Extrapulmonary Latent Tuberculosis Reactivation ...

CASE REPORT

Extrapulmonary Latent Tuberculosis Reactivation After Negative Screening Tests in a Liver Transplant Recipient Jose Armando Gonzales Zamora, MD,* Sanjeev Patil, MD,† Arvind R. Murali, MD,† and Sarah Hoehnen, MD‡

Background: Posttransplant tuberculosis (TB) is an uncommon complication following liver transplantation (LT). Given its high mortality, it is advocated to screen for latent TB with tuberculin skin test (TST), interferon γ release assay and/or chest radiography before LT. Case Report: A 52-year-old Filipino gentleman was admitted with an 8-week history of abdominal pain, hematochezia, and weight loss. His pre-LT screening for latent TB with TST and chest radiography was negative. Colonoscopy revealed an ulcerated polypoid lesion in the terminal ileum. The cause of ulceration was histologically indeterminate. Because a lymphoproliferative disorder was suspected, a right hemicolectomy was done during which hard white studding was noted in the distal small bowel. Induration and a mass formation in the terminal ileum and the cecum were also seen. Histopathology showed necrotizing granulomas. Stain for acid– fast bacilli was negative. The strong suspicion for TB prompted us to obtain a chest computed tomography scan, which showed calcified perivascular and left hilar lymph nodes reflecting prior granulomatous disease. QuantiFERON-TB Gold In-Tube Test was positive. Treatment with standard anti-TB regimen was initiated. Two weeks later, cultures from intestinal tissue grew Mycobacterium tuberculosis. The patient reported a complete resolution of his symptoms at 3-month follow-up. Conclusions: Chest computed tomography scan and interferon γ release assays in conjunction with TST and chest radiograph may improve the detection of latent TB in transplant candidates. Combining these tests to diagnose latent TB is a strategy that needs to be evaluated in future studies. Key Words: chest computed tomography scan, gastrointestinal tuberculosis, interferon γ release tests, latent tuberculosis, liver transplantation, tuberculin test (Infect Dis Clin Pract 2017;00: 00–00)

L

iver transplant (LT) candidates are screened for latent TB before transplantation with tuberculin skin test (TST), interferon γ release assays (IGRAs), and chest radiograph. However, there is no criterion standard to confirm a diagnosis of latent TB, and hence, assessments of the accuracy of these tests are difficult. It is plausible that some patients with latent TB are missed during pre-LT screening, and they may present with active TB infection after LT as a result of their immunosuppressed state. Because of its rarity in the United States, the detection of a TB case is often delayed, which could become catastrophic in the posttransplant period.

From the *Division of Infectious Diseases, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL; †Gastroenterology Department, University of Iowa Hospitals and Clinics, Iowa City, IA; and ‡AIDS Healthcare Foundation, Cleveland, OH. Correspondence to: Jose Armando Gonzales Zamora, MD, Division of Infectious Diseases, Department of Medicine, University of Miami, Miller School of Medicine, 1120 NW 14th St, Suite 863B, Miami, FL 33136. E‐mail: [email protected]. This case was presented as a poster in the 2015 American College of Gastroenterology Meeting, which took place in Honolulu, HI. The authors have no funding or conflicts of interest to disclose. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1056-9103

CASE REPORT A 52-year-old gentleman, originally from the Philippines, received an orthotopic LT for decompensated cirrhosis from hepatitis B. His other comorbidities included schizophrenia, hypertension, and diabetes mellitus type 2. Prior to LT, he had a negative screening for latent TB by means of TST and chest radiograph. The epidemiologic history did not reveal any prior TB exposure or incarceration. His immunosuppressive regimen consisted of tacrolimus and mycophenolate mofetil. His hepatitis B viral load was suppressed with adefovir and lamivudine. Two years after LT, the patient was admitted to the hospital with complaints of intermittent hematochezia and abdominal pain in the last 8 weeks. He also noticed a 70-lb weight loss. Physical examination revealed tenderness to palpation in the right upper and lower abdominal quadrant, but no rebound or guarding was noted. Bowel sounds were hyperactive. An abdominal computed tomography (CT) scan showed marked thickening of ascending colon, cecum, appendix, and terminal ileum with associated mesenteric stranding.1 No ova or parasites were detected in stool. Strongyloides serology was negative. Fecal Clostridium difficile polymerase chain reaction was positive, and treatment with metronidazole was initiated. Repeat C. difficile testing was negative. Given continuousness of symptoms, the patient had a colonoscopy, which showed a 50% circumferential ulcerated polypoid mass at the junction of the cecum and ileocecal valve. Histopathology revealed fragments of inflammatory-type polyp with ulceration without dysplasia or malignancy.1 The cause of ulceration was indeterminate by means of histology. Immunostaining was negative for herpes simplex virus, cytomegalovirus, and acid– fast bacilli. Culture was negative for Mycobacterium tuberculosis. Xpert MTB/Rif was not done. At 1-month follow-up, the patient complained of an additional 30-lb weight loss, occasional vomiting, and night sweats. Because of concern for post-LT lymphoproliferative disease, he was taken for a right hemicolectomy. In the operating room, upon entering the bowel, hard white studding was noted throughout the entire small bowel (Fig. 1). Induration and a masslike conglomeration were appreciated in the terminal ileum and cecum. Multiple samples were sent for frozen section, which revealed granulomas. The patient underwent a right hemicolectomy with removal of involved cecum and terminal ileum and endend anastomosis. Because of strong suspicion for tuberculosis (TB), a chest CT scan was done. It showed few small calcified perivascular left hilar lymph nodes reflecting prior granulomatous disease. QuantiFERON-TB Gold In-Tube Test (QFT-GIT) was also requested and yielded a positive result. Final histopathology from operating room specimens revealed severe and extensive transmural enterocolitis and necrotizing granulomas in the ileum, colon, appendix, and several regional lymph nodes (Fig. 2). Stains for acid–fast bacilli and fungi were negative. The patient was started on 4-drug therapy for TB with isoniazid, rifampin, pyrazinamide, and ethambutol. Two weeks later, cultures grew acid–fast bacilli that were identified as M. tuberculosis

Infectious Diseases in Clinical Practice • Volume 00, Number 00, Month 2017

www.infectdis.com

Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

1


Gonzales Zamora et al

with DNA probe. At 3-month follow-up, the patient reported complete resolution of symptoms.

DISCUSSION Posttransplant TB is a well-described complication for solid organ transplant recipients especially in endemic areas. In India, TB complicates 12% to 20% of renal transplants, resulting in a mortality rate of 20% to 25% in affected patients. In developed countries, the frequency is much lower and ranges from 1.2% to 6.4%.2 This number represents an incidence 25 to 50 times higher than that observed in the general population. Several trials have described multiple factors associated with TB in transplant recipients. A study conducted at Columbia University Medical Center in New York has identified renal transplantation and nonwhite ethnicity as factors associated with this infection.3 Other reported factors include immunosuppressive treatment with OKT3 or anti–T-cell antibodies, diabetes mellitus, and coexisting infections. Posttransplant TB is even more uncommon following LT with a prevalence of 0.6% in the United States and Canada. The immunocompromised state of these patients makes them prone to develop atypical manifestations for any infection. Tuberculosis in particular has a propensity to involve extrapulmonary sites. As a matter of fact, Holty and colleagues4 hold that extrapulmonary TB is the most common manifestation of TB in LT recipients and can occur in 67% of TB cases. Gastrointestinal TB corresponds to the fifth major affected site of extrapulmonary TB after LT with a reported frequency of 6% among these patients.4 When TB affects the intestinal tract, the most frequent site of involvement is the ileocecal junction followed by the ileum, cecum, and ascending colon. The diagnosis of this form of extrapulmonary TB can be challenging. Endoscopic studies may show a variety of mucosal changes that include ulcerative and proliferative lesions. Computed tomography is an important diagnostic tool to evaluate the extension of the disease; however, it cannot provide a definitive diagnosis because it shows only nonspecific mucosal thickening.5 Laparotomy with biopsy may be needed for making a diagnosis in certain patients with nondiagnostic colonoscopic findings or in patients presenting with complications such as perforation and intestinal obstruction. Histopathology features are not pathognomonic for intestinal TB and can resemble inflammatory bowel disease, particularly Crohn disease. Isolation of M. tuberculosis is the only way to achieve a definitive diagnosis, which is

FIGURE 1. Macroscopic view of small bowel showing white studding of the terminal ileum.

2

www.infectdis.com

FIGURE 2. Histopathologic examination of the terminal ileum showing a necrotizing granuloma (hematoxylin-eosin stain, original magnification 200).

usually difficult given the scarce number of bacilli found in extrapulmonary TB. Our patient had an extensive disease affecting the ileum, cecum, and ascending colon. To complicate his presentation, he also had a proliferative form of this disease, making intestinal TB easily confounded with a malignant process. Fortunately, we were able to make a definitive diagnosis based on a positive culture for M. tuberculosis obtained from intestinal tissue. Given the high mortality of this infection in transplant recipients, it is advocated as a general rule to screen for latent TB infection. There are 2 available tests that can be used for this purpose, the TST and the IGRA; however, both tests have low sensitivity in immunocompromised hosts. Current guidelines recommend that all the patients should have a TST performed prior to solid organ transplantation.6 Few studies have evaluated IGRAs in this population. In patients with end-stage renal disease and advanced liver disease, IGRAs seem to have a higher sensitivity than TST. For this reason, their use in these cases is preferred.7,8 One of the caveats of IGRAs in LT candidates is their high rate of indeterminate results, which can be as high as 40%.9 Two IGRAs that have been approved by the US Food and Drug Administration are commercially available in the United States: QFT-GIT and T-SPOT.TB test (T-Spot). The IGRA used in our patient was QFT-GIT. Many approaches have been proposed to improve the sensitivity of these screening tools. One of them is the performance of a second TST 1 week after an initial negative result, which can lead to the identification of an additional 10% of patients because of the boosting phenomenon.10 Another measure that has been tried is sequential testing with IGRAs and TST. By this means, the yield of latent TB detection can increase from 46.3% to 55.8%, especially in immunocompromised patients such as LT candidates.7 The same scenario has been observed in HIV patients in whom TST in combination with IGRA can improve the sensitivity of latent TB diagnosis in 17%.11 This evidence has led the European Centre for Disease Prevention and Control to adopt the use of TST and IGRA in combination as the best method of latent TB diagnosis in high-risk patients.12 We have to be cognizant about the potential boosting effect of TST on IGRA responses. This phenomenon can confound the interpretation of IGRA results. The studies have shown that this boosting effect can occur after 3 days of TST placement and can persist for up to 3 months.13 Our patient had an IGRA done 2 years after the placement of TST; therefore, his positive IGRA result cannot be attributed to a TST boosting phenomenon. © 2017 Wolters Kluwer Health, Inc. All rights reserved.



Extrapulmonary Latent TB Reactivation

REFERENCES

Other important factors to consider in the evaluation of latent TB infection are close contact with a person with active TB and radiographic changes consistent with prior granulomatous disease. The presence of these factors should prompt treatment for latent TB infection regardless of tuberculin reactivity or IGRA results, especially in patients coming from endemic countries. It is important to mention that chest CT scan has also been evaluated for the diagnosis of latent TB in LT candidates and has demonstrated a higher detection rate when compared with chest radiograph in a setting of high TB endemicity. Lyu and colleagues14 found that in patients who developed TB after LT a chest CT scan performed in the pretransplant period suggested healed TB in 40% of the cases. Chest radiograph was able to detect abnormalities in only 25% of these patients. Of note, our patient had a negative PPD and a normal chest radiograph before undergoing LT; however, a QFT-GIT done afterward was positive. In addition, a chest CT scan performed after surgery showed evidence of prior granulomatous disease. Based on these findings, we postulate that our patient developed intestinal TB as a result of reactivation of latent TB infection in a setting of severe immunosuppression. We think that this case of latent TB could have been detected in the pretransplant period if IGRA and chest CT scan had been done as part of the screening evaluation.

4. Holty JE, Gould MK, Meinke L, et al. Tuberculosis in liver transplant recipients: a systematic review and meta-analysis of individual patient data. Liver Transpl. 2009;15:894–906.

CONCLUSIONS

8. Ferguson TW, Tangri N, Macdonald K, et al. The diagnostic accuracy of tests for latent tuberculosis infection in hemodialysis patients: a systematic review and meta-analysis. Transplantation. 2015;99:1084–1091.

The development of TB as a result of reactivation in the posttransplant period poses multiple challenges. The atypical presentation and high frequency of extrapulmonary involvement may lead to a delay in diagnosis and treatment. Our case illustrates the poor sensitivity of TST for the detection of latent TB in LT candidates secondary to the high frequency of anergy in this population. In addition, it suggests that a more detailed TB risk assessment is needed in the pretransplant period and should include not only TST, chest radiograph, and epidemiologic factors, but also IGRAs and potentially chest CT scan especially in patients coming from high-endemic areas. This suggested approach has the disadvantage of raising costs significantly and could demand state-of-the-art technology in order to diagnose latent TB. Therefore, treating all the LT candidates for latent TB could be the most cost-effective measure specifically in patients coming from high-endemic countries. These strategies need to be evaluated in future studies. ACKNOWLEDGMENTS The authors thank Sonal Patel, PharmD, for helping them with the manuscript edition.

© 2017 Wolters Kluwer Health, Inc. All rights reserved.

1. Patil AMS, Gonzales Zamora J, Hoehnen S. Intestinal tuberculosis after liver transplantation: are current pre-transplant latent TB screening tests adequate? Am J Gastroenterol. 2015;110(1):S359. 2. Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clin Infect Dis. 1998;27:1266–1277. 3. Lopez de Castilla D, Schluger NW. Tuberculosis following solid organ transplantation. Transpl Infect Dis. 2010;12:106–112.

5. Ozbülbül NI, Ozdemir M, Turhan N. CT findings in fatal primary intestinal tuberculosis in a liver transplant recipient. Diagn Interv Radiol. 2008;14: 221–224. 6. Fischer SA, Lu K, AST Infectious Diseases Community of Practice. Screening of donor and recipient in solid organ transplantation. Am J Transplant. 2013;13(suppl 4):9–21. 7. Casas S, Muñoz L, Moure R, et al. Comparison of the 2-step tuberculin skin test and the QuantiFERON-TB Gold In-Tube Test for the screening of tuberculosis infection before liver transplantation. Liver Transpl. 2011;17:1205–1211.

9. Theodoropoulos N, Lanternier F, Rassiwala J, et al. Use of the QuantiFERON-TB Gold interferon-gamma release assay for screening transplant candidates: a single-center retrospective study. Transpl Infect Dis. 2012;14:1–8. 10. Muñoz P, Palomo J, Muñoz R, et al. Tuberculosis in heart transplant recipients. Clin Infect Dis. 1995;21:398–402. 11. Elzi L, Steffen I, Furrer H, et al. Improved sensitivity of an interferon-gamma release assay (T-SPOT.TB™) in combination with tuberculin skin test for the diagnosis of latent tuberculosis in the presence of HIV co-infection. BMC Infect Dis. 2011;11:319. 12. European Centre for Disease Prevention and Control (ECDC). Use of interferon-gamma release assays in support of TB diagnosis. Available at: http://ecdc.europa.eu/en/publications/publications/1103_gui_igra.pdf. Accessed March 2016. 13. Van Zyl-Smit RN, Pai M, Peprah K, et al. Within-subject variability and boosting of T-cell interferon-gamma responses after tuberculin skin testing. Am J Respir Crit Care Med. 2009;180:49–58. 14. Lyu J, Lee SG, Hwang S, et al. Chest computed tomography is more likely to show latent tuberculosis foci than simple chest radiography in liver transplant candidates. Liver Transpl. 2011;17:963–968.

www.infectdis.com


3