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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 16  |  Issue : 5  |  Page : 23-33

Diarrhea in solid organ transplant recipients in the South Asian Region - Expert group opinion for diagnosis and management


1 Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
2 Institute of Infectious Diseases, Apollo Hospital, Chennai, Tamil Nadu, India
3 Department of Nephrology and Renal Transplantation, Sanjay Gandhi Postgraduate Institute Medical Sciences, Lucknow, Uttar Pradesh, India
4 Department of Nephrology and Renal Transplant Medicine, Medanta Kidney and Urology Institute, Medanta Medicity, Gurugram, Haryana, India

Date of Submission31-Aug-2021
Date of Acceptance14-Feb-2022
Date of Web Publication18-Oct-2022

Correspondence Address:
Dr. Govind K Makharia
Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_79_21

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  Abstract 


Diarrhea after solid organ transplantation is a common problem. Posttransplant diarrhea can lead to dehydration, weight loss, graft dysfunction, frequent hospitalization and increased mortality. Posttransplant diarrhea is seen in 20%–25% of patients within 2 years of transplantation and it can be both due to infections and the drugs. The most common cause of drug causing diarrhea is mycophenolate mofetil, and tacrolimus. The common infective causes of diarrhea in posttransplant recipients include viral infections (norovirus, sapovirus, cytomegalovirus [CMV]), bacterial infections (Salmonella, Clostridium difficile, Aeromonas, Campylobactor, Enterotoxigenic, and Enterohemorrhagic Escherichia coli) and parasitic infections (Cryptosporidium, Giardia lamblia, Microsporidia Cyclospora, Strongyloidiasis etc.). Because of overall poor hygienic conditions, infective diarrhea is common in South Asian region. Since most cases of acute diarrhea are infective, and many with viral etiologies, conservative management using oral rehydration solution, antidiarrheal drugs, and where appropriate, a short course of antibiotics helps in the resolution of most cases. A detailed evaluation should be performed in patients with chronic diarrhea, recurrent diarrhea, and those with graft dysfunction. The evaluation of diarrhea should include stool microscopy for ova and cysts, special stains for opportunistic parasitic infection, and molecular diagnostic tools like multiplex Polymerase chain reaction. Colonoscopic and upper gastrointestinal endoscopic examination with biopsies are required to investigate for CMV infection, malabsorption syndrome, inflammatory bowel diseases and posttransplant lymphoproliferative disorder. Although the causes of diarrhea are numerous, an algorithmic approach should be followed both for the diagnosis and the treatment of diarrhea in an organ transplant recipient.

Keywords: Immunosuppression, infective diarrhea, kidney transplantation, posttransplantationposttransplantation diarrhea


How to cite this article:
Mohta S, Sridharan S, Gopalakrishnan R, Prasad N, Bansal SB, Makharia GK. Diarrhea in solid organ transplant recipients in the South Asian Region - Expert group opinion for diagnosis and management. Indian J Transplant 2022;16, Suppl S1:23-33

How to cite this URL:
Mohta S, Sridharan S, Gopalakrishnan R, Prasad N, Bansal SB, Makharia GK. Diarrhea in solid organ transplant recipients in the South Asian Region - Expert group opinion for diagnosis and management. Indian J Transplant [serial online] 2022 [cited 2022 Dec 2];16, Suppl S1:23-33. Available from: https://www.ijtonline.in/text.asp?2022/16/5/23/358664




  Introduction Top


While diarrhea is a common illness in the general population, it is far more common amongst immunocompromised individuals, including organ transplant recipients.[1],[2],[3] The global data suggests that diarrhea, both acute and chronic, can cause significant morbidity and mortality in high-risk individuals.[1],[2],[3] Prolonged diarrhea in an organ transplant recipient may lead to complications such as weight loss, dehydration, graft dysfunction, and fluctuation in the blood levels of immunosuppressive drug (s). Furthermore, recurrent episodes of diarrhea in transplant recipients can lead to frequent hospitalization, extended hospital stays, and even an increase in mortality.[4],[5],[6]

In this review, we have discussed important aspects of diarrhea in solid organ transplantation (SOT) recipients, specific to South Asia.


  Epidemiology Top


Incidence of diarrhea in organ transplant recipients

There is a lack of uniform definitions of diarrhea and its timelines after transplantation, due to heterogeneity in the published studies regarding the incidence rates, the etiological factors, and the characteristics of diarrhea among the SOT recipients. In one of the largest studies involving 40,000 organ transplant recipients, 22% developed diarrhea with an annual incidence of 11.5% by the end of the 1st year and 17.5% by the end of the 2nd year.[4] In an MITOS study from Spain, which included 1788 organ transplant recipients of whom 1132 had renal transplantations, nearly half reported episodes of diarrhea over a median follow-up period of 5.4 years.[7] Similarly, in other studies in SOT recipients, approximately half of them developed episodes of diarrhea.[8],[9],[10] Overall 20%–25% of solid organ transplant recipients develop diarrhea within the first 2 years after the organ transplantation.[11],[12]

Large scale and well-structured studies addressing the prevalence and incidence of diarrhea in the immunocompromised state are not available from the South-East Asian region, and the data in this region is limited to case series and case reports. Diarrhea is predominantly an infectious disease, and considering the large burden of infectious diseases in South-East Asia along with the wider prevalence of poor general hygiene, high population density, and limited resources, it would not be surprising if the magnitude of infectious diarrhea in solid organ transplant recipients would be higher than in more developed world regions. In addition to the above factors, poor financial status plays a role in high prevalence in transplant recipients who are unable to use sanitizers, clean sanitation facilities, and other personal protection measures.

Temporal relationship between diarrhea and time since transplantation

A consistent temporal relationship has been observed between the type of infections in the organ transplant recipients and the time since transplantation[5],[13] [Table 1]. This is true not only for the gastrointestinal (GI) infections but also for the other infections. The temporal relationship is attributable to the risk of infection with varying level of use of immunosuppressive drugs over time. Approximately 13.5% of organ transplant recipients develop diarrhea within the first month, 23% develop within 1–6 months, and approximately 55% after 6 months.[23] Although there are a lack of data regarding temporal variation in the risk of infection in post organ transplant recipients from the South East Asian region, we believe that the number of infections decreases with the passage of time since transplantation.[4] For example, community-acquired infections as well as transplant specific infections such as cytomegalovirus (CMV) are more common during the first 6 months of transplantation.[33]
Table 1: Causes of infectious diarrhea as per time-period postorgan transplantation

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Table 2: Common parasitic causes of diarrhea and their management in transplant recipients

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Risk factors of diarrhea

GI infections are a common cause of acute or chronic diarrhea in SOT recipients. There are many other non-infectious causes, including immunosuppressive drugs (i.e. mycophenolate mofetil (MMF), or the use of a combination of tacrolimus and MMF), other medications, and the concomitant presence of other immunocompromised states (i.e., diabetes or retroviral illness)[4] [Figure 1]. Although very rare in South-East Asia, serological discordance for CMV (donor positive and recipient negative) is notorious for the higher rate of reactivation of CMV infection in the posttransplant period.[20] The use of broad-spectrum antibiotics for any other infection in transplant recipients also increases the risk of Clostridium difficile infection (CDI).[26]
Figure 1: Risk factors

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  Etiology of Diarrhea in Solid Organ Transplant Recipients Top


The causes of diarrhea in SOT recipients are summarized in [Table 3].[33] The causes of diarrhea vary in different studies because of differences in the prevalence of various infections in different regions and differences in the use of diagnostic tests/algorithms.[18],[28] For this review and summarizing of causes of diarrhea, we have considered a few significant and relevant studies reporting the etiology of diarrhea in the posttransplant setting [Table 4]. In the below section, we have discussed a few important diseases in a detail.
Table 3: Important causes of diarrhea in organ transplant recipients

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Table 4: Outcome of diarrhea in posttransplant recipient patients

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  Infectious Causes Top


Bacterial diarrhea

Few common causes of bacterial diarrhea in a SOT recipient are discussed below:

Clostridium difficile

The single most important risk factor for the development of CDI is antibacterial exposure. Although all antibacterial are associated with CDI, penicillin, cephalosporins, clindamycin, and fluoroquinolones are associated with the highest risk. In a study from the Southern part of India, the risk of CDI was significantly associated with exposure to proton-pump inhibitor (Odds ratio [OR]: 3.52, P = 0.014), immunosuppressants (OR: 3.62, P = 0.013), and increased duration of antibiotics.[35]

Colonic inflammation due to CDI commonly presents as watery diarrhea, low-grade fever, and crampy abdominal pain. The posttransplant recipients are at higher risk of developing severe/fulminant CDI than those with the competent immune system. The incidence rates for CDI in organ transplant recipients vary from <1% to 23%, with the lowest incidence in kidney transplant recipients and the highest incidence in the liver and lung transplant recipients.[36],[37] CDI can be diagnosed using appropriate diagnostic tests including either a two-step including assay for GDH enzyme screen followed by C. difficile toxin assay) or a Polymerase chain reaction (PCR) based C. difficile assay followed by toxin assay.[38]

The treatment of CDI posttransplant recipients is similar to that for non-transplant patients. The first step in the treatment of CDI is stopping of the causative antibiotic. The drug of choice for CDI is oral vancomycin 125 mg four times a day for 10 days. Alternative drugs are fidaxomicin or metronidazole.[39],[40]

For severe and fulminant CDI, higher doses of vancomycin (500 mg orally four times a day) should be used. Bezlotoxumab, a monoclonal antibody which prevents attachment of toxin to the colonic epithelial cells, may also be used in fulminant CDI in posttransplant recipients.[38]

The CDI may recur either because of reinfection or incomplete eradication of C. difficile. In patients having recurrent CDI, faecal microbial transplantation is the treatment of choice.[41] Patients with confirmed CDI and continued diarrhea despite appropriate therapy should be evaluated for other causes of diarrhea, including coinfection with other pathogens.

Campylobacter enteritis

Campylobacter jejuni and Campylobacter coli are the most common species causing enteritis/colitis. Transmitted by oral-fecal route, C. jejuni or C. coli can lead to acute inflammatory enteritis resulting in abdominal pain, fever, watery diarrhea, or even dysentery with blood and pus in the stools. This syndrome has been associated with reactive arthritis and Guillain–Barre syndrome. In general, immunocompromised patients are at risk of severe disease and warrant treatment. Diagnosis can be made by blood/stool culture. Non-culture-based techniques such as nucleic acid amplification tests, including reverse transcription-PCR, are increasingly utilized for the diagnosis.[42]

Most patients with mild-to-moderate C. jejuni enterocolitis do not require treatment however, severely ill patients, especially those who are immunocompromised, appear to benefit from erythromycin or ciprofloxacin. A meta-analysis of 11 small randomized trials reported that antimicrobial therapy reduced the duration of intestinal symptoms by only 1.3 days.[43] Azithromycin is recommended. Azithromycin used as 500 mg once daily for three days or until resolution of symptoms or given as 1 g single dose are equally effective.


  Salmonellosis Top


Salmonella enterocolitis is characterized by fever, cramping abdominal pain, and diarrhea that begins 8 to 48 h after ingestion of an infective dose, usually with food, and it usually lasts up-to 3 to 5 days. While the typhoidal Salmonella species, such as Salmonella typhi or Salmonella paratyphi cause systemic manifestation more often and diarrheal disease less frequently, whereas the diarrhea-causing nontyphoidal Salmonella which is also transmitted via the fecal-oral route from pet animals or humans causes more diarrhea.

Antibiotic selection depends upon the severity of illness, local resistance patterns, whether oral medications are feasible, the clinical setting, and available resources. Uncomplicated enteric fever is usually treated with a single agent, either cotrimoxazole or azithromycin. Fluoroquinolones have been increasingly associated with resistance and hence are not preferred as initial empiric choice. Patients requiring admission may require combination therapy with ceftriaxone and azithromycin.[44] Carbapenems are reserved for resistant strains. Aztreonam has been effective in small trials and can be used for individuals who cannot take cephalosporins because of allergies.


  Aeromonas Top


Aeromonas species have been isolated from various aquatic environments such as freshwater, brackish water, to polluted water. Aeromonas infection can lead to acute diarrhea, traveller's diarrhoea, acute dysentery or even chronic diarrheal disease. Immunocompromised patients, if infected by Aeromonas, are at risk of bacteraemia. Most episodes of Aeromonas-associated diarrhea are self-limiting and can be managed with supportive therapy, including oral and intravenous rehydration. Based on anecdotal data, antibiotics may be of value in patients with severe diarrhea and/in those who are immunocompromised. Pending culture reports, the choice of an initial antibiotics are fluoroquinolone, TMP/SMX, or a third-generation cephalosporin.[45] Treatment should be guided by clinical response ranging from three days for diarrhea to 14 days for bacteraemia.


  Shiga Toxin-producing and Enterohemorrhagic Escherichia coli Top


E. coli contains genes that encode for Shiga toxins 1 and 2. These Shiga toxin-producing E. coli (STEC) affect children more commonly. Infection with such species can lead to painful and bloody diarrhea. These patients can develop the hemolytic uremic syndrome, which is one of the serious complications. Fever is uncommon in these patients. Since these patients are at high risk for developing hemolytic-uremic syndrome (HUS), adequate administration of isotonic saline should be instituted to prevent acute kidney injury. Antibiotics are not recommended in uncomplicated subjects. Antibiotics however can shorten the duration of illness in immunocompromised individuals. In a meta-analysis of mainly observational studies including over 1800 patients with STEC infection, there was a non-significant trend towards a higher risk of HUS with antibiotic use (pooled OR 1.33, 95% confidence interval [CI] 0.89–1.99). However, subgroup analysis of studies with a low risk of bias and those used a stringent definition of HUS, the association between use of antibiotics and occurrence of HUS was stronger (pooled OR 2.24, 95% CI 1.45–3.36).[46]


  Traveller's Diarrhea Top


The incidence of traveler's diarrhea in SOT recipients is approximately 10% to 40% depending on the travel destination. The risk of having diarrhea is highest during the first 7 days of travel and then the risk progressively decreases. The most common causes of traveler's diarrhea include Enterotoxigenic E. coli followed by enteroaggregative E. coli and then Shigella and Salmonella infection. Traveler's diarrhea is characterized by an increase in the frequency of bowel movements and a change in consistency of the stool (soft to liquid) that usually begins within 2 to 3 days of arrival in a new country. Fluids and electrolytes should be replaced aggressively because diarrhea-induced dehydration can result in renal insufficiency and enhance the potential toxicities of anti-rejection medications.

Empiric antibiotic therapy is recommended for SOT recipients having 3 or more stools per day and for all those with bloody stools or systemic illness such as fever. The first empiric drug of choice for traveler's diarrhea is azithromycin as a single dose. While single-dose azithromycin, in comparison to 3 days azithromycin for traveler's diarrhea had better efficacy and had less side effects in general population,[47] in transplant recipients, a 3-day course should be preferred until further evidence is available.


  Viral Infections Top


Cytomegalovirus

CMV infection follows through different phases starting from a latent phase, an asymptomatic phase which lasts for a variable period, and ultimatly symptomatic disease that occur only in a few individuals. The CMV infection most commonly occurs within 30-90 days after SOT and earlier than 30 days in the case of hematopoeitic-stem cell transplantation. In a study from India, CMV colitis was detected in 4% of patients with CMV infection.[48] Transplant recipients, who receive lymphocyte-depleting antibodies and those who are seronegative but receive organs from seropositive donors, are at the highest risk of developing CMV infection. The most frequent GI complications of CMV infection are CMV enteritis and CMV esophagitis. A high index of suspicion is the key to the diagnosis and the clinician should use appropriate tests, including pp65 antigen assay, CMV-PCR quantitative assessment of the viral load, and the histological demonstration of inclusion bodies for diagnosis. The presence of CMV infection, such as a positive CMV-PCR, does not always mean that the colitic illness has been caused by CMV, therefore physicians should take a judicious decision before instituting treatment for CMV-associated disease. A study from India has shown that colonic infiltration with CMV in the absence of CMV viremia can lead to diarrheal infection, as demonstrated by CMV staining in the colonic biopsy.[49] The treatment of invasive CMV disease is intravenous ganciclovir at a dose of 5 mg/kg twice daily for a period of 3 weeks. The CMV PCR should be repeated after 2 weeks of treatment. The treatment phase is followed by prophylaxis with tablet valgnaciclovir 900 mg/day to complete a period of 3 months. The dose of ganciclovir and valacyclovir should be adjusted for GFR.


  Norovirus Top


Norovirus is a single-stranded RNA virus belonging to the Caliciviridae family. It has recently emerged as an important cause of diarrhea amongst immunocompromised individuals and organ-transplant recipients. It may lead to an acute episode of diarrhea, and after an initial resolution of symptoms, diarrhea may persist and convert to chronic diarrhea with continued viral shedding. Many patients might have infection and shedding of the virus, but may remain asymptomatic. With the advent of newer molecular techniques, Norovirus and other viral diseases are now detected more commonly, which might not have been diagnosed earlier. The diagnosis of the infection is made by virus-specific PCR testing of the stool specimen. There is no specific anti-viral drug at this point. The mainstay of treatment of this condition includes symptomatic treatment with reduction in the doses of immunosuppressive drugs. Drugs such as ribavirin, immunoglobulins, and nitazoxanide have been tried, but evidence to support of their use is weak.[50],[51] A vaccine against Norovirus is being developed, however, its efficacy is yet to be proven.

Parasitic infections

Parasitic infections of the intestine are more common in transplant recipients than that in healthy controls. Approximately 5%–40% of all diarrheal episodes are caused by parasitic infections.[29],[52],[53] Even those parasites that remain asymptomatic in healthy people, can produce a disease in transplant recipients. In a recent comprehensive review of the literature describing parasitic infections in SOT recipients, approximately 40% were found to be infested with some form of parasitic infection.[29] The most common parasites in decreasing order of prevalence include Cryptosporidium, Giardia lamblia, Microsporidia, Blastocystis, and others. Cryptosporidium has been discussed in detail elsewhere in another review. There is limited data on the prevalence of G. lamblia in transplant individuals in the South-East Asian region. The population prevalence of Giardia infection in diarrheal samples in South-East Asian countries such as Nepal (9.1%–15%), India (5.5%–24.6%), China (4.8%–7.8%), Bangladesh (11%), and others have been reported in small case series.[54] Careful examination of the fresh stool using direct microscopy (after formalin ether sedimentation, Sheather's floatation) and special staining with modified acid-fast staining are the first step test for the diagnosis. Detection of parasitic-specific antigen and molecular methods for the detection of parasitic DNA are getting popular. The first-line treatment of giardiasis are nitroimidazoles such as metronidazole or tinidazole, however with emergence of Giardia sps resistant to the first-line drugs, other drugs such as nitazoxanide and albendazole may be used.[55],[56]

Strongyloidiasis is a tropical disease caused by Strongyloides stercoralis, which occurs in the setting of poor personal, food, and water hygiene. Even though there is a lack of prevalence data, it is clearly more common in developing countries.[57] Strongyloidosis, in immunocompromised individuals, can become disseminated and may result in high mortality rate. The disease in SOT recipients may occur either from the reactivation of the latent infection (more common) or it may be donor derived. The clinical spectrum of strongyloidosis ranges from acute diarrheal illness to a hyperinfection syndrome leading to multiple organ failure and even death. The hyperinfection with S. stercolaris may cause intestinal ulceration and increased bacterial translocation leading to sepstisemia.[58] The median time for the occurrence of strongyloidosis after transplantation is about 3 months. Infection rates as high as 11.2% in India, 7.6% in Indonesia, and 29.8% in Bangladesh have been reported.[59] Diagnosis of strongyloidosis is made by demonstration of eggs or rhabditiform larva in the stool, sputum, or duodenal aspirate. Serological tests are also available, which are more sensitive. Ivermectin remains the treatment of choice. While ivermectin for 2 days is sufficient for uncomplicated infection, prolonged treatment in combination with antibiotics however may be needed for disseminated infection.


  Noninfectious Causes Top


Mycophenolate mofetil

MMF is a widely used immunosuppressive drug in SOT recipients, however, it has been implicated as the most common immunosuppressive drug causing diarrhea in them.[23],[24] The active component of MMF, mycophenolic acid, inhibits inosine monophosphate dehydrogenase which catalyzes a key step in the de novo purine synthesis, thus inhibiting the cell cycles in rapidly dividing cells.[60] Like T-and B lymphocytes, the enterocytes also have high turnover, and thus their replication is highly dependent on de novo purine synthesis. One of the mechanisms of diarrhea due to the use of MMF is the inhibition of replication of cells in the crypts in the intestine.[61],[62] Approximately 14% to 50% of organ transplant recipients receiving MMF develop diarrhea at some point of time.[63] The incidence of diarrhea is higher when MMF is used in combination with other immunosuppressive drugs.[5] Furthermore, patients receiving MMF are at a higher risk of developing invasive infections, especially CMV that itself can result in a diarrheal episode.

If MMF is suspected as a cause of diarrhea in an organ transplant recipient, several strategies have been described to mitigate MMF induced diarrhea. While switching MMF to enteric-coated mycophenolate sodium has been suggested, the evidence of its efficacy is not well established.[64],[65] Reduction in the dose of the MMF, rather than stopping all together, is another option. The persistence of diarrhea despite the reduction in the daily dose of MMF in the absence of any other alternative cause of diarrhea may mandate withdrawal of MMF, at least temporarily. An optimum time for withdrawal of MMF along with replacement by an alternative immunosuppressive drug is when the patient is unable to tolerate even 50% of the recommended dose of MMF.[18] Stoppage of diarrhea with the withdrawal of MMF not only confirms that the episode of diarrhea was MMF induced but such a step is therapeutic too.

Inflammatory bowel disease

Inflammatory bowel disease (IBD) may manifest as a de novo disease after SOT. Prolonged use of immunosuppression in organ transplant recipients leads to dysbiosis, which can act as a second hit and lead to the clinical presentation of a preexisting silent IBD. The risk of developing IBD in the organ-transplant recipients is approximately 5–10 fold higher than that in the general population.[66] The occurrence of a new IBD is not uncommon, however the exacerbation of preexisting known IBD is more worrisome. Because of its association with autoimmune hepatitis and primary sclerosing cholangitis, IBD is often described in patients who have received liver transplantation for primary sclerosing cholangitis.[67],[68] About 30% of IBD patients worsen after liver transplantation and a similar number tend to improve after liver transplantation.[69] Potential risk factors for worsening of IBD include tacrolimus-based immunosuppression, active IBD, and cessation of 5-aminosalicylates at the time of transplantation.[70] The clinical presentation of IBD in organ-transplant recipients is similar to that of non-transplant recipients. The diagnosis of new IBD may be delayed as most bloody diarrhea in the transplant setting are presumed to be due to GI infections.

The management of de novo IBD is relatively simple, and the patient responds to immunosuppressive drugs and aminosalicylates. Recurrence of symptoms from preexisting disease is more difficult to treat and requires escalation of medical therapy and even consideration for surgical treatment.[69]

Microscopic colitis, including two main subtypes, lymphocytic colitis, and collagenous colitis, has been described as a cause of chronic diarrhea in organ-transplant recipients. Generally, SOT recipients are at 50-fold higher risk of developing microscopic colitis than the general population.[71] The mucosal appearance of the colon is normal in patients with microscopic colitis, and the diagnosis is based on histological characteristics. Hence, colonic mucosal biopsies should be obtained even when colonic mucosa appears normal in patients undergoing evaluation for chronic unrelenting diarrhea. Oral steroids such as budesonide is the drug of choice.

Posttransplant lymphoproliferative disorder

Posttransplant lymphoproliferative disorders (PTLDs) are the most serious complications that can occur in organ transplant recipients and they occur majorly as a consequence of prolonged use of immunosuppressive drugs. Fortunately, only a minority of them (~1%) ever develop PTLD. The majority (50%–70%) of PTLDs are associated with Ebstein Barr Virus infection. While the period for the development of PTLD is not uniform; almost 90% patients, develop within the first 5 years of transplantation. The clinical presentation of PTLD is often subtle and nonspecific such as fever, weight loss, and fatigue. Approximately half of the patients with PTLD have the extranodal disease and the most common extranodal organs involved are GI tract and central nervous system. GI tract get involved in about a quarter of patients having PTLDs, however proximal small intestine is the most common site of invovement resulting in chronic diarrhea, abdominal pain, GI bleeding, anemia, and hypoalbuminemia. The diagnosis of PTLD is based on macroscopic characteristics as seen on the endoscopic examination and the histopathological features. The characteristic appearance at endoscopic examination includes thickening of the intestinal folds and raised and erythematous lesions with central ulceration. Microscopic examination reveals monomorphic infiltration of B lymphocytes in the lamina propria and the submucosa with the destruction of nearby structures. The management of PTLD is centered around a reduction in the doses of immunosuppressive drugs. However, in patients in whom the disease has evolved into lymphoma, are treated based upon the stage and the localization of the disease, and other relevant factors. Medical oncologists should be involved for the treatment planning and follow-up of all such patients. A combination of systemic chemotherapy with Rituximab, the anti-CD 20 monoclonal antibodies, is generally used for PTLD.

i. In addition to the above-mentioned causes of diarrhea, a few other relevant causes that occur less commonly in the postsolid organ transplant setting, are summarized briefly in [Table 5].
Table 5: Miscellaneous causes of diarrhea in solid organ transplant recipients

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  Diagnostic Algorithm and Therapeutic Strategy Top


In general, an episode of diarrhea remains self-limiting in most of the SOT recipients. The two most common reactions, such as starting antibiotic therapy without appropriate investigations and inappropriate and rapid reduction in the immunosuppressive regimen, should be avoided. The authors of the DIDACT study, who evaluated the cause of diarrhea prospectively in organ-transplant recipients, have suggested a logical approach for stepwise assessment of the cause of diarrhea. With some modification, we propose and discuss a combined algorithm for diagnosis and management of diarrhea in post SOT recipients in the South-East-Asian region [Figure 2]. Organ-transplant recipients, are prescribed many other drugs, in addition to immunosuppressive drugs including anti-hypertensives, diuretics, metformin, and proton-pump inhibitors and many of these has the potential to cause diarrhea. Therefore, a detailed review of the drug chart is an important first step, and any medication with the potential to cause diarrhea may be withdrawn temporarily and substituted appropriately. In the DIDACT study, such a step had led to the resolution of diarrhea in 6% of patients having diarrhea in organ-transplant recipients. Since GI infectious are the most common etiology of diarrhea in SOT recipients, the next appropriate step is to identify the responsive infectious agent by using stool microscopic examination and stool culture. The opportunistic parasites such as Cryptosporidium, Isospora, Microsporidia, and Strongyloides require special stains such as acid-fast staining and Kinyoun staining, which are not practiced routinely in most microbiological laboratories, and therefore special request should be made for such tests. The microbiological slides should be seen by experienced microbiologists/parasitologists and repeated examinations on consecutive days should be done to enhance the yield of the test. At present time, molecular techniques using multiplex PCR not only detect multiple organisms at one time, but they also increase the diagnostic yield. While they are easy to perform and add to the diagnosis, their use is generally less because of cost and limited availability. Another downside of the molecular diagnostic test is the overidentification of organisms which may not be the real cause of diarrhea in the index of that particular patient.
Figure 2: Diagnostic algorithm and therapeutic strategy

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Once common infective causes have been either treated or ruled out, other causes such as CMV and C. difficile should be investigated by using specific tests as described above. The use of a hydrogen breath test to investigate for small intestinal bacterial overgrowth is generally not required unless a strong suspicion of small intestinal overgrowth is considered. Esophagogastroduodenoscopy and/or colonoscopy should be performed in patients early if there is a clinical suspicion of PTLD (those having significant malabsorption), and IBD (bloody diarrhea, family history of IBD, obstructive symptoms), respectively. While conducting UGI endoscopy, duodenal aspirate and brush smears should also be obtained for detection of trophozoites of G. lamblia and larva of S. stercoralis. If there is clinical suspicion of IBD, tuberculosis, or CDI, colonoscopy examination should be performed, and multifocal multiple biopsies should be obtained from the macroscopic lesions not only for histological evaluation but also for microbiological tests. Furthermore, colonic mucosal biopsies should also be obtained even if the colonic mucosa appears normal to rule out microscopic colitis.

As the next step, if the cause of diarrhea remains unresolved and diarrhea persists, a reduction in the immunosuppressive medications, especially MMF, should be considered. Reduction in MMF dose may lead to transplant rejection, so an appropriate balance should be made in the doses of other immunosuppressive drugs. In a proportion of patients, with continuing diarrhea without resolution of a definite etiology despite extensive investigation and withholding of immunosuppression, a course of broad-spectrum antibiotics should be prescribed. Antidiarrheal drugs can also be used in such patients for symptomatic relief. Appropriate fluid and electrolyte supplementation and checking their values should always be considered.

Since a large number of episodes of acute diarrhea are infective and mostly viral in etiology not only in immunocompetent but immunocompromised patients also, conservative management using oral rehydration solution, antidiarrheal drugs, and where appropriate, a short course of antibiotics may be helpful in a large subset of patients. A detailed evaluation, as described above, should be performed in patients with alarming features, chronic diarrhea, recurrent diarrhea, and those with graft dysfunction. Although the above algorithm depicts a stepwise approach, many steps are often taken simultaneously, such as drug review and ruling out infections at the same time.


  Prevention Top


As discussed in the previous sections, diarrhea is an important problem in posttransplant setting. The primary prevention should be focused on personal as well as food and water hygiene. Measures such as regular hand washing, use of sanitizers, proper washing of raw food materials plays an important role in the prevention of transmission of infection. This is especially needed for South-Asian countries where infectious agents constitute the bulk of the burden of diarrhea in posttransplantation settings. In posttransplantation settings, polypharmacy is often necessary, so impulsive reactions to use over-the-counter drugs should be kept at a minimum to prevent unforeseen adverse events and drug interactions. In those who have already acquired an infection, early diagnosis holds the key which can only be achieved by careful history and a protocolized approach.

Future perspectives and research

With the continuous rise in chronic diseases, the number of organs transplanted as well as the number of centers performing transplants is increasing. The DIDACT study has been an exemplary study in demonstrating the value of the protocolized approach to patients with organ transplantation having diarrhea. Since the data on this subject is limited from the South East Asian region, there is a need for prospective well-designed studies to develop efficient stepwise algorithms for the diagnosis and treatment of diarrhea in posttransplant recipients. This is thus relevant that the transplant centers in the South-East Asian region join hands together and develop evidence-based guidelines in managing diarrhea in organ transplant recipients in this region.


  Conclusions Top


Diarrhea, both acute and chronic, is a common complication in solid organ-transplant recipients. While there is heterogeneity in the approach followed at different centers, it is ideal that a stepwise diagnostic and therapeutic approach, as described above, is followed. Not only the landscape of infections in organ transplant recipients is changing, but also resistant organisms are appearing; therefore we advocate local modification as per local centers infection and antibiotic sensitivity profile. Newer molecular methods that provide multiplexing of tests to detect multiple organisms at the same time in the same biological sample should be utilized optimally. Since the pattern of infections are likely to be different in different countries, it is thus most appropriate that the investigators in South East Asia conduct a multicenter study to develop an evidence-based approach for the diagnosis and management of diarrhea in solid organ-transplant recipients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Introduction
Epidemiology
Etiology of Diar...
Infectious Causes
Salmonellosis
Aeromonas
Shiga Toxin-prod...
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Viral Infections
Norovirus
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