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Treating chronic diarrhea: A systematic review on Immunoproliferative Small Intestinal Disease (IPSID)

  • Daniele Evangelista-Leite ,

    Roles Conceptualization, Investigation, Methodology, Writing – original draft, Writing – review & editing

    devangelsilva@gmail.com

    Affiliation Department of Gastroenterology, School of Medicine, Faculdade de Medicina do ABC, Santo André, São Paulo, Brazil

  • Breno Affonso Madaloso,

    Roles Conceptualization, Investigation, Methodology, Writing – original draft, Writing – review & editing

    Affiliation Department of Gastroenterology, School of Medicine, Faculdade de Medicina do ABC, Santo André, São Paulo, Brazil

  • Bruno Shouta Yamashita,

    Roles Conceptualization, Investigation, Methodology, Writing – original draft, Writing – review & editing

    Affiliation Department of Gastroenterology, School of Medicine, Faculdade de Medicina do ABC, Santo André, São Paulo, Brazil

  • Francesco Enrico Aloise,

    Roles Conceptualization, Investigation, Methodology, Writing – original draft, Writing – review & editing

    Affiliation Department of Gastroenterology, School of Medicine, Faculdade de Medicina do ABC, Santo André, São Paulo, Brazil

  • Lucas Polito Verdasca,

    Roles Conceptualization, Investigation, Methodology, Writing – original draft, Writing – review & editing

    Affiliation Department of Gastroenterology, School of Medicine, Faculdade de Medicina do ABC, Santo André, São Paulo, Brazil

  • Murilo Lopes de Mello,

    Roles Conceptualization, Investigation, Methodology, Writing – original draft, Writing – review & editing

    Affiliation Department of Gastroenterology, School of Medicine, Faculdade de Medicina do ABC, Santo André, São Paulo, Brazil

  • Renan Murata Hayashi,

    Roles Conceptualization, Investigation, Methodology, Writing – original draft, Writing – review & editing

    Affiliation Department of Gastroenterology, School of Medicine, Faculdade de Medicina do ABC, Santo André, São Paulo, Brazil

  • Ethel Zimberg Chehter

    Roles Conceptualization, Supervision, Writing – review & editing

    Affiliation Department of Gastroenterology, School of Medicine, Faculdade de Medicina do ABC, Santo André, São Paulo, Brazil

Treating chronic diarrhea: A systematic review on Immunoproliferative Small Intestinal Disease (IPSID)

  • Daniele Evangelista-Leite, 
  • Breno Affonso Madaloso, 
  • Bruno Shouta Yamashita, 
  • Francesco Enrico Aloise, 
  • Lucas Polito Verdasca, 
  • Murilo Lopes de Mello, 
  • Renan Murata Hayashi, 
  • Ethel Zimberg Chehter
PLOS
x

Abstract

Immunoproliferative Small Intestinal Disease (IPSID) is a disease characterized by extra-nodal marginal zone B-cell lymphoma with villous atrophy in the small intestine, causing chronic intermittent non-bloody diarrhea. Although originally associated with the Mediterranean region, this disease is present in many countries worldwide and may have been underreported due to its complicated diagnosis and scarce scientific literature, especially in regards to treatment. This study aims to review IPSID clinical features, therapeutic options, and treatment outcomes to help physicians identify and treat IPSID. Using PRISMA guidelines, a systematic review of articles was conducted on PubMed database with search terms including IPSID, therapy, treatment, and outcomes. Inclusion and exclusion criteria were used to select 33 English language articles published from the year 2000–2020 that included relevant clinical information about IPSID treatment. Data were extracted independently by at least two authors to reduce the introduction of potential bias. There were 22 case reports, 7 reviews, 1 research article, 1 prospective study, 1 letter to the editor and 1 memoriam in which 76 patients were identified. Epidemiological analysis showed a mean patient age of 32 years old, 2.4:1 mal to female ratio and heterogeneous ethnicities, with 16 Europeans (43.2%) and 12 Asians (32.4%). Chief symptoms included chronic diarrhea (53/76, 69.7%), weight loss (49/76, 64.4%), malabsorption (38/76, 50%), abdominal pain (32/76, 42.1%), and finger clubbing (24/76, 31.6%). Patients stratified into the early disease stage (Galian A) were treated with tetracycline antibiotics, corticosteroids, and non-pharmacological supplements with mostly with complete or partial remission. Late stages (Galian B or C), were treated mostly with anthracycline-based chemotherapy, and occasionally surgery, radiotherapy, or rituximab. This work offers a targeted approach to diagnosing and treating IPSID to aid physicians and serve as a treatment guideline recommendation for future public policies and clinical studies.

Introduction

Immunoproliferative Small Intestinal Disease (IPSID) is a rare extra-nodal marginal zone B-cell lymphoma, a variant of mucosa-associated lymphoid-tissue lymphoma (MALT Lymphoma). IPSID has had many synonyms due to its broad symptomatic spectrum. In the early 1960s, young adults from Israel were reported to present small intestinal lymphoma associated with malabsorption symptoms, coining the term Mediterranean Lymphoma to this disease, as it was predominantly found in patients from that geographical region [1, 2]. In 1965, Bracha was the first to describe 13 patients in Tel-Hashomer hospital with this syndrome [3, 4]. In 1968, Mediterranean lymphoma was associated with the term α-heavy chain disease due to discovering an abnormal IgA molecule in patients’ serum and other body fluids [1]. This IgA molecule lacked light chains and had a truncated alpha-heavy chain protein, which rendered this disease a new name: “alpha-chain disease” [1, 5, 6]. Alpha chain disease may affect different anatomical structures, dividing it into three types: digestive, respiratory, and lymphoid [5]. The digestive alpha chain disease is now called Immunoproliferative Small Intestinal Disease.

Although initially associated with the Mediterranean, IPSID is found worldwide due to poverty and poor sanitation [6, 7], and improvements in living conditions reduced its incidence [8]. IPSID has only a few cases reported globally [9], but has a higher incidence in children and young adults in the second and thirds decades of life [2, 5, 6]. There is no clear preference for a specific ethnicity or race, but the incidence was higher in men with a male to female ratio of 2.4:1 [2]. Its clinical features include chronic intermittent non-bloody diarrhea associated with nutrient malabsorption, abdominal pain, weight loss, and finger clubbing [10, 11]. Because these are common symptoms of other diseases, diagnosis is challenging. Although IPSID is hardly the first diagnostic hypothesis, doctors should be aware of this possibility in their differentials to search for pathological features such as CD20 positive lymphoid cells and CD138 positive plasma cells in intestinal biopsies that allow for the correct diagnosis [2].

The number of publications on this topic is scarce and generally describes isolated or regional cases. Systematically revising the information from the last 20 years regarding IPSID would be beneficial for building up-to-date clinical guidelines and guiding therapeutics. Therefore, this work revises IPSID clinical features, therapeutic options, and treatment outcomes from the few articles that have been published in the last 20 years in order to analyze treatments with the best outcomes. The final goal is to produce a treatment flowchart divided by disease stages, which may aid health professionals, students, and public policy advocates when considering IPSID patients.

Methodology

This review aims to answer the following question: What are the most used treatment options with the most favorable outcomes reported globally in the last 20 years for treating IPSID patients?

Although no review protocol was registered, a systematic search following PRISMA 2009 guidelines [12] was conducted for potentially relevant studies discussing different IPSID treatment regimens. The stepwise approach for this review was: identifying the goal, choosing keywords, establishing eligibility criteria, searching for articles in the database, and screening articles by first adjusting at the advanced search parameters on the database, reading the abstract, applying exclusion criteria, and finally reading the entire article before deciding to include it in the review. Inclusion criteria were any type of literature like academic articles, case reports, reviews, short communication and letters to the editor. Articles published before January 1st, 2000, not written in English, unavailable for download, and lacking clinical information about IPSID treatment were excluded. Article search was conducted in Pubmed starting on September 4th, 2020 and ending on September 6th, 2020. The following search terms were used: “((IPSID) or (immunoproliferative small intestine disease)) and ((TREATMENT) or (OUTCOMES) or (TREAT) or (THERAPY)).” Database searches were supplemented with a search for unpublished (grey) literature, including a review of clinical trials via ClinicalTrials.gov and greylit.org, but no results were found on IPSID.

After applying inclusion and exclusion criteria, selected downloaded articles were stored in the cloud using Google Drive, and references were saved in the Endnote citation manager. No data abstraction tool was used. All authors independently searched articles and screened abstracts. Full article screening to select the final articles was decided by all seven reviewers together. To ensure reliable data detection and collection, more than one person extracted data from every article selected to minimize errors and reduce the introduction of potential biases by authors. Data extraction from reports was done by filling up tables electronically using Google drive. At the very least, information that involved IPSID treatment and outcomes was extracted independently by two people.

Due to the limited pool of articles, being most of them case reports, it was not possible to analyze the level of evidence, grade rating and bias analysis required in the PRISMA protocol Therefore, some items of the PRISMA checklist could not be applied here. All articles selected according to our search criteria were included in this review, despite their PRISMA rating grade, evidence level or bias. It was equally challenging to present their risk of bias, outcome level assessment and strength of evidence. Therefore, this review may lack some of this information, but the cases chosen were analyzed in detail.

Results

Study selection

The Pubmed search first yielded 117 articles. Articles were screened and those published before January 1st, 2000 were excluded, resulting in 44 articles. Articles abstracts were revised to apply inclusion and exclusion criteria. In this step, five French articles, one German and one Chinese were excluded because of language and another for being unavailable to download. In total, 36 articles were eligible to read in full text and screen for relevant clinical information. Three articles were excluded because they did not discuss IPSID treatment, yielding 33 articles in this review (Fig 1).

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Fig 1. Inclusion and exclusion criteria following PRISMA protocol.

https://doi.org/10.1371/journal.pone.0253695.g001

Study characteristics

In the 33 articles selected for the study, there were 22 case reports, 7 reviews, 1 research article, 1 prospective study, 1 letter to the editor and 1 memoriam. The case reports evaluated a total of 76 IPSID patients (Table 1). After analyzing patients’ age, sex and location, an epidemiological profile was drawn. IPSID patients had a mean age of 32 years old and were primarily men, in a male to female ratio of 2.4:1 (52 male, 20 female and 4 non-reported). A total of 65 patients reported their ethnicities, from which 28 were Middle Eastern (43%), 19 European (29%), 11 Asian (17%), 3 Oceanian (5%), 2 American (3%) and 2 African (2%).

Clinical features and diagnosis

The most common sites affected by IPSID is the duodenum (63%), followed by the jejunum (17%) [6] and the most common symptoms observed are a chronic diarrhea (53/76, 69.7%) associated or not with weight loss (49/76, 64.4%), nutrient malabsorption (38/76, 50%), abdominal pain (32/76, 42.1%), and digital clubbing (24/76, 31.6%) (Table 2).

Symptoms may be interspaced in early disease stages, but increase in frequency as it progresses. The time between symptom onset and diagnosis is highly variable and is determined disease stage and progression. Fever is present in late stages, usually low and intermittent. Steatorrhea, cachexia, and weakness are less common, while amenorrhea, dehydration, carpopedal spasm and night sweats are rare. Intestinal obstruction is not a regular feature, but its presence has a bad prognosis as it indicates disease progression into lymphoma [16]. Interestingly, some reports mention a correlation between transplanted kidney patients displaying duodenal villous atrophy and developing IPSID, with persistent diarrhea in 2.16 ± 0.8 years [31]. A visual representation of the most frequent symptoms was reported in this review (Fig 2).

Differential diagnose.

Mal-absorption syndromes are common and are usually associated with celiac disease and chronic intestinal infection. Patients with IPSID often have a history of being misdiagnosed with celiac disease or chronic intestinal infection because of shared symptoms, being with gluten-free diet with only slight symptom improvement [5]. Celiac disease initial screening consists of measuring transglutaminase and antiendomysial antibodies [11]. It may present mild plasma cell infiltration in the proximal intestine, but IPSID’s mucosal infiltration is more intense and may be present throughout the small intestine [5]. Chronic infectious diarrhea can be ruled out if no pathogenic bacteria are found in the stool culture test, and the presence of certain pathogens like Campylobacter jejuni should prompt IPSID investigation if other diseases are unlikely [19].

Lamina propria infiltration with round cells and villus changes are common findings in other diseases and need to be differentiated from tropical sprue, AIDS enteropathy and Whipple’s disease. In these cases, the symptoms added to the histological features are sufficient to perform the differential diagnosis. In tropical sprue, the enterocyte layer often maintains a columnar shape and both enterocyte layer and lamina propria are infiltrated with lymphocytes. In AIDS, the enterocyte layer often maintains a columnar shape and the lamina propria has a dense infiltration of round cells. In Whipple’s disease, enterocytes columnar shape is maintained, keeping a normal luminal surface, while the lamina propria is usually packed with histiocytes detected by positive periodic acid-Schiff staining and has villus widening. However, in IPSID, the enterocytes layer maintains a columnar shape and there is mild lymphocytes and plasma cells, while the lamia propria is packed with lymphocytes that can infiltrate up the muscular layer and frequently causes villous widening [10].

Diagnose.

With an initial clinical case of chronic watery diarrhea, malabsorption and weight loss, it is important to start with general diagnostic exams to narrow down the etiology for a malabsorption syndrome, and then investigate more specific diseases that are part of the differential diagnosis (e.g. lymphoma, celiac disease, giardia). Laboratory exams to order include: Hemogram, electrolytes, liver enzymes (AST, ALT, gamma glutamyl transferase, alkaline phosphatase), albumin, creatinine, calcium, stool and parasite exam, stool culture test with microbiological identification, Helicobacter pylori breath test and serology for IgA, human immunodeficiency virus (HIV), and autoimmune antibodies [5]. If increased levels of IgA are found (>3820 mg/L), bone marrow aspiration should be performed to exclude lymphoma, plasmoma, multiple myeloma and other abnormalities [5]. Percentage of mature and immature plasma cells and morphology should be analyzed in bone marrow smear.

An upper gastrointestinal endoscopy is indicated to investigate the diarrhea and malabsorption. During the exam atrophic nodular mucosa, thickened mucosal folds and edema may be observed. Duodenum biopsies should be obtained for pathological examination [6, 32]. Biopsy histological evaluation is strong diagnostic tool as it shows lymphoplasmocytic infiltration of the lamina propria and villi blunting. IPSID is associated with some radiologic patterns such as enlargement of mesenteric lymph nodes, thickening of the small intestinal wall, dilations and strictures of small bowel loops that may be visualized with a barium contrasted abdominal X-ray or computed tomography [32, 33]. Abdominal ultrasonography can also identify enlarged mesenteric lymph nodes and thick small intestinal wall. Capsule endoscopy may show mucosal edema and villi swelling in small intestine. Double balloon enteroscopy (DBE) is a recently developed endoscopic modality hat can also be used to diagnose small bowel disorders, including IPSID [34].

In the cases analyzed, the most common features presented by IPSID patients were elevated serum IgA (39.5%) with α-heavy chain proteins (35.5%), low or normal serum IgM and IgG (17.1%), anemia (11.8%), lymphocytosis (6.8%), electrolyte disorder with hypokalemia and (9.2%) hyponatremia (1.3%), hypocalcemia (2.6%), and hypoalbuminemia (9.2%) (Table 3). Stool test confirmed steatorrhea (14.5%) and microbiology testing showed a number of pathogens like Helicobacter pylori (6.8%) and Campylobacter jejuni (3.9%). Computed tomography and upper gastrointestinal endoscopy were the most cited to show alterations in the intestinal mucosa, thickening of the intestinal wall and enlargement of mesenteric lymph nodes.

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Table 3. Most common exam findings found in IPSID patients.

https://doi.org/10.1371/journal.pone.0253695.t003

Classification

IPSID was classified by Galian et al. in three stages (A, B, and C), depending upon its histopathological features, namely the type of cellular infiltrate and mesenteric nodal involvement [5].

Stage A is characterized by lymphoplamacytic infiltration of the lamina propria with inconstant and variable villi atrophy in the small intestine mucosa [35]. Moreover, there is also plasmacytic infiltration of mesenteric or other abdominal and retroperitoneal lymph nodes, resulting in limited disorganization of the lymph node histological structure [35].

In stage B, there is atypical lymphoplasmacytic infiltration of the lamina propria and atypical immunoblast-like cells spreading to the submucosa with subtotal or total villi atrophy [35]. Mesenteric and other abdominal lymph nodes also are populated with atypical plasmacytic and immunoblast-ike cells severe alteration of the lymph node architecture [35].

Stage C is the most advanced with the proliferation of histiocytes (Hodgkin sarcoma) in all layers of the intestinal wall. This sarcomatous proliferation extends to the mesenteric and other abdominal lymph nodes altering the whole lymph node architecture [35]. In stage C large masses are formed and transformed into malignant lymphoma.

Treatment

Treatment of patients with IPSID has evolved through time. In the early 1960s, Bracha et al. had described the outcome of the disease when in antibiotic treatment, insinuating an infectious cause [4]. In the late 1980s, the recommendation was that early stage-disease was prescribed tetracycline and metronidazole [36, 37]. These antibiotics were kept for at least 6 months and if there were no marked improvements or no remission within one year, patients were given anthracycline-based combined chemotherapy, like CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone). For patients that initially presented at late-stage disease, CHOP was given together with antibiotics [1, 6, 32, 33].

More recently, IPSID treatment protocols have been updated to reflect the Galian stages. For stages B and C, a combination of drugs were used, including COP (cyclophosphamide, vincristine and prednisolone), CHOP, nitrogen mustard, MOPP (procarbazine), BACOP (bleomycin, phosphamide, vincristine, prednisolone), CHVP (cyclophosphamide, doxorubicin, teniposide and prednisone) and ABV (doxorubicin, bleomycin, and vinblastine), although the most commonly used is still CHOP [1, 6]. If abnormal cells express CD20, rituximab can be added to the regimen following guidelines for localized extra-nodal marginal zone lymphomas [7, 17, 33, 37].

In addition, supportive measures had to be implemented as most patients were suffering from malabsorption and chronic diarrhea. Supplementation of essential vitamins, minerals and nutrients by parenteral nutrition is key to patient recovery in all chemotherapy regimens.

When the tumor has already developed into a malignant sarcoma with a bulky mass, surgery and radiotherapy present themselves as a palliative strategy to be used before chemotherapy, but not ways to achieve complete remission [6, 33].

Alternatives such as autologous stem cell transplant after high dose chemotherapy and life-long immunosuppression have been proposed, but without consistent data in th records [6, 32]. A comprehensive review of all treatments and their respective outcomes can be consulted in Table 4.

Table 4 was analyzed according to the following parameters: studies in which the results were provided with sequential follow-up periods, the latest was considered; when the outcome was unavailable or when the number of patients was not reported, the data was not considered for the treatment efficacy percentage calculation.

In stage A, tetracycline alone or combined with ampicillin or metronidazole, was used in 78.2% (43/55) of the patients in this stage. Tetracycline alone achieved 77.1% (27/35) of PR or CR, which was within the 33–71% CR reported in other studies [32, 39]. Doxycycline had 100% PR or CR, but only in 3 patients with only short follow-up periods, which could mean that the patients may have relapsed and were not accounted for. Prednisone also achieved 100% PR or CR, but in only 2 patients, with a 30-year follow-up period in one of them.

In stages B or C, surgery was discarded as a consistent treatment, since it was done in only 3 patients with a different procedure in each one due to other comorbidities. Anthracycline-based chemotherapies were used in 63.5% (40/63) of patients reported in this stage, being the most used therapeutic approach. The overall outcome for patients in anthracycline-based regimens was 62.2% (23/37) PR or CR in their follow-up periods. Other chemotherapy regimens achieved were used to treat 36.5% (23/63) of patients in stages B or C and had 60.9% (14/23) PR or CR rate. Other studies have reported CHOP, ABV or CHVP regimens with overall remission rate of 67% in 5 years [6], which is similar to the values obtained in this review. Antibiotics were associated in 66.7% (42/63) of patients, with a PR or CR rate of 59.5% (25/42). Rituximab was used in 93,1% (27/29) of the cases, specially those with more serious conditions including blown-up lymphomas. Rituximab had a substantial remission rate of 46%, being a very considerable choice among the therapeutic options for stage C.

In sum, stage A has a good clinical response to antibiotics and/or corticoids. Stage B, although treated as stage A in some cases, it can commonly progress to stage C when chemotherapy is not used. Therefore, in order to prevent this unwanted outcome, chemotherapy combined with antibiotics should be offered to treat stage B and C. Moreover, the treatment of stage C with advanced lymphoma should include rituximab.

Prognosis

When detected in the early stage and appropriately treated, IPSID may be resolved, but relapses are frequently observed [6]. Although the presence of microbial gastrointestinal infection is not a requirement for the establishment of IPSID, pathogens such as C. jejuni have been associated with IPSID transformation into aggressive diffuse large B-cell lymphoma (DLBCL) in previously healthy individuals [7]. In spite of several treatment regimens, late stages of IPSID (Galian stage C) have a poor prognosis with high mortality rates with a 5-year survival rate of around 67% [1, 6, 38].

The prognostic evaluation of the IPSID can be made with flow cytometry studies. Resistance to chemotherapy can be associated with high S phase of cell cycle and aneuploid DNA indices [39]. On the other hand, a normal S phase and DNA ploidy can be associated with a better response to chemotherapy and, in this case, patients can survive up to 10 years [39].

IPSID patients tend to progress to high grade lymphoma within a few years from the initial symptoms, but Lin et al. reported a case of a 30-year IPSID history without lymphoma conversion, questioning the idea of IPSID as a pre-lymphomatous condition [10]. The explanation for this disease not evolving in this case is still not known and probably involves a different pathogenic mechanism [6].

Discussion

IPSID is a rare lymphoproliferative disease that cause chronic diarrhea and malabsorption symptoms and evolve into a more severe enteropathy, and even B-cell lymphoma of MALT. The primary goal of this review was to investigate what were the best IPSID treatments in the last 20 years around the world. This goal was significantly constrained by the limited number of literature available on the topic, as IPSID is a rare and neglected disease often associated with developing countries in the Middle East and Africa [23, 32]. This bias was challenged in this review, because although Middle East was the first most reported place of origin for IPSID patients, Europe was the second. Other epidemiological data, like higher male to female ratio [2], and age mean close to the third decade of life was in agreement with earlier studies [2, 21, 32].

The absence of clinical trials specifically for IPSID is another major limitation. Although the Galian stage treatment suggestions made in this review are based on past case reports, research articles and review articles, there was no clinical trial information to corroborate this recommendation. Ideally in the future, medical researchers could collaborate to conduct a controlled clinical study to test different IPSID treatments at each stage using a multicentric approach since local patient recruitment would be a complicated task due the reduced number of patients.

IPSID has confusing diagnostic criteria with many differential diagnosis and complicated treatment regimens, requiring months of antibiotics and/or chemotherapy. This lack of clarity reinforces the need of reviews like this that propose treatment recommendations based on empirical results until structured controlled clinical studies are organized to prove what treatments work best.

Part of the reason why IPSID diagnosis is not straightforward is because IPSID pathogenesis is not fully elucidated. Although it has been associated with chronic antigenic stimulation by gastrointestinal infections, most notably Campylobacter jejuni [7], the exact mechanism whereby C. jejuni precipitates IPSID is still unknown. The main hypothesis is that the exposure to this bacterial toxin in conjunction with previous contact with cholera toxin, can lead to monoclonal lymphoplasmacytic expansion [2, 6, 7, 32]. It has been speculated that Vibrio cholerae toxin modulates functional changes in immunological cells, leading defects in B-lymphocytes, T-helper, T-suppressor and natural killer cells. These alterations combined could lead to an acquired deficiency in both cellular and humoral immunity. This hypothesis is supported by reports showing IPSID cases in the same areas affected by cholera epidemic [39].

With an impaired immune system, patients may not be able to effectively clear C. jejuni. Lymphocytes undergo intense proliferation due to the recurrent antigen stimulation and this intense duplication or the action of C. jejuni toxins themselves can induce genomic damage in immunoglobulin producing cells [6]. However, no definite causative agent has been identified.

A hypothesis of genetic predisposition was brought on after the development of IPSID in relatives living in different socioeconomic conditions and apart from each other [6, 41]. Elevated levels of alkaline phosphatase were found in members of the same family of a patient diagnosed with this disease [39]. Also, a strong relation between IPSID and human leukocyte antigens AW19, A9 and B12, along with the B blood group, has been reported [6, 7, 42], strengthening the hypothesis for a natural predisposition to IPSID.

Moreover, IPSID pathogenesis starts with immunoglobulin α-heavy chain gene mutations. In this gene, the first constant heavy chain (CH1) domain is responsible for associating α-heavy chains with α-light chains or degrading them by proteasomes. In a mutated gene, this domain is deleted along with a variable heavy (VH) chain component that participates in antigen recognition [6, 32]. Thus, these mutated genes form an abnormal α-heavy chain that cannot be destroyed by proteasomes and alters the immunoglobulin function, leading to immunoglobulin α-heavy chain accumulation. It is interesting to highlight that almost always, α1 is the damaged protein chain [6, 32]. Also, the expression of α-light chain genes is reduced, either by the absence of a transcription factor or by a inhibitory stimulus for the α-light chain transcription [2, 43]. Both these alterations may occur due to clonal abnormalities involving p32 heavy chain locus on chromosome 14 and light chain locus in chromosomes 2 and 22 [32]. There are insertions in the α-heavy chain genes too, but they seem to have no effect since the amino acid sequence encoded by them is not present in the final protein, probably because of an intracellular cleavage [32]. Combined, these factors result in a secretion of truncated α-heavy chain proteins by neoplastic plasma cells, which would not occur without the light chain in normal immunoglobulins and are present even in early stages of the disease [32].

In B lymphocytes, the B-cell receptor has heavy chains in its composition. In IPSID, the truncated α-heavy chain stimulates these receptors, leading to proliferation without an antigen, expanding the number of tumorous cells [6, 30]. Even though mutated B cells have all these abnormalities, their membranes do not present any variable region, allowing them to evade the immune system and contributing to their neoplastic fate [6, 32]. The involvement of Pax5, AML1 and other oncogenes mutations associated with these features previously presented may lead to the full-blown lymphoma due to IPSID, but their role is still uncertain in the pathogenesis [6, 32].

The hallmark lesion of the disease is achieved when intense plasma cell and lymphocyte proliferation and abnormal immunoglobulin secretion associated with an inflammatory process cause structural alterations in the small intestine, such as edema, flattening of the mucosa and villous blunting [2, 6]. Because of the unproven relationship between bacterial infections and IPSID development, antibiotics such as tetracycline, doxycycline and ampicillin have been the most used to treat early IPSID stages, preventing the symptom progression with many cases achieving complete remission. However, since there are other factor contributing to IPSID pathogenesis, it is frequent that patients experience partial remission with symptoms relapse and in some cases, progression into more advanced stages with diffuse large B-cell lymphoma [2, 16]. In more advanced stages, it is recommended the use of anthracycline-based chemotherapy combined or not with antibiotics, and in more extreme cases immunotheraphy can also be used with anti-CD20 monoclonal antibody, rituximabe. Overall, late stags of IPSID do not hold a good prognosis with a patient history marked by several chemotherapy cycles and the need for nutritional support.

Conclusion

No definite treatment regimen has been stablished for managing IPSID. Therefore, this review characterized IPSID in terms of its clinical features, therapeutic options and treatment outcomes by analyzing English-language articles published in the last 20 years around the world and available in Pubmed. Although IPSID is often cited as a rare condition [6] with diagnostic importance in developing countries, this review identified 76 patients from many continents including Europe, Asia and Oceania, with wealthy countries such as Japan, Italy and Australia included. This information helps to question previously defined paradigms that IPSID is a disease from developing countries. Perhaps, IPSID has been underdiagnosed due to its difficult diagnose and peculiar uncertain association with intestinal bacterial. It would not be hard to imagine that some IPSID cases might have been treated as a bacterial infection and as being treated with antibiotics, has been resolved. Cases that do not curse with bacterial infections and remain untreated can evolve to B-cell lymphoma and thus it is important to raise awareness about this disease and develop an appropriate treatment regimen.

Clinical features from 76 patients were analyzed and classified according to their reported frequencies. To our knowledge, no other review publication has recently analyzed IPSID clinical features focusing on treatment options and outcomes. This information is important because 1) it may aid physicians to diagnose and treat IPSID patients, and 2) it may help public health workers to update clinical guidelines concerning this disease.

IPSID symptoms included chronic watery diarrhea as the most frequently reported symptom, followed by weight loss, malabsorption, abdominal pain, finger clubbing, vomiting, fever and anemia. For triage, the suggested diagnostic investigation includes: hemogram, electrolytes, liver enzymes, creatinine, fecal exam, stool culture, and serology for IgA, HIV, autoimmune antibodies, upper gastrointestinal endoscopy and computed tomography. Lymphocytosis and elevated serum IgA with intestinal endoscopic and radiological alterations suggest IPSID. Diagnosis requires biopsy showing immunohistochemical alterations with lymphoplasmocytic infiltration and villous atrophy of the small intestinal lamina propria.

A treatment recommendation flowchart was developed based on 1) the most commonly prescribed treatment in all the reported cases, and 2) the best treatment outcomes (Fig 3). In early stages, antibiotics like tetracycline, metronidazole and ampicillin should be used, alone or combined, with a significant therapeutic effect. Due to frequent relapses, a long period antibiotic treatment may be considered. Non-responsive early diseases after 6 months, intermediate and advanced stages require anthracycline-based chemotherapy, which is superior to non-anthracycline-based regimens. Antibiotics previously cited should also be a part in more advanced diseases. The use of rituximab is not well explained and established yet against IPSID, but had satisfactory outcomes. Co-infections with commonly associated pathogens such as Campylobacter jejuni must be eradicated if possible.

Early stages of IPSID (Galian stage A) have favorable therapeutic response, so it is important for physicians to consider IPSID as a differential diagnosis in difficult and mysterious cases of chronic diarrhea. Advances stages (B-C) of IPSID confirmed with biopsy have worse prognosis with lower 5-year rate survival, so appropriate therapy is essential.

In this review, it was observed that IPSID seems to be one of the last diagnoses to be considered, which could explain the scarce number of cases often reported in the articles. Another factor to consider is the unequal access to medical services across the globe. Considering Europe was second in the number of cases, perhaps this can be explained by the high quality of medical care in European countries and the overall more egalitarian health system. With an ever more globalized society and a growing number of challenging social conditions related to immigration and refugee camps, physicians from all around the world may be challenged with difficult-to-diagnose chronic diarrheas. In such cases, this review can aid doctors to narrow down their differentials and to diagnose IPSID. Hence, knowledge about this illness will be useful for health professionals and public policy workers everywhere.

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