Differential diagnosis of Crohn’s disease and intestinal tuberculosis based on ATR-FTIR spectroscopy combined with machine learning

BACKGROUND Crohn’s disease(CD)is often misdiagnosed as intestinal tuberculosis(ITB).However,the treatment and prognosis of these two diseases are dramatically different.Therefore,it is important to develop a method to identify CD and ITB with high accuracy,specificity,and speed.AIM To develop a method to identify CD and ITB with high accuracy,specificity,and speed.METHODS A total of 72 paraffin wax-embedded tissue sections were pathologically and clinically diagnosed as CD or ITB.Paraffin wax-embedded tissue sections were attached to a metal coating and measured using attenuated total reflectance fourier transform infrared spectroscopy at mid-infrared wavelengths combined with XGBoost for differential diagnosis.RESULTS The results showed that the paraffin wax-embedded specimens of CD and ITB were significantly different in their spectral signals at 1074 cm^(-1) and 1234 cm^(-1) bands,and the differential diagnosis model based on spectral characteristics combined with machine learning showed accuracy,specificity,and sensitivity of 91.84%,92.59%,and 90.90%,respectively,for the differential diagnosis of CD and ITB.CONCLUSION Information on the mid-infrared region can reveal the different histological components of CD and ITB at the molecular level,and spectral analysis combined with machine learning to establish a diagnostic model is expected to become a new method for the differential diagnosis of CD and ITB.

Intestinal tuberculosis with small bowel stricture and hemorrhage as the predominant manifestation: Three case reports

BACKGROUND Intestinal tuberculosis is a chronic disease caused by Mycobacterium tuberculosis that mainly affects the ileum and cecum.Small bowel tuberculosis,characterized by predominant involvement of the small intestine,is an extremely rare condition with highly atypical clinical presentations,making diagnosis even more challenging.CASE SUMMARY We report three cases of small intestinal tuberculosis,two of the patients pre-sented primarily with abdominal pain,and one presented with gastrointestinal bleeding.All patients underwent blood tests and imaging examinations.Small bowel endoscopy(SBE)revealed that the main lesions in these patients were in-testinal stenosis or gastrointestinal bleeding caused by small intestinal ulcers.One patient ultimately underwent surgical treatment.Following a complex diagnostic process and comprehensive analysis,all patients were confirmed to have small intestinal tuberculosis and received standard antituberculosis treatment,leading to an improvement in their condition.CONCLUSION Patients with SBTs present with nonspecific symptoms such as abdominal pain,weight loss,and occasional gastrointestinal bleeding.Accurate diagnosis requires a thorough evaluation of clinical symptoms and various tests to avoid misdiagno-sis and complications.

Diagnosis of intestinal tuberculosis using a monoclonal antibody to Mycobacterium tuberculosis

AIM:To investigate the utility of immunohistochemical(IHC) staining with an antibody to Mycobacterium tuberculosis(M.tuberculosis) for the diagnosis of intestinal tuberculosis(TB).METHODS:We retrospectively identified 10 patients(4 males and 6 females;mean age = 65.1 ± 13.6 years) with intestinal TB.Clinical characteristics,including age,gender,underlying disease,and symptoms were obtained.Chest radiograph and laboratory tests,including sputum Ziehl-Neelsen(ZN) staining,M.tuberculosis culture,and sputum polymerase chain reaction(PCR) for tubercle bacilli DNA,as well as Tuberculin skin test(TST) and QuantiFERON-TB gold test(QFT),were examined.Colonoscopic records recorded on the basis of Sato's classification were also reviewed,in addition to data from intestinal biopsies examined for histopathological findings,including hematoxylin and eosin staining,and ZN staining,as well as M.tuberculosis culture,and PCR for tubercle bacilli DNA.For the present study,archived formalin-fixed paraffin-embedded(FFPE) intestinal tissue samples were immunohistochemically stained using a commercially available species-specific monoclonal antibody to the 38-kDa antigen of the M.tuberculosis complex.These sections were also stained with the pan-macrophage marker CD68 antibody.RESULTS:From the clinical data,we found that no patients were immunocompromised,and that the main symptoms were diarrhea and weight loss.Three patients displayed active pulmonary TB,six patients(60%) had a positive TST,and 4 patients(40%) had a positive QFT.Colonoscopic findings revealed that all patients had type 1 findings(linear ulcers in a circumferential arrangement or linear ulcers arranged circumferentially with mucosa showing multiple nodules),all of which were located in the right hemicolon and/or terminal ileum.Seven patients(70%) had concomitant healed lesions in the ileocecal area.No acid-fast bacilli were detected with ZN staining of the intestinal tissue samples,and both M.tuberculosis culture and PCR for tubercle bacilli DNA were negative in all samples.The histopathological data revealed that tuberculous granulomas were present in 4 cases(40%).IHC staining in archived FFPE samples with anti-M.tuberculosis monoclonal antibody revealed positive findings in 4 patients(40%);the same patients in which granulomas were detected by hematoxylin and eosin staining.M.tuberculosis antigens were found to be mostly intracellular,granular in pattern,and primarily located in the CD68 + macrophages of the granulomas.CONCLUSION:IHC staining with a monoclonal antibody to M.tuberculosis may be an efficient and simple diagnostic tool in addition to classic examination methods for the diagnosis of intestinal TB.

Comparative study of intestinal tuberculosis and primary small intestinal lymphoma

AIM: To characterize the clinical, radiological, endoscopic and pathological features of intestinal tuberculosis (ITB) and primary small intestinal lymphoma (PSIL).

Temporal trends in the misdiagnosis rates between Crohn's disease and intestinal tuberculosis

AIM To investigate the temporal trends in the misdiagnosis rate between Crohn's disease(CD) and intestinal tuberculosis(ITB) in South Korea. METHODS We retrospectively reviewed the medical records of patients managed for CD or ITB at Asan Medical Center, a tertiary referral hospital, Seoul, Korea between 1996 and 2014. The temporal trends in the misdiagnosis rates between the two diseases were analyzed. The demographic and clinical characteristics were compared between CD patients who were initially misdiagnosed as ITB(final CD group) and vice versa(final ITB group). Final diagnostic criteria for ITB and medication for CD before definite diagnosis of TB were also analyzed in final ITB group.RESULTS In total, 2760 patients were managed for CD and 772 patients for ITB between 1996 and 2014. As well, 494 of the 2760 CD patients(17.9%) were initially misdiagnosed as ITB and 83 of the 772 ITB patients(10.8%) as CD. The temporal trend in misdiagnosing CD as ITB showed a decrease(OR = 0.89, 95%CI: 0.87-0.91, P < 0.001), whereas the temporal trend in misdiagnosing ITB as CD showed an increase(OR = 1.06, 95%CI: 1.01-1.11, P = 0.013). Age at diagnosis, presenting symptoms, and proportion of patients with active/past perianal fistula and active/inactive pulmonary tuberculosis(TB) were significantly different between final CD group and final ITB group. Forty patients(48.2%) in final ITB group were diagnosed by favorable response to empirical anti-TB treatment. Seventeen patients(20.5%) in final ITB group had inappropriately received corticosteroids and/or thiopurines due to misdiagnosis as CD. However, there were no mortalities in both groups. CONCLUSION Cases of CD misdiagnosed as ITB have been decreasing, whereas cases of ITB misdiagnosed as CD have been increasing over the past two decades.

Esophageal tuberculosis complicated with intestinal tuberculosis: A case report

BACKGROUND Although the overall incidence of tuberculosis in underdeveloped areas has increased in recent years, esophageal tuberculosis(ET) is still rare. Intestinal tuberculosis(ITB) is relatively more common, but there are few reports of ET complicated with ITB. We report a case of secondary ET complicated with ITB in a previously healthy patient.CASE SUMMARY A 27-year-old female was hospitalized for progressive dysphagia, retrosternal pain, acid regurgitation, belching, heartburn, and nausea. Upper gastrointestinal endoscopy showed a mid-esophageal ulcerative hyperplastic lesion. Endoscopic ultrasonography showed a homogeneous hypoechoic lesion, with adjacent enlarged lymph nodes. Biopsy histopathology showed inflammatory exudation,exfoliated epithelial cells and interstitial granulation tissue proliferation.Colonoscopy revealed a rat-bite ulcer in the terminal ileum and a superficial ulcer in the ascending colon, near the ileocecal region. The ileum lesion biopsy showed focal granulomas with caseous necrosis. Polymerase chain reaction for Mycobacterium tuberculosis was positive in the esophageal and ileum lesion biopsies. The T-cell spot tuberculosis test was also positive. The patient was diagnosed with secondary ET infiltrated by mediastinal lymphadenopathy and complicated with ITB, possibly from the Mycobacterium tuberculosis-infected esophageal lesion. After 2 mo of anti-tuberculosis therapy, her symptoms improved significantly, and upper gastrointestinal endoscopy showed healing ulcers.CONCLUSION When dysphagia or odynophagia occurs in patients at high-risk for tuberculosis,ET should be considered.

Immune thrombocytopenic purpura induced by intestinal tuberculosis in a liver transplant recipient

A variety of clinical manifestations are associated directly or indirectly with tuberculosis. Among them, haematological abnormalities can be found in both the pulmonary and extrapulmonary forms of the disease. We report a case of immune thrombocytopenic purpura(ITP) associated with intestinal tuberculosis in a liver transplant recipient. The initial management of thrombocytopenia, with steroids and intravenous immunoglobulin, was not successful, and the lack oftuberculosis symptoms hampered a proper diagnostic evaluation. After the diagnosis of intestinal tuberculosis and the initiation of specific treatment, a progressive increase in the platelet count was observed. The mechanism of ITP associated with tuberculosis has not yet been well elucidated, but this condition should be considered in cases of ITP that are unresponsive to steroids and intravenous immunoglobulin, especially in immunocompromised patients and those from endemic areas.

Clinical and Laboratory Diagnosis of Intestinal Tuberculosis

Background： Tuberculosis （TB） remains a worldwide problem. Intestinal TB （ITB） constitutes a major public health problem in developing countries and has been associated with significant morbidity and mortality. The aim of this study was to characterize the clinical, radiological, endoscopic, and pathological features of ITB and to define the strategy for establishing the diagnosis. Methods： A retrospective study （from January 2000 to June 2015） was carried out in Peking Union Medical College Hospital and all hospitalized cases were diagnosed as ITB during the study period were included. The relevant clinical information, laboratory results, microbiological, and radiological investigations were recorded. Results： Of the 85 cases, 61 cases （71.8%） were ranged from 20 to 50 years. The ileocecal region was involved in about 83.5% （71/85） of patients. About 41.2% （35/85） of patients had co-existing extra ITB, especially active pulmonary TB. Abdominal pain （82.4%） was the most common presenting symptom followed by weight loss （72.9%） and fever （64.7%）. Both T-cell spot of TB test （T-SPOT.TB） and purified protein derivatives （PPD） tests were performed in 26 patients： 20 （76.9%） positive T-SPOT.TB and 13 （50.0%） positive PPD were detected, with a statistical significant difference （P- 0.046）. Twenty cases （23.5%） were histopathology and/or pathogen confirmed TB; 27 cases （31.8%） were diagnosed by clinical manifestation consistent with ITB and evidence of active extra ITB; 38 cases （44.7%） were diagnosed by good response to diagnostic anti-TB therapy. Conclusions： ITB is difficult to diagnose even with modem medical techniques due to its nonspecific clinical and laboratory features. At present, combination of clinical, endoscopic, radiological, and pathological features continues to be the key to the diagnosis of ITB.

Genome-wide gene expression analysis for target genes to differentiate patients with intestinal tuberculosis and Crohn’s disease and discriminative value of FOXP3 mRNA expression

Background and aims:Crohn’s disease(CD)and intestinal tuberculosis(ITB)are both chronic granulomatous conditions with similar phenotypic presentations.Hence,there is need for a biomarker to differentiate between both these two diseases.This study aimed at genome-wide gene expression analysis of colonic biopsies from confirmed cases of ITB and CD in comparison with controls.To evaluate the role of T regulatory cells,forkhead box P3(FOXP3)mRNA expression was quantified in serum as well as in colonic biopsies from patients with ITB and with the controls.Methods:Paired samples,including serum and colonic biopsies,were taken from 33 study subjects(CD,ITB and controls),and total RNA was extracted.Human whole genome gene expression microarray analysis was performed using the Illumina HumanWG-6 BeadChip Kit with six total RNA samples of the three groups in duplicates.Real-time PCR for FOXP3 mRNA expression was analyzed in serum samples and colonic biopsy samples(4-CD,5-ITB,4-controls).Results:In CD and ITB there was 1.5-fold upregulation of 92 and 382 genes and 1.5-fold downregulation of 91 and 256 genes,respectively.Peroxisome proliferators via the PPARc pathway were most significantly downregulated(P<0.005)in CD.Additionally,the IL4/5/6 signaling pathways and Toll-like receptor signaling pathway were identified as significantly differentially regulated(P<0.005)at>2-fold change.In ITB,the complement activation pathway,specifically the classical pathway,was the most significantly upregulated.FOXP3 mRNA expression was significantly elevated in colonic biopsies obtained from ITB patients as compared with CD cases(4.7062.21 vs 1.4860.31,P=0.016).Conclusions:FOXP3 mRNA expression in colonic mucosa could be a discriminatory marker between ITB and CD.Upregulation of the complement activation pathway in ITB suggests that pathogenetic mechanisms for ITB are similar to those of pulmonary tuberculosis.In CD,downregulation of PPARc was seen in colonic tissue,suggesting that restoration of PPARc-dependent anti-microbial barrier function may be a therapeutic target.

VALUE OF POLYMERASE CHAIN REACTION ASSAY IN DIAGNOSIS OF INTESTINAL TUBERCULOSIS AND DIFFERENTIATION FROM CROHN'S DISEASE

It is difficult to make a precise diagnosis of intestinal tuberculosis and to differentiate it from Crohn's disease. For evaluating Polymerase Chain Reaction (PCR) assay in these two aspects, 36 specimens of intestinal tuberculosis from surgical resections and endoscopic biopsies and 26 Crohn's disease samples were subjected to PCR assay. 21 specimens of normal colon tissue surrounding cancer were used as the control. Oligonucleotides derived from the IS 6110 sequence, which is repeated in M. tuberculosis chromosome and highly specific for the M. tuberculosis complex, were used as a primer. The amplified PCR products were detected by examination of ethidium-bromide-stained polyacrylamide gels. The specificity of PCR products was confirmed by digestion with Sal 1 restrictive endonuclease and southern blot hybridization using digoxigenin-labeled probe. The results showed that the M. tuberculosis DNA was identified in 27 / 36 intestinal tuberculosis, but none of 26 Crohn's disease. Acid fast bacilli were only found in 16 / 36 intestinal tuberculosis. In conclusion, as a rapid, sensitive, and specific pathogenic method in diagnosis of intestinal tuberculosis, PCR assay has been developed in this study, and is considered valuable in the differentiation between intestinal tuberculosis and Crohn's disease.

Efficacy of thalidomide therapy in pediatric Crohn's disease with evidence of tuberculosis

AIM To evaluate the efficacy of thalidomide for treating troublesome cases of pediatric Crohn's disease(CD) with tuberculosis infection.METHODS A retrospective study of clinical outcome among children treated with thalidomide was conducted. All patients had evidence of tuberculosis infection with a failure of anti-tuberculosis treatment for more than one year,and were subsequently diagnosed with CD. All the patients received thalidomide treatment with a starting dose of 1.2-2.5 mg/kg per day. Remission was defined as pediatric CD activity index less than or equal to 10.RESULTS Ten patients with CD were treated with thalidomide at an average age of 7.2 years and followed up for a median of 22.2 mo. Clinical remission rate was 60% after 9-12 mo of thalidomide treatment. One patient with no response had an interleukin-10 receptor alpha gene mutation. Erythrocyte sedimentation rate,C-reactive protein and platelet count showed a dramatic decrease; hemoglobin level and weight improved significantly after thalidomide treatment when compared with the baseline values.CONCLUSION Thalidomide is an effective and safe drug for remission of CD in pediatric patients who have been treated for tuberculosis.

Diagnostic classification of endosonography for differentiating colorectal ulcerative diseases: A new statistical method

AIM To establish a classification method for differential diagnosis of colorectal ulcerative diseases, especially Crohn's disease(CD), primary intestinal lymphoma(PIL) and intestinal tuberculosis(ITB).METHODS We searched the in-patient medical record database for confirmed cases of CD, PIL and ITB from 2008 to 2015 at our center, collected data on endoscopic ultrasound(EUS) from randomly-chosen patients who formed the training set, conducted univariate logistic regression analysis to summarize EUS features of CD, PIL and ITB, and created a diagnostic classification method. All cases found to have colorectal ulcers using EUS were obtained from the endoscopy database and formed the test set. We then removed the cases which were easily diagnosed, and the remaining cases formed the perplexing test set. We re-diagnosed the cases in the three sets using the classification method, determined EUS diagnostic accuracies, and adjusted the classification accordingly. Finally, the re-diagnosing and accuracy-calculating steps were repeated.RESULTS In total, 272 CD, 60 PIL and 39 ITB cases were diagnosed from 2008 to 2015 based on the in-patient database, and 200 CD, 30 PIL and 20 ITB cases were randomly chosen to form the training set. The EUS features were summarized as follows: CD: Thickened submucosa with a slightly high echo level and visible layer; PIL: Absent layer and diffuse hypoechoic mass; and ITB: Thickened mucosa with a high or slightly high echo level and visible layer. The test set consisted of 77 CD, 30 PIL, 23 ITB and 140 cases of other diseases obtained from the endoscopy database. Seventy-four cases were excluded to form the perplexing test set. After adjustment of the classification, EUS diagnostic accuracies for CD, PIL and ITB were 83.6%(209/250), 97.2%(243/250) and 85.6%(214/250) in the training set, were 89.3%(241/270), 97.8%(264/270) and 84.1%(227/270) in the test set, and were 86.7%(170/196), 98.0%(192/196) and 85.2%(167/196) in the perplexing set, respectively.CONCLUSION The EUS features of CD, PIL and ITB are different. The diagnostic classification method is reliable in the differential diagnosis of colorectal ulcerative diseases.

Enterolithiasis

Enterolithiasis or formation of gastrointestinal concretions is an uncommon medical condition that develops in the setting of intestinal stasis in the presence of the intestinal diverticula, surgical enteroanastomoses, blind pouches, afferent loops, incarcerated hernias, small intestinal tumors, intestinal kinking from intra-abdominal adhesions, and stenosing or stricturing Crohn&#x02019;s disease and intestinal tuberculosis. Enterolithiasis is classified into primary and secondary types. Its prevalence ranges from 0.3% to 10% in selected populations. Proximal primary enteroliths are composed of choleic acid salts and distal enteroliths are calcified. Clinical presentation includes abdominal pains, distention, nausea, and vomiting of occasionally sudden but often fluctuating subacute nature which occurs as a result of the enterolith tumbling through the bowel lumen. Thorough history and physical exam coupled with radiologic imaging helps establish a diagnosis in a patient at risk. Complications include bowel obstruction, direct pressure injury to the intestinal mucosa, intestinal gangrene, intussusceptions, afferent loop syndrome, diverticulitis, iron deficiency anemia, gastrointestinal hemorrhage, and perforation. Mortality of primary enterolithiasis may reach 3% and secondary enterolithiasis 8%. Risk factors include poorly conditioned patients with significant obstruction and delay in diagnosis. Treatment relies on timely recognition of the disease and endoscopic or surgical intervention. With advents in new technology, improved outcome is expected for patients with enterolithiasis.

Colonic Bleeding Due to Histoplasma and Mycobacterium Coinfection in Renal Transplant Patient

Introduction： Histoplasmosis is a rare infectious condition caused by the fungus Histoplasma capsulatum that can be presented from asymptomatic to severe forms. Tuberculosis, still an endemic infection in some developing countries, can also have variable clinical presentations. Both diseases involve the lungs mostly, but in immunocompromised patients, especially those with advanced HIV infection and transplant patients, disseminated forms are more frequently found. Gastrointestinal involvement is unusual, and digestive bleeding is an even rarer complication. Case presentation： We report the case of a 39-year-old female who was diagnosed with a Mycobacterium tuberculosis and Histoplasma capsulatum coinfection occurring 11 years after a living-donor-related renal transplant. The patient presented a severe gastrointestinal bleeding caused by an ulcer in the ascending colon. She improved after a combined treatment with tuberculostatic and fungicidal drugs. Conclusions： Simultaneous gastrointestinal involvement by histoplasmosis and tuberculosis, presenting as severe digestive bleeding, with minimal respiratory symptoms associated, make this an extremely rare case and a diagnostic challenge. Therefore, it is important to keep a high clinical suspicion of opportunistic infection, especially in immunocompromised patient who presents with LGB.