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CASE REPORT
Year : 2018  |  Volume : 21  |  Issue : 10  |  Page : 1387-1390

Crohn's disease with positive Ziehl–Neelsen stain: Three case reports


1 Department of Gastroenterology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
2 Department of Pathology, West China Hospital of Sichuan University, Chengdu, Sichuan, China

Date of Acceptance20-Jun-2018
Date of Web Publication8-Oct-2018

Correspondence Address:
Dr. Y Zhang
Department of Gastroenterology, West China Hospital of Sichuan University, 37 Guoxue Street, Chengdu, Sichuan
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_31_18

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   Abstract 


Because of the similarity of the clinical symptoms, endoscopic, and pathological features, the differential diagnosis between Crohn's disease (CD) and intestinal tuberculosis (ITB) remains difficult, especially in a high-incidence area of tuberculosis (TB). Here we reported three patients with positive Ziehl–Neelsen stain in endoscopic mucosal biopsy specimens. They had a poor response to anti-TB therapy but a good response to immunosuppresses, infliximab, or surgery, and were finally diagnosed as CD. It was not clear that they were CD concomitant with mycobacteria infection or CD induced by mycobacteria infection. Further studies including more clinical cases and related animal models are needed. Our cases highlight the importance of considering the presence of CD in patients with positive Ziehl–Neelsen stain, which were failure to respond to anti-TB treatment.

Keywords: Crohn's disease, intestinal tuberculosis, Ziehl–Neelsen stain


How to cite this article:
Zhou D, Ouyang Q, Xiong M, Zhang Y. Crohn's disease with positive Ziehl–Neelsen stain: Three case reports. Niger J Clin Pract 2018;21:1387-90

How to cite this URL:
Zhou D, Ouyang Q, Xiong M, Zhang Y. Crohn's disease with positive Ziehl–Neelsen stain: Three case reports. Niger J Clin Pract [serial online] 2018 [cited 2018 Nov 15];21:1387-90. Available from: http://www.njcponline.com/text.asp?2018/21/10/1387/242843




   Introduction Top


Crohn's disease (CD) is a chronic idiopathic inflammatory disorder of the gastrointestinal tract without clear etiology. For lack of gold standard, its diagnosis is usually very difficult. Many diseases need to be excluded, especially intestinal tuberculosis (ITB). Here, we presented three patients with positive Ziehl–Neelsen stain who were initially diagnosed as ITB, but proved to be CD at last.


   Case Reports Top


Case 1

A 25-year-old male was admitted to our hospital with diarrhea (3–4 times per day) for 7 years. He was diagnosed as ITB 7 years ago when lots of acid-fast bacilli on Ziehl–Neelsen stain were found in his colon biopsy sample. He received standard first-line anti-tuberculosis therapy (ATT) for 5 months, then second courses of first-line ATT for 3 months without any improvement. On admission, the physical examination only revealed mild tenderness on peri-umbilicus. Laboratory tests showed mild leukocytosis, anemia, significantly increased C-reactive protein (CRP) levels, and erythrocyte sedimentation rate (ESR). Purified protein derivative (PPD) skin test and TB interferon-gamma release assay (TB-IGRA) were both negative. Chest computed tomography (CT) was normal. CT enterography indicated diffuse thickening of the walls of the colon and rectum, multiple enlarged lymph nodes along the mesenteric vessels. Colonoscopy revealed multiple longitudinal ulcers and polypoid bulge scattered in the colon [Figure 1]a. Mycobacterial culture of biopsy specimens from colon revealed the presence of mycobacterium. Second-line ATT was given. Two months later, he was admitted again with fever and diarrhea. Left psoas abscess were found and drainage was performed. Four months later, he presented with left iliac fossa abscess and colonic fistula, and the following-up colonoscopy did not show any improvement. The Ziehl–Neelsen stain found one acid-fast bacilli in the biopsy samples from the rectum [Figure 1]b. Polymerase chain reaction (PCR) for TB was negative. Subtotal colectomy was performed. Pathology showed crypt abscess and noncaseating granulomas [Figure 1]c. Both PCR and Ziehl–Neelsen stain were negative. CD was diagnosed and azathioprine 33 mg daily (gradually increase the dose to 75 mg daily) was prescribed. Diarrhea slowly resolved. A repeat colonoscopy performed 8 months later, demonstrated marked improvement.
Figure 1: Endoscopic and histologic findings. Patient 1. (a) Colonoscopic finding. It shows multiple longitudinal ulcers in the rectum. (b) Histopathology of a rectum biopsy. It found one acid-fast bacilli (Ziehl–Neelsen stain, ×400). (c) Histopathology of the colon after subtotal colectomy. It showed crypt abscess and noncaseating granulomas (H and E stain, ×100)

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Case 2

A 20-year-old male came to our hospital with a history of diarrhea (7–8 times per day) for 5 months and hematochezia (4–5 times per day) for 4 months. The physical examination was unremarkable. Laboratory tests showed increased CRP and ESR. His hemoglobin and white blood cell count were normal. PPD skin test and TB-IGRA were both negative. ASCA and ANCA were also negative. Colonoscopy revealed multiple longitudinal ulcers in the rectum and sigmoid colon [Figure 2]a. Ziehl–Neelsen stain found six acid-fast bacilli in the biopsy from the sigmoid colon [Figure 2]b. PCR was negative. Small-bowel magnetic resonance imaging revealed the walls of sigmoid colon descending colon and splenic flexure of colon were slightly thick with obvious enhancement. The patient was started on first-line ATT for 4 months, but the following-up colonoscopy did not show any improvement. Then second-line ATT was given for 3 months, but the colonoscopy still had no change. He was treated with prednisolone 50 mg daily (tapered off slowly after 3 months) followed by azathioprine 100 mg/day. He noticed a gradual decrease of blood in his feces, then a disappearance of the blood. Weight gain was 25 kg.
Figure 2: Endoscopic and histologic findings.Patient 2. (a) Colonoscopic finding. It shows multiple longitudinal ulcers in the sigmoid colon. (b) Histopathology of a sigmoid colon biopsy. It found three acid-fast bacilli (Ziehl-Neelsen stain, ×400). Patient 3. (c) Colonoscopic finding. It shows extensive polypoid lesions and irregular ulcers in the hepatic flexure of colon. (d) Histopathology of a hepatic flexure of colon biopsy. It demonstrates acid-fast bacilli (Ziehl-Neelsen stain, ×400)

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Case 3

A 16-year-old male was admitted to our hospital with diarrhea for 2 month, and a 10-day history of fever (37–38°C). The physical examination was normal. The laboratory results were as follow: anemia, increased CRP levels, and ESR. TB-IGRA and chest CT for TB were negative. PPD skin test was 1+ positive. ASCA-IgG and AYMA-IgG were positive. ASCA-IgA was suspicious positive. CT enterography scans showed segmental thickened wall of ileum, ascending colon, and sigmoid colon. Colonoscopy revealed extensive polypoid lesions and irregular ulcers [Figure 2]c. Ziehl–Neelsen stain was positive [Figure 2]d and PCR for TB was negative. He was started on first-line ATT for 4 months, then second-line ATT for 3 months. However, both his symptoms and colonoscopic manifestation had no improvement. Infliximab (5 mg/kg) was given. After 3 doses of infliximab, his symptoms disappeared, CRP and ESR returned to normal. The repeat colonoscopy was performed at another hospital. Colonoscopy revealed remarkable healing of the ulcers.


   Discussion Top


TB continues to be a major health problem in the developing countries like China. TB primarily affects the lung, but any other parts of the body can also be involved. Gut is the sixth most common location of extrapulmonary involvement. Many literatures had reported cases of ITB without lung involvement.[1],[2] In a Chinese study, active TB was found only in 33.8% of ITB patient.[1] The causes of ITB can be summarized into four mechanisms: swallowing of infected sputum; hematogenous spread; ingestion of unpasteurized milk and milk products; or direct spread from adjacent organs.[3] According to a report from China, the ratio of human Mycobacterium bovis infection was 4.2%, and in some places reached 10.6%.[4] This seems to be one reason why primary ITB is common.



The Ziehl–Neelsen stain, known as the common acid-fast stain, is an important method for the diagnosis of ITB. The specificity of acid-fast bacilli detection is reported to be as high as 94%.[5] However, the sensitivity is very low and variable, from 5% to 40.5%.[6] Thus, the negative result of acid-fast bacilli does not always rule out ITB, but a positive result usually leads to highly suspicious of ITB. In this study, all the Ziehl–Neelsen stains are performed by our skilled professionals and double checked by the pathologists. Thus, the chance of false positivity is small. In our study, we found evidences of AFB in the patients. Empiric ATT should be considered first. But there is no improvement of endoscopic and clinical symptoms after 3–4 months of therapeutic trial with ATT. On the contrary, they had a good response to immunosuppresses, infliximab, or surgery, and were finally diagnosed as CD. We suggested repeating colonoscopy at 2 months of ATT.[7] Early mucosal responses to ATT can be used to differentiate between ITB and CD. Lacking of ulcer healing may suggest drug resistant ITB or underlying CD.

How to explain CD patients presented with positive Ziehl–Neelsen stain? Could be CD concomitant with ITB infection? In countries with such a high TB prevalence, it is possible that they had both coexisting ITB and CD, but the chance is small. To our knowledge, only one literature reported CD patients with positive Ziehl–Neelsen stain.[8] There is no improvement of endoscopic and clinical symptoms after ATT for at least 1 year. And the patients were finally diagnosed as CD. Could TB act as an infective “trigger” mechanism for the development of CD in persons who are genetically predisposed? Literatures had showed there was an increased risk of some autoimmune diseases after TB infection, such as systemic lupus erythematosus.[9] Molecular mimicry has been suggested as a possible mechanism.[10] Diverse autoantibodies were detected following TB infections.[11],[12] Then “mimicking molecules” cause the autoantibodies to react with host antigen, which could contribute to systemic lupus erythematosus development.[9] However, at present there is no conclusive evidence supporting M. tuberculosis as a cause of CD. M. avium subspecies paratuberculosis (MAP) is suspected of causing CD in humans. Several authors have demonstrated a significant association between CD and detection of MAP-DNA. Sechi et al. reported that MAP DNA was detected in intestinal mucosal biopsies of approximately 63% (19/30) of CD patients versus 10.3% (3/29) of controls.[13] Bentley et al. found a strong overrepresentation of MAP-DNA in patients with CD compared to control patients (33.8% vs 21.5%, P = 0.002).[14] Some reports even suggested that MAP may directly infect endothelial cells and adipocytes, which were involved in the formation of unique pathology to CD.[15]

In our patients, it was not clear that they were CD along with mycobacteria infection or mycobacteria-induced CD. Further studies are needed. Our cases also emphasize the importance of considering the presence of CD in patients with positive Ziehl–Neelsen stain, which were failure to respond to anti-TB treatment.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgment

Yan Zhang and Qin Ouyang conceived the study; Dandan Zhou, Moli Xiong, Li Zhao collected and interpreted the data; Dandan Zhou drafted the manuscript; Yan Zhang critically revised and approved the final manuscript. All authors read and approved the final manuscript. No author has any financial conflict of interest to declare.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Shi XC, Zhang LF, Zhang YQ, Liu XQ, Fei GJ. Clinical and Laboratory Diagnosis of Intestinal Tuberculosis. Chin Med J (Engl) 2016;129:1330-3.  Back to cited text no. 1
    
2.
Niriella MA, Kodisinghe SK, De Silva AP, Hewavisenthi J, de Silva HJ. Intestinal tuberculosis masquerading as difficult to treat Crohn disease: A case report. BMC Res Notes 2016;9:417.  Back to cited text no. 2
    
3.
Donoghue HD, Holton J. Intestinal tuberculosis. Curr Opin Infect Dis 2009;22:490-6.  Back to cited text no. 3
    
4.
Chen Y, Chao Y, Deng Q, Liu T, Xiang J, Chen J,et al. Potential challenges to the Stop TB Plan for humans in China; cattle maintain M. bovis and M. tuberculosis. Tuberculosis (Edinb) 2009;89:95-100.  Back to cited text no. 4
    
5.
Park JS, Kang YA, Kwon SY, Yoon HI, Chung JH, Lee CT,et al. Nested PCR in lung tissue for diagnosis of pulmonary tuberculosis. Eur Respir J 2010;35:851-7.  Back to cited text no. 5
    
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Rana S, Farooqui MR, Rana S, Anees A, Ahmad Z, Jairajpuri ZS. The role of laboratory investigations in evaluating abdominal tuberculosis. J Family Community Med 2015;22:152-7.  Back to cited text no. 6
    
7.
Sharma V, Mandavdhare HS, Dutta U. Letter: Mucosal response in discriminating intestinal tuberculosis from Crohn's disease-when to look for it? Aliment Pharmacol Ther 2018;47:859-60.  Back to cited text no. 7
    
8.
Wang L, Hong Y, Wu J, Leung YK, Huang Y. Efficacy of thalidomide therapy in pediatric Crohn's disease with evidence of tuberculosis. World J Gastroenterol 2017;23:7727-34.  Back to cited text no. 8
    
9.
Lin YC, Liang SJ, Liu YH, Hsu WH, Shih CM, Sung FC, et al. Tuberculosis as a risk factor for systemic lupus erythematosus: Results of a nationwide study in Taiwan. Rheumatol Int 2012;32:1669-73.  Back to cited text no. 9
    
10.
Ribeiro FM, Szyper-Kravitz M, Klumb EM, Lannes G, Ribeiro FRE, Albuquerque EMM,et al. Can lupus flares be associated with tuberculosis infection. Clin Rev Allergy Immunol 2010;38:163-8.  Back to cited text no. 10
    
11.
Shoenfeld Y, Vilner Y, Coates AR, Rauch J, Lavie G, Shaul D,et al. Monoclonal anti-tuberculosis antibodies react with DNA, and monoclonal anti-DNA autoantibodies react with Mycobacterium tuberculosis. Clin Exp Immunol 1986;66:255-61.  Back to cited text no. 11
    
12.
Isenberg DA, Maddison P, Swana G, Skinner RP, Swana M, Jones M,et al. Profile of autoantibodies in the serum of patients with tuberculosis, Klebsiella and other gram-negative infections. Clin Exp Immunol 1987;67:516-23.  Back to cited text no. 12
    
13.
Sechi LA, Scanu AM, Molicotti P, Cannas S, Mura M, Dettori G,et al. Detection and Isolation of Mycobacterium avium subspecies paratuberculosis from intestinal mucosal biopsies of patients with and without Crohn's disease in Sardinia. Am J Gastroenterol 2005;100:1529-36.  Back to cited text no. 13
    
14.
Bentley RW, Keenan JI, Gearry RB, Kennedy MA, Barclay ML, Roberts RL. Incidence of Mycobacterium avium subspecies paratuberculosis in a population-based cohort of patients with Crohn's disease and control subjects. Am J Gastroenterol 2008;103:1168-72.  Back to cited text no. 14
    
15.
Pierce ES. Where are all the Mycobacterium avium subspecies paratuberculosis in patients with Crohn's disease. PLoS Pathog 2009;5:e1000234.  Back to cited text no. 15
    


    Figures

  [Figure 1], [Figure 2]



 

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