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 ~ Introduction
 ~  Materials and Me...
 ~ Results
 ~ Discussion
 ~ Conclusion
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  Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 38  |  Issue : 3  |  Page : 409-414
 

Microsporidia infection in patients with autoimmune diseases


1 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia; Department of Medical Parasitology, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
2 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia; Department of Molecular and Clinical Parasitology, National Liver Institute, Menoufia University, Menoufia, Egypt
3 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia; Department of Medical Microbiology and Immunology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
4 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia; Department of Medical Microbiology and Immunology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
5 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt; Department of Medical Microbiology and Immunology, Faculty of Pharmacy, Taif University, Taif, Saudi Arabia
6 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
7 Department of Forensic and Toxicology, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
8 Department of Internal Medicine, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
9 Department of Medical Parasitology, Faculty of Medicine, Ain-Shams University, Cairo, Egypt

Date of Submission20-Jul-2020
Date of Decision21-Aug-2020
Date of Acceptance31-Aug-2020
Date of Web Publication4-Nov-2020

Correspondence Address:
Dr. Khadiga Ahmed Ismail
P. O. Box 11099, Taif 21944

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmm.IJMM_20_325

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 ~ Abstract 


Purpose: Microsporidium is a spore-forming intracellular parasite that affects a wide range of hosts including humans. The tumor necrosis factor alpha (TNF-α) plays a key role in the immunity to infection with microsporidia. Recently, the TNF-α antagonists have proven successful in treating variable autoimmune diseases. In the current study, we aimed to investigate the impact of using TNF-α antagonists as a therapeutic regimen in the prevalence of infections with microsporidia. Materials and Methods: Diarrheal patients with distinct autoimmune diseases (n = 100) were assigned to the study. Patients taking anti-TNF-α medications (n = 60) were allocated to Group 1A and those undergoing non-TNF-α inhibitor treatment (n = 40) to Group 1B. Furthermore, patients with diarrhea without autoimmune disorders (n = 20) were allocated as controls. Stool specimens, 3 per patient, were collected and microscopically examined for microsporidia spores. A microsporidia-specific stool polymerase chain reaction was used to confirm the microscopic findings. Results: Microsporidia infection was identified in 28.3% (17/60), 10% (4/40), and in 5% (1/20) of patients in Group 1A, Group 1B, and in the control group, respectively. Overall, infection was significantly high in cases compared to the controls and in patients receiving TNF-α antagonists compared to patients not given TNF-α inhibitors (P < 0.05). Finally, infection was significantly higher in cases treated with TNF-α antagonists for ≥2 months compared to cases treated for <2 months of duration (P < 0.05). Conclusion: There was a significant increase in microsporidia infection in autoimmune disease patients undergoing treatment with TNF-α antagonists, and the duration of treatment is one of the risk factors. The study highlights the importance of microsporidia testing in immunocompromised patients, particularly those undergoing treatment with anti-TNF-α drugs and emphasises the need for awareness among clinicians regarding this opportunistic parasite.


Keywords: Autoimmune diseases, microsporidia, tumor necrosis factor alpha antagonists


How to cite this article:
Ismail KA, Hawash YA, Saber T, Eed EM, Khalifa AS, Alsharif KF, Alghamdi SA, Khalifa AM, Khalifa OM, Althubiti HK, Alsofyani GM. Microsporidia infection in patients with autoimmune diseases. Indian J Med Microbiol 2020;38:409-14

How to cite this URL:
Ismail KA, Hawash YA, Saber T, Eed EM, Khalifa AS, Alsharif KF, Alghamdi SA, Khalifa AM, Khalifa OM, Althubiti HK, Alsofyani GM. Microsporidia infection in patients with autoimmune diseases. Indian J Med Microbiol [serial online] 2020 [cited 2020 Nov 24];38:409-14. Available from: https://www.ijmm.org/text.asp?2020/38/3/409/299833





 ~ Introduction Top


Microsporidia are eukaryotic obligate intracellular microorganisms that affect a wide variety of hosts including humans.[1] Reports of the origin of microsporidia are uncertain, but recent phylogenetic and genetic studies postulate the hypothesis that microsporidia may be real fungi. These species tend to have a very special evolutionary link to zygomycetes.[2],[3] There are the many species of microsporidia and the most common species causing human infections are Enterocytozoon bieneusi and Encephalitozoon intestinalis.[4] Immunocompromised host such as AIDS patients with CD4+ T-cell count below 100/μl are at high risk for microsporidia infection. In this category of patients, infection can be life-threatening.[5] The prevalence rate of infection with Microsporidium ranges from 0% to 50% worldwide.[6] Microsporidia infection may be asymptomatic or associated with symptoms such as diarrhea, myositis, keratitis, bronchitis and rarely encephalitis.[7]

The size of microsporidia spores is small with diagnostic difficulties using microscopy. Moreover, the protozoa have slowly infecting properties with asymptomatic infection. Therefore, there are many undetermined cases of microsporidia-associated diarrhoea worldwide. For microscopic visualisation and identification of microsporidia, special stains and qualified personnel are required. There is a need for more robust diagnostic tests other than microscopy because microscopic examination has some limitations in the identification of the very tiny microsporidia spores.[8] The molecular-based diagnostic methods have improved exponentially to resolve these constrains.[9]

The autoimmune diseases result from an abnormal immune response to a normal body parts due to unexplained etiology. Certain cases of autoimmune disorders have a family history as systemic lupus erythematosus (SLE) or may be triggered by infections or caused by exposure to the environmental factors such as celiac disease, diabetes mellitus type 1, Graves' disease, ulcerative colitis (UC), Crohn's disease, multiple sclerosis, psoriasis and rheumatoid arthritis (RA).[10] The prevalence rate of autoimmune diseases is around 3% of the world populations. High prevalence rate was reported in females as compared to males. Individuals with insufficient or non-functional immunoregulatory mechanisms toward an environmental pathogen are prone to autoimmune disorders.[11],[12],[13]

The traditional therapeutic approaches for autoimmune diseases are unsatisfactory.[14] The aim is to decrease immune activation, and thus, the inflammatory damage by using either single or combined anti-inflammatory and immunosuppressive drugs.[15],[16] New therapeutic regimens have been developed to prevent cell damage during imbalanced pro-and anti-inflammatory cytokine expression, including soluble receptors, monoclonal antibodies and molecular mimetics intended to enhance or slowly replace traditional immunosuppressive therapies.[17] New treatment line has been introduced which targets the adaptive immune response pathways. Abnormal regulation of the development of tumor necrosis factor alpha (TNF-α) characterises many autoimmune responses. TNF is a proinflammatory cytokine that is elevated during autoimmune lesions along with other cytokines.[18],[19] The TNF-α is more than just a proinflammatory cytokine. It has an immunoregulatory role that can alter the balance of T-regulatory cells and has a role in physiological homeostasis.[20],[21],[22]

Anti-TNF-α therapy has a good effect on controlling the activity of autoimmune diseases, although it has a number of side effects, especially when used in the combination with classical immunosuppressive agents or corticosteroids.[23] The use was related to disease activity when administered to patients with opportunistic infections such as microsporidia and Mycobacterium tuberculosis.[24]

A small number of studies were conducted to identify microsporidia in immunocompromised patients such as patients with uncontrolled infection with human immunodeficiency virus, patients with distinct forms of cancers, and those undergoing immunosuppressive treatment for an organ transplantation surgery or an autoimmune disorder.[25],[26] Therefore, the current research was carried out aiming to detect the opportunist microsporidia in patients with autoimmune diseases, particularly those undergoing treatment with anti-TNF-α drugs.


 ~ Materials and Methods Top


A case–control prospective study was performed on patients attending King Abdulaziz Specialized Hospital between September 2018 and May 2019 with or without clinical and/or biochemical evidences of autoimmune diseases. Patients were allocated into two groups: Group 1 (G1; cases) included 100 diarrhoeal patients with various autoimmune disorders and Group 2 (G2; controls) included 20 diarrhoeal patients without autoimmune disorders.

Both cases and controls were age and sex matched. Cases were subdivided into two categories: Group 1A (G1A) comprised 60 patients undergoing treatment of their autoimmune disorder through the use of anti-TNF-α drugs and Group 1B (G1B) consisted of 40 patients taking therapeutic regimens for their autoimmune diseases other rather than anti-TNF-α drugs.

All the study participants were subjected to comprehensive history, clinical examination and investigated for autoimmune diseases markers such as rheumatoid factors, anti-double stranded DNA, anti-nuclear antibodies and faecal calprotectin. Importantly, any diarrhoeal patient with recent antibiotics or antiprotozoal treatment was excluded from participation in the study.

Stool samples collection

Three stool samples were obtained from each patient for the detection of helminths ova, protozoa cysts, and/or trophozoites. Every stool specimen was divided into two parts: one of which was fixed in 70% alcohol and immediately stored in the freezer for DNA extraction and subsequent polymerase chain reaction (PCR) testing, the remaining part was kept unpreserved and examined directly under the microscope using wet mount preparations stained with iodine, acid-fast and trichrome-staining procedures.[27]

Microsporidia-specific stool polymerase chain reaction

DNA was extracted from the stool samples using the genomic DNA purification Kit QIA amp® Fast DNA Stool Mini Kit (cat. No. 51604 QIAGEN-Germany) following the manufacturer's protocol. DNA sequence of 1200 bp of a highly conserved region of the small-subunit rRNA gene of microsporidia was amplified using a previously-published primer pair: forward primer, 5′ CACCAGGTTGATTCTGCC-3′ and reverse primer, 5′ GTGACGGGCGGTGTGTAC-3'.

Reaction set up was carried out using 50 μl of Go Tag® Green master mix (Promega, USA), 10 μl of DNA extract and 0.8 μg/μl of each primer. The target DNA sequence was amplified through 40 cycles, each consisted of 1 min of denaturation at 90°C, 2 min of annealing at 56°C, and 1 min of primer extension at 72°C with an additional extension at 72°C for 5 min after the last cycle.

In each PCR run, both positive and negative external controls were added to the test samples. The positive control was DNA retrieved from the pooled stool samples proved positives for microsporidia spores, whereas the negative control was a DNA-free blank with all PCR reagents.

For the detection of PCR amplification products, about 10 μl of each amplification reaction and the DNA molecular size marker were electrophoresed in a 1.2% agarose gel for 1 h, stained with a 0.5 μg/ml ethidium bromide, and lastly visualised in a ultraviolet transilluminator.

Statistical analysis

Computerised software program SPSS version 22 (Chicago, US) was used in the analysis of the results. The Chi-square test was adopted to test the variables significant difference. A probability value of <0.05 was considered statistically significant.

Ethical considerations

The present study was carried out “On patients from King Abdulaziz Specialized Hospital” and ethically accepted through the Taif University Ethical Committee. Patients involved in the study were told about the study objectives plus, a written signed consent was obtained from each participant.


 ~ Results Top


In addition to the control group (n = 20), the study included 100 diarrheal patients with various autoimmune diseases. Among these patients, 25 suffered from SLE, 25 from RA, 20 from UC, 20 from Crohn's disease and 10 from psoriasis. [Table 1] shows the microsporidia positivity rates in patients in Group 1A and Group 1B. As shown in table, out of 100 cases, 21 were found microsporidia positives, with a prevalence rate of 21%. Furthermore, 17 out of 60 (28.3%) cases treated with anti-TNF-α drugs were found positive for microsporidia. In contrast, 10% (4/40) of cases undergoing treatment without anti-TNF drugs were found infected.
Table 1: Microsporidia positivity rates in Group 1A and Group 1B of cases

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[Table 2] reports the microsporidia positivity in both cases and control groups participated in the study. As shown in the table, the incidence of microsporidia infection was significantly high in cases compared to the controls (P < 0.05). Infections were demonstrated in 21% (21/100) of cases and in 5% (1/20) only of the controls.
Table 2: Microsporidia positivity rates in both cases and controls

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[Table 3] exhibits the microsporidia positivity in cases treated with anti-TNF-α drugs (G1A) and the control groups (G2). As shown in the table, the incidence of microsporidia infection was significantly high in cases belonging to G1A compared to the controls (P < 0.05). Infections were demonstrated in 28.3% (17/60) of cases and in 5% (1/20) only of the controls.
Table 3: Microsporidia positivity rates in cases treated with the anti-tumor necrosis factor drugs and the controls

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[Table 4] describes the microsporidia positivity in cases treated with anti-TNF-α drugs (G1A) and in cases not treated with anti-TNF-α drugs (G1B). As shown in the table, the incidence of microsporidia infection was significantly high in cases belonged to G1A compared to patients in G1B (P < 0.05). Infections were demonstrated in 28.3% (17/60) of cases in G1A and in 10% (4/40) of cases in G1B.
Table 4: Microsporidia positivity in autoimmune disease patients belonged to subgroup A and subgroup B

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[Table 5] shows the microsporidia positivity in cases treated without anti-TNF drugs (G1B) and in the controls (G2). Although microsporidia infection was detected more in cases belonged to G1B compared to compared to the controls, this difference was not statistically significant (P > 0.05). Infections were demonstrated in 10% (4/40) of cases in G1B and in just 5% (1/20) of the controls.
Table 5: Microsporidia positivity in patients in subgroup B (G1B) and the control group (G2)

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[Table 6] demonstrates the microsporidia positivity in cases treated with anti-TNF drugs (G1A) according to the duration. As shown in the table, microsporidia infection positivity rates was significantly more in cases treated with ani-TNF drugs for 2 months or more duration than in cases treated for <2 months duration (P < 0.05). Infections were demonstrated in 20.8% (10/48) of cases given anti-TNF-α for <2 months and in 58.3% (7/12) of patients given treatment for ≥2 months.
Table 6: Microsporidia positivity and duration of biological treatment

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[Table 7] shows enteric parasites other than microsporidia that were identified in the study participants. As shown in the table, Blastocystis hominis was microscopically identified in 16 patients all of them were patients with various autoimmune disorders (cases). The B. hominis was diagnosed in parallel with microsporidia in 7 cases and as a sole parasitic infection in 9 cases. Giardia lamblia was the second in the raw, diagnosed in conjunction with microsporidia in 4 cases and alone in 5 cases. Finally, Entamoeba histolytica was identified in 6 cases, half of them were found also positives for microsporidia infections. Overall, there was significant presence of other intestinal parasites in cases have microsporidia infection (P < 0.05).
Table 7: Intestinal parasites other than Microsporidia that were identified in cases (G1)

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 ~ Discussion Top


The treatment options for autoimmune disorders have been substantially improved in recent years, thanks to the introduction of TNF-α antagonists. The anti-TNF-α drugs have been used to induce or maintain a remission, to reduce the frequency of flare or relapse and to ensure disease control. In general, these therapies appear to be acceptably well tolerated, but taking into account the increased risk of infection, the situation is less optimistic, probably due to the inhibition of this crucial molecule, which plays a key role in the early phase of host defence against bacterial, viral and parasitic infections.[27] In fact, patients with autoimmune disorders, particularly those given TNF-α antagonists therapy have been reported to be at high risk for general infections[28] including intestinal pathogenic parasite infestations such as Strongyloides stercoralis.[29] Nevertheless, there is no sufficient data on the risk of microsporidia infection in these patients, to our knowledge.

Our study is the first to identify a high frequency of Microsporidia infections associated with diarrhea in autoimmune disease Saudi patients, particularly those undergoing anti-TNF-α therapies, in agreement with Didier et al.,[6] Askari et al.[30] and Angela and Suresh.[31] In these earlier studies, the Microsporidia infection was identified in 31.3% of cancer-positive patients, and in only 3.4% healthy cases and the difference between the two groups was significant. Unlike our result, a study done by Hamamcı et al.[32] reported that ~ 70% of cancer patients had microsporidia infection. This controversy may be related to the disparity among studies regarding the study population and the geographical area and/or the techniques used for microsporidia detections. Furthermore, in our study, there was a significant increase in microsporidia infection in cases, especially those under the treatment with biological drugs in comparison to the controls and to those not given biological drugs for the treatment. Moreover, there was non-significant rise in the prevalence of microsporidia infection in cases not given biological drugs in comparison to controls. One study reported that intestinal microsporidiosis is common in patients undergoing concomitant TNF-α antagonists/disease-modifying anti-rheumatic drug therapy. The most likely reason for this outcome was that host defences were compromised due to the combination of underlying disease and immunosuppressive therapy.[33]

In addition, in our study, we reported that the prevalence of microsporidia infection in patients treated with TNF-α antagonists was affected by the duration of treatment. The risk of infection increased in cases with TNF-α antagonist for more than 2 months. A Japanese study, aimed at investigating associations between continuous treatment of TNF-α antagonists and risk of developing serious infections over 3 years, reported that continuous anti-TNF-α therapy was significantly associated with increased risk of developing infection during but not after the first year.[34]

The current research study design has several advantages, including the inclusion of patients with well-established autoimmune disease criteria based on clinical as well as laboratory findings.[35] In addition, the acid-fast stain along with the PCR-based diagnostic methodology used in our study to increase the sensitivity of faecal detection.[9] Various methods are used in the detection of microsporidia. Among these methods, molecular diagnostics offer an effective and accurate diagnosis of microsporidia, as immunocompromised patients need an accurate diagnosis of opportunistic diseases in order to avoid serious problems they cause and to avoid interference with the disease control process.[36],[37],[38] In addition, external factors, such as socio-economic conditions for patients, may influence the prevalence of infections.[39] This potential bias has been given cause for concern in the current study and has been significantly reduced by matching our cases with a control group with the same socio-financial distribution.

In addition, our study was not free of limitations. One of these limitations was the relatively small number of patients in the control group compared to our cases. This can be attributed to the relatively short duration of the analysis. For the same reason, and due to lack of money, we could not genotype microsporidia-positive cases to identify and correlate the exact species with the other findings of the study. microsporidia affects a wide variety of hosts. Human hosts are prone to a global distribution of microsporidia infection.[40] Seven genera are considered to be pathogenic in humans: Encephalitozoon, Enterocytozoon, Nosema, Pleistophora, Vittaforma, Trachypleistophora and Microsporidium, the later incorporating all the species with undetermined status. Most of these genera are considered to be opportunistic pathogens in immunocompromised patients.[41]


 ~ Conclusion Top


There was a significant increase in microsporidia infection in patients with autoimmune disease undergoing treatment with TNF-α antagonists, and duration of treatment is one of the risk factors. The study highlights the importance of microsporidia testing in immunocompromised patients, particularly those undergoing treatment with anti-TNF-α drugs and emphasises the need for awareness among clinicians regarding this opportunistic parasite.

Acknowledgements

The authors would like to thank King Abdulaziz Specialized Hospital nurses, technicians, and physicians for their assistance and encouragement while collecting data and clinical samples from the patients. This study is part of an award-winning large-scale research project financed by Taif University Researchers Supporting Project Number (TURSP-2020/117).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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2004 - Indian Journal of Medical Microbiology
Published by Wolters Kluwer - Medknow

Online since April 2001, new site since 1st August '04