Transmission of Mycobacterium Tuberculosis Via Lung Transplantation
2004; Elsevier BV; Volume: 4; Issue: 9 Linguagem: Inglês
10.1111/j.1600-6143.2004.00536.x
ISSN1600-6143
AutoresKevin Winthrop, B. Kubak, David A. Pegues, Catherine Hufana, Pam Costamagna, Ed Desmond, C A Sanders, PAUL T. SHEN, Laura Flores, Eugene Osborne, David A. Bruckner, Jennifer Flood,
Tópico(s)Infectious Diseases and Tuberculosis
ResumoAmerican Journal of TransplantationVolume 4, Issue 9 p. 1529-1533 Free Access Transmission of Mycobacterium Tuberculosis Via Lung Transplantation Kevin L. Winthrop, Corresponding Author Kevin L. Winthrop Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, GA Division of Communicable Disease Control, California Department of Health Services, Berkeley, CA *Corresponding author: Kevin L. Winthrop, kwinthro@dhs.ca.govSearch for more papers by this authorBernard M. Kubak, Bernard M. Kubak Division of Infectious Diseases, University of California at Los Angeles Medical Center,Los Angeles, CASearch for more papers by this authorDavid A. Pegues, David A. Pegues Division of Infectious Diseases, University of California at Los Angeles Medical Center,Los Angeles, CASearch for more papers by this authorCatherine Hufana, Catherine Hufana San Joaquin County Public Health Services Tuberculosis Control Program, Stockton, CASearch for more papers by this authorPam Costamagna, Pam Costamagna San Joaquin County Public Health Services Tuberculosis Control Program, Stockton, CASearch for more papers by this authorEd Desmond, Ed Desmond Division of Communicable Disease Control, California Department of Health Services, Berkeley, CASearch for more papers by this authorCynthia Sanders, Cynthia Sanders San Joaquin County Public Health Services Tuberculosis Control Program, Stockton, CASearch for more papers by this authorPaul Shen, Paul Shen Department of Epidemiology, University of California at Berkeley, Berkeley, CASearch for more papers by this authorLaura Flores-Ibarra, Laura Flores-Ibarra Department of Epidemiology, University of California at Berkeley, Berkeley, CASearch for more papers by this authorEugene Osborne, Eugene Osborne California Donor Transplant Network, Oakland, CASearch for more papers by this authorDavid Bruckner, David Bruckner Division of Infectious Diseases, University of California at Los Angeles Medical Center,Los Angeles, CASearch for more papers by this authorJennifer Flood, Jennifer Flood Division of Communicable Disease Control, California Department of Health Services, Berkeley, CASearch for more papers by this author Kevin L. Winthrop, Corresponding Author Kevin L. Winthrop Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, GA Division of Communicable Disease Control, California Department of Health Services, Berkeley, CA *Corresponding author: Kevin L. Winthrop, kwinthro@dhs.ca.govSearch for more papers by this authorBernard M. Kubak, Bernard M. Kubak Division of Infectious Diseases, University of California at Los Angeles Medical Center,Los Angeles, CASearch for more papers by this authorDavid A. Pegues, David A. Pegues Division of Infectious Diseases, University of California at Los Angeles Medical Center,Los Angeles, CASearch for more papers by this authorCatherine Hufana, Catherine Hufana San Joaquin County Public Health Services Tuberculosis Control Program, Stockton, CASearch for more papers by this authorPam Costamagna, Pam Costamagna San Joaquin County Public Health Services Tuberculosis Control Program, Stockton, CASearch for more papers by this authorEd Desmond, Ed Desmond Division of Communicable Disease Control, California Department of Health Services, Berkeley, CASearch for more papers by this authorCynthia Sanders, Cynthia Sanders San Joaquin County Public Health Services Tuberculosis Control Program, Stockton, CASearch for more papers by this authorPaul Shen, Paul Shen Department of Epidemiology, University of California at Berkeley, Berkeley, CASearch for more papers by this authorLaura Flores-Ibarra, Laura Flores-Ibarra Department of Epidemiology, University of California at Berkeley, Berkeley, CASearch for more papers by this authorEugene Osborne, Eugene Osborne California Donor Transplant Network, Oakland, CASearch for more papers by this authorDavid Bruckner, David Bruckner Division of Infectious Diseases, University of California at Los Angeles Medical Center,Los Angeles, CASearch for more papers by this authorJennifer Flood, Jennifer Flood Division of Communicable Disease Control, California Department of Health Services, Berkeley, CASearch for more papers by this author First published: 12 August 2004 https://doi.org/10.1111/j.1600-6143.2004.00536.xCitations: 44AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Organ donors are not routinely screened for tuberculosis (TB) in the United States. We investigated a case of pulmonary TB in a double-lung transplant recipient. We reviewed the donor's and recipient's records, and used molecular methods to compare the lung recipient's isolate with others from three sources: her hospital, the California state health department's genotyping database, and the donor's resident-nation of Guatemala. A respiratory specimen obtained from the lung recipient 1 day after transplantation grew Mycobacterium tuberculosis. Donor chest radiograph had a previously unnoticed pulmonary opacity that was present on post-transplant recipient chest radiographs and computed tomographs. The recipient's isolate was molecularly distinct from others at her hospital and in the state database, but was identical to two isolates from Guatemala. Tuberculosis was transmitted from lung donor to recipient. As organ transplantation becomes more common worldwide, similar cases could occur. Screening for TB in potential organ donors should be considered. Introduction Solid-organ transplantation is becoming increasingly commonplace throughout the world (1, 2). In the United States alone, the annual number of organs transplanted has nearly doubled since 1988. In 2002, there were more than 12 500 individuals who donated one or more organs to nearly 25 000 recipients (3). Mycobacterium tuberculosis is an important pathogen in transplant recipients, particularly in populations with relatively high frequencies of tuberculosis (TB) infection. Rates of active TB in transplant recipients vary worldwide from 0.3 to 15%, depending on the region studied (4). Post-transplant TB infections can occur via the receipt of infected organs, reactivation of latent disease within the immunosuppressed recipient, or acquisition of new infections. In most cases, the source of post-transplant TB is usually unknown or not investigated (4). In September 2002, we were notified of a patient diagnosed with TB shortly after receiving a double lung transplant. We undertook an investigation to determine the source of this M. tuberculosis infection. Case Report The index patient was a 49-year-old, white, American-born female who had previously received a single lung transplant for idiopathic pulmonary fibrosis in 1996. Her clinical course was complicated by end-stage bronchiolitis obliterans, and she underwent bilateral sequential lung re-transplantation on August 4, 2002. On postoperative day 1, bronchoscopy was performed to ensure bronchial hygiene before extubation and to ensure the integrity of the anastomosis. The study showed good mucosal blood flow without purulence. Bronchoalveolar lavage specimens from a wide subsegment of the lingula were smear-negative for acid-fast bacilli (AFB); 3 weeks later, cultures of these specimens were found to be positive for M. tuberculosis. Repeat bronchial washings from postoperative day 10 were also positive for M. tuberculosis on culture. Four weeks after transplant, a computerized tomograph (CT) of the chest revealed small subcentimeter nodules primarily within the apical posterior left upper lobe and a right pleural effusion (Figure 1). Figure 1Open in figure viewerPowerPoint Chest-computed tomogram of double-lung recipient taken 4 weeks post-transplant. Multiple small subcentimeter nodules are present within the apical posterior left upper lobe also involving the right apex. A moderately sized right pleural effusion is present. Pleural thickening and nodular adhesions are apparent. The patient was treated with isoniazid, rifabutin, ethambutol, and pyrazinamide. When uveitis developed, rifabutin was discontinued. After her isolate was shown to be sensitive to all first-line TB drugs, she was maintained on isoniazid, pyrazinamide, and levofloxacin. She received anti-TB therapy for a total of 36 weeks. At 31 months post-transplant, allograft function remained good, parenchymal nodules and pleural effusion had resolved, and she has had no recurrence of mycobacterial disease. Methods Clinical/epidemiological investigation We requested the clinical records of the organ donor, and of all recipients associated with this donor, from the organ procurement organization (OPO) and the hospitals where the transplantations occurred. We reviewed patient medical histories, laboratory test results, bronchoscopy reports, and in the case of the donor and lung-recipient, pre- and post-transplant chest radiographs and computed tomography (CT) scans. We alerted organ recipient physicians to the potential that their patients may have received organs from a donor with TB. These physicians were encouraged to screen recipients for tuberculosis with tuberculin skin testing (TST), chest X-ray, and in the case of the renal recipients, with serial urine cultures. In addition, we conducted an investigation of the donor's close contacts to identify other possible cases of TB. Laboratory investigation Lung recipient: From the lung-recipient's hospital, we requested all M. tuberculosis isolates from cultures processed with, and in the 2 months before, the lung-recipient's culture. These isolates were sent to the state of California's Microbial Disease Laboratory (MDL) for restriction fragment length polymorphism (RFLP) analysis using standard IS 6110 methodology (5). The RFLP pattern of the case's isolate was compared using Genomic Solutions software (BioImage Systems, Jackson, MI) with more than 5000 TB isolates at MDL obtained from throughout the state between 1996 and 2003 for routine genotyping. Because the donor had recently arrived in the United States from Guatemala, DNA from the lung-recipient's isolate was also sent to the University of California at Berkeley for comparison with 62 isolates from Guatemala collected between 2001 and 2002 as part of a molecular epidemiological study with the Clinical Familiar Luis Angel Garcia in Guatemala. Isolates were first screened for relatedness using double-repetitive element-polymerase chain reaction (DRE-PCR) (6), which has been shown to be highly efficient and discriminatory in the comparison of tuberculosis isolates when used in combination with spoligotyping (7). Accordingly, samples with the same number and pattern of bands by DRE-PCR were subjected to more definitive comparison using standard spoligotyping methods. Results of spoligotyping were interpreted using previously described methods (8, 9). Organ donor: We requested that the OPO send all remaining donor tissues to MDL for further analysis. The only donor specimens remaining included serum and several vials of frozen lymphocytes that had been harvested from unspecified lymph nodes during the time of organ harvest. Lymphocyte specimens underwent Amplicor® PCR (Roche, Indianapolis, IN) and mycobacterial culture at Contra Costa County Laboratory (Martinez, CA). Lymphocyte specimens also were cultured at MDL using standard mycobacterial liquid and solid culture methods (10). Serum samples were sent to Mossman Associates Laboratory (Blackstone, MA) for lipoarabinomannan IgG immunoassay (MycoDot®). Lymphocyte samples were also sent to Oregon Health Sciences University (Portland, OR) for TB-reactive lymphocyte analysis (Elispot). Results Clinical/epidemiologic investigation The organ donor was a previously healthy 21-year-old male with no history of lung disease or risk factors for TB other than being born in Guatemala. Family members reported that he was in the United States only 2 weeks before suffering traumatic brain death, and they denied any history of TB in the patient or in any family or household members in Guatemala. The patient reportedly had no previous history of TST testing. While hospitalized, he had 10 portable chest radiographs performed over the course of 1 week; all were read as no active cardiopulmonary disease. Neither chest CT nor bronchoscopy was performed before lung removal. Respiratory secretions were obtained via tracheal aspiration for routine culture and gram stain. Routine cultures showed only light growth of oropharyngeal flora. Gram stain and fungal stain were negative for organisms with more than 25 white blood cells per low power field. No acid-fast smears or cultures for mycobacteria were performed. Our review of the donor's chest radiograph found one pretransplant chest X-ray from August 3, 2002 with a faint opacity visible in the left upper lobe (Figure 2A). Several small nodular calcifications were also present in the mid-lung bilaterally. Comparison with lung-recipient chest radiographs obtained in the 4 weeks after transplant confirmed the presence of this left upper lobe opacity in the recipient (Figure 2B). A CT scan of the lung recipient obtained at this time showed micronodular infiltrate in the same region of the lung (Figure 1). Figure 2Open in figure viewerPowerPoint (A,B) Chest radiograph of donor taken 1 day before organ recovery (left), and of lung recipient taken 4 weeks post-transplant (right). A faint opacity is noted in the left upper lung field in both radiographs. Review of bronchoscope records from the recipient's hospital indicated that the bronchoscope used on the lung recipient was used on 25 patients in the 2 months preceding her bronchoscopy. None of these 25 persons had a diagnosis of TB. Contact investigation of the donor's family and household members identified a total of eight contacts; all were foreign born. No persons reported a previous history of TB or TST testing. Family members denied a history of TB or other severe lung disease in family members remaining in Guatemala. Among the eight contacts evaluated, four were positive by TST. No cases of active TB were identified. Other organ recipients Three additional patients received organs from the donor: one patient received the left kidney and pancreas, one patient received the right kidney and liver, and one patient received the heart. No other tissues were donated. All three reported a history of a negative TST at sometime before transplant; only one reported having a TST in the 2 years before transplantation. None had a previous history of TB or known contact with a case of TB before transplantation. Their ages ranged from 49 to 65 years old, and all patients were male. To date, none of the nonpulmonary organ recipients have developed clinical evidence or symptoms suggestive of TB. Post-transplant screening for TB in these individuals included chest X-ray (negative in all three), TST in the heart recipient only (negative at 5 weeks after surgery), and urine cultures in one of the renal recipients (three consecutive negative cultures obtained in the first 2 months post-transplant). To date, all three were receiving isoniazid therapy, and the heart-recipient was also being followed with periodic chest radiograph. Laboratory investigation A total of four TB isolates from the lung-recipient's hospital underwent molecular comparison. These isolates included two from the lung recipient, as well as isolates from two other patients collected in the two previous months. No other isolates were processed at the hospital during this time period. The RFLP patterns from the index patient's two isolates were identical and did not match those of the other two patients. Comparison of the lung-recipient's isolate with others in the California state database yielded no matching isolates. The DRE-PCR comparison of the isolate with those from Guatemala found the isolate to have two bands and to share this pattern with three others. Spoligotyping of these four isolates yielded two unique pattern, with the lung-recipient's isolate identical to two of the Guatemalan isolates (Figure 3). Figure 3Open in figure viewerPowerPoint Spoligotyping results comparing the lung-recipient isolate with those of Guatemalan origin. From top to bottom: Lane 1, negative control; Lane 2, positive control (bcg); Lanes 3–5: samples b, c, and a are Mycobacterium tuberculosis isolates from Guatemala; Lane 6, sample x is the M. tuberculosis isolate from the lung recipient. Attempts to isolate M. tuberculosis from donor tissue were unsuccessful and limited, as the only specimens available for analysis were 2 mL of banked serum and several frozen lymphocytes. PCR and culture of lymphocytes were negative for M. tuberculosis. Mycodot testing of serum was negative for lipoarabinomannan IgG. Lymphocyte specimens were nonviable for Elispot testing. Discussion We have documented a case of pulmonary TB in a lung-recipient who acquired infection via transplantation from a donor. Review of radiologic evidence from both donor and recipient suggested that disease present in the donor before transplant was later present in the lung recipient. Genotypic analysis of the lung recipient's isolate suggested it was a strain present in the donor's home country of Guatemala from which he recently had arrived. Our investigation found no evidence for laboratory cross-contamination or bronchoscopy transmission that could have otherwise explained this case. Post-transplantation TB infections are not uncommon and can cause significant morbidity and mortality for those infected. Previous studies from around the world have shown that rates of such infections can be as high as 15% in areas with a high prevalence of TB (11). Even in the U.S., where the prevalence of TB is low, case-rates of TB in transplant recipients are estimated to be between 36 and 74-fold higher than in the normal population (4). Further, the mortality rate in post-transplant TB has been reported to be as high as 40%, and allograft tissue rejection can be seen in a substantial number of post-transplant TB patients (4). The extent to which post-transplant TB infections are due to active or reactivated latent infection within allograft tissue is unknown, although it is likely that infections acquired in this manner are under-recognized. Given that most post-transplant TB infections onset 3–12 months after transplantation, their source is frequently not investigated or known (4). Tuberculosis transmission via infected allograft material has been reported rarely with renal, liver, and lung transplantation (4). Infected donor lungs have been proposed as the source of recipient pulmonary TB in only eight cases, with the first such case reported in 1990 (12-17), and in only one instance was definitive evidence available to prove donor-to-recipient transmission occurred (12). In our case, the donor was foreign-born and had recently traveled to the United States. While he had no known history of TB, he was at high risk for latent TB infection (LTBI) given his birth-nation status and the appearance of his chest radiographs (bilateral nodular calcifications were present) before transplant. Given the lung-recipient had a positive culture obtained just 1 day after transplant, it is likely that the donor had very early reactivated LTBI based on the appearance of his chest films. Various methodologies have been proposed to screen organ donors for active TB disease in the cadaveric setting (12, 17). The use of chest CT could offer a more sensitive method of detecting active parenchymal disease than chest radiograph, but would not be necessarily specific for TB. In this case report, it is likely that chest CT of the donor would have shown his disease with greater resolution than did chest radiography, and therefore, alerted transplant physicians to the possibility of pulmonary TB being present in the donor. In the future, transplant physicians could consider using chest CT, particularly in donors at high risk for TB. Such persons would include those with a history of latent or active TB, contact to a TB case, birth in a country with high TB prevalence, or other medical risk factors associated with TB (18). Abnormal CT findings could be followed with more definitive diagnostic procedures such as bronchoscopy with direct microscopy, culture, or PCR of respiratory specimens. However, the utility and cost-effectiveness of routinely screening cadaveric organ donors for active TB with chest CT and/or other methodologies is unknown. Unfortunately, screening for latent infection in donors before organ recovery is also difficult. In most cases, TST is not a feasible screening tool given the time requirements for organ procurement and transplantation, and for placing and reading a TST in a prospective donor. In the future, transplant physicians may choose to assess organ donors with whole blood gamma interferon assay (QuantiFERON®, Cellestis, Valencia, CA, USA), a test recently approved by the Food and Drug administration (FDA) for the diagnosis of LTBI. This test appears similar in sensitivity to TST, and might offer higher specificity in the diagnosis of LTBI (19). Although a positive test result might not preclude organ harvest and transplantation from an otherwise healthy donor, it could alert the transplant surgeon that the patient receiving lungs or other organs from an infected donor might be at risk for developing active TB following transplantation. The probability of such persons developing active TB is unknown, but these patients could be treated with preventive therapy or monitored clinically for TB disease. The World Health Organization currently estimates that approximately one-third of the world's population is infected with tuberculosis (20). The donor base within California, and throughout the nation, has become increasingly ethnically diverse over the last decade (3). As organ transplantation becomes more frequent in populations with higher rates of TB infection, screening organ donors for TB could become increasingly important. Acknowledgments We are indebted to the following persons for their assistance with this investigation: Val Garrick, Eduardo Aratoon, Ana Maria Xet-mull, Drs Charles Daley, Robert Jasmer, Sundari Mase, Ernie Haeusslein, Sang-Mo Kang, Steve Tomlanovich, David Lewhinson, and Lee Riley. All research was performed by public health agencies. No external sources of funds were used to conduct his investigation. References 1 European Liver Transplant Registry. Accessed September 8, 2003: http://www.eltr.org/results.htm. Google Scholar 2 Organizacion Nacional de Transplantes. Accessed September 8, 2003: http://www.msc.es/ont/ing/data/f_data.htm. 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