
==== Front
Curr Opin Crit Care
Curr Opin Crit Care
COCCA
Current Opinion in Critical Care
1070-5295
1531-7072
Lippincott Williams & Wilkins Hagerstown, MD

39034915
MCC300514
10.1097/MCC.0000000000001191
00010
3
SEVERE INFECTIONS: Edited by Andre C. Kalil
Acute diarrhea in the hospitalized immunocompromised patient: what is new on diagnostic and treatment?
Castillo Almeida Natalia E.
Gomez Carlos A.
Department of Internal Medicine, Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA
Correspondence to Natalia E. Castillo Almeida, MD, Assistant Professor, Department of Internal Medicine, Division of Infectious Diseases, University of Nebraska Medical Center, 988106 Nebraska Medical Center, Omaha, NE 68198-8106, USA. E-mail: ncastilloalmeida@unmc.edu
10 2024
19 7 2024
30 5 456462
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

Purpose of review

This article aims to provide an intuitive framework for diagnosing and managing healthcare-associated diarrhea (HCAD) in the immunocompromised (IC) host.

Recent findings

Our understanding of diarrhea in hospitalized IC patients has significantly evolved. However, the challenge lies in distinguishing between these patients’ numerous causes of diarrhea. The incorporation of gastrointestinal (GI) multiplex polymerase chain reaction (PCR) panels has led to a paradigm shift in our approach to diarrhea. However, using these panels judiciously is of utmost importance, as their misuse can lead to over-testing, overtreatment, and increased hospital costs. We propose a stepwise diagnostic algorithm that ensures diagnostic stewardship, optimal patient care, and resource utilization.

Summary

Diarrhea is a common complication in hospitalized IC patients and is associated with significant morbidity and rare mortality. The advent of new diagnostics, such as GI multiplex PCR panels, holds promise in facilitating the detection of recognized pathogens and may allow for improved outcomes using pathogen-targeted therapy.

Keywords

Clostridioides difficile
cytomegalovirus
diarrhea
gastrointestinal panel
syndromic testing
OPEN-ACCESSTRUE
==== Body
pmcINTRODUCTION

Acute diarrhea in hospitalized patients who are immunocompromised (IC) presents a significant clinical challenge due to their increased susceptibility to various infectious agents and the potential for severe complications. For this review, we refer to IC patients to those with predisposing conditions such as solid organ transplant (SOT), hematopoietic stem cell transplant (HSCT), and patients with hematological malignancy, including those receiving chimeric antigen receptor (CAR)-T cell therapies. The approach to diarrhea in patients with HIV/AIDS is reviewed elsewhere [1].

The etiology of diarrhea in IC patients is often multifactorial, primarily involving viral and bacterial agents and, less frequently, parasitic and fungal pathogens. Noninfectious causes of diarrhea are more frequent than infectious causes in hospitalized IC patients [2]. Indeed, common culprits are medications such as antimicrobials, chemotherapy agents, immunosuppressive agents, nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors, laxatives, and metformin [3]. In HSCT patients, graft-vs.-host disease (GVHD) is a significant noninfectious cause, and radiation enteritis following abdominal or pelvic radiation therapy further adds to the complexity of managing diarrhea in hospitalized HSCT patients. Other noninfectious conditions responsible for diarrhea in HSCT and hematological patients include mucositis, neutropenic enterocolitis, ischemic colitis, engraftment syndrome, gut microbiota dysbiosis, bacterial overgrowth, transplant-associated microangiopathy and immunotherapy-induced colitis [4]. Each condition requires specific diagnostic and therapeutic approaches tailored to the underlying cause.

Diarrhea is typically defined as three or more loose or watery stools in 24 h in the absence of laxative use. Depending on the duration of symptoms, diarrhea can be categorized as acute (<14 days), persistent (14–30 days), or chronic (>30 days)[2]. In hospitalized IC hosts, acute diarrhea can range from a self-limited presentation with minor disruption of the quality of life to severe and life-threatening.

Diagnosing acute diarrhea in hospitalized patients is complicated by the need to differentiate infectious causes from noninfectious etiologies [5]. Recent advancements in diagnostic tools have focused on developing and implementing multiplex polymerase chain reaction (PCR) assays, also known as syndromic or multiplex gastrointestinal panels (GIPs) [6,7]. These panels allow for the rapid and sensitive detection of a wide range of pathogens in a single assay, significantly enhancing the diagnostic yield compared to traditional methods [8]. However, there are limitations to these assays, such as the potential for detecting harmless pathogens and the inability to determine antimicrobial susceptibilities [9]. Despite these challenges, multiplex PCR has the potential to significantly improve the diagnosis and management of diarrhea in hospitalized patients, particularly those who are IC. This review aims to discuss the current epidemiology of acute diarrhea in the hospital setting, propose a diagnostic algorithm that includes syndrome multiplex GIPs, and highlight the management of diarrhea in this population and areas for further research. 

Box 1 no caption available

EPIDEMIOLOGY OF DIARRHEA IN THE HOSPITALIZED IMMUNOCOMPROMISED HOST

Solid organ transplant

Diarrhea is a common condition among SOT patients, with a wide range of causes. The main infectious culprits include Clostridioides difficile infection (CDI), cytomegalovirus (CMV), and norovirus. The prevalence of diarrhea in SOT recipients is high, ranging from 20% to 50%, and it can lead to significant complications such as dehydration, medication toxicity, and potential organ rejection [10–12]. In a retrospective analysis of hospitalized SOT recipients over 18 months, out of 112 patients with hospital-onset diarrhea, most episodes had no identified cause and resolved on their own. The most frequently reported cause was CDI (11.8%), followed by norovirus (3%), CMV (2.7%), with protozoan causes being rare. Coinfections were infrequent, occurring in a small percentage of hospital-onset cases [13].

Noninfectious causes such as medication-induced diarrhea, especially immunosuppressants like mycophenolate and tacrolimus, are also significant culprits. Studies show that female gender and the use of tacrolimus, either alone or in combination with mycophenolate, are major risk factors for developing diarrhea [14]. Despite a thorough evaluation, many diarrheal episodes in SOT recipients often remain without an identifiable cause [15].

Hematopoietic stem cell transplant and hematological patients

The epidemiology of diarrhea in HSCT patients is complex and varies depending on the stage posttransplant. During the early period posttransplant (<30 days or preengraftment period), noninfectious diarrhea caused by mucosal injury from conditioning regimens and cytotoxic medications is common. CDI and neutropenic enterocolitis are the most common infectious causes [16]. In the peri-transplant period, CDI is the predominant cause, with 95% of cases occurring within the first 6 months posttransplant [17]. It is important to note that CDI poses a nine-fold higher risk in HSCT patients compared to the general population, with an incidence ranging between 6% and 9% [18]. Later in the postengraftment period (from 1 month to 1 year posttransplant), GVHD and viral enteritis agents such as CMV, adenovirus, and norovirus become leading causes. Distinguishing GVHD from viral enteritis requires histopathological evaluation with immunohistochemistry stains [19]. In the late posttransplant period (more than one year posttransplant), recurrent CDI, late-onset CMV, and foodborne bacterial infections such as Salmonellosis and Campylobacter are common, alongside parasitic infections like strongyloidiasis and giardiasis in endemic areas.

Advanced molecular testing has revolutionized our understanding of the epidemiology of infectious diarrhea in HSCT patients, shedding light on a higher incidence of pathogens such as Campylobacter spp., sapovirus, adenovirus, and various diarrheagenic Escherichia coli strains [20,21▪]. Emerging pathogens such as sapoviruses, astroviruses, and diarrheagenic E. coli (e.g., enteroaggregative E. coli [EAEC], enteropathogenic E. coli [EPEC], and enterotoxigenic E. coli [ETEC]) are also gaining recognition [22].

DIAGNOSTIC APPROACH FOR ACUTE DIARRHEA IN THE HOSPITALIZED IMMUNOCOMPROMISED HOST

Diarrhea in hospitalized patients with immunocompromised conditions differs from diarrhea in the community. Community-onset diarrhea is often longer, more severe, and unlikely to develop after 72 h of hospitalization [5]. Hospital-associated diarrhea occurs in a hospitalized patient after at least 72 h of hospitalization or up to 3 days after discharge [5]. When clinicians in the hospital setting care for IC adults with diarrhea, three important decision points include whether the patient has diarrhea, when to perform stool testing, and how to determine asymptomatic carriage [23]. Thus, we proposed the following stepwise approach to aid in the systematic diagnostic approach of this common syndrome (Fig. 1).

FIGURE 1 Systematic diagnostic approach of diarrhea in the hospitalized immunocompromised host.

The first step in evaluation is to clearly define diarrhea and eliminate other conditions that can be mistaken for diarrhea. Fecal incontinence is often confused with diarrhea, but it is primarily caused by dysfunction of the anal sphincter, not by irregular absorption of intestinal fluid or electrolytes [24]. Another condition that can be mislabeled as diarrhea is fecal impaction caused by overflow diarrhea resulting from liquid stool passing around the impaction [25,26]. Once diarrhea has been confirmed, the range of potential causes in hospitalized patients with immunocompromised conditions is broad and includes infectious and noninfectious causes.

Noninfectious causes of diarrhea are ubiquitous among hospitalized patients [2]. A prevalent and identifiable cause of diarrhea is medication-induced diarrhea [27]. The most frequently involved medications are antimicrobials, laxatives, magnesium-containing antacids, lactose – or sorbitol-containing products, NSAIDs, enteral feeding, anticancer therapies (e.g., checkpoint inhibitors), and immunosuppressive agents [3,28–32]. These agents may incite intestinal inflammation and cause intestinal or colonic crypt damage, resulting in apoptotic colopathy [33].

After thoroughly reviewing the patient's medication list, an FDA-cleared GIP should be considered in the first two days due to its increased diagnostic performance, with sensitivity and specificity generally above 95% [34]. After 72 h, a GIP harbors limited utility, hinders additional laboratory testing costs, and increases the likelihood of false positivity due to chronic or residual shedding [7]. However, a lower threshold for testing in IC patients may be justified in selected cases with relevant epidemiological and immunological risk factors suggesting a specific pathogen. There may also be important infection control implications for some inpatients utilizing gastrointestinal (GI) panel testing. For example, the use of GIP testing has been shown to be cost-effective due to a significant reduction in isolation days for patients with noninfectious causes of diarrhea [35].

While syndromic testing like GIP has improved diagnostic accuracy, this approach still faces issues such as distinguishing between active infection and asymptomatic shedding [36]. Careful consideration must be given to the use of GIP in IC patients due to their limitations, including the potential detection of clinical false-positives (including C. difficile), imperfect inclusivity (GIP gaps or holes), and risk for analytical false-positives from infrequent targets [37]. The use of GIP in hospitalized IC patients should be integrated with the clinical context, patient history, and a thorough understanding of the patient's immune status to address potential challenges.

Among infectious causes, CDI is the leading cause of infectious diarrhea in hospitalized HSCT and SOT recipients [13,21▪,38]. C. difficile is included in many FDA-cleared GIPs, which cannot differentiate between colonization and true infection, making it challenging for clinical decision-making [39]. The carriage rates of toxigenic C. difficile strains are similar between outpatient populations and hospitalized ones (6.6 vs. 8%) [40,41]. Thus, exclusive molecular testing for CDI diagnosis without tests for toxins or host response is likely to result in overdiagnosis, overtreatment, and increased healthcare costs without outcome benefits. A prospective, observational cohort study of 1416 hospitalized patients tested for CDI 72 h or longer after admission showed comparable outcomes in those with negative toxin EIA but positive PCR and those without C. difficile by either method. Therefore, a specific C. difficile testing algorithm [e.g., antigen, toxin A/B EIA, or nucleic acid amplification test (NAT)] is recommended. Multistep algorithms not only provide better diagnostic performance but are also the most cost-effective [42].

After excluding CDI, viral etiologies not included in the GIP should be considered. CMV is a widespread herpes virus. It can range from asymptomatic to mild when controlled by a robust immune system. However, if the immune system is compromised, CMV can replicate at high levels, leading to severe end-organ disease. Various studies have shown that a high CMV DNA load in the blood compartment is among the most significant risk factors for disseminating to multiple organs [43,44]. Viremia remains a reliable biomarker for viral replication, and quantitative PCR assay is the preferred method of detecting the virus [45]. A negative PCR does not rule out the possibility of localized CMV end-organ disease. Studies have shown that CMV disease is compartmentalized in organs such as the lungs and the gastrointestinal tract, resulting in low or undetectable levels of CMV in the blood [46,47]. This concept of low or absent CMV PCR levels with concurrent CMV colitis poses a massive challenge in diagnosing and treating CMV disease. Thus, in IC patients with diarrhea, clinicians should investigate organ-specific involvement regardless of CMV PCR levels in the blood [48].

CMV reactivation was initially observed in transplant patients but has also been reported in individuals receiving biological therapies and nonimmunocompromised critically ill patients who are CMV-seropositive, often leading to poor outcomes [49,50]. However, additional research is needed to identify patient groups at higher risk of developing CMV infection [51]. To diagnose CMV gastrointestinal disease, a colonoscopy with biopsy for histological analysis is generally required. Biopsy samples are typically stained for CMV using immunohistochemical stains to confirm the presence of replicating virus in the tissue and help diagnose other potential causes, such as host-specific conditions like graft-vs.-host disease in HSCT. In cases with a high likelihood of CMV colitis, patients may be treated presumptively for end-organ disease to avoid invasive testing [52].

If diarrhea persists without a diagnosis despite previous interventions, other fecal testing modalities such as ova and parasite microscopy, and special stains such as modified acid-fast staining (Mycobacterium avium complex, Cryptosporidium spp.), trichome (Giardia and Entamoeba), modified Kinyoun (Cryptosporidium spp.), periodic acid-Schiff (PAS) stain (Candida spp. and Tropheryma whipplei) should be considered based on clinical context [4]. Additionally, infectious diseases consultation is recommended.

Chronic conditions such as pancreatic insufficiency, lactose intolerance, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac disease, microscopic colitis, irritable bowel syndrome, and small intestinal bacterial overgrowth may rarely contribute to diarrhea in the hospital setting [5,53].

TREATMENT

When treating diarrhea, the primary approach involves replacing fluids and replenishing electrolytes as necessary [2]. For individuals who are critically ill or immunocompromised, a more aggressive treatment approach may be essential. In some instances, immediate treatment is warranted due to the severity of the illness, the patient's condition, and the clinical syndrome. For example, a hospitalized patient with recent antibiotic use, acute onset of diarrhea, septic shock, and ileus may require immediate treatment for CDI along with a surgical consultation [54]. It is crucial to evaluate the situation thoroughly. If a drug is judged to be contributing to diarrhea, the initial approach involves making changes, discontinuing the offending drug (if considered safe), or treating the condition on a case-by-case basis. When a causative pathogen is identified, targeted treatment is typically recommended to expedite recovery and prevent further recurrences (Table 1).

Table 1 Practical reference for the treatment of diarrhea in the hospitalized immunocompromised host

Culprit	Treatment	Comments	
Medication-induced diarrhea			
 Laxatives, NSAIDs, antimicrobials, and proton pump inhibitors.	Modify, discontinue the offending drug (if considered safe)	For SOT and HSCT patients, weigh risks and benefits of reducing or stopping IS	
 Chemotherapy related diarrhea	Conservatively management (e.g., intravenous fluids, AAs, octreotide)	If neutropenic induced colitis AND no evidence of CDI recommend antibiotic therapy
Consider surgical consultation in severe cases.	
 Checkpoint inhibitors	Steroids		
GVHD	Systemic and/or oral nonabsorbable corticosteroids	Following HSCT, patients should receive GVHD prophylaxis	
Infectious			
 CDI	Based on clinical severity (i.v. metronidazole + oral vancomycin [severe/ileus], oral vancomycin or fidaxomicin)	Consider bezlotoxumab (a monoclonal antibody that binds to toxin B) for CDI prevention.	
 Norovirus	Supportive therapy and reduction of IS	Limited role of nitazoxanide	
 CMV	Antiviral (e.g., valganciclovir, ganciclovir, maribavir) or investigational (CMV-specific T-cell therapies)	Following HSCT or SOT, patients receive preemptive or universal CMV prophylaxis pending on CMV risk.	
 Adenovirus	Decrease IS ± cidofovir	Other investigational agents only available in clinical trials (e.g., brincidofovir)	
AA, antimotility agent; CDI, Clostridioides difficile infection; CMV, cytomegalovirus; GVHD, graft-vs.-host disease; HSCT, hematopoietic stem cell transplant; SOT, solid organ transplant.

The use of antimotility agents (AAs) to reduce the number of diarrhea days and diarrhea-related complications has been reported as a beneficial adjunctive therapy. In patients with active CDI, AAs have traditionally been avoided due to the fear of gastrointestinal complications. However, loperamide may be safe as an adjunct to specific antibacterial therapy for CDI [54]. In an observational retrospective study of 339 patients, adding AAs to appropriate antimicrobial treatment for patients with hematologic malignancies and CDI posed no additional risk [55]. Prospective and randomized studies are needed to elucidate the role of AAs in infectious diarrhea. Guidelines are available for the management of chemotherapy-induced diarrhea, and empiric treatment with oral corticosteroids may be warranted in immune checkpoint inhibitor-mediated diarrhea [30,56,57].

Several probiotics have shown promise in the prevention and treatment of diarrhea, mainly in CDI. However, none has demonstrated significant and reproducible efficacy in controlled clinical trials. Moreover, in IC, caution should be used with probiotics as there is an increased risk of gut translocation and rare cases of bacteremia [58]. In a matched case-control study, single-center, a total of 112 patients (28 cases and 84 controls) were included, and significantly higher odds of probiotic use among those patients with invasive infections compared to those without invasive infections [59]. Data suggest that using probiotics and prebiotics before or on the day of liver transplantation may be effective in reducing infectious complications [60,61]. The efficacy of probiotics has not been proven yet in other organs and bone marrow transplant recipients, given a theoretical safety concern [62]. Further research is needed to elucidate the role of probiotics in different IC populations and critically ill patients.

CONCLUSION

Acute diarrhea in hospitalized IC patients requires a multifaceted diagnostic and therapeutic approach due to the diverse etiologies involved. The advent of multiplex PCR assays represents a significant advancement, offering faster and more sensitive diagnostics. Despite their limitations, these tools improve clinical outcomes through precise and timely treatment. Management strategies should include rehydration, nutritional support, discontinuing offending agents when clinically feasible, and targeted antimicrobial therapy based on pathogen identification. Further research is needed to refine diagnostic algorithms, evaluate the cost-effectiveness of newer diagnostic methods, and address their limitations.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest
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