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Esophageal Tuberculosis Infection in a Simultaneous Pancreas and Kidney Transplant Recipient

S Rahmatulla1, A Marshall2, S Bhagani3, GL Jones1 and DP Gale1*
1Centre for Nephrology, Royal Free Hospital, University College London, UK
2Centre for Gastroenterology, Royal Free Hospital, London, UK
3Department of Infectious Diseases/HIV Medicine, Royal Free Hospital, London, UK
Corresponding Author : Daniel P Gale
Centre for Nephrology, Royal Free Hospital
University College London, NW3 2PF, UK
Tel: 02078302695
Fax: 02073178591
E-mail: [email protected]
Received May 22, 2014; Accepted June 30, 2014; Published August 20, 2014
Citation: Rahmatulla S, Marshall A, Bhagani S, Jones GL, Gale DP (2014) Esophageal Tuberculosis Infection in a Simultaneous Pancreas and Kidney Transplant Recipient. Gen Med (Los Angel) 2:144. doi: 10.4172/2327-5146.1000144
Copyright: © 2014 Rahmatulla S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Solid organ transplant recipients are at increased risk of opportunistic infections, including tuberculosis, which may be caused by re-activation of latent disease or acquired de novo. Tuberculosis can affect any organ, present atypically, is diagnostically challenging and potentially fatal. Esophageal tuberculosis is generally rare, and usually secondary to infection in adjacent mediastinal structures. We report a case of esophageal tuberculosis in a simultaneous pancreas-kidney transplant recipient, who presented with symptoms of odynophagia, retrosternal chest pain, weight loss and dry cough, three years post-transplantation. Initial upper gastrointestinal endoscopy revealed non-specific inflammation but no identifiable cause. Repeat endoscopy revealed severe ulceration with a lower esophageal stricture. Multiple esophagealbiopsies taken demonstrated granulomatous inflammation, and evidence of acid-fast bacilli on Ziehl- Neelsen staining. Polymerase Chain Reaction (PCR) assay was specific for Mycobacterium tuberculosis. Computerized tomography (CT) of the patient’s thorax showed evidence of pulmonary disease and fully sensitive Mycobacterium tuberculosis was cultured from the esophageal tissue biopsies, confirming a diagnosis of secondary esophageal tuberculosis.The patient was treated with 6 months of anti-tuberculous therapy, following which she had made a full recovery. This case illustrates firstly an unusual manifestation of tuberculosis in an immunocompromised patient; secondly the importance of thorough and persistent investigation of unexplained symptoms in this group; and thirdly that tuberculosis should always be considered as it may occur even in patients who do not fulfill conventional criteria for prophylactic therapy.

Tuberculosis; Esophageal tuberculosis; Renal transplant; Simultaneous pancreas-kidney transplant
Renal and other solid organ transplant recipients are at a significantly increased risk of pulmonary and extra-pulmonary tuberculosis compared with the general population [1,2], particularly in the first year post-transplant. Diagnosis of post-transplant tuberculosis is a challenge, especially in the setting of extra-pulmonary disease. In the face of immunosuppression the disease may present with atypical or non-specific symptoms that can be attributed to other conditions. The absence of pathognomic features on imaging and frequently inconclusive histopathology findings can make the diagnosis difficult to make. Delayed institution of treatment, coupled with drug interactions during therapy, is linked to the high morbidity and mortality in this condition. A high index of clinical suspicion is therefore paramount [2,3].
Mycobacterial infection of the esophagus is a rare but serious condition, which can be difficult to diagnose, especially where evidence of extra-esophageal tuberculosis is lacking. Most previously reported cases are secondary to spread from infected mediastinal lymph nodes, or lungs [4].
We report the case of a simultaneous pancreas-kidney transplant recipient with secondary esophageal tuberculosis associated with subclinical pulmonary disease.
Case Report
A 47-year-old United Kingdom (UK) born woman of Jamaican ancestrywas seen in the renal transplant outpatient clinic with a 2-month history of odynophagia, retrosternal chest pains and 3-kilogramweight loss. She also had a dry cough, which had been previously investigated and diagnosed as gastro-esophageal reflux disease. Seven months prior to presentation, she had a fine needle aspiration of a painless enlarged right submandibular lymph node, which showed no evidence of malignant disease. The swelling subsequently resolved.
The patient had no history of previous tuberculosis infection and had no close contact withanyone diagnosed with tuberculosis. There was no history of smoking, alcohol or illicit drug use and there had been no recent foreign travel.
She had a background of insulin dependent diabetes mellitus since the age of ten with resulting nephropathy, peripheral neuropathy and retinopathy. She had been approaching end stage renal disease when she received a simultaneous pancreas-kidney transplant 3 years previously. Her induction therapy was Alemtuzumab and she was maintained on dual immunosuppressive therapy with tacrolimus and mycophenolatemofetil. Otherthan a single episode of Gram negative bacterial transplant pyelonephritis, she had been well with no delayed graft function or acute rejection episodes. The function of both kidney and pancreas transplants were good with a creatinine of 120 μmol/l and a normal glycatedhemoglobin, without the requirement for insulin. Other past medical history included hypertension andHerpes simplex virus (HSV) genital ulcers treated with aciclovir.
Clinical examination revealed mild epigastric tenderness. There was no lymphadenopathy, hepatosplenomegaly, oro-cutaneous lesions or oral thrush. She had a mild normochromic normocytic anemia (Hb 11.4 g/dL, MCV 89fL), suppressed lymphocyte count of 0.61×109/L, stable kidney allograft function, with a creatinine of124 μmol/l, and elevated C-reactive protein (CRP) of 63g/dL. Amylase was47 IU/L and tacrolimus levels were 5.2 ng/mL. Serum PCR tests for Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) DNA were negative. Human immunodeficiency virus (HIV) -1 and -2 was negative and Helicobacter pylori stool antigen was negative. Urine and blood microscopy and cultures were negative.
An upper gastrointestinal endoscopy showed severe esophagitis and duodenitis. Histological examination of the sampled tissue revealed squamous epithelium and underlying stroma with marked chronic active inflammation and ulceration. There was nohistological evidence of dysplasia, malignancy, granulomata, fungi or viral inclusions and tissue PCR tests for CMV and HSV were negative. She was initially thought to have severe gastro-esophageal reflux or a complication of her mycophenolate therapy and was commenced on lansoprazole with conversion of mycophenolatemofetil to azathioprine.
Despite management with multiple combinations of Histamine H2 receptor antagonists, proton pump inhibitors, coating agents and prokinetics there was no symptomatic improvement. Over the following 2 months she developed dysphagia and occasional night sweats with a further 7 kilograms weight loss. Her chest X-ray was normal but given the history of coughwith night sweats and weight loss in an immunocompromised patient, a CT scan of the chest/abdomen/ pelvis was performed. This showed minimal upper lobe tree in bud appearances in the right apex, with no evidence of lymphadenopathy (Figure 1a) and thickening of the distal esophagus (Figure1b).
A repeat upper gastrointestinal endoscopy revealedesophagitis commencing at 26 cm with confluent ulceration (Figure 2a) and an esophageal stricture at 35 cm that could not be passed with an endoscope (Figure 2b). The stricture had not been apparent on endoscopy two months earlier. A nasogastric tube was inserted with endoscopic guidance and feeding was commenced due to malnourishment.
Histological examination of multiple specimens obtained from the ulcerated areas and the stricture showed granulomatous inflammation with evidence of necrotizing granuloma (Figure 3a). Ziehl-Neelsen staining showed the presence of acid-fast bacilliin keeping with mycobacterial infection (Figure 3b). Immunohistochemistry was negative for HSV and CMV. PCR assay of the biopsy tissue confirmed the presence of rifampicin-sensitive Mycobacterium tuberculosis.No mycobacteria were identified in an induced sputum specimen and the patient was unable to tolerate a bronchoscopy.
The histological findings together with the clinical presentation confirmed the diagnosis of tuberculosis affecting the esophagus and the patient was commenced on anti-tuberculosis therapy with isoniazid, rifampicin, pyrazinamide and ethambutol, which was well tolerated. Constitutional symptoms resolved rapidly, however odynophagia and dysphagia persisted requiring an extended period of feeding via a naso-jejunal tube. A subsequent endoscopy six weeks later revealed persistence of the tight esophageal stricture that was unable to accept the endoscope. Culture of the biopsies confirmedinfection with a fully sensitive Mycobacterium tuberculosis.The patient was treated for 6 months with anti-tuberculous therapy over which period naso-jejunal feeding was no longer required. One year after diagnosis (at most recent follow up) she reported no odynophagia or dysphagia and had regained all of her previous weight.
Compared with the general population, solid organ transplant recipients are more susceptible to infections (Table 1) [5-6], including Mycobacterium tuberculosis, and prognosis is less favorable. While the lungs are the most commonly affected site, tuberculosis can affect virtually any organ. Extra-pulmonary manifestations post transplantation is more common than in the general population and early detection with appropriate treatment is crucial for successful outcome [1-3].
Post-transplantation infection with tuberculosis occurs more commonly in people with a previous history of tuberculosis [7], possibly due to reactivation of latent disease but other risk factors have been described [8-10]. In our case, risk factors were long-standing diabetes pre-transplantation and immunosuppressive agents. Ethnic groups with an increased risk of tuberculosis have been described [11]. Patients born in endemic countries and residing in the UK for <5 years are at a significantly increased risk and screening, with subsequent chemoprophylaxis, is routinely considered [11]. Our patient might have been considered to be at increased risk for tuberculosis given her non-UK ancestry, however tuberculosis is not endemic in Jamaica [12,13] and her UK birth and residence meant that she did not fulfill local criteria for prophylactic anti-tuberculous therapy. It is not clear whether the infection in our case was due to reactivation of latent infection or primary progressive disease, however the 3-year interval between transplantation and presentation favors the latter in our case, since reactivation of latent tuberculosis tends to manifest in the first 12 months following transplantation [14,15].
Esophageal tuberculosis is rare in both immunocompetent and immunocompromised patients, even in endemic areas [4,16], accounting for 0.3% of all reported gastrointestinal tuberculosis cases [17]. This is likely due to protective oesophageal mechanisms, including the mucus- and saliva-coated stratified squamous epithelial lining of the oesophagus and peristalsis that encourages rapid transit and prevents stasis of swallowed material that might lead to mucosal invasion by pathogens [18]. Primary esophageal tuberculosis is extremely rare and most reported cases are due to secondary esophageal infection by direct extension from infection in the lungs, mediastinal lymph nodes, thoracic spine, or larynx or by lymphohematagenous spread [16,19]. A CT chest is mandatory to look for evidence of pulmonary disease, which was suggestive in our case.
Endoscopic features of tuberculosis are variable and non-specific. While tuberculosis can affect any segment of the esophagus, it occurs most commonly at the mid esophagus because of its close proximity to the hilar and mediastinal lymph nodes around the bifurcation of the trachea and the most common macroscopic endoscopic finding is a solitary shallow linear ulcer with smooth edges and a necrotic base [16,19]. Commonly, these linear ulcers are associated with an extrinsic bulge of the mid esophagus [20]. Other findings at mid-esophagus include larger polypoid or ulcerated mass lesions and submucosal ulcers, which may occupy nearly half of the esophageal lumen [16]. Such mass lesions may mimic the appearance of an esophageal neoplasm especially when associated with a stricture [21] and indeed the two co-morbidities may co-exist [19]. Less common endoscopic findings include fistula [22], sinus, diverticulum [4] and esophageal stricture [19], which was evident in our case. Less frequently, tuberculous involvement of the proximal esophagus may occur and resembles multiple large deep ulcers with irregular margins [23], while distal involvement may present either as ulceration or manifest as hyperemic patches and nodules, features also seen in peptic esophagitis [24].
Dysphagia is the most common presenting complaint of esophageal tuberculosis. Odynophagia, retrosternal chest pains and non-specific constitutional symptoms such as fevers, weight loss and malaise may also be present [4,14,17]. In a transplant recipient, dysphagia and odynophagia are often associated with infections such as candidiasis and viruses such as CMV and HSV. Non-infective causes of esophageal ulceration include use of corticosteroids and mycophenolatemofetil [25]. Therefore the diagnosis was not immediately suspected. To our knowledge, this is the first reported case of esophagitis as the presenting feature of tuberculosis infection in a transplant recipient.
Histological diagnosis from endoscopic tissue showing caseatingtuberculous granulomas is present in only 50% of cases, and demonstration of acid-fast bacilli on Ziehl-Neelsen stainingis present in less than 25% of cases following a single endoscopy session [22,26]. As in the first endoscopic examination in this case, histology is often inconclusive and shows non-specific inflammation [4]. This could be due to inadequate sampling, under-representation of submucosal tissue at biopsy, where tuberculous granulomas tend to reside [27], and its pauci-bacillary existence in extra-pulmonary organs [28]. Repeat endoscopy with multiple tissue sampling was crucial to making the diagnosis in our case.
Esophageal tuberculosis is treated with standard quadruple antituberculosis agents. Close monitoring is required given the risk of hepatotoxicity and interaction with immunosuppressive agents [1]. Rifampicin will reduce levels of tacrolimus and can precipitate acute graft rejection [29]. Dilation of stricture has been performed [30] and surgery is reserved forcomplications such as fistulating disease [22].
Tuberculosis is a multi-systemic disease and involvement of unexpected organs such as the esophagus is a serious consequence, especially in the context of an immunosuppressed transplant recipient. Diagnosis of esophageal tuberculosis can be challenging and delayed due to non-specific histopathology findings. This case highlights:
1. The value of repeating an initially non-diagnostic endoscopic examination.
2. The importance of a high index of suspicion for mycobacterial infection causing clinical features more commonly caused by drugs or infection with bacteria, fungi or viruses, especially when accompanied by prolonged systemic symptoms such as fevers and night sweats.
3. The need to consider tuberculosis even in patients who do not fulfill the criteria for prophylaxis.
The authors would like to thank the patient. DPG is supported by an MRC Clinician Scientist Fellowship. SR and DPG wrote the manuscript with contributions from all authors who looked after the patient.

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