Tuberculosis in a renal allograft recipient presenting with intussusception

Abstract

Extra-pulmonary tuberculosis (TB) is more common in renal allograft recipients and may present with dissemination or an atypical features. We report a renal allograft recipient with intestinal TB presenting 3 years after transplantation with persistent fever, weight loss, diarrhea, abdominal pain and mass in the abdomen with intestinal obstruction. He was diagnosed to be having an ileocolic intussusception which on resection showed a granulomatous inflammation with presence of acid-fast bacilli (AFB) typical of Mycobacterium tuberculosis. In addition, AFB was detected in the tracheal aspirate, indicating dissemination. He received anti-TB therapy (ATT) from the fourth postoperative day. However, he developed a probable immune reconstitution inflammatory syndrome (IRIS) with multiorgan failure and died on 11^th postoperative day. This is the first report of intestinal TB presenting as intussusception in a renal allograft recipient. The development of IRIS after starting ATT is rare in renal allograft recipients. This report highlights the need for a high index of suspicion for diagnosing TB early among renal transplant recipients and the therapeutic dilemma with overwhelming infection and development of IRIS upon reduction of immunosuppression and starting ATT.

Introduction

Tuberculosis (TB) is a common cause of morbidity and mortality among renal allograft recipients in developing countries. It presents frequently with disseminated disease and extra-pulmonary manifestations. Though T-cell immunosuppression advances the onset of TB, in some patients it manifests late with heavy net immunosuppression. The prevalence of post-transplant TB (PTTB) has been estimated to be 13.3% and 11.8% among renal allograft recipients in tertiary center reports from southern and northern India, respectively.[1,2] TB of intestine is rare and usually manifests as part of disseminated disease in immunosuppressed individuals.[3] Intestinal TB presenting with intussusception is not reported in renal allograft recipients. We report a case of a renal allograft recipient with intestinal TB who presented with intussusception 3 years after transplantation and developed features of a probable immune reconstitution inflammatory syndrome (IRIS) after starting anti-TB therapy (ATT).

Case Report

A 27-year-old man with end-stage kidney disease from chronic glomerulonephritis received a renal allograft from his mother in 2005 using prednisolone, cyclosporine and azathioprine, without induction therapy. During the immediate post transplant period, he received three intravenous pulses of methylprednisolone 1 g each daily for acute cellular rejection. He did not develop major infections till the current episode. His weight was 58 kg. He had stable graft function, with serum creatinine at 1.6 mg/dl and was on prednisolone 10 mg/d, azathioprine 100 mg/d and cyclosporine 175 mg/d, with the trough (C0) and 2-hour (C2) cyclosporine levels being 368 and 1280 ng/ml, respectively, at 6 months after transplantation.

Three years after transplantation, he presented to us with 4 months history of fever, weight loss of 16 kg in 4 months, episodic small volume diarrhea and diffuse abdominal pain with occasional hematochezia. He did not have pulmonary or other gastrointestinal symptoms. He discontinued cyclosporine 4 months prior to visiting our center. At presentation, he was on prednisolone (10 mg/d) and azathioprine (100 mg/d). On examination, his weight was 38 kg, and pulse rate, blood pressure, respiratory rate were normal. He was pale but did not have icterus or peripheral lymphadenopathy or allograft tenderness. He had a diffuse, ill-defined, firm, tender mass (9 × 7 cm) in the right hypochondrium. There was no hepatosplenomegaly or ascites.

Laboratory investigations revealed anemia (hemoglobin of 6.7 g/dl), a total leukocyte count of 4200/mm³, a normal platelet count and serum albumin of 2.2 g/dl. He had renal allograft dysfunction (serum creatinine of 3.1 mg/dl) with normal electrolyte profile and liver enzymes. His chest radiograph revealed an ill-defined minimal haziness in the right upper and midzones with minimal pleural effusion. Ultrasonogram of abdomen showed an intussusception mass measuring 7.1 × 5.0 × 10.1 cm in the right hypochondrium with a few enlarged mesenteric nodes and fat within and adjacent to it [Figure 1a]. The renal allograft appeared normal. Computed tomogram (CT) scan of abdomen with rectal contrast revealed an ileocolic intussusception up to the hepatic flexure with multiple enlarged mesenteric nodes and mesenteric fat pulled into it [Figure 1b]. The ascending colon was thick. The para-aortic, mesenteric and para-iliac nodes were enlarged and showed central necrosis.

Figure 1.

(a) Ultrasound image showing the echogenic mesenteric fat (arrow) within the intussusception. (b) Non-contrast enhanced CT scan image shows findings suggestive of an intussusception. The mesenteric fat around the intussusceptum is seen entering into the intussuscipiens

The patient underwent an emergency exploratory laparotomy with resection of the ileocolic intussusception, the adjacent ascending colon and terminal ileum [Figure 2a]. Histopathological examination of the ileocolic intussusception revealed fragments of a lymph node with extensive caseation necrosis and many acid-fast bacilli (AFB). The proximal polypoidal lesion of the intussusceptum and the mucosal ulcerations of the intussuscepient colonic segment revealed dense inflammatory infiltrates of lymphocytes and plasma cells, along with microabscesses in the submucosa and lamina propria, transmural granulomas with epitheloid histiocytes, lymphocytes; Langhans type multinucleated giant cells and central foci of caseation [Figure 2b and d]. Long, curved and beaded AFB, morphologically typical of Mycobacterium tuberculosis (MTB), were detected in all the above-mentioned lesions [Figure 2c].

Figure 2.

(a) Surgical specimen of the resected intussusception mass showing the terminal ileum (arrow) intususscepting into the colon (^*). The lumen is demonstrated by the clamp. (b) Histopathological examination of the colonic wall showing submucosal caseating granulomata and several Langhans type multinucleate giant cells (Hematoxylin and Eosin, ×50). (c) Acid-fast staining of the tissue specimen revealed numerous long, curved and beaded pink staining acid-fast bacilli (Ziehl-Neelson, ×1000). (d) Langhans multinucleate giant cells are formed by the fusion of epithelioid macrophages with nuclei arranged in a horse-shoe pattern at the periphery of the cell (Hematoxylin and Eosin, ×100)

On the first postoperative day, the patient received hydrocortisone 100 mg thrice daily, but azathioprine was discontinued due to leukopenia (WBC count 1900/mm³). He received granulocyte colony stimulating factor for leukopenia. On the second postoperative day, he was weaned off mechanical ventilation. On the fourth postoperative day, he received ATT with isoniazid 300 mg/d, rifampicin 450 mg/d, pyrazinamide 750 mg/d and ethambutol 400 mg/d. On the fifth postoperative day, 36 hours after starting ATT, he developed tachycardia, tachypnea, hypotension, oliguria and worsening of pulmonary oxygenation [partial pressure to inspired fraction of oxygen ratio (P–F ratio)]. The chest radiograph revealed worsening of the preexisting haziness. However, there was no bacteremia or evidence of invasive fungal infection.The total leukocyte count had remained about 4500 cells/mm³ during this period. His condition subsequently worsened, and he received broad-spectrum antibiotics (piperacillin with tazobactam) while routine cultures remained sterile. A tracheal aspirate showed numerous AFB morphologically typical of MTB, though there was no growth in culture. In addition, tracheal aspirate grew mixture of non-fermenting gram negative bacilli and Candida glabrata, which were probably contaminants. He continued to develop worsening features of a systemic inflammatory response syndrome, lung infiltrates, and disseminated intravascular coagulation. Steroids were continued, antibiotics were changed empirically to meropenem with teicoplanin and liposomal amphotericin B. The patient died on the 11^th postoperative day. The next of kin declined post-mortem examination.

Discussion

The prevalence of PTTB in renal allograft recipients is 0.3–1.7% in the United States and Europe,[2,4,5] but comparatively higher in the developing countries (3.1–15.2%).[1,2,6] Renal allograft recipients commonly present with extra-pulmonary TB (51.8%). Among them, disseminated TB is the commonest (19.3%), followed by pyrexia of unknown origin (15.7%), TB lymphadenopathy (4.8%), involvement of skin and soft tissue (4.2%), intestine (3%), central nervous system (1.8%), bone (1.2%), pericardium (1.2%) or urinary tract (0.6%).[1] T-cell immunosuppression favors dissemination of mycobacteria and varied presentation.

Prevalence of gastrointestinal tuberculosis (GITB) ranges from 0.2 to 0.6% among renal allograft recipients[5,7] and accounts for 3% of the cases of PTTB in developing countries.[1] Post-transplant GITB is even rarer in developed countries (one in 15,870 renal allograft recipients).[8]

The time of presentation of PTTB varies with the type of immunosuppression. Cyclosporine advances the onset of PTTB from a median of 26 months (for patients on prednisolone and azathioprine regimen) to 11.5 months.[1] Patients receiving cyclosporine seldom develop recrudescent TB later than 6 years.[1,9,10] The median time to onset of TB in renal transplant recipients is longer than that for other solid organ transplants (11.5 vs. 3.5–4 months).[11] GITB usually presents within 2 years of transplantation: 32% being in 1^st year and 64% by 2 years. Our patient presented 3 years after transplantation, despite being on cyclosporine. The classical risk factors implicated in the development of TB such as a longer period on hemodialysis, pre-transplant diabetes mellitus, induction immunosuppression with anti-CD25 monoclonal antibodies, >3 episodes of rejection and treatment of rejection with antilymphocyte globulin and bolus corticosteroids[12,13] were absent in our patient.

The common presenting symptoms of GITB in non-transplant patients are abdominal pain, weight loss, fever and change in bowel habit. However, in renal allograft recipients, the most common symptom is GI bleed, followed by fever and abdominal pain. Most common sites of involvement of GITB are the ileocecal and jejunoileal regions (>75%) in the general population,[11,14] often presenting as colitis, cecal perforation and acute abdomen.[15,16] Our patient presented with weight loss, hematochezia, and an abdominal mass suggesting an ulcerative lesion, often seen with gastrointestinal malignancies. Though GITB commonly involves the ileocecal region, intussusceptions have not been reported among adults. Barium enema and small bowel series may show ulceration or nodularity of the GI mucosa, in terminal ileum though these changes are non-specific. CT imaging may show inflammation, ascites and lymphadenopathy. The gold standard remains characteristic histomorphological findings with demonstration of AFB and/or growth of MTB in culture.[17]

Paradoxical deterioration after initiation of ATT was described less than a decade ago in human immunodeficiency virus infected patients with immune recovery following introduction of highly active antiretroviral therapy (HAART). It appears to be an unexpected consequence of HAART in patients suddenly experiencing clinical deterioration after a biological response to treatment.[18] In patients with HIV infection, there have been few proposed criteria for the definition of IRIS.[19] Though there is no standard consensus definition of IRIS in non-HIV settings, there is substantial evidence to show that improvement in immune function could result in pathological inflammation. This type of paradoxical response has been seen in non–HIV-infected patients treated for MTB infection.[20] This is presumed to be reversal of immunosuppression that MTB infection induces.[20] This effect also has been seen in patients with Mycobacterium leprae infection and also in patients post stem cell transplantation during immune recovery.[21,22] This is normally associated with clinical deterioration.

The proposed pathogenesis in IRIS is complex and points toward a pro-inflammatory response.[18] On one hand, antitimicrobial agents and iatrogenic immunosuppressant result in an immunological milieu which is anti-inflammatory and immunosuppressive. On the other hand, appropriate antimicrobial therapy, withdrawal of immunosuppressant and administration of immunostimulatory agents like colony stimulating factors result in a pro-inflammatory response that finally results in IRIS.[18] One of the reasons of our patient's clinical deterioration, we believe, was related most probably to IRIS. His cyclosporine was withdrawn 4 months ago and azathioprine in the immediate post-surgical period, he was started on appropriate antimicrobial therapy in combination with ATT therapy and he had received G-CSF. All these are presumed to tilt the balance toward a pro-inflammatory state and promote the occurrence of IRIS. His clinical deterioration was marked by tachypnea, tachycardia, and hypotension and worsening of a preexisting lung infiltrate.

This clinical syndrome in the absence of evident bacterial or fungal infection is suggestive of an IRIS. IRIS was observed in 5% of solid organ transplantation recipients with systemic mycosis.[18] Though TB related IRIS has been reported in a heart lung transplant recipient,[23] this is probably the first report of a probable IRIS in a renal allograft recipient with TB. IRIS could masquerade as failure of therapy or relapse of TB. It is important to recognize this syndrome and institute appropriate and timely therapeutic alteration.

Mortality among renal allograft recipients with PTTB varies from 23 to 32%[2,8] GITB is associated with a mortality rate up to 55%.[4] The occurrence of IRIS would contribute a further increase in the mortality rate.

This case report is noteworthy for the late presentation of disseminated TB manifesting an intussusception and a probable IRIS after initiation of ATT.

Conclusion

Disseminated TB manifesting with intestinal involvement and intussusception is distinctly unusual in a transplant recipient, and ATT along with clinically appropriate alteration of immune status with withdrawal of immunosuppressants or use of immunostimulants could trigger an IRIS. The diagnosis and management of PTTB can be complex and challenging.