Candidiasis Part 2: Laboratory Testing Options

In part one of Clinical Consequences and Considerations of Chronic Candidiasis, I discussed various pathogenicity mechanisms of invasive candida, including increased intestinal permeability leading to a leaky gut phenomenon, arabinose toxicity and immune dysfunction. In this article (part 2 of 3) I will outline some laboratory test options for the detection of intestinal candida, as well as options for analyzing the invasive nature of these fungal organisms.

This article will profile three detection methods two of which are commonly used in functional and integrative medicine, namely stool analysis and organic acids test (OAT). The third method, serum testing, is more commonly associated with conventional medicine. We begin this discussion with serum testing for candida.

Serum Testing

Serum tests for candida antibodies, which may include immunoglobulins IgA, IgG and IgM, can be acquired from many commercial labs. In general, antibodies are blood proteins produced in response to a specific antigen for the purpose of immune recognition and neutralization of its activity. An antigen can be any substance which the body recognizes as foreign, including an allergen, bacteria, fungus, or viruses (1).

Many laboratories provide both IgM and IgG antibodies. IgM is the antibody that rises first before IgG is produced. IgG follows IgM production providing longer term immunity and stays elevated longer than IgM (2). IgA serum testing is available too, but since IgA circulates at lower concentrations in the blood compared to IgM and IgG, it is not a commonly analyzed serum immunoglobulin.

Being that many species of candida can normally inhabit the digestive system at low levels it has been debated if elevated antibodies carry any clinical significance. For example, reference material from a major laboratory in the United States mentions the following with regards to Candida IgG antibody testing:

A positive test does not necessarily indicate infection since antibodies to Candida species can be detected in uninfected individuals because of their exposure to commensal yeasts. This assay is unable to differentiate antibodies formed during mucosal colonization from those produced during deep infection. Consequentially, antibodies are found in many hospitalized patients who have no obvious Candida infection. A negative result does not rule out the possibility of deep-seated candidiasis in immunocompromised patients (3).

As discussed in part one of this article series, candida can move from a mucosal colonization phase to a more invasive form. Some labs have established reference ranges that correlate to higher concentrations of Candida-specific immunoglobulins indicating higher infectivity. For example, Great Plains Laboratory (CLIA certified 17D0919496) lists the following with regards to its IgG Candida antibody analysis (4):

The Candida albicans scale has been updated to account for the observation that Candida-specific immunoglobulins are present in the specimens of virtually all individuals tested. The new scale is intended to provide a clearer indication of clinical significance and was established according to population percentile ranks obtained from a random subset of 1,000 patients. Specifically, the range of insignificant and low IgG values correspond to the first and second quartiles of the distribution, while moderate values denote individuals in the 51st to 97.5th percentiles. Those with an IgG value greater than the 97.5th percentile are considered to have a high concentration of Candida-specific immunoglobulins.

Therefore, antibody testing, particularly of IgG can be an effective method for the detection of higher concentrations of Candida that may be adversely affecting an individual’s health. Like all testing, the data obtained from a laboratory analysis should be correlated with the clinical presentation of the individual.

Stool Testing

Stool analysis for the detection of Candida has been used by functional and integrative medicine practitioners for years. In this method, fecal samples are collected then analyzed for either visual appearance of yeast through microscopy or growth of the organism in a culture medium.

Being that Candida and other forms of yeast are common to the digestive system, it is not unusual to see a positive finding on microscopy. This is commonly listed as “moderate” or “many” yeasts detected, but the actual type of species is determined by stool culture analysis.

The culture component is more specific to isolating which type of yeast organisms are present. For example, Candida albicans is the most common type of candida found in the digestive system, but the culture method may detect others such as Candida glabrata or Candida tropicalis. One of the benefits of differentiating yeast strains through culture is the ability of the lab to provide sensitivity testing that may determine which botanical or medication is most effective in eradicating the organism. Unfortunately, however, stool analysis for Candidiasis through culture is not 100% accurate and can miss detection even though a patient may be symptomatic of candida overgrowth.

Polymerase chain reaction (PCR) has become a popular method of pathogen detection and this includes PCR analysis for candida in stool samples. PCR is a widely used method to help make billions of copies of DNA accessible for study (5).

The pros of PCR testing are that its more sensitive than conventional laboratory techniques for pathogens because it allows through a sample amplification process to detect organism at low numbers. Unfortunately, PCR testing does not differentiate between non-viable (non-living, not capable of reproducing) from viable (capable of reproduction) candida. Other considerations regarding PCR testing are that it can detect multiple pathogens but may not differentiate the causative organism and it may show false positives if the stool sample is collected too soon after previous treatments (antibiotics or antifungals).

Again, like positive serum antibody testing, any positive PCR detection should be correlated to the clinical presentation of the individual prior to a treatment decision.

Organic Acids Test (OAT)

Organic acids are metabolic compounds containing carbon, oxygen, and other atoms such as hydrogen, sulfur, and nitrogen. They are naturally occurring compounds linked to cellular metabolism or may be present because of problems in biochemical processing.

Some organic acids are produced by organisms in the digestive system, including bacteria, candida, and yeast species. These gut-produced organic acids get absorbed systemically then highly concentrate in the urine. Certain organic acids from yeast metabolism represent overgrowth within the digestive tract, while others are linked to invasive candida at the mucosal barrier within the small and large intestine. One such organic acid called Arabinose, which was discussed in part 1 of this article series, is reflective of invasive candida.

Arabinose

Arabinose, a sugar aldehyde, closely related to a sugar alcohol known as arabinitol (6), has been used for years as an indicator of invasive candidiasis. It is often high in those with autism (7) but has prevalence to various other health disorders such as Alzheimer’s disease.

The production of Arabinose (and other compounds) occurs secondary to oxidative reactions against hyaluronic acid which can be initiated by invasive candida and its production of hyaluronidase (8). Therefore, elevations of arabinose on organic acids tests reveals active invasion into the mucosal lining of the digestive system and a higher degree of candida severity.

Arabinose, as discussed previously, has various important pathogenicity mechanisms that are worth considering:

•  It can bind with the amino acid lysine forming a compound called Pentosidine (9). This complex can alter normal biological function, including neuronal structures through glycation end-product formation.
• Pentosidine is known to cause various adverse neurological reactions, including myelin damage, neurofibrillary tangle development and Alzheimer’s disease (10).
• The epsilon amino group of lysine is a functional component of many enzyme systems that also depend on cofactor binding from vitamin B6, lipoic acid and biotin (11). High amounts of pentosidine, which block these binding sites, may lead to functional deficiencies even when nutritional intake of these nutrients is adequate.

Conclusion

There are many testing options available for the detection of intestinal candida that can determine overgrowth and the degree of invasiveness. Candidiasis, defined as a fungal infection linked to any form of candida species that is detected via serum, stool or organic acid analysis does not necessarily indicate that a patient is suffering from Candidemia which is linked to actual fungal species found in the bloodstream. Unfortunately, blood cultures for candida are often unreliable (12) but understanding the clinical application of the aforementioned methods can provide specific data to help identify individuals clinically affected by candida overgrowth.

In short, the organic acids test is a preferred option because it shows mucosal reactivity to invasive candida even when a stool analysis reports no evidence of candida overgrowth. Often, a serum IgG test will report high levels of candida which may correlate with an elevated arabinose on the OAT. However, this is not always the case. Therefore, my preference is to use the OAT as a primary test for candida assessment and incorporate stool analysis and/or serum testing as complementary methods.

In part 3 of this article series we will explore various treatment options for chronic candidiasis, both from a conventional medicine and integrative medicine standpoint, as it is important to understand the pros and cons of each.

References:

1.  K. Abbas, Abul; Lichtman, Andrew; Pillai, Shiv (2018). Cellular and molecular immunology (Ninth ed.). Philadelphia: Elsevier. p. 97.
2. Pier GB, Lyczak JB, Wetzler LM (2004). Immunology, Infection, and Immunity. ASM Press.
3. LabCorp website - https://www.labcorp.com/tests/163135/i-candida-i-antibodies-iga-igg-igm-elisa
4. Great Plains Laboratory website https://www.greatplainslaboratory.com/igg-food-allergy-test
5. Saiki, R.; Gelfand, D.; Stoffel, S.; Scharf, S.; Higuchi, R.; Horn, G.; Mullis, K.; Erlich, H. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. 1988; Science. 239 (4839): 487–491.
6. Kiehn T, Bernard E, Gold J, Armstrong D. Candidiasis: detection by gas-liquid chromatography of D-arabinitol, a fungal metabolite, in human serum. Science. 1979; 206(4418): 577-580.
7. Shaw W, Kassen E, Chaves E. Increased excretion of analogs of Krebs cycle metabolites and arabinose in two brothers with autistic features. Clin Chem. 1995;41(8):1094-1104.
8. Jahn M, et al. Carbohydr Res. 1999, 321:228-34. 2. Shimizu MT et al. J Med Vet Mycol. 1995, 33:27-31
9. Sell D, Monnier V. Structure elucidation of a senescence cross-link from human extracellular matrix. Implication of pentoses in the aging process. J Biol Chem. 1989;264(36): 21597-21602.
10. Smith MA, Taneda S, Richey PL, et al. Advanced Maillard reaction end products are associated with Alzheimer disease pathology. Proc Natl. Acad. Sci U S A. 1994; 91(12): 5710-5714.
11. Mahler H, Cordes E. Biological Chemistry. 1966; Harper and Row, NY. Pgs 322-375.
12. Cornelius J. Clancy and M. Hong Nguyen. Finding the Missing 50%” of Invasive Candidiasis: How Nonculture Diagnostics Will Improve Understanding of Disease Spectrum and Transform Patient Care, 2013-04-04 Oxford Journals, Medicine & Health, Clinical Infectious Diseases, Volume 56, Issue 9 Pp. 1284-1292.