:

• Azoles
• Echinocandins
• Polyenes – The medication known as amphotericin B is a common kind of polyene drug.

There are a number of side effects when using the majority of the above systemic antifungal drugs. These can include nausea, vomiting, hepatitis, headaches, kidney-toxicity and even lupus-like symptoms (this is an autoimmune, inflammatory condition wherein the immune system will attack its own tissues resulting in joint pain, fatigue and sometimes brain fog).

Identifying and removing the source of infection such as a device (i.e. a catheter) or drug that is compromising the immune system is critical.

In some cases, surgical debridement (wherein the site of infection is surgically removed) may also be required.

 

References

^{21. Statistics | Invasive Candidiasis | Candidiasis | Types of Diseases | Fungal Diseases | CDC. Cdc.gov. https://www.cdc.gov/fungal/diseases/candidiasis/invasive/statistics.html. Accessed May 23, 2019.}

^{22. Yapar N. Epidemiology and risk factors for invasive candidiasis. Ther Clin Risk Manag. 2014;(10):95-105.doi:10.2147/tcrm.s40160}