Chest
Volume 112, Issue 5, November 1997, Pages 1175-1179
Journal home page for Chest

Clinical Investigations: Lung Transplantation
FK 506 ‘Rescue’ Immunosuppression for Obliterative Bronchiolitis After Lung Transplantation

https://doi.org/10.1378/chest.112.5.1175Get rights and content

Preliminary experience

In a consecutive case series (level V evidence) involving 10 recipients of unilateral lung transplantation (LT) with bronchiolitis obliterans, in conjunction with Fujisawa protocol 93-0-003, the physiologic responses to FK 506 (tacrolimus) “rescue” immunosuppression were assessed. Recipients were 22±18 months post-LT and demonstrated progressive allograft dysfunction that was refractory to pulsed-dose methylprednisolone therapy. All recipients received induction immunosuppression with Minnesota antilymphocyte globulin (10 to 15 mg/kg/d) for 5 to 10 days, cyclosporine (CsA) (whole-blood Abbott TDXTM fluorescence polarization immunoassay (Abbott Inc, Abbott Park, IL)=600 to 800 ng/mL), azathioprine (2 mg/kg/d), and prednisone (tapered to 0.2 mg/kg/d). The “rescue” regimen consisted of oral FK 506 adjusted to maintain a whole-blood Abbott IMX™ microparticle enzyme immunoassay (Abbott Inc, Abbott Park, IL) of 10 to 15 ng/mL with an initial increase in prednisone (1.0 mg/kg/d) during conversion that was subsequently tapered to 0.2 mg/kg/d. Spirometry was performed monthly in accordance with accepted American Thoracic Society criteria. Recipients were classified in accordance with the International Society for Heart and Lung Transplantation (ISHLT) “Working Formulation for Standardization of Nomenclature and for Clinical Staging of Chronic Dysfunction in Lung Allografts” as stages Ib (n=2), IIb (n=4), and IIIb (n=4) upon entry to the protocol. The ΔFEV1/month relationships during CsA- and FK 506-based regimens were analyzed by linear regression and compared by signed rank test (p<0.05).

Results

The AFEV1/month slopes were —0.0687±0.0221 and +0.0300±0.033 L/mo (mean±SEM) for CsA and FK 506, respectively (p=0.037). Although no significant spirometric improvement was noted in most recipients, no further decline in FEV1 occurred after conversion to FK 506. Recipients with less severe chronic dysfunction (ie, obliterative bronchiolitis [OB] stages Ib and IIb) stabilized their spirometric indexes at higher levels. Two recipients with OB stage Mb died of hypercapnic respiratory failure at 6 and 8 months after conversion.

Conclusions

The ΔFEV1/mo slopes stabilized after FK 506 conversion. Earlier conversion may be beneficial in stabilizing FEV1 at a higher plateau. Significant economic impact may be anticipated with FK 506 compared to alternative cytolytic strategies for OB. However, multicenter prospective controlled investigations are necessary to further address the potential role of FK 506 after LT (level I evidence). Furthermore, the ISHLT “Staging of OB Syndrome” may have significant clinical implications vis-à-vis prognosis and potential therapies.

Section snippets

MATERIALS AND METHODS

In a case series (level V evidence), 10 patients who were between 5.5 and 55 months (27.6±6.7, mean±SEM) post-LT had developed histologically confirmed OB that was deemed “clinically progressive” by sequential spirometric evaluation, despite repeated courses of pulsed-dose methylprednisolone. Patients were enrolled in the study between October 1, 1993, and April 1, 1996. The Fujisawa protocol 93-0-003 for “salvage” in CR had been approved by our Institutional Review Board and informed consent

RESULTS

Overall prevalence of OB in our program is currently 31%; (11/36 patients). As defined by the International Society for Heart and Lung Transplantation criteria, patients were categorized as having OB stages Ib (n=2), IIb (n=4), and IIIb (n=4) upon entry to the study protocol between October 1, 1993, and April 1, 1996. The study commenced during Fujisawa protocol 93-0-003 for chronic or refractory acute allograft rejection. At that time, only recipients with histologically confirmed OB were

DISCUSSION

Long-term survival after LT has been limited by the development of OB with a variously reported incidence between 10 and 70%;.3,9, 10 Although augmented immunosuppression may result in transient stabilization of allograft function, infectious complications may be increased.5 Data derived from orthotopic liver transplantation have suggested a decreased incidence as well as potential stabilization of CR with FK 506 immunosuppression.6, 7 The vanishing bile duct syndrome as a manifestation of CR

REFERENCES (18)

There are more references available in the full text version of this article.

Cited by (58)

  • Monitoring of nonsteroidal immunosuppressive drugs in patients with lung disease and lung transplant recipients: American College of Chest Physicians evidence-based clinical practice guidelines

    2012, Chest
    Citation Excerpt :

    It has also been used to treat graft-vs-host disease, rheumatologic disorders (lupus erythematosus, rheumatoid arthritis, scleroderma, polymyositis), inflammatory bowel disease, various skin conditions other than atopic dermatitis, and uveitis. Table 13 summarizes the 16 clinical trials reporting on the use of tacrolimus for various lung diseases.151,152,179–192 The FDA has issued a black box warning for increased susceptibility to infection and the possible development of lymphoma.193

  • Bronchiolitis Obliterans Disclaimer: Copyright Note

    2008, Pediatric Respiratory Medicine
  • Bronchiolitis Obliterans

    2008, Pediatric Respiratory Medicine
  • Conversion From Cyclosporine to Tacrolimus Stabilizes the Course of Lung Function in Lung Transplant Recipients With Bronchiolitis Obliterans Syndrome

    2007, Transplantation Proceedings
    Citation Excerpt :

    Already in 1997, a small study of 15 patients by Kesten et al3 found that conversion from a CsA-based regimen to a tacrolimus-based regimen was associated with a decrease in the rate of decrease of lung function in patients with BOS, although stabilization of lung function was not achieved in their study. In the same year, Ross et al4 also, in a very short series of 10 patients, did not find a significant spirometric improvement, but noted that no further decrease in lung function occurred after conversion and that patients with less severe stages of BOS were the ones who benefited most from conversion. In 2000, however, another small retrospective study in 10 patients found a significant reduction in the slope of the FEV1-time curve after conversion from CsA to tacrolimus.5

  • Efficacy and safety of inhaled tacrolimus in rat lung transplantation

    2007, Journal of Thoracic and Cardiovascular Surgery
View all citing articles on Scopus
View full text