Lung Transplant Rejection


Continuing Education Activity

As the number of lung transplants annually in the US and worldwide has increased, so has the occurrence of lung transplant rejection. Lung transplant rejection can be categorized as hyperacute, acute, and chronic. This activity reviews the evaluation and treatment of lung transplant rejection and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

  • Review the pathophysiology of lung transplant rejection.
  • Describe the appropriate evaluation of lung transplant rejection patients.
  • Outline the optimal management options for lung transplant rejection.
  • Summarize the importance of improving communication and care coordination amongst the interprofessional team to improve outcomes for patients affected by lung transplant rejection.

Introduction

The number of lung transplants annually in the US and worldwide has increased in recent years. This is due to the systemization of nationwide database and allocation, improved surgical techniques, and the advent of a new generation of immunosuppressants. However, lung transplantation recipients continue to have a high rate of short term and long term failure rates compared to other solid organs. The 5-year survival rate is reported at 58%.[1]

While post-surgical complications, vascular complications, and infections do contribute substantially to both early and late postoperative failure, transplant rejections are also commonly seen. Recently reported incidence rates to vary between 50% acute rejection rate in 1 year and 45% chronic rejection incidence in 5 years post-transplant.  

Based on the timeline of occurrence and diagnosis post-transplant, lung transplant rejection can be categorized into the following subtypes.[2]

  1. Hyperacute transplant rejection - Within the first 24 hours
  2. Acute transplant rejection - 1st week - 1st Year
  3. Chronic lung allograft dysfunction (CLAD) - > 1 year

Etiology

Hyperacute lung transplant rejection is mostly caused by preformed antibodies in the recipient against the human leukocyte antigen (HLA) of the donor.[3][4] 

Acute cellular rejection can be caused by both T-lymphocyte mediated (acute cellular rejection), and antibody-mediated reaction directed against major histocompatibility complex antigens in the donor's lung and usually occurs within the first year of transplant.[5]

Chronic lung transplant rejection usually has no clear single identifiable etiology, and experts relate it to multiple processes contributing to each other. Contributing conditions could be recurrent subclinical acute rejection episodes, transplant infection, and aspiration with gastroesophageal reflux disease.[6] A panel of experts organized by the International Society for Heart and Lung Transplantation (ISHLT) and subsequent studies have categorized various risk factors as probable, potential, or hypothetical.

Probable Risk Factors

  • Acute rejection
  • Lymphocytic bronchitis
  • Cytomegalovirus (CMV) pneumonitis
  • Medication non-compliance

Potential Risk Factors

  • CMV infection without pneumonitis
  • Organizing pneumonia
  • Bacterial, fungal, or non-CMV viral infection
  • Older donor age
  • Large graft ischemic time
  • Donor antigen-specific reactivity

Hypothetical Risk Factors

  • Underlying disease
  • HLA-mismatching
  • Genotype of recipient
  • Gastroesophageal reflux with aspiration

Epidemiology

Antibody-mediated lung transplant is currently a rare type of rejection.[7][8] This is mainly a result of the pretransplant screening for HLA antibodies in the recipient and avoiding incompatible donors. The process is called “virtual crossmatch.”[9] 

The Registry of the International Society for Heart and Lung Transplantation reported that at least 29% of 12980 lung transplant recipients in-between 2004 and 2014 had at least one rejection episode in the first year after discharge.[10] Estimated chronic rejection between 1994 and 2014 was 50% and 67% within 5 and 10 years after transplantation, respectively.[11]

Pathophysiology

Acute Allograft Rejection is Classified into Two Pathophysiological Subtypes

  1. Acute cellular rejection- A more common form of acute rejection mediated by a T cell immune response against major histocompatibility complex antigens in the donor's lung and usually occurs within the first year of transplant.
  2. Acute antibody-mediated rejection- As the name suggests, a few weeks to months after the transplant, a separate antibody-mediated pathological process against donor HLA antigens or autoantigens can cause acute respiratory impairment.

Chronic Lung Allograft Dysfunction (CLAD)

CLAD is a term coined for any evidence of a decline in lung function beyond a year after transplant and persisting for more than 3 weeks. Based on the physiology of pulmonary function impairment and the microscopic pathology, it has two distinct phenotypes:

  1. Bronchiolitis obliterans syndrome (BO)– predominantly obstructive disease

      2. Restrictive allograft syndrome– predominantly restrictive disease

Histopathology

Acute Cellular Reaction

Pathology shows lymphohistiocytic infiltrates on small arterioles and venules, as well as bronchioles. Acute cellular rejection is thus graded by severity of inflammation separately in the vascular compartment (A0 to A4) and airway (B0 to B2R).

Acute Antibody-mediated Rejection

The distinguishing feature from acute cellular rejection is a form of acute lung injury with diffuse alveolar damage without capillaritis.

Bronchiolitis Obliterans Syndrome (BOS)

Histopathology demonstrates a fibrotic process obliterating the lumen of small bronchioles resulting in an irreversible, progressive obstructive disease.

Restrictive Allograft Syndrome (RAS)

The pathological process involves pleuroparenchymal fibroelastosis involving upper lobes. Acute fibrinoid organizing pneumonia (AFOP) has also been reported in transbronchial biopsies. Bronchioles are patent, unlike BOS with peribronchial and alveolar fibrin deposits.

History and Physical

Hyperacute lung rejection usually happens within 24 hours after the procedure with a rapid onset of respiratory distress and severe hypoxia resulting from acute pulmonary edema and diffuse alveolar damage. The clinical presentation is thus similar to acute respiratory distress syndrome (ARDS), carrying a high fatality rate. Imaging is significant for diffuse opacities in the transplanted lung.[5][12][13]      

Acute cellular lung rejection can present up to 2 years but is most prevalent in the first 6 months.[14] The presentation can range from no symptoms to low-grade fever, cough, dyspnea, or severe respiratory distress. The physical examination might be normal or reveal non-specific findings as decreased breath sounds and/or crackles.[15] 

Bronchiolitis obliterans can present with an asymptomatic decline in forced expiratory volume 1s (FEV1). Symptoms, if present, are non-specific and can range from upper respiratory tract infection symptoms, such as dry cough, dyspnea on exertion, occasionally a low-grade fever to a rapid decline in pulmonary function and respiratory failure.[16][17]

Evaluation

Evaluation for hyperacute rejection in a lung transplant rejection starts with immunologic testing for HLA antibodies and reviewing pretransplant virtual crossmatch results. Evaluation for other diagnoses includes complete blood count, cardiac enzymes, brain natriuretic peptide, electrocardiogram and echocardiogram, and or swan Ganz catheterization to evaluate for left ventricular dysfunction. Computed tomography (CT) imaging to evaluate for pulmonary embolism and surgical complications and pleural disease is also routinely performed. Bronchoscopy with bronchoalveolar lavage (BAL) is done to evaluate the airway anastomosis site and obtain samples for microbial studies and pathology. Asymptomatic patients can be diagnosed based on transbronchial biopsy from routine surveillance bronchoscopy itself, while CT findings in symptomatic patients lead to targeted bronchoscopic biopsy. If the lungs have diffuse changes, transbronchial biopsies are obtained from lower lobes. Otherwise, CT helps in localizing the area of maximal disease and diagnostic yield by biopsy.

The diagnosis of acute cellular rejection is based on the exclusion of infections (especially cytomegalovirus) and transbronchial lung biopsy findings of characteristic histopathologic changes in the specimen. Laboratory studies and imaging findings are neither sensitive nor specific.[18][19]

A definitive diagnosis of acute antibody-mediated rejection requires demonstration of donor-specific circulating antigen, histopathological findings as above, and immunostaining positive for complement 4d. It is less common among acute allograft rejections and is more challenging to establish.

As far as CLAD is concerned, quantitative criteria involve a 20% or greater decline in FEV1 or forced vital capacity (FVC) from the best postoperative value. Detection of CLAD necessitates an urgency in establishing etiology and to attempt a reversal of function. As the response is time-sensitive, there has been an increasing consensus to label a > 10% sustained drop in FEV1 as “suspected CLAD.” Investigations to rule out alternative etiologies other than rejection can therefore start immediately. Studies include sputum culture, bronchoscopy with bronchoalveolar lavage, endobronchial and transbronchial biopsy, and CT of the chest with both inspiratory and expiratory imaging.

Laboratory, imaging, and bronchioalveolar lavage findings are not very helpful in the diagnosis of bronchiolitis obliterans but should be obtained to exclude other potential causes of the decline in pulmonary function. The hallmark for raising the alarm is an obstructive defect in pulmonary function test (PFT) with a sustained decrease in FEV1 for > 3 weeks and a >20 % decline from baseline. CT imaging in the expiratory phase demonstrates a mosaic appearance consistent with air trapping. In a study utilizing micro CT, greater than 60% of the airways beyond 6 generation bronchiole demonstrated obstruction and constrictive bronchiolitis.[20] Establishing a diagnosis by transbronchial biopsy is challenging due to sampling errors and low sensitivity and specificity both. However, bronchoscopy still is of value to rule out infection, aspiration, and reflux induced damage.

The distinctive PFT feature of restrictive allograft syndrome to differentiate it from BO is a restrictive pattern of a defect with > 10 % drop in total lung capacity (TLC). Since patients self-monitored spirometers do not capture TLC, an alternative PFT based approach is to detect a sustained drop in FEV1 but progressive rise of FEV1/FVC ratio. CT shows central or peripheral ground glass changes followed by upper lobe predominant traction bronchiectasis, fibrosis, and hilar retraction. RAS seems to occur in 30% of CLAD patients over 5 years.

Before establishing a diagnosis of BOS, it is crucial to be aware of and exclude the possibility of 2 clinical entities that can have an identical clinical presentation, PFT findings, and CT features.

They are gastroesophageal reflux-related bronchiolitis obliterans and neutrophilic reversible allograft dysfunction, also known as azithromycin-responsive allograft dysfunction. Both conditions prognostically differ from classic BOS by nature of their reversibility if appropriate treatment is pursued (fundoplication in the former and azithromycin three times a week prolonged course in the latter). Response to azithromycin in a subgroup of BOS patients with near normalization of FEV1 has traditionally been correlated with BAL neutrophilia (>15%). However, the correlation with neutrophilic predominance does not always correlate with azithromycin response.[21][22] One approach, therefore, has been to initiate a 3 month trial of azithromycin in all patients with “suspected CLAD.” The chest CT in the responsive patients usually starts with the peribronchiolar tree in bud infiltrates.

Treatment / Management

Prevention of Rejection

Like other solid organ transplants, an initial induction regimen with antilymphocyte/anti-thymocyte globulin (ALG/ATG) has a well-demonstrated role in reducing the incidence of acute rejection. However, their use in clinical practice has fallen since the introduction of the interleukin 2 (IL-2) receptor antagonists basiliximab and daclizumab (the latter is no longer available commercially in the US).[23] They selectively target IL-2 receptors on activated T cells and inhibit their proliferation and differentiation. According to the ISHLT registry, the IL-2 antagonist mediated induction regimen was used in 71% of lung transplants in the year 2018. Basiliximab is administered intraoperatively and again on the 4th post-transplant day. Muromonab-CD3, another induction therapy agent, is no longer preferred because of its severe toxicity profile.

ISHLT recommends a variety of maintenance immunosuppression regimens involving corticosteroids and 2 other agents. The most commonly adopted regimen is a calcineurin inhibitor – cyclosporin or tacrolimus with mycophenolate mofetil and prednisone.[24] Cyclosporin inhibits calcineurin, which is involved in T cell activation and IL-2 production. Similarly, tacrolimus inhibits IL-2 production by binding to an immunophilin. Cyclosporin is particularly poorly absorbed in patients with cystic fibrosis requiring escalation of dose. Tacrolimus is used more often these days in comparison to cyclosporin. Head to head studies shows no significant survival difference in 1 and 2 years but a significant reduction in BOS and acute rejection. Similarly, mycophenolate mofetil is currently preferred over azathioprine due to its safety profile and increased selectivity.

Treatment of Rejection

  • Antibody-mediated

There are no approved medications for the treatment of antibody-mediated lung transplant rejection. The therapeutic principle of interventions involves a reduction in circulating antibodies through intravenous immunoglobulins, exchange plasmapheresis, anti CD20 monoclonal antibodies (rituximab), or proteasome inhibitors such as bortezomib. Treatment choice is based on the severity of illness, clinical course, and response to therapy. In hyperacute rejection, antimicrobial therapy can be started until infection is ruled out.[7][25][26]

  • Acute Cellular

Treatment decision depends on two factors, the clinical features and degree of rejection on biopsy. Treatment is usually recommended for grade 3A and 4A. With lower grades of rejection, the decision may differ in between transplant centers and can be based on clinical presentation along with clinician and patient preference.[27][28] For patients where infection is a possibility or cannot be ruled out, empiric antimicrobial therapy is usually started.[29] The main treatment is pulse dose glucocorticoids. The preferred agent is intravenous methylprednisolone 15 mg/kg/day for 3 days.[27][28] The dose is tapered down to a baseline steroid dose. Early rejections seemed to have a better response to steroids.[30] The role and interval of follow-up bronchoscopy are not clear. In one study of follow-up bronchoscopy after treatment of lung rejection, a correlation between histologic and clinical improvement was found in only half of the cases.[31] For refractory rejection after pulse dose steroids, options are repeated steroid course or switching to maintenance immunosuppression cyclosporine to tacrolimus.[32][33] More refractory cases may need treatment with antibody therapy.[34][35]

  • Bronchiolitis Obliterans Syndrome

There is no clearly recommended protocol or guidelines for treatment. International Society of Heart and Lung Transplant /American Thoracic Society/ European Respiratory Society (ISHLT/ATS/ERS) suggested a trial of oral azithromycin for new-onset bronchiolitis obliterans, which may stop or reverse lung function deterioration. The dose is 250 mg per day for 5 days and then at 250 mg three times per week for a minimum of 3 months. There is no clear evidence of whether azithromycin should be continued long-term with a therapeutic response or discontinued without response.[36] It is also important to re-evaluate the current immunosuppressive regimen and try to optimize it. Cyclosporine can be switched to tacrolimus,[37] and azathioprine can be switched to mycophenolate.[38] 

If there is still a decline in the functional tests (FEV1/FVC) despite previous interventions, then plasmapheresis, extracorporeal photopheresis, inhaled cyclosporine, mTOR inhibitors are other potential treatments and might be used based on case-by-case selection. As gastroesophageal reflux disease (GERD) has been presented as a risk factor for BOS, testing for GERD is done for patients with new-onset BOS, and those patients who have confirmed reflux disease might benefit from evaluation for potential fundoplication. Although the corticosteroids are the mainstay of treatment for acute lung transplant rejection, they are not recommended for the management of bronchiolitis obliterans syndrome.[36] When BOS progresses to end-stage disease refractory to all other therapies, re-transplant evaluation is recommended with the same selection process as used for first-time lung transplantation.[36] Only re-transplantation provides a meaningful possibility of long term survival.[36]

Treatment strategies of RAS are similar to BOS with high failure rates. There are anecdotal reports of some improvement with pirfenidone and a CD 52 antagonist alemtuzumab. More importantly, unlike BOS, retransplant outcomes in RAS are worse, and therefore lung allocation on a diagnosis of RAS involves stricter criteria.

Differential Diagnosis

Antibody-mediated Rejection

  • Primary graft dysfunction
  • Pulmonary edema caused by left ventricle dysfunction (myocardial infarction), or fluid overload
  • Pneumonia despite prophylactic antibiotics
  • Vascular anastomosis complications
  • Pulmonary embolism
  • Occlusion of the venous anastomosis
  • Pleural complication (effusion or hemothorax)
  • Transfusion-related acute lung injury (TRALI)
  • Aspiration pneumonitis

Acute Cellular Rejection

  • Humoral rejection
  • Bronchiolitis obliterans syndrome
  • Recurrence of primary pulmonary disease
  • Infection
  • Airway anatomical complications

Chronic Rejection

  • Late-onset acute cellular rejection
  • Azithromycin responsive allograft dysfunction
  • Esophageal reflux-related bronchiolitis obliterans
  • Infection
  • Airway complications of lung transplantation
  • Recurrence of the underlying lung disease
  • Post-transplant lymphoproliferative disorder
  • Native lung hyperinflation

Prognosis

In a case series of 21 recipients with a confirmed acute antibody-mediated rejection (AMR), fifteen recipients improved clinically and survived to hospital discharge, but 6 died of refractory antibodies-mediated rejection. The median survival after the diagnosis of antibody-mediated rejection was 593 days.[7] Survival estimates range from 3-5 years unless re-transplanted. Early-onset BOS and grade 2 or 3 BOS are predictive of worse survival.

In one study, the development and progression of chronic allograft rejection after lung transplantation (bronchiolitis obliterans syndrome Grades 2 and 3) is associated with a 3-fold increase in the risk of death at each stage.[39] In another study of 109 lung transplant patients with the development of bronchiolitis obliterans syndrome, post-BOS onset survival was 51% at 3 years. BOS onset conferred an increased risk of death with a hazard ratio (HR) of 5.96.[40] Mortality was 28% in another study (22 of 77 patients) with BOS.[41]

Although less common, restrictive allograft syndrome has worse outcomes with survival estimates between 6- 18 months from diagnosis. Bronchiolitis obliterans syndrome can occasionally progress into restrictive allograft syndrome. It goes without saying that patients with such transformation portend the worst prognosis. Patients with AFOP also have a worse prognosis with a median survival of only 0.3 years.

Risk factors include BAL eosinophilia, sarcoidosis, or interstitial lung disease (ILD) as an indication for transplant, CMV donor/receptor mismatch, younger age, and female sex.

Complications

Acute lung transplant rejection may increase the risk of a recurrence of acute rejections and the development of bronchiolitis obliterans syndrome.

Deterrence and Patient Education

The two most common complications after lung transplant are infection and rejection, and they cannot be differentiated based on presentation, as they both have the same signs and symptoms; they both can also be present without any symptoms. Rejection is very common within the first six months following a lung transplant but can occur at any time, and patients should be educated that lifelong follow-up, testing, and treatment with anti-rejection medications are essential to carefully monitor for lung transplant complications.

Enhancing Healthcare Team Outcomes

Lung transplant rejection is a common complication after a single or double lung transplant, and it can progress rapidly or subtly. Early diagnosis and management are essential to decrease morbidity and mortality. It is best managed by an interprofessional team approach. Communication and coordination between the patient, the primary clinician, the pulmonologist, and the transplant surgeon in regard to posttransplant testing and follow-up are essential for prevention.


Article Details

Article Author

Ali Mrad

Article Editor:

Rebanta Chakraborty

Updated:

3/1/2021 11:42:57 AM

References

[1]

Yusen RD,Edwards LB,Kucheryavaya AY,Benden C,Dipchand AI,Dobbels F,Goldfarb SB,Levvey BJ,Lund LH,Meiser B,Stehlik J, The registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplant report--2014; focus theme: retransplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2014 Oct     [PubMed PMID: 25242125]

[2]

Verleden GM,Raghu G,Meyer KC,Glanville AR,Corris P, A new classification system for chronic lung allograft dysfunction. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2014 Feb     [PubMed PMID: 24374027]

[3]

Yousem SA,Zeevi A, The histopathology of lung allograft dysfunction associated with the development of donor-specific HLA alloantibodies. The American journal of surgical pathology. 2012 Jul;     [PubMed PMID: 22510758]

[4]

Masson E,Stern M,Chabod J,Thévenin C,Gonin F,Rebibou JM,Tiberghien P, Hyperacute rejection after lung transplantation caused by undetected low-titer anti-HLA antibodies. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2007 Jun;     [PubMed PMID: 17543791]

[5]

Martinu T,Chen DF,Palmer SM, Acute rejection and humoral sensitization in lung transplant recipients. Proceedings of the American Thoracic Society. 2009 Jan 15;     [PubMed PMID: 19131531]

[6]

Estenne M,Maurer JR,Boehler A,Egan JJ,Frost A,Hertz M,Mallory GB,Snell GI,Yousem S, Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2002 Mar;     [PubMed PMID: 11897517]

[7]

Witt CA,Gaut JP,Yusen RD,Byers DE,Iuppa JA,Bennett Bain K,Alexander Patterson G,Mohanakumar T,Trulock EP,Hachem RR, Acute antibody-mediated rejection after lung transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2013 Oct;     [PubMed PMID: 23953920]

[8]

Daoud AH,Betensley AD, Diagnosis and treatment of antibody mediated rejection in lung transplantation: a retrospective case series. Transplant immunology. 2013 Jan;     [PubMed PMID: 23220148]

[9]

Bosanquet JP,Witt CA,Bemiss BC,Byers DE,Yusen RD,Patterson AG,Kreisel D,Mohanakumar T,Trulock EP,Hachem RR, The impact of pre-transplant allosensitization on outcomes after lung transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2015 Nov;     [PubMed PMID: 26169666]

[10]

Yusen RD,Edwards LB,Kucheryavaya AY,Benden C,Dipchand AI,Goldfarb SB,Levvey BJ,Lund LH,Meiser B,Rossano JW,Stehlik J, The Registry of the International Society for Heart and Lung Transplantation: Thirty-second Official Adult Lung and Heart-Lung Transplantation Report--2015; Focus Theme: Early Graft Failure. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2015 Oct;     [PubMed PMID: 26454740]

[11]

Chambers DC,Cherikh WS,Goldfarb SB,Hayes D Jr,Kucheryavaya AY,Toll AE,Khush KK,Levvey BJ,Meiser B,Rossano JW,Stehlik J, The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-fifth adult lung and heart-lung transplant report-2018; Focus theme: Multiorgan Transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2018 Oct;     [PubMed PMID: 30293613]

[12]

Frost AE,Jammal CT,Cagle PT, Hyperacute rejection following lung transplantation. Chest. 1996 Aug;     [PubMed PMID: 8697867]

[13]

Bittner HB,Dunitz J,Hertz M,Bolman MR 3rd,Park SJ, Hyperacute rejection in single lung transplantation--case report of successful management by means of plasmapheresis and antithymocyte globulin treatment. Transplantation. 2001 Mar 15;     [PubMed PMID: 11292295]

[14]

Burton CM,Iversen M,Scheike T,Carlsen J,Andersen CB, Minimal acute cellular rejection remains prevalent up to 2 years after lung transplantation: a retrospective analysis of 2697 transbronchial biopsies. Transplantation. 2008 Feb 27;     [PubMed PMID: 18347533]

[15]

De Vito Dabbs A,Hoffman LA,Iacono AT,Zullo TG,McCurry KR,Dauber JH, Are symptom reports useful for differentiating between acute rejection and pulmonary infection after lung transplantation? Heart     [PubMed PMID: 15597291]

[16]

Boehler A,Estenne M, Post-transplant bronchiolitis obliterans. The European respiratory journal. 2003 Dec;     [PubMed PMID: 14680094]

[17]

Hayes D Jr, A review of bronchiolitis obliterans syndrome and therapeutic strategies. Journal of cardiothoracic surgery. 2011 Jul 18;     [PubMed PMID: 21767391]

[18]

Stewart S,Fishbein MC,Snell GI,Berry GJ,Boehler A,Burke MM,Glanville A,Gould FK,Magro C,Marboe CC,McNeil KD,Reed EF,Reinsmoen NL,Scott JP,Studer SM,Tazelaar HD,Wallwork JL,Westall G,Zamora MR,Zeevi A,Yousem SA, Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2007 Dec;     [PubMed PMID: 18096473]

[19]

Millet B,Higenbottam TW,Flower CD,Stewart S,Wallwork J, The radiographic appearances of infection and acute rejection of the lung after heart-lung transplantation. The American review of respiratory disease. 1989 Jul;     [PubMed PMID: 2502057]

[20]

Verleden SE,Vasilescu DM,Willems S,Ruttens D,Vos R,Vandermeulen E,Hostens J,McDonough JE,Verbeken EK,Verschakelen J,Van Raemdonck DE,Rondelet B,Knoop C,Decramer M,Cooper J,Hogg JC,Verleden GM,Vanaudenaerde BM, The site and nature of airway obstruction after lung transplantation. American journal of respiratory and critical care medicine. 2014 Feb 1     [PubMed PMID: 24354907]

[21]

Federica M,Nadia S,Monica M,Alessandro C,Tiberio O,Francesco B,Mario V,Maria FA, Clinical and immunological evaluation of 12-month azithromycin therapy in chronic lung allograft rejection. Clinical transplantation. 2011 Jul-Aug     [PubMed PMID: 21418327]

[22]

Vanaudenaerde BM,Meyts I,Vos R,Geudens N,De Wever W,Verbeken EK,Van Raemdonck DE,Dupont LJ,Verleden GM, A dichotomy in bronchiolitis obliterans syndrome after lung transplantation revealed by azithromycin therapy. The European respiratory journal. 2008 Oct     [PubMed PMID: 18827151]

[23]

Knoop C,Haverich A,Fischer S, Immunosuppressive therapy after human lung transplantation. The European respiratory journal. 2004 Jan     [PubMed PMID: 14738248]

[24]

Trulock EP,Christie JD,Edwards LB,Boucek MM,Aurora P,Taylor DO,Dobbels F,Rahmel AO,Keck BM,Hertz MI, Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official adult lung and heart-lung transplantation report-2007. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2007 Aug     [PubMed PMID: 17692782]

[25]

Hachem RR,Yusen RD,Meyers BF,Aloush AA,Mohanakumar T,Patterson GA,Trulock EP, Anti-human leukocyte antigen antibodies and preemptive antibody-directed therapy after lung transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2010 Sep;     [PubMed PMID: 20558084]

[26]

Ensor CR,Yousem SA,Marrari M,Morrell MR,Mangiola M,Pilewski JM,D'Cunha J,Wisniewski SR,Venkataramanan R,Zeevi A,McDyer JF, Proteasome Inhibitor Carfilzomib-Based Therapy for Antibody-Mediated Rejection of the Pulmonary Allograft: Use and Short-Term Findings. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2017 May;     [PubMed PMID: 28173620]

[27]

Levine SM, A survey of clinical practice of lung transplantation in North America. Chest. 2004 Apr;     [PubMed PMID: 15078729]

[28]

Martinu T,Pavlisko EN,Chen DF,Palmer SM, Acute allograft rejection: cellular and humoral processes. Clinics in chest medicine. 2011 Jun;     [PubMed PMID: 21511091]

[29]

Fishman JA, Infection in solid-organ transplant recipients. The New England journal of medicine. 2007 Dec 20;     [PubMed PMID: 18094380]

[30]

Fuehner T,Simon A,Dierich M,Dewall C,Laenger F,Pletz MW,Welte T,Gottlieb J, Indicators for steroid response in biopsy proven acute graft rejection after lung transplantation. Respiratory medicine. 2009 Aug;     [PubMed PMID: 19398195]

[31]

Guilinger RA,Paradis IL,Dauber JH,Yousem SA,Williams PA,Keenan RJ,Griffith BP, The importance of bronchoscopy with transbronchial biopsy and bronchoalveolar lavage in the management of lung transplant recipients. American journal of respiratory and critical care medicine. 1995 Dec;     [PubMed PMID: 8520773]

[32]

Sarahrudi K,Estenne M,Corris P,Niedermayer J,Knoop C,Glanville A,Chaparro C,Verleden G,Gerbase MW,Venuta F,Böttcher H,Aubert JD,Levvey B,Reichenspurner H,Auterith A,Klepetko W, International experience with conversion from cyclosporine to tacrolimus for acute and chronic lung allograft rejection. The Journal of thoracic and cardiovascular surgery. 2004 Apr;     [PubMed PMID: 15052212]

[33]

Meiser BM,Uberfuhr P,Fuchs A,Schulze C,Nollert G,Mair H,Martin S,Pfeiffer M,Reichenspurner H,Kreuzer E,Reichart B, Tacrolimus: a superior agent to OKT3 for treating cases of persistent rejection after intrathoracic transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 1997 Aug;     [PubMed PMID: 9286771]

[34]

Ensor CR,Rihtarchik LC,Morrell MR,Hayanga JW,Lichvar AB,Pilewski JM,Wisniewski S,Johnson BA,D'Cunha J,Zeevi A,McDyer JF, Rescue alemtuzumab for refractory acute cellular rejection and bronchiolitis obliterans syndrome after lung transplantation. Clinical transplantation. 2017 Apr;     [PubMed PMID: 28008661]

[35]

Reams BD,Musselwhite LW,Zaas DW,Steele MP,Garantziotis S,Eu PC,Snyder LD,Curl J,Lin SS,Davis RD,Palmer SM, Alemtuzumab in the treatment of refractory acute rejection and bronchiolitis obliterans syndrome after human lung transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2007 Dec;     [PubMed PMID: 17924993]

[36]

Meyer KC,Raghu G,Verleden GM,Corris PA,Aurora P,Wilson KC,Brozek J,Glanville AR, An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome. The European respiratory journal. 2014 Dec;     [PubMed PMID: 25359357]

[37]

Cairn J,Yek T,Banner NR,Khaghani A,Hodson ME,Yacoub M, Time-related changes in pulmonary function after conversion to tacrolimus in bronchiolitis obliterans syndrome. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2003 Jan;     [PubMed PMID: 12531413]

[38]

Whyte RI,Rossi SJ,Mulligan MS,Florn R,Baker L,Gupta S,Martinez FJ,Lynch JP 3rd, Mycophenolate mofetil for obliterative bronchiolitis syndrome after lung transplantation. The Annals of thoracic surgery. 1997 Oct;     [PubMed PMID: 9354506]

[39]

Burton CM,Carlsen J,Mortensen J,Andersen CB,Milman N,Iversen M, Long-term survival after lung transplantation depends on development and severity of bronchiolitis obliterans syndrome. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2007 Jul;     [PubMed PMID: 17613397]

[40]

Heng D,Sharples LD,McNeil K,Stewart S,Wreghitt T,Wallwork J, Bronchiolitis obliterans syndrome: incidence, natural history, prognosis, and risk factors. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 1998 Dec;     [PubMed PMID: 9883768]

[41]

Sundaresan S,Trulock EP,Mohanakumar T,Cooper JD,Patterson GA, Prevalence and outcome of bronchiolitis obliterans syndrome after lung transplantation. Washington University Lung Transplant Group. The Annals of thoracic surgery. 1995 Nov;     [PubMed PMID: 8526624]