Evaluation and treatment of acute cellular lung transplant rejection

INTRODUCTION — Acute allograft rejection is a significant problem in lung transplantation. Despite advances in induction immunosuppression and use of aggressive maintenance immunosuppression, more than a third of lung transplant recipients are treated for acute rejection in the first year after transplant [1-3]. Acute rejection is responsible for approximately 4 percent of deaths in the first 30 days following transplantation [2,3].

The clinical manifestations, evaluation, and treatment of acute cellular lung transplant rejection and the role of routine monitoring for rejection will be reviewed here. The immunobiology of transplantation, induction and maintenance immunosuppression after lung transplantation, primary graft dysfunction, humoral rejection, and chronic lung transplant rejection are discussed separately.

●(See "Transplantation immunobiology".)

●(See "Induction immunosuppression following lung transplantation".)

●(See "Maintenance immunosuppression following lung transplantation".)

●(See "Primary lung graft dysfunction".)

●(See "Evaluation and treatment of antibody-mediated lung transplant rejection".)

●(See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

●(See "Chronic lung allograft dysfunction: Restrictive allograft syndrome".)

DEFINITIONS

●Acute cellular rejection – Acute cellular rejection is the predominant type of acute lung transplant rejection and is mediated by T lymphocyte recognition of foreign major histocompatibility complexes (MHC), also known as human leukocyte antigens (HLA) in humans, or other antigens [1,4,5].

●Humoral rejection – Humoral rejection, which is less common than acute cellular rejection, is mediated by antibodies directed against donor HLA or other epitopes. These antibodies may have been present in the recipient at a low level prior to transplant or may develop afterwards. Generally, if HLA antibodies are identified in the potential recipient, the corresponding HLA antigens are avoided in a donor (so-called virtual cross-match).

●Hyperacute rejection – Hyperacute rejection is a form of humoral rejection that occurs in the first 24 hours following lung transplantation in recipients who have pre-formed anti-HLA antibodies. With improved sensitivity of HLA antibody testing, hyperacute rejection now rarely occurs.

●Chronic lung allograft dysfunction – Chronic lung transplant rejection is manifest pathologically as dense fibrous scar tissue affecting the small airways. Clinically, chronic lung transplant rejection is known as chronic lung allograft dysfunction (CLAD), which manifests as persistent airway obstruction that is defined as a decline in forced expiratory volume in one second (FEV₁). In addition, a form of restrictive CLAD (CLAD – restrictive allograft syndrome [RAS]) has been described and appears to have significant prognostic implications [6]. Less commonly, chronic vascular rejection with atherosclerosis in the pulmonary vasculature is also present.

Discussions of humoral lung transplant rejection, including hyperacute rejection, and chronic lung transplant rejection are provided separately. (See "Evaluation and treatment of antibody-mediated lung transplant rejection" and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome" and "Chronic lung allograft dysfunction: Restrictive allograft syndrome".)

PATHOLOGY — Our knowledge of the pathology of lung allograft rejection comes from both clinical and experimental observations [7-12]. The histopathologic manifestation of acute cellular rejection is a lymphocyte-predominant inflammatory response centered on blood vessels and/or airways, the mechanism of which is discussed separately. (See "Transplantation immunobiology".)

The International Society for Heart and Lung Transplantation (ISHLT) has developed a "Working Formulation of the Standardization of the Nomenclature in the Diagnosis of Lung Rejection," which was revised in 2007 (table 1) [13-15]. This schema classifies rejection according to the anatomic structures involved and the severity of the abnormality. The key histopathologic features of acute cellular rejection are:

●A vascular component consisting of perivascular mononuclear infiltrates that may extend to the subendothelium; this lymphocyte infiltration can spread to involve the alveolar walls in higher grades of rejection (picture 1A-B). The specific alloantigens responsible for this vasocentric inflammatory response remain undefined. The grades range from A0 (no rejection) to A4 (severe).

●An airway component with a lymphocytic response initially in the submucosa of bronchioles and with increasing severity extending through the basement membrane. Bronchiolar inflammation may occur either in isolation or simultaneously with vascular inflammation. Ulceration of the airway epithelium may occur in more advanced cases (picture 2A-B). The grades range from B0 (no rejection) to B2R (high grade, revised 2007 system) [15].

Occasional eosinophils may be present in the vascular and bronchiolar components of acute cellular rejection. The presence of hyaline fibrosis in airways and vessels remains the key histologic discriminator between acute and chronic rejection of the lung [15].

RISK FACTORS FOR ACUTE REJECTION — The risk of acute lung transplant rejection is greatest in the first few months after transplant and decreases with time. Several factors have been implicated as contributing to the development of acute cellular rejection. The potential factors include:

●Human leukocyte antigens (HLA) mismatching – An increasing degree of HLA mismatch between the donor and recipient increases the risk of acute cellular rejection [2]. A multi-center observational study demonstrated a higher frequency of acute rejection in the first post-transplant year in patients with four or more HLA mismatches [16]. However, mismatch at certain HLA loci may be more important than at others [17].

●Genetic factors – Genetic variants in interleukin (IL)-10, multidrug resistance genotype, CCL4L chemokine, and toll-like receptor 4(TLR4) may influence the risk of acute rejection [18-21].

●Immunosuppression regimen – In the International Society for Heart and Lung Transplantation (ISHLT) registry, the rate of acute rejection in the first year was highest among recipients on cyclosporine-based regimens and lowest among those on tacrolimus-based regimens [22]. In addition, induction therapy with an interleukin-2R antagonist was associated with a lower rate of acute rejection than other induction regimens. (See "Maintenance immunosuppression following lung transplantation", section on 'Calcineurin inhibitors' and "Induction immunosuppression following lung transplantation", section on 'Induction agents'.)

●Age – More rejection episodes were reported among recipients in the lowest age category (18 to 34 years) than in older age categories, although this data from the ISHLT registry was not adjusted for underlying disease or other potentially confounding factors [23].

●Vitamin D deficiency − In a cohort of 102 lung transplant recipients, episodes of acute cellular rejection were more frequent among those with deficiency (<30 ng/mL) in 25-hydroxyvitamin D (25-OH D) near the time of transplantation, than among those with normal 25-OH D levels (incidence rate ratio 2.43, 95% CI 1.30 to 4.52) [24].

CLINICAL MANIFESTATIONS — Acute cellular rejection is most likely to occur in the first six months following lung transplantation [25,26]. Often, patients are asymptomatic, and the diagnosis is made from surveillance transbronchial biopsies. When present, symptoms are nonspecific and are shared by other common complications that occur during this period. They include low-grade fever, shortness of breath, and cough with or without sputum production (table 2) [1,27].

During long-term follow-up of 120 lung transplant recipients, shortness of breath and cough were more common in those with clinically significant acute rejection (grade ≥A2) than those without (grade A0 or A1) (table 1), but comparable in frequency to those with pulmonary infection. For predicting grade >A2 rejection, the sensitivity and specificity were 68 and 50 percent for cough and 63 and 68 percent for shortness of breath, respectively.  

Lung examination may reveal clear lung fields, crackles, or decreased breath sounds when a pleural effusion is present as part of the acute rejection. High grade rejection may be associated with respiratory distress [27].

EVALUATION OF SYMPTOMATIC PATIENTS — When lung transplant recipients present with nonspecific respiratory symptoms, the differentiation between acute allograft rejection, airway stenosis, and infection requires a combination of pulmonary function testing, imaging, and bronchoscopy [27]. As acute rejection requires intensification of immunosuppression, which could be deleterious in the presence of opportunistic infection, a definitive diagnosis is highly desirable. In most circumstances this can be achieved by a transbronchial biopsy.

Laboratory testing — Laboratory testing in patients with suspected acute lung transplant rejection is generally nonspecific. Peripheral eosinophilia may be present; however, specific blood markers for rejection are not available. As infection is in the differential diagnosis, microbiologic stains and cultures are obtained from sputum, and bronchoalveolar lavage or bronchial washing samples. Cytomegalovirus (CMV) viral load testing is performed on peripheral blood. (See "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients", section on 'Pneumonitis'.)

Pulmonary function tests — Spirometry is typically obtained at routine follow-up visits following lung transplantation and if dyspnea develops or worsens. The typical pulmonary function test abnormalities in acute cellular lung transplant rejection are airflow obstruction manifest by a decrease in forced expiratory volume in one second (FEV₁) [28], or restriction manifest by a reduction in both forced vital capacity (FVC) and FEV₁. The sensitivity of a decrease in FEV₁ for detecting acute rejection is approximately 60 percent [2,27,28]. Thus, stable pulmonary function as determined by spirometry does not exclude acute lung transplant rejection [28]. Among lung transplant recipients, respiratory infection is associated with a similar decrease in FEV₁, so spirometry does not differentiate between these entities [28]. Bronchial stenosis is in the differential diagnosis of airflow limitation following lung transplantation and provides additional rationale for bronchoscopy to evaluate new respiratory symptoms or a decline in lung function.

Limited data are available on changes in total lung capacity (TLC) and diffusing capacity (DLCO) in association with acute lung transplant rejection. Among heart-lung transplant recipients, acute rejection is associated with decreases in TLC and DLCO [28].

Imaging — A chest radiograph is typically obtained as part of routine assessment and to assess the cause of new onset of dyspnea or cough in lung transplant recipients. Its main role in this setting is to identify diseases other than acute rejection. In early episodes of rejection (within the first three months), the chest radiograph may demonstrate perihilar opacities and interstitial edema with or without a pleural effusion [1]. However, the sensitivity and specificity of the chest radiograph are low [1]. The chest film is unchanged in approximately 80 percent of later episodes of rejection [29,30].

High resolution computed tomography (HRCT) is often obtained to assess the severity and distribution of the disease process or to guide the bronchoscopist in choosing sites for bronchoalveolar lavage or transbronchial biopsy. HRCT findings of acute lung transplant rejection include ground glass opacities, septal thickening, volume loss, and pleural effusion [1]. However, HRCT findings are neither sensitive nor specific and do not differentiate between infection and rejection [1,31].

Pleural fluid analysis — Pleural effusions are common in the first two weeks following lung transplantation and do not require fluid analysis unless the effusion is large or the patient has signs of infection. When a new onset pleural effusion is identified after the first couple of weeks, ultrasound guided thoracentesis is usually performed to obtain fluid for analysis and culture. Among patients with a pleural effusion associated with acute cellular lung transplant rejection, the pleural fluid is typically lymphocytic, although this finding is not specific. Chylothorax, another cause of lymphocytic effusions following lung transplantation, can develop due to disruption of the thoracic duct or as a complication of lymphangioleiomyomatosis. (See "Pleural complications in lung transplantation", section on 'Pleural effusions'.)

Flexible bronchoscopy — When patients present with a clinical syndrome suggestive of rejection or infection, most centers perform bronchoscopy with bronchoalveolar lavage and transbronchial biopsy in an attempt to establish a specific diagnosis (table 3). The techniques of bronchoalveolar lavage (BAL) and transbronchial biopsy (TBB) are discussed separately [32]. (See "Basic principles and technique of bronchoalveolar lavage" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease" and "Flexible bronchoscopy in adults: Overview" and "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Transbronchial biopsy'.)

Common clinical practice is to sample multiple segments of a single lung allograft. In patients with focal radiographic abnormalities, BAL and biopsies are concentrated in the area of the radiologic abnormality. Samples are sent for cell count and differential, microbiologic stains and cultures, cytology, and histopathology.

●Bronchoalveolar lavage ─ During the first three months following lung transplantation, total BAL cell counts are elevated, and a neutrophilic alveolitis (eg, 25 to 50 percent neutrophils) is common [33]. In contrast, acute cellular rejection is associated with a lymphocytic alveolitis (eg, 10 to 60 percent lymphocytes) with a decreased CD4/CD8 ratio. However, these findings are nonspecific and lymphocytic alveolitis is also seen in viral pneumonias and obliterative bronchiolitis [33]. Data is conflicting, but the degree of BAL lymphocytosis does not correlate well with the histologic grade of rejection [33,34].

●Transbronchial biopsy ─ When imaging studies suggest diffuse disease or are normal, transbronchial biopsies are typically obtained from the lower lobes; when disease is radiographically patchy, biopsies are obtained from diseased areas [35]. Practices vary concerning the number of transbronchial biopsies obtained for adequate sampling. Animal studies suggest that three good transbronchial biopsies have a sensitivity of 92 percent in identifying moderate to severe rejection and five biopsies have a similar sensitivity in identifying mild rejection [15,36]. Most centers try to obtain 6 to 10 biopsies in order to achieve 5 "adequate" or "good" specimens, defined as samples with at least five alveoli. The sensitivity of transbronchial biopsy for diagnosing acute rejection is 61 to 94 percent and the specificity greater than 90 percent with an experienced pulmonary pathologist [37,38]. The sensitivity for the diagnosis of cytomegalovirus pneumonia is approximately 90 percent [37].

Generally, only one lung is biopsied during a single bronchoscopy in heart-lung or bilateral lung recipients. The major exception to this practice is in patients who have received bilateral living-donor lobar transplants. In these patients, the lower lobes come from two different donors, and rejection is typically limited to one of the donor lobes and is rarely bilateral. As a result, living-donor recipients with no localizing signs or radiographic abnormalities may need to have both lower lobes biopsied [39]. Fluoroscopy can be used to document the absence of pneumothorax on the first side before proceeding to biopsy the contralateral side.

Adverse events reported with flexible bronchoscopy in lung transplant recipients are infrequent and include transient hypoxemia (10 percent), bleeding greater than 100 mL (4 percent), postprocedure pneumonia (2 percent), pneumothorax (1 to 3 percent), and arrhythmia (1 to 4 percent) [2,26,40,41].

MONITORING ASYMPTOMATIC PATIENTS — Acute cellular rejection of the lung allograft is a major risk factor for development of CLAD – bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) [42]. Thus, an important goal of monitoring for acute allograft rejection in asymptomatic patients is to reduce the likelihood of late complications by preemptive treatment of acute cellular rejection. The two main forms of monitoring are spirometry and transbronchial biopsy. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

The use of biomarkers to detect asymptomatic allograft dysfunction is an area of active research.

Spirometry — Office spirometry is considered a critical tool for monitoring allograft function. However, the frequency of office spirometry and the use of home spirometry vary among transplant centers.

Office spirometry is typically performed at the time of follow-up visits after lung transplantation. Once postoperative function has stabilized the variation in forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) is less than 5 percent. Spirometry has been reported to have a sensitivity of 60 percent in detecting rejection (grade ≥A2) or infection among bilateral lung transplant recipients (table 1) [1,43]. A decline of 10 percent in spirometric values that persists for more than two days has been reported to indicate either rejection or infection [43-45]. In single lung transplant recipients, spirometry is less helpful as changes may reflect progression of the underlying disease in the native lung [46].

Performance of patient-administered home spirometry several times a week may lead to earlier detection of CLAD, but the effect on long-term outcomes is less clear [47]. The potential benefit of frequent spirometry remains an area of active research.

Surveillance bronchoscopy — The role of surveillance bronchoscopy with transbronchial biopsy remains controversial, and the performance of routine surveillance transbronchial biopsies varies between lung transplant centers [40,48-50], but the majority of lung transplant programs perform surveillance bronchoscopy. The technique of transbronchial biopsy is discussed separately. (See "Flexible bronchoscopy in adults: Overview" and "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Transbronchial biopsy'.)

The rationale for surveillance biopsy protocols is based upon studies that show a substantial prevalence of pathologic evidence of rejection in asymptomatic patients. As examples:

●Retrospective evidence that up to 25 percent of surveillance transbronchial biopsies demonstrate evidence of allograft rejection [40,50].

●Among 121 surveillance bronchoscopies, acute rejection, grade 2 or higher, was noted in 16 percent [40].

●Among 1770 bronchoscopies, lymphocytic bronchiolitis grade 1 or higher was noted in 14 percent [42].

●Retrospective analysis demonstrating that lymphocytic bronchiolitis (grade B acute rejection) (table 1) is a risk factor for subsequent development of CLAD [42]. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

However, a survival benefit of surveillance biopsies has not been demonstrated [50]. A single-center, randomized trial of 47 recipients did not demonstrate any clinical benefit from surveillance biopsies [41]. A separate retrospective study found that the presence of lymphocytic bronchiolitis, but not vascular rejection on transbronchial biopsy correlated with reduced survival [42]. This observation raised the possibility that previous studies that failed to demonstrate a benefit to surveillance bronchoscopy were looking at the wrong pathologic feature (ie, acute vascular rejection rather than lymphocytic bronchiolitis). Further research is needed to determine whether early treatment of lymphocytic bronchiolitis based on surveillance bronchoscopy results reduces the risk of CLAD and improves survival.

In a 2004 survey, approximately 69 percent of North American lung transplant centers performed surveillance transbronchial biopsies, although a wide variety of protocols was used [48,51]. A representative surveillance biopsy schedule is: 1 month, 3 months, 6 months, 12 months, 18 months, and 24 months [48]. Reports in the literature suggest a much lower yield after 24 months, and most centers do not routinely perform biopsies after this point. Some centers perform bronchoalveolar lavage (BAL) without transbronchial biopsy after the first year [40]. Other centers use the history of rejection in the first four months to determine the frequency of surveillance biopsies at 6 months and beyond [42].

Imaging — Chest imaging studies, including high resolution computed tomography (HRCT), have a low sensitivity (as low as 35 percent) for acute lung transplant rejection and are typically not used for screening [1,31].

DIAGNOSIS — The diagnosis of acute cellular rejection in lung transplant recipients is based on the presence of characteristic histopathologic changes on transbronchial lung biopsy specimens (table 1) and exclusion of infection [15]. Transbronchial lung biopsies need to be interpreted by a pathologist with experience in lung transplantation. When the patient undergoes biopsy at a site other than a transplant center, it is common practice to send the biopsy slides to the transplant center for review. (See 'Pathology' above and 'Flexible bronchoscopy' above.)

For symptomatic patients, additional support for a diagnosis of acute cellular rejection includes the absence of airway stenosis at the time of flexible bronchoscopy and confirmation of negative microbiologic assays, stains, and cultures. (See "Airway complications after lung transplantation" and "Bacterial infections following lung transplantation" and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients" and "Viral infections following lung transplantation" and "Fungal infections following lung transplantation".)

Clinical assessment without transbronchial biopsy is frequently inaccurate, as noted in a study from an experienced center in which only a 54 percent concordance rate was found between the clinical impression and the final pathologic diagnosis. Transbronchial lung biopsies improve the yield for a specific diagnosis to approximately 70 percent. (See 'Flexible bronchoscopy' above.)

If the transbronchial biopsy does not yield a specific diagnosis and the patient has progressive respiratory impairment, repeat transbronchial biopsy, a video-assisted thoracoscopic lung biopsy, or, in the setting of acute lung injury, empiric therapy may be needed.

DIFFERENTIAL DIAGNOSIS — In addition to acute cellular rejection, the differential diagnosis of a decline in allograft function after initial recovery includes infection, humoral rejection, airway complications (eg, stenosis at the bronchial anastomosis, airway malacia and granulation tissue), chronic rejection (chronic lung allograft dysfunction [CLAD ], thromboembolism, and recurrent primary disease [52,53]. These alternate diagnoses are typically excluded by studies such as PCR (polymerase chain reaction) assays for cytomegalovirus, fiberoptic bronchoscopy to examine the airway, D-dimer assessment, extensive microbiologic stains and cultures of bronchoalveolar lavage specimens, and histopathologic examination of transbronchial biopsies. (See "Evaluation and treatment of antibody-mediated lung transplant rejection", section on 'Diagnosis and differential diagnosis' and "Airway complications after lung transplantation" and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome" and "Noninfectious complications following lung transplantation", section on 'Recurrent primary disease' and "Bacterial infections following lung transplantation" and "Fungal infections following lung transplantation" and "Viral infections following lung transplantation" and "Noninfectious complications following lung transplantation", section on 'Venous thromboembolism'.)

Features that suggest infection include the presence of:

●Acute inflammatory cells such as polymorphonuclear leukocytes in the bronchoalveolar lavage

●Predominantly alveolar inflammation rather than vascular or airway-centered inflammation on biopsy (see 'Pathology' above)

●Viral inclusions on cytology or transbronchial biopsy

●The presence of infectious pathogens on special stains or culture

Infection and acute rejection can also occur together, and it can be difficult or impossible to make the diagnosis of acute rejection in the presence of viral infections (cytomegalovirus, metapneumovirus, adenovirus, and severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] in particular) because of the lymphocytic infiltrate that accompanies such infections. In the presence of active cytomegalovirus (CMV) infection, a common approach is to treat the infection and then repeat the biopsies to assess any contribution of rejection to the patient's clinical syndrome. The alternative of empirically treating possible acute cellular rejection by intensifying immunosuppression is avoided due to concern that it would impair clearance of the CMV infection. (See "Viral infections following lung transplantation" and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients".)

In addition, cellular and humoral rejection may occur concomitantly, and antibody-mediated rejection should be considered particularly in the setting of refractory acute cellular rejection. (See "Evaluation and treatment of antibody-mediated lung transplant rejection".)

TREATMENT OF ACUTE CELLULAR REJECTION

Deciding when to treat — The decision to treat patients with histologic evidence of acute cellular rejection is based upon the clinical features and the histopathologic severity of rejection (table 1). There is widespread agreement that moderate or severe rejection (grade A3, A4) should be treated [2,48]. The management of minimal or mild rejection (grade A1, A2) is more variable and often depends on the clinical setting and/or physician and patient preference and philosophy [2]. In a large single center study (441 lung transplant recipients), there was no association between A1 rejection and subsequent development of CLAD, except in the subset who had higher concentrations of the chemokine CXCL9 in bronchoalveolar lavage (BAL) fluid [54]. Additional research is needed to determine the clinical utility of BAL assessments for deciding which patients with minimal cellular rejection merit treatment. In a small observational study, patients with clinically silent and untreated A2 rejection were more likely to progress to higher grade rejection or develop obliterative bronchiolitis [55]. Maintenance immunosuppression may be adjusted in some patients who do not meet criteria for treatment of acute rejection.

As examples:

●Immunosuppression is usually not acutely increased in patients who have surveillance biopsies showing minimal rejection (A1), but no clinical signs or symptoms suggestive of rejection, and stable pulmonary function (table 1). (See "Maintenance immunosuppression following lung transplantation".)

●Practices are variable concerning the management of mild rejection on surveillance biopsies (A2) without clinical signs or symptoms of rejection or lung function decline (table 1). Some centers elect not to treat asymptomatic A2 rejection but will perform repeat surveillance bronchoscopy with biopsies in three to eight weeks. Our practice is to initiate treatment for A2 rejection even in the absence of symptoms or decline in pulmonary function.

●Most centers, including ours, augment immunosuppression in patients with histologic evidence of minimal or mild rejection and a clinical syndrome suggestive of rejection.

For symptomatic patients or those with airway secretions at bronchoscopy or radiographic abnormalities, empiric antibiotics are often initiated while waiting for culture results (figure 1). (See "Bacterial infections following lung transplantation", section on 'Pneumonia'.)

High-dose glucocorticoids — The optimal regimen for treating acute rejection has not been determined, so treatment choices are based on clinical experience. Typically, treatment is initiated with high dose parenteral glucocorticoids, such as intravenous methylprednisolone (15 mg/kg, or 500 mg to 1 g intravenously per day) for three days [2,48]. Dose adjustment is often considered in patients on azole antifungals, as itraconazole markedly prolongs the half-life of methylprednisolone (table 4). Pulse glucocorticoids can be done as an inpatient or outpatient, depending on patient symptoms, co-morbidities and available clinical infrastructure.

Symptomatic improvement usually occurs over 24 to 48 hours in patients with symptoms of rejection, and the physiologic abnormalities begin to improve in the same time frame and return to baseline over several weeks. In a series of 85 patients with symptomatic acute lung transplant rejection, 47 (55 percent) responded to a glucocorticoid pulse [56]. The strongest predictor of glucocorticoid response was onset a shorter time after transplantation.

After high-dose intravenous methylprednisolone, patients are returned to their baseline glucocorticoid dose or transitioned to a tapering course of oral glucocorticoids (starting at 0.5 to 1 mg/kg of prednisone). Although specific regimens vary, the typical practice is to taper back to the baseline glucocorticoid dose over a several week period. Drug levels of tacrolimus need more frequent monitoring, as high-dose methylprednisolone has been associated with increased tacrolimus levels.

Follow-up bronchoscopy — Clinical practice for follow-up after treatment of an episode of acute cellular rejection is not standardized. Centers that perform surveillance bronchoscopy to evaluate suspected acute rejection will also generally perform follow-up bronchoscopy. We typically perform follow-up bronchoscopy with bronchoalveolar lavage and transbronchial biopsies approximately three to four weeks after therapy (range of two to eight weeks).

In a retrospective study of 242 bronchoscopies performed to assess response to treatment for acute rejection, a pathologic abnormality was noted in 62 percent. The clinical impression of whether the patient had responded to treatment was accurate in only one-half of cases [57]. Decisions about therapy for persistent rejection seen on follow-up biopsies are typically made by criteria like those outlined above for the initial diagnosis. (See 'Surveillance bronchoscopy' above.)

Persistent or refractory acute cellular rejection — Therapy for persistent or refractory acute rejection is not well-established. Failure to respond to therapy for acute cellular rejection should prompt investigation for concomitant antibody-mediated rejection, if not already addressed. (See "Evaluation and treatment of antibody-mediated lung transplant rejection", section on 'Diagnosis and differential diagnosis'.)

Several approaches to refractory acute cellular rejection have been reported, and scientific data to support one over another are lacking. For persistent acute cellular rejection, our approach has been to treat a second time with intravenous glucocorticoids (eg, intravenous methylprednisolone) for three days. An alternative, for patients on a cyclosporine-based regimen, is to switch the maintenance immunosuppressive agent from cyclosporine to tacrolimus [2,58-60]. (See 'High-dose glucocorticoids' above and "Maintenance immunosuppression following lung transplantation", section on 'Calcineurin inhibitors'.)

If the subsequent biopsy shows a lower grade of rejection and the patient is getting better clinically, we often observe and repeat biopsies in three to four weeks. On the other hand, if evidence of rejection grade ≥A2 persists after two courses of glucocorticoids, we typically use antibody therapy for lymphodepletion (eg, antithymocyte globulin [ATG] or alemtuzumab) and/or add a mechanistic target of rapamycin (previously mammalian target of rapamycin [mTOR]) inhibitor (sirolimus or everolimus) [17,48,61-63]. (See "Maintenance immunosuppression following lung transplantation", section on 'mTOR inhibitors'.)

If rejection appears severe or if the response to antibody therapy is incomplete, we also consider extracorporeal photopheresis (ECP) [64-67] or pulse cyclophosphamide [68]. ECP consists of infusion of ultraviolet-A irradiated autologous peripheral lymphocytes which have been collected by apheresis and incubated with 8-methoxypsoralen. The mechanism by which ECP decreases immune responses in transplant recipients is unclear but may involve enhancement of the number of peripheral regulatory T cells [65,69]. (See "Treatment of acute graft-versus-host disease", section on 'Extracorporeal photopheresis'.)

Methotrexate, maintenance cyclophosphamide, and total lymphoid irradiation have been used in the past for patients with recurrent rejection but are rarely used now [70-72].

Adjusting maintenance immunosuppression — Re-evaluating and optimizing the maintenance immunosuppression regimen is appropriate in patients with acute or persistent rejection. This may include assessing blood levels of the immunosuppressive agents and the patient’s adherence to their immunosuppression regimen, as well as adjusting the regimen. The following potential changes depend on the individual patient’s maintenance regimen and the preferences of the local transplant team:

●Changing the maintenance immunosuppression from cyclosporine to tacrolimus [59,60,73]. (See "Maintenance immunosuppression following lung transplantation", section on 'Calcineurin inhibitors'.)

●Changing the maintenance immunosuppression from azathioprine to a mycophenolic acid precursor. (See "Maintenance immunosuppression following lung transplantation", section on 'Nucleotide blocking agents'.)

●Adding a mTOR inhibitor (sirolimus or everolimus) to the maintenance regimen, if the time since lung transplantation is more than three months. (See "Maintenance immunosuppression following lung transplantation", section on 'mTOR inhibitors'.)

Aerosolized cyclosporine has been evaluated as an alternative therapy for acute lung transplant rejection [74,75] and for prevention of allograft rejection [76]. In a study of refractory acute rejection, eighteen patients who failed to improve following high-dose glucocorticoid and antilymphocyte globulin therapy were treated with aerosolized cyclosporine [75]. Two patients were unable to tolerate treatment, but 14 had improvement in histologic rejection grade. A pilot study of aerosolized cyclosporine suggested a survival benefit but did not demonstrate a reduction in acute rejection [76]; moreover, in preliminary results, a multi-center trial failed to demonstrate efficacy for aerosolized cyclosporine (CYCLIST trial) in prevention of acute rejection [77]. Aerosolized cyclosporine is not commercially available and remains under investigation in clinical trials. (See "Maintenance immunosuppression following lung transplantation", section on 'Future directions'.)

Experience with the selective T cell co-stimulatory blocker, belatacept, is limited to retrospective reports of short term effectiveness for patients intolerant of calcineurin inhibitors, for prevention of acute cellular rejection or renal-sparing [78,79]. However, recent reports suggest an increased risk for acute cellular rejection when belatacept is used without a calcineurin inhibitor [80]. Further study will be necessary to define its role, if any, for treatment of refractory ACR and prevention of acute and chronic rejection.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lung transplantation".)

SUMMARY AND RECOMMENDATIONS

●Definition and pathophysiology – Acute cellular rejection is the predominant type of acute lung transplant rejection and is mediated by T lymphocytes directed against the donor major histocompatibility complexes (MHC), also known as human leukocyte antigens (HLA) in humans, or other antigens in the allograft. The risk of acute cellular rejection is greatest in the first few months after lung transplant and decreases with time. (See 'Definitions' above.)

●Pathology – Acute cellular rejection is a lymphocyte predominant inflammatory response. Vascular (picture 1A-B) and airway (picture 2A-B) components are described, either in isolation or simultaneously. The grading of acute cellular rejection is described in the table (table 1). (See 'Pathology' above.)

●Clinical manifestations – Patients with acute rejection may be asymptomatic, may have a decline in lung function, or may have low-grade fever, shortness of breath, or cough with or without sputum production. (See 'Clinical manifestations' above.)

●Surveillance – Monitoring of asymptomatic patients usually includes spirometry and surveillance bronchoscopy with transbronchial biopsies of lower lobe subsegments to enable early diagnosis and treatment of acute rejection, and thus hopefully reduce the risk of chronic lung allograft dysfunction (CLAD). (See 'Monitoring asymptomatic patients' above.)

●Evaluation – The evaluation of patients with suspected acute cellular rejection typically includes laboratory testing for evidence of infection, chest imaging, spirometry, and flexible bronchoscopy. During bronchoscopy, bronchoalveolar lavage and transbronchial biopsies (usually 6 to 10 biopsies to achieve at least five adequate samples) are obtained from areas of focal radiographic abnormality or from lower lobe subsegments. (See 'Evaluation of symptomatic patients' above.)

●Diagnosis – The diagnosis of acute lung transplant rejection is based on the presence of characteristic histopathologic changes on transbronchial lung biopsy specimens (table 1). (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of declining allograft function occurring in the weeks to months after transplant includes infection, airway complications (eg, airway stenosis, malacia, or granulation tissue), chronic rejection (CLAD – bronchiolitis obliterans syndrome [BOS] or restrictive allograft syndrome [RAS]), volume overload, pleural effusion, thromboembolism, and recurrent primary disease. (See 'Differential diagnosis' above.)

●Initial treatment – The decision to treat patients with histologic evidence of acute cellular lung allograft rejection is dependent upon the clinical setting and the severity of the rejection (table 1). (See 'Deciding when to treat' above.)

•For patients with moderate or severe rejection (grade A3, A4) without evidence of lung infection, we suggest treatment with intravenous glucocorticoids rather than other acute immunosuppressive regimens, such as antithymocyte globulin (ATG) or alemtuzumab (Grade 2C).

•For patients with mild rejection (grade A2) and patients with minimal rejection (grade A1) and symptoms of rejection or lung function decline, we suggest treatment with intravenous glucocorticoids after excluding lung infection rather than early repeat surveillance transbronchial biopsy alone (Grade 2C).

•Conversely, patients with minimal acute cellular rejection (grade A1) who have no symptoms of rejection and no lung function decline are not typically treated with additional immunosuppression but are instead monitored clinically and with continued standard transbronchial biopsy surveillance.

•For initial treatment of acute cellular rejection, we typically use intravenous methylprednisolone (15 mg/kg, or 0.5 to 1 gram IV per day) for three days. After clinical response, patients are transitioned to oral glucocorticoids, typically 0.5 to 1 mg/kg of prednisone/day, which is tapered to the patient’s baseline dose over several weeks. (See 'High-dose glucocorticoids' above.)

●Follow-up surveillance – Guidelines for follow-up bronchoscopy after treatment of an episode of acute cellular rejection are not standardized. We typically perform a follow-up bronchoscopy approximately three to four weeks after treatment (range of two to eight weeks). (See 'Follow-up bronchoscopy' above.)

●Additional treatment for persistent or refractory disease

•For patients with persistent acute cellular rejection, we suggest a second course of intravenous glucocorticoids (eg, methylprednisolone, 0.5 to 1 gram IV daily for three days) (Grade 2C). An alternative or adjunctive therapy, for occasional patients using a cyclosporine-based regimen, is to change the maintenance calcineurin inhibitor from cyclosporine to tacrolimus. (See 'Persistent or refractory acute cellular rejection' above.)

•If evidence of acute cellular rejection persists on follow-up biopsies after two courses of glucocorticoids, an alternate immunosuppressive agent, such as ATG or alemtuzumab, is usually administered for acute treatment. (See 'Persistent or refractory acute cellular rejection' above and "Induction immunosuppression following lung transplantation", section on 'Induction agents'.)

•The maintenance immunosuppression regimen is usually adjusted in patients with recurrent acute or persistent evidence of rejection on follow-up biopsies. Potential changes include substituting tacrolimus for cyclosporine or mycophenolate for azathioprine or adding a mammalian target of rapamycin (mTOR) inhibitor. (See 'Adjusting maintenance immunosuppression' above and "Maintenance immunosuppression following lung transplantation".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John Reilly, Jr., MD, who contributed to earlier versions of this topic review.