Donor: How Do You Select and Screen Candidate Donors for Fecal Microbiota Transplantation?

How Do You Select and Screen Candidate Donors for Fecal Microbiota Transplantation?

Shrish Budree, MBChB, DCH, FCPaeds, Cert. Paeds Gastro.

The selection and screening of a donor is one of the most important steps to ensure that fecal microbiota transplantation (FMT) is as safe as possible. Broadly, there are 2 general approaches to identifying an appropriate donor: patient-selected and universal. Donor screening is one of the more challenging aspects of the FMT process, both clinically and logistically.¹ In this chapter we will review the best available evidence with regard to how to select stool donors as well as appropriate screening procedures.

Patient-Selected Donors

In the patient-selected donor model, the donor is known to the patient and may be a close relative, spouse, or friend. The candidate donor is identified by the patient, and the treating physician will be required to screen the donor and collect and process their material before performing the FMT procedure. Should the candidate donor not pass the screening tests, another donor will need to be sought, which may be time-consuming. Historically, this model was the most common approach for FMT donor section, and it is still used by some centers today.2,3

The advantages of patient-selected donors include a higher likelihood of the donor sharing a similar microbiome profile as the recipient; reduced risk of exposure to allergy-triggering antigens in the stool of donors who are from the same household, often perceived as more acceptable by patients when they know the person who donated the material; and less risk of a donor-related adverse event affecting multiple recipients (Practical Pearl 6-1).⁴ However, there are a number of limitations with the patient-selected model, including ethical concerns about coercion and lack of voluntary admission of engagement in risky behavior associated with infectious diseases; the high costs associated with screening donors, which may not be covered by the patient’s medical insurance and may lead to physicians performing fewer screening tests; more physician-related barriers, such as the processing of donor material; and the delay in obtaining material for treatment.¹

Universal Donors

Following expansion of knowledge in the FMT field showing similar efficacy for fresh vs frozen material in recurrent Clostridioides difficile infection (CDI) and the growth of the stool bank model, most centers in the United States and Europe now use universal stool donor material to treat their patients. In the universal donor model, the stool donor is not known to the patient, similar to a blood bank. Donors are sourced and thoroughly screened by the stool bank (Figure 6-1). Once donors have successfully passed the screening process, they donate material regularly and the material is processed and stored in -80º C freezers until requested by the physician. Upon request, the material can be shipped under temperature control to the treating center (Practical Pearl 6-2).

The advantages of the universal stool donor model include more rapid access to material to treat the patient, particularly for severe and fulminant CDI; thoroughly screened donors; lower overall system costs; centralized quality control and safety monitoring of the FMT material; and fewer barriers for physicians and patients to access safe material for treatment. One limitation with this model includes the risk of affecting multiple recipients if there is a donor-related adverse event (eg, the donor is found to be colonized by a pathogenic organism).

Practical Pearl 6-1

Are There Scenarios Where Patient-Selected Stool Donation Would Be Preferred?

There are several scenarios where you and the patient may feel more comfortable using a patient-directed stool donor as opposed to a universal donor. These include the following:

Severe food-related allergy/anaphylaxis: If the patient has anaphylactoid allergies to any food substance, first confirm this allergy with an allergist if there is any clinical uncertainty. If medically confirmed, consider using a patient-selected donor and advise the donor to avoid that allergen. General guidance is avoidance for at least 1 week; however, there are no data to guide the ideal time.
Cytomegalovirus (CMV)– and Epstein-Barr virus (EBV)–negative immunocompromised: If a patient is immunocompromised and has never been exposed to CMV or EBV (ie, serum immunoglobulin G [IgG] levels are negative for CMV or EBV), you may want to consider using a donor that has also never been exposed to CMV or EBV. Epidemiology data suggest the majority of donors have a history of EBV and CMV exposure; therefore, it is not part of routine donor screening, and there would be a theoretical risk of CMV- or EBV-associated infection in a vulnerable patient.
Pregnancy: FMT in a pregnancy should be avoided if possible; however, if strongly indicated, using the pregnant patient’s partner as the donor is the recommended approach.

Donor Consent

Stool donation must be voluntary. Donors should be informed about the risks and benefits of becoming a stool donor and provide written informed consent. Prior to signing the consent form, donors should be made aware of the detailed screening process and the possibility of incidental findings, and measures should be taken to ensure donor confidentiality. Candidate donors will need to be consented for screening and commit to providing truthful answers to medical questionnaires. In addition, the consent should include specific sections on material storage for future safety testing and sequencing analysis.

Figure 6-1. Donor screening for fecal microbiota transplantation and qualification rate of candidate donors. (Adapted from Kassam et al.5)

Practical Pearl 6-2

What Are the Differences Between the Universal Donor and the Patient-Selected Models?

Universal

Patient-Selected

Safety

Standardized, comprehensive screening.
Accounts for seroconversion delay.
Centralized adverse events reporting and auditing.
Possible risk of donor transmitting disease to many patients.

Safety

Screening variability between providers.
Potentially less comprehensive screening.
Voluntary adverse events reporting.
Risk of donor transmitting disease is contained to a small patient population.

Access

No physician time or expertise required to locate and screen qualified donors.
No time or expertise needed for material preparation.
For all universal donation, no delay in patient care.
Enables broad patient access.

Access

Physician needs time and expertise to locate and screen qualified donors.
Time and expertise needed for material preparation.
Potential delay in patient care.
Likely limited to academic centers where comprehensive screening can be performed.

Cost

Lower overall cost to the system.
Predictable costs to obtain donor material.

Cost

Higher overall cost to the system (1 donor per patient).
Unpredictable costs to obtain donor material.

*Universal donor associated with stool bank.

Adapted from Edelstein et al.6

Donor Screening

Medical History Screening

Candidate donors should undergo detailed medical history, infectious disease risk assessment, and clinical evaluation for possible microbiome-mediated diseases. It should be noted that, similar to blood banking, there is limited direct evidence on the need to screen for these specific types of conditions; however, the recommendations that follow are current best practice based on expert opinion and guideline statements. Donors should be healthy without gastrointestinal (GI) disease and on no antibiotics in the 3 months prior to donation.7,8 Clinical questionnaires are usually based on blood bank or organ transplant questionnaires and are aimed at assessing infectious disease risk in candidate donors. Questions should focus on travel history to countries with endemic diseases, use of illicit drugs, and high-risk sexual behavior. In addition, the clinical assessment should be directed at determining the presence of known microbiome-mediated disease. There are currently several diseases that have been associated with the microbiome. Although the directionality of causation remains to be fully understood, there are data to suggest associations with autoimmune disease, atopy, inflammatory bowel disease (IBD), colorectal cancer, chronic pain syndromes (eg, fibromyalgia, chronic fatigue), neurologic or neurodevelopmental disorders, certain neuropsychiatric conditions, metabolic syndrome, and obesity.^9,10 Personal history of such diseases should exclude candidate donors. The donor clinical assessment should include weight, height, abdominal circumference, body mass index (BMI), and general systems assessment. Donor age is an important consideration with most centers, with ages ranging from 18 to 50 years, because the microbiome is most stable during this time of life.^11,12 A framework for a candidate clinical questionnaire is provided in Table 6-1.

Stool and Serological Testing

Candidate donors who pass the initial clinical assessment screen should undergo serological and stool testing, predominantly aimed at excluding transmissible infectious diseases (Table 6-2).

Baseline Metabolic Tests

Some centers recommend performing baseline hematology, electrolyte, renal function, liver function, and inflammatory marker tests on donors (see Table 6-2). Clinically significant abnormalities in these baseline tests may excluded candidate donors depending on the underlying etiology of the test abnormality. The significance of raised nonspecific inflammatory markers such as C-reactive protein and fecal calprotectin in an asymptomatic healthy individual is unknown, so the utility of this test remains questionable.

Infectious Disease Panel

Recommendations for testing vary slightly from one guideline to another based on local disease prevalence; however, there are certain mandatory tests that must be performed in all donors that are consistent across guidelines. These include testing for HIV, hepatitis A, hepatitis B, hepatitis C, syphilis, and Strongyloides. Mandatory stool testing includes screening for antibiotic-resistant bacteria (ARB; vancomycin-resistant Enterococcus [VRE], extended-spectrum beta-lactamase [ESBL]–producing organisms, carbapenem-resistant Enterobacteriaceae [CRE], and methicillin-resistant Staphylococcus aureus [MRSA; nasal swab permissible]), common enteric pathogens, C. difficile, Giardia lamblia, Cryptosporidium, Isospora, and Microsporidia and examination for ova and parasites.^3,9–11 Tests that vary across guidelines include testing donor stool for viruses (adenovirus, norovirus, rotavirus). Helicobacter pylori fecal antigen has been recommended for upper route delivery.⁸

In June 2019, the US Food and Drug Administration (FDA) released a safety alert after an FMT-related death of an immunocompromised patient from ESBL bacteremia from a hospital FMT program that did not appropriately screen donors.¹³ The FDA guidance following this unfortunate event advises that all donors be screened for increased risk of ARB colonization such as health care workers, extended hospital admissions, persons residing in long-term care facilities, persons who frequently attend outpatient units, and those who engage in medical tourism. In addition, all donor stool must be tested for ARBs such as VRE, ESBL, CRE, and MRSA (nasal/peri-rectal swab permissible).

Recommendations for testing for CMV and EBV in donors vary. A large proportion of the healthy adults are exposed to these viruses with positive serology (IgG), and this could lead to the inappropriate exclusion of healthy donors.^9,10 To date, there are no documented cases of CMV/EBV transmission related to FMT. Therefore, donors should not be excluded if they are CMV/EBV exposed (ie, IgG positive). Special consideration should be given to immunocompromised populations at risk of CMV/EBV disease who are receiving an FMT. These recipients should be tested to determine whether they are seronegative, and, if so, a seronegative donor should be sought or the recipient should be thoroughly counseled about the risk of CMV/EBV-associated transmission through FMT.

Table 6-1. Clinical Assessment for Donor Screening

Clinical Screening Criteria
Medical History of, or Risk Factors for, Infectious Diseases	History of HIV, hepatitis B or C viruses, syphilis, human T-lymphotropic virus I and II Current systemic infection Use of illegal drugs High-risk sexual behavior Previous tissue/organ transplant Recent hospitalization or discharge from long-term care facilities High-risk travel/engaged in medical tourism Recent (≤ 6 months) needle stick accident Recent (≤ 6 months) body tattoo, piercing, acupuncture Recent (≤ 2 months) enteric pathogen infection Recent (≤ 2 months) acute gastroenteritis with or without confirmatory test History of receiving growth hormone, insulin from cows, or clotting factor concentrates Recent (≤ 2 months) history of vaccination with a live attenuated virus, if there is a possible risk of transmission Demographics That Impact the Microbiome Age 18 to 50 years Employment Health care worker with patient exposure or other risk factors for colonization by multi-drug resistant organisms
Clinical Screening Criteria
Disorders Potentially Associated With Perturbation of the Gut Microbiota	Personal history of chronic GI disease, including functional GI disorders, IBD, celiac disease, other chronic gastroenterological diseases Personal history of systemic autoimmune disorders Personal history of cancer, including GI cancers or polyposis syndrome Recent abnormal GI symptoms (eg, diarrhea, hematochezia) Personal history of neurological/neurodegenerative disorders Personal history of psychiatric/neurodevelopmental conditions Obesity (BMI > 30 kg/m²) and/or metabolic syndrome/diabetes First-degree family history of premature colon cancer or first-degree family history of early-onset polyposis syndrome
Drugs That Can Alter Gut Microbiota	Recent (≤ 3 months) exposure to systemic antimicrobial drugs, immunosuppressant agents, chemotherapy Chronic treatment (≥ 3 months) with daily use of proton pump inhibitors Adapted from Cammarota et al.¹⁰