Two single-center randomized placebo-controlled trials (RCT) evaluated azithromycin for CLAD prevention (203 patients) [20, 21]. Azithromycin or placebo was administered either from discharge (initiated on average at 36 days post-transplant) for 2 years [16] or preoperatively until 31 days post-transplant [21], respectively. In the latter study, open-label azithromycin was prescribed after 90 days post-transplant and continued in 91% (prior placebo) and 97% (prior azithromycin) of included patients. Long-term outcomes (>2 years) of the first trial were later assessed in a retrospective post-hoc analysis (n = 83) [22].

Azithromycin significantly reduced CLAD incidence at 2 years compared with placebo (13% vs. 44%; p = 0.017) [20]. At a median follow-up of 5.5 years, azithromycin-treated patients from Vos et al. still showed a lower incidence of CLAD (28% vs. 51%; p = 0.048) and significantly longer CLAD-free survival [22].

Two additional retrospective single-center studies assessed the effects of azithromycin prophylaxis. One reported increased overall survival (p = 0.002) and reduced risk of BOS in patients receiving azithromycin, although not significant (p = 0.07) [23]. The other study found that azithromycin prophylaxis, initiated at week 3 post-transplant or later than 3 weeks post-transplant, compared to patients not receiving azithromycin, was associated with a significantly lower risk of CLAD, with the earliest initiation showing the lowest incidence [24].

In summary, data suggest that azithromycin delays and may prevent the onset of CLAD post-transplant; but there is yet no clear evidence from RCTs that prophylactic azithromycin reduces graft loss and improves overall survival, although longer follow-up data are needed for these outcomes. Evidence on optimal initiation time is limited, though early initiation post-transplant may be preferred [24]. It is currently unclear whether the beneficial effects of azithromycin prophylaxis are more pronounced in specific patient populations.

Across the RCTs and post-hoc analysis, adverse effects, including serious allergic, cardiac, neurological, gastrointestinal events (requiring treatment discontinuation in 5% in the azithromycin group vs. 0% in the placebo group), and QT interval changes, were comparable between groups or clinically insignificant [20–22]. Similarly, the two retrospective single-center studies found no increased risk of adverse events, renal dysfunction, or malignancy associated with azithromycin [23, 24]. Of note, azithromycin prophylaxis did not affect the bronchial bacterial microbiota of lung transplant recipients [25].

In contrast, clinical experience indicates that gastrointestinal intolerance to azithromycin, related to its gastroprokinetic properties, may necessitate dose reduction or discontinuation. Ototoxicity was not assessed in the included studies, but prior data from patients with chronic lung disease have shown an association between long-term azithromycin use and increased risk of hearing impairment, which physicians should be aware of [26].

Overall, azithromycin is generally well tolerated. However, some adverse effects, such as ototoxicity, have not been systematically studied, and the long-term impact of continuous use remains uncertain.

The Task Force supports the use of azithromycin for CLAD prevention, based on evidence demonstrating a clinically meaningful reduction in CLAD incidence and a generally favorable safety profile with mild and infrequent adverse events.

Oral administration of azithromycin can be initiated during index admission or at routine follow-up visits. No additional monitoring beyond standard post-transplant care is required.

Future research on azithromycin should address the optimal timing of initiation after lung transplantation and whether treatment should be applied universally or targeted to specific risk groups. Studies should also incorporate patient-reported outcome measures and further evaluate long-term effects, including impact on graft and overall survival.

Task Force members had mixed opinions on whether a large multi-center randomized trial of azithromycin to prevent CLAD is needed. Better evidence would be useful, especially on giving the drug to all patients versus only higher-risk ones, and on the best timing. However, a placebo-controlled trial raises ethical and practical problems: the drug is already widely used, recruiting patients would be difficult and the study would need long follow-up. The main uncertainty is therefore not whether azithromycin works overall, but how and when it should be used, including which patients to treat, how long to treat them, and when to stop. Pragmatic randomized trials or large multi-center observational studies may be more realistic ways to answer these questions.

Four RCTs were identified (662 patients; 329 tacrolimus, 333 cyclosporine), with follow-up duration ranging from 507 days to 3 years [4, 27–29].

Across included trials, tacrolimus was associated with a significantly lower incidence of CLAD with moderate certainty of evidence [4, 27–29]. No statistically significant difference between groups was observed for overall survival (RR 0.91, 95% CI 0.68–1.21, p = 0.63–52) [4, 24–26] and graft loss (RR 0.70, 95% CI 0.6–1.06, p = 0.10) [4, 27, 29], but studies were not primarily powered for these outcomes.

Serious adverse events were only reported in the ScanCLAD trial [4] and were comparable between groups. Pooled data showed similar rates of infection [4, 27–29]; kidney dysfunction (serum creatinine >2 mg/dL) occurred significantly more often with tacrolimus [27–29] and this was also observed in the ScanCLAD trial [4]. In this study, however, upon switching from extended-release tacrolimus to immediate-release tacrolimus (protocol change during the study), the incidence of kidney dysfunction was no longer higher than with cyclosporine. No significant difference in malignancy was reported with tacrolimus compared to cyclosporine treatment [4, 27, 28].

In addition to the RCTs, three quasi-randomized trials [30–32], three observational studies [8, 33, 34] and a recent large registry study [35] were identified.

Reported overall survival was similar [34] or higher [8, 33] with tacrolimus compared to cyclosporine. In the quasi-randomized trials, one-year survival did not differ significantly in two studies [30, 31], while it was higher in the tacrolimus group in the other [27]. CLAD incidence was lower with tacrolimus compared with cyclosporine [31, 32]. The large registry study demonstrated that receiving cyclosporine for maintenance immunosuppression (compared with tacrolimus) was associated with an increased risk of developing CLAD (HR 1.16, 95% CI 1.08–1.23, p < 0.001) and with an increased overall risk of death/retransplant (HR 1.16, 95% CI 1.09–1.23, p < 0.001).

It should be noted that trough levels varied across studies, and there is currently no consensus on optimal trough targets at different time points after transplantation. The target trough levels for tacrolimus used in the ScanCLAD trial were 10–14 ng/mL at 0–3 months, 8–12 ng/mL at 3–6 months, 8–10 ng/mL at 6–12 months, and 6–8 ng/mL beyond 12 months [4].

Across solid organ transplantation, tacrolimus provides superior early rejection control and short-term graft survival compared with cyclosporine in kidney [36] and liver [37] transplants and is at least non-inferior in heart transplants [38]. However, robust, direct evidence that tacrolimus prevents late chronic allograft dysfunction beyond these surrogate benefits is limited.

No differences in infection rates and kidney dysfunction between tacrolimus and cyclosporine were reported [32, 33]. Tacrolimus was associated with a higher risk of post-transplant diabetes, neurotoxicity and gastrointestinal side effects in liver and kidney transplants [36, 37] but lower risk of hypertension [39].

Conversion from twice-daily, immediate release to once-daily, extended-release tacrolimus formulation appears safe for renal, metabolic, and allograft function and may improve adherence [40], but additional benefits regarding adverse effects remain uncertain. The ongoing Revolution Trial (NCT05001074) compares extended- and immediate-release tacrolimus in lung transplant recipients, assessing renal function and other clinical outcomes [41]. Results expected in 2026 may give insights into the optimal formulation.

Data supports the use of maintenance tacrolimus over cyclosporine in reducing CLAD incidence. Mortality and re-transplantation appeared neutral within the limited time frame of most studies, which were not adequately powered to detect a clinically meaningful effect. The registry study, which included a longer follow-up up to 14 years post-transplant, demonstrated an increased overall risk of death/retransplant in cyclosporine-treated patients. Overall certainty of evidence was considered low based on the low certainty of evidence for the critical outcomes graft loss and overall survival, despite moderate certainty of evidence for the outcome CLAD, necessitating recommendation downgrading for risk of bias and imprecision according to GRADE. The moderate certainty of evidence for CLAD is in line with other Refs. [12, 42, 43], but our overall certainty was rated low because of GRADE methodology [44]. However, given the moderate certainty of evidence for the CLAD outcome, the Task Force issued a strong recommendation for the use of tacrolimus even though data on its effect on long-term graft and overall survival are limited.

There are no major implementation concerns, as both tacrolimus and cyclosporine are widely available and included on the WHO Model List of Essential Medicines [35]. It remains insufficiently clear whether once-daily dosing with extended-release formulation offers advantages over twice-daily dosing with immediate-release formulation in terms of adverse events and side effects. Ongoing and future studies may help clarify this issue. Cyclosporine continues to serve as an essential therapeutic option for patients who experience unacceptable side effects with tacrolimus.

Future research should prioritize long-term patient and graft survival, renal outcomes and adverse effects of different tacrolimus formulations and dosing schedules, and management of severe adverse events. Further study is needed on quality of life, optimal CNI trough levels, therapeutic drug monitoring and dose reduction strategies. Cost-effectiveness of tacrolimus formulations and versus cyclosporine could also be important.

Two multicenter, randomized prospective open-label studies (399 patients) compared post-lung transplant outcomes between AZA and MMF [45, 46], with just one study reporting CLAD onset [45].

Six-month overall survival rates were similar in one study (86% vs. 82%; p = 0.57) [40], while the other study reported an overall three-year patient survival of 75% in the MMF group and 69% in the AZA group (p = 0.18) [45]. CLAD incidence at 3 years post-randomization, CLAD grade, time to onset and survival did not differ between groups, but analysis of the composite endpoint (CLAD, death, re-transplantation for graft failure, or withdrawal due to lack of therapeutic response) showed a significant advantage for MMF over AZA, largely driven by a higher rate of treatment withdrawal in the AZA group [45].

With respect to side effects, no significant differences between AZA and MMF were reported in the incidence of CMV infection or disease [46], rates of opportunistic infections, sepsis, abnormal kidney function, or malignancy [45].

Several retrospective studies assessed CLAD incidence, yielding inconsistent results [8, 33, 47–51].

One study found a numerically, but not statistically, higher incidence of CLAD in the MMF group (58% MMF vs. 49% AZA) [48]. Three studies reported similar rates of CLAD incidence, graft loss, and survival between MMF and AZA [8, 49, 51]. By contrast, Speich et al. reported a significantly lower graft loss rate and a trend toward better survival in the MMF group; however, interpretation of these findings is limited because of substantial cross-over (42% of patients receiving AZA were switched to MMF) [50].

According to the 2022 consensus on maintenance immunosuppression in solid organ transplantation [7], mycophenolic acid may be more effective than AZA in preventing acute rejection across solid organ transplants, including kidney, pancreas, liver, and heart. Although not a predefined outcome of our guideline, it is worth mentioning that the RCTs found no significant difference in the incidence of acute cellular rejection at 6 months, 1 year and 3 years between MMF and AZA [45, 46]. Conversely, a lower risk with MMF was reported in some retrospective studies [47, 50–52].

Similar adverse events were generally reported across studies, although a trend toward increased gastrointestinal problems with MMF and a higher incidence of anemia with AZA were observed [47, 50]. Rates of infections, malignancy and diabetes were comparable between groups [8, 49]. By contrast, one study reported lower CMV-related disease with MMF [50].

Regarding drug discontinuation, one study found a higher frequency in the MMF group (not significant, p = 0.19), mainly due to leukopenia and gastrointestinal issues [46], while another showed higher rates in the AZA group (p = 0.026) [50]. Gastrointestinal tolerance may be improved by spreading daily dose throughout the day (e.g., three times daily instead of twice daily) or switching to enteric-coated mycophenolate sodium, which delays release of mycophenolic acid until the small intestine. The latter has been associated with improved gastrointestinal symptoms, health-related quality of life, and psychological wellbeing in case series of solid organ transplant recipients, and may limit dose reductions, interruptions or discontinuation [53, 54].

It should be noted that a higher incidence of cutaneous squamous cell carcinoma has been observed in solid organ transplant recipients exposed to AZA [55].

Switching drugs (e.g., MMF to AZA for fertility reasons) or omitting cell cycle inhibitors for a longer time may increase the risk of developing de novo DSAs and acute rejection [56].

Finally, MMF warrants caution in patients (both females and males) planning pregnancy due to its teratogenic potential [57].

Evidence shows no significant difference in effectiveness between AZA and MMF, and both have acceptable safety profiles. Accordingly, the Task Force does not suggest the use of one agent over the other. Overall, there has been an increased utilization of MMF over time. The Task Force additionally reported a modest clinical preference for MMF, primarily attributed to its perceived lower risk of acute cellular and antibody-mediated rejection [7].

MMF is considered easy to manage in clinical practice, although, unlike AZA, it is not included in the 2025 WHO Model List of Essential Medicines [58]. Regarding individual susceptibility, the U.S. Food and Drug Administration advise thiopurine S-methyltransferase (TPMT) genotyping/phenotyping prior to commencing AZA, due to the risk of severe myelotoxicity in TPMT-deficient individuals [59]. MMF effectiveness and side effects are influenced by polymorphisms in UDP-glucuronosyltransferases enzymes, which regulate bioavailability of its active metabolite; routine pharmacogenetic testing is not yet standard but may guide individualized MMF dosing [60]. Prescribers should be aware that cyclosporine can significantly lower MMF blood levels, necessitating higher doses to achieve the same area under the curve dose level, by inhibiting its enterohepatic recirculation. Finally, caution is advised with both AZA and MMF in patients with documented short telomere syndrome due to increased myelotoxicity, which may necessitate a dose reduction or discontinuation of the cell cycle inhibitor.

Out of the scope of this systematic review is the role of proliferation signal inhibitors, which may represent an alternative in patients intolerant to both MMF and AZA.

Long-term real-world data may complement RCTs by comparing cell cycle inhibitors in lung transplantation. Key unresolved questions include DSA development with MMF vs. AZA, optimal and individualized dosing, identification of patient subgroups that may benefit preferentially from one agent, long-term drug effects, management of MMF during infections, and guidance on treatment interruption around vaccinations.

Currently, there are no published RCTs on the use of ECP in CLAD. We identified seven cohort studies with a control group assessing 182 CLAD patients treated with ECP compared to 364 controls [61–67]. All studies suffered from significant selection or indication bias; the ECP group often included patients with more advanced CLAD stages or rapid decliners. Treatment protocols varied with different numbers of cycles per month and in total.

Concerning critical outcomes, one study found a higher re-transplantation rate in the ECP group compared with controls (35% vs. 15%; p = 0.004) [63]; of note, in this study, the ECP group included more patients with higher CLAD stages and more rapid decliners than the control group. Two studies showed 31%–55% graft loss during follow-up between 12 and 36 months in both ECP and control groups [62, 67]. Four studies found no difference in overall survival compared with controls [61, 62, 65, 67], whereas the study by Pecoraro et al. documented significantly higher survival in the ECP group (155 vs. 114 months; p = 0.03) [66]. In Jaksch et al., survival benefit for ECP was only found in responders, not in the overall ECP group, compared to controls [63].

Different methods were used to measure the effect on forced expiratory volume in one second (FEV1) evolution. One study reported an overall positive effect on FEV1 of ECP compared to controls [66], while two studies found no differences [64, 65]. Greater FEV1 decline in the ECP group was observed in two studies 61,63], and in one study assessment was not possible due to a high rate of early mortality in the ECP group [62].

Response rate—defined as FEV1 stabilization and/or improvement—ranged from 33% to 80%. This variation likely reflects differences in patient populations or CLAD stages. For instance, Del Fante et al. found 60% stable ECP vs. 70% stable controls, but with less CLAD stage I patients in the ECP group; over time, overall treatment failure occurred in 67% of patients in the ECP group compared with 93% of controls [61].

Regarding undesirable effects, no difference in infection rates between groups was reported in three studies [63, 65, 66], but one study observed a significantly lower incidence of CMV infections in the ECP group [63]. A decrease in bacterial and CMV infections after ECP initiation compared with the pre-ECP period has also been reported, despite lack of direct comparison to the control group [61]. Serious complications associated with ECP were infrequent across studies.

Thirteen additional observational studies evaluating ECP in CLAD were identified, with sample sizes ranging from 8 to 631 patients and some patient overlap among larger cohorts [68–80].

Survival outcomes varied widely. The largest study (631 patients) reported overall survival of 86% at 6 months and 77% at 12 months, with 5-year post-ECP graft survival ranging from 70% in responders, to 56% in stable patients and 35% in non-responders [79], while another large cohort (373 patients) reported 46% overall survival and 41% graft survival at a median follow-up of 92 months [73]. Other studies reported a median overall survival of 7 years, with 50% 10-year graft survival [71], 66% 5-year overall survival [75], or median survival ranging from 2.6 years post-ECP initiation [72] to a mean of 15 months [80].

Most studies focused on graft function, particularly FEV1 evolution before and after ECP initiation. In the largest cohort [79], FEV1 stabilization or improvement was observed in 62% of patients at 6 months and 51% at 12 months, while other studies reported response rates of 19%–80% [68–70, 72, 74, 79, 80]. Interestingly, a recent randomized trial evaluated the preventive use of ECP in the early post-operative course and found a significantly lower incidence of CLAD at year 3 in the ECP group [81].

Several subgroup analyses attempted to identify responder profiles. Patients with a BOS phenotype generally demonstrated better responses than those with a RAS phenotype [65, 74, 79], although findings were inconsistent [61]. Similarly, patients with earlier CLAD stages (I–II) tended to respond better than those with advanced disease (III–IV) [63, 73, 75, 79], although this association was not uniformly observed [61, 66, 74]. Rapid FEV1 decliners showed reduced or trending toward reduced responses in some studies [63, 74], while others reported no effect [64] or even better responses [77].

Adverse effects were generally infrequent. Since ECP is thought to have mainly immunomodulatory rather than immunosuppressive effects, it may cause fewer infections [79] compared to other treatments. Treatable line-related infections occurred in 13%–14% of patients requiring central venous access [69, 72]. Venous access is a notable concern and may pose a significant barrier to treatment with ECP; based on our experience, the use of central lines varies considerably across centers. No ECP-specific long-term toxicities were reported, with long-term follow-up studies showing reassuring safety profiles [71, 75]. Fatigue and iron deficiency anemia, though underreported, are observed in clinical practice and warrant monitoring. In a RCT where ECP was used as a preventive immunomodulatory treatment to reduce the risk of CLAD, the main adverse event attributable to ECP was anemia, reported as a reason for discontinuation in 38% [81].

In conclusion, the actual efficacy of ECP in the treatment of CLAD remains uncertain. Multiple sources of bias were identified across studies, including logistical and co-intervention bias, and the lack of adequately matched control groups limited the ability to distinguish treatment effects from the natural history of CLAD. Results from the ongoing randomized eCLAD trial (UK, NCT05721079) are awaited to provide more robust evidence [82].

Quality of life and patient-reported outcome measures were not assessed in the published studies, representing an important gap. Given the burden of long-term, repeated ECP sessions, patient engagement, counseling, and stopping protocols are essential.

Although ECP shows few severe side effects, the limited and not well-established desirable effects, along with the significant therapeutic and logistical burden for patients and hospitals, preclude the group from making a recommendation either for or against the use of ECP in the management of CLAD. This recommendation may require revision when additional data become available, especially following the results of the ongoing multicenter randomized controlled eCLAD trial.

High procedure costs (see Table 2), requirement for specialized equipment and trained personnel at hospitals, potential need for a central line, and coordination of travel logistics for the patients should be considered when assessing ECP indication. Reimbursement policies across healthcare systems are variable.

Further research on ECP in established CLAD should clarify treatment response, define responder subgroups, standardize treatment schedules, and assess biological samples to elucidate its mechanism of action, patient-reported outcomes, side effects, and cost-effectiveness. Additional studies are also needed to evaluate the role of ECP in CLAD prevention.

We identified nine retrospective observational studies assessing ATG as a treatment for CLAD (390 treated patients, 10–108 per study) [83–91].

Graft survival ranged from 77% to 80% at a median follow-up of 10–63 months [84, 88]; in one study with an ATG-free control group, median graft survival was lower in ATG-treated patients (26 vs. 45 months; p = 0.021), possibly reflecting more severe baseline disease and residual confounding despite propensity matching [90]. Overall survival was 95% at 6 months [87], 90% at 10 months [84], 54% at 12 months [89] and 56% at 17 months [86]. The study by Padhye et al. showed a lower 1-year post-CLAD mortality compared with CLAD patients who did not receive ATG, although not significant (SHR 0.66, 95%CI 0.39–1.14, p = 0.134) [91].

Across studies, FEV1 response rates varied depending on the definition applied. Improvement in FEV1 was observed in 13%–40% of patients, while improvement or stabilization was reported in 23%–52% [83, 85, 86, 88, 89]. A >20% reduction in FEV1 decline occurred in 40%–65% of cases [87, 90]. Padhye et al. reported no difference in rate of FEV1 decline post- vs. pre-ATG and compared with non-ATG treated patients, although no pre-defined lung function period was assessed; i.e., the rate of decline 3 months after CLAD diagnosis to last follow-up was compared with lung function evolution from transplant up to 3 months before CLAD diagnosis [91].

Reported undesirable effects included skin cancer (9%–19%) and other types of malignancy (7%–8%) [88, 90]. Post-transplant lymphoproliferative disorder (PTLD) occurred in 0%–10% of cases [83, 84].

The rate of FEV1 decline as a predictor of ATG response yielded inconsistent results. A trend toward a better response in rapid decliners [90] and CLAD stage I-II patients [88, 89] was observed, although this association was not consistently reported [87, 90]. No association between response and CLAD phenotype was reported in three studies [87, 88, 90].

There was wide variability across studies in terms of follow-up and time between CLAD diagnosis and ATG treatment. Studies also differed in total dose and type of ATG administered, as well as monitoring of lymphopenia. ATG was generally used as a second- or third-line therapy, with prior treatments varying across studies.

The Task Force judged that the evidence for a positive effect was limited, mostly because most studies lacked control groups. However, clinical experience suggests that ATG may contribute to lung function stabilization in some cases.

Treatment tolerance varied across studies. Fever and chills were common [84, 86, 87, 89], while most adverse events were mild [84, 89]. Infusion-related reactions ranged from 4% [86] to 15% cytokine release syndrome and 22% serum sickness [87]. Overall, severe reactions appeared rare, and premedication with corticosteroids, acetaminophen, and/or antihistamines may reduce symptoms.

Bacterial and/or viral infection rates ranged from 12% to 35%, with serious infections occurring in 8%–14% of patients [88, 89]. Cytopenia was inconsistently reported: severe leukopenia occurred in 4% of patients [86] and neutropenia in up to 14% [89].

Additional safety information can be derived from ATG use as an induction therapy. A systematic review of six small RCTs found no clear evidence of a higher risk of adverse outcomes associated with T-cell antibody induction (including ATG) compared with no induction or with each other, in lung transplantation [92].

Although ATG increases overall immunosuppressive burden, retrospective studies showed no clear increase in the risk of PTLD in lung or other solid organ transplantation [93]. Current expert opinion favors use of the lowest effective dose, with caution in EBV-seronegative recipients and other high-risk populations.

There is no high-quality data supporting the use of ATG in the management of CLAD, although existing studies and Task Force members’ clinical experience suggest potential for lung function stabilization. The main limitation of ATG therapy is an increased risk of infections. Overall, ATG may be considered as a treatment option in selected CLAD patients, including those with concomitant ACR.

Availability of this therapy may be limited in certain countries, and treatment necessitates hospitalization and intravenous access. Administration of ATG via a central line or large-bore intravenous access is generally preferred given the risk of local irritation and thrombophlebitis. At present, no definitive recommendations exist on the optimal dosing, duration of treatment, and monitoring of its effects.

RCTs are warranted to better define efficacy and safety. Additional evidence is required to determine optimal dosing, treatment duration, and appropriate monitoring strategies. Furthermore, data is lacking for high-risk groups, such as EBV-mismatched recipients at increased PTLD risk, and for specific clinical subgroups, including different CLAD phenotypes.

Three small retrospective observational studies were identified (41 patients; 10–17 per study) [65, 94, 95], including one with a control group of 78 untreated patients [65].

No significant difference in overall survival was observed between the treatment group and controls at 6–12 months [65]. The other studies reported graft and patient survival of 69% at 1 and 2 years [94] and 5-year overall survival of 76% [95].

In one study, mean FEV1 did not improve following alemtuzumab treatment [94]. In another cohort, a >10% increase in FEV1 was observed at 30 days, followed by a 10% decline by day 120 [95]. In the controlled study, alemtuzumab was associated with a slower decline in FEV1 at 1 month, but not at later time points [65]. Reams et al. observed improvement in BOS grade in 40% of patients, stability in 30%, and worsening in 30% [94]. Ensor et al. reported 53% freedom from BOS progression at 6 months [95].

Overall, alemtuzumab was associated with short-term attenuation of spirometric decline, mainly in BOS and early-stage disease patients, but no survival benefit was shown, and effects beyond 3–6 months remain unclear [65, 94, 95]. Interpretation of the results is limited by selection bias, as alemtuzumab was preferentially used for rapidly progressive disease. Further data is needed to determine the true effect size. Nonetheless, experience from some Task Force centers suggests possible stabilization of lung function, and alemtuzumab may be a potential option in patients with prior DSAs.

In the identified studies, infection rates ranged from 50% to 77% while infection-related mortality ranged from 10% to 30% [65, 94, 95]. Patients with CLAD already have an increased baseline infection risk; alemtuzumab may further increase the incidence.

In kidney transplant studies, alemtuzumab or ATG treatment for acute T-cell–mediated or glucocorticoid-resistant rejection was associated with good long-term graft survival and function, but frequent infections and reduced patient survival were reported compared with patients not requiring alemtuzumab [96–98]. Infection rates were comparable between the alemtuzumab- and ATG-treated groups [97].

In a study of alemtuzumab induction therapy in lung transplantation, 44% of patients developed (mostly viral) infections under prophylaxis (27% hospitalized, 4% ICU), nearly 50% occurring within 6 months. Malignancies occurred in 9% of patients (2% PTLD, 7% non-PTLD) [99].

Although data does not demonstrate a clear increase in post-transplant malignancies with alemtuzumab in kidney or lung recipients, clinical experience supports cautious use in patients with a prior history of cancer.

Alemtuzumab may stabilize lung function in selected patients, but its effect size remains uncertain, and further data is warranted. Its use is supported by limited clinical experience, and potential infection risks should be carefully weighed in clinical decision-making.

Alemtuzumab may have limited availability in some regions, potentially affecting access. It is generally administered intravenously, though subcutaneous or intramuscular routes are alternative options. The costs of the drug and management of potential adverse events should be carefully evaluated during treatment planning.

RCTs are necessary to establish definitive evidence regarding the efficacy, safety, optimal dosing and scheduling of alemtuzumab. Future research should additionally assess risk factors for adverse events (e.g., PTLD risk in patients with EBV mismatch) and focus on specific subgroups, such as different CLAD phenotypes and patients with DSAs.

Two RCTs have evaluated pirfenidone use in lung transplant recipients [100, 101]. No published studies of nintedanib were identified at the time of writing, although there is a recently completed RCT in BOS (NCT03283007) [102].

The STOP-CLAD trial did not meet enrollment goals and was prematurely ended; therefore, it was underpowered for the primary outcome, which was change in radiographic assessment of small airways disease. The study included 23 patients (14 BOS and 9 RAS; 12 pirfenidone and 11 placebo), and there was no significant difference in FEV1 change over the 24-week study period between pirfenidone and placebo (−3.1% vs. −3.7%; p = 0.90). No life-threatening adverse events were reported. Five serious adverse events requiring medical intervention occurred, all in the placebo group, including four infections requiring antibiotic treatment and one case of hyponatremia [100].

In the EPOS trial (90 BOS patients; 48 pirfenidone and 42 placebo), both the pirfenidone and control groups showed a similar continued FEV1 decline. Secondary endpoints (graft loss, death, re-transplantation) and the incidence of serious adverse events were similar between groups [101].

As pirfenidone did not demonstrate superiority over placebo and standard care, we do not recommend it for treating BOS.

In addition to serious adverse events, the RCTs reported a similar overall number of adverse events in the pirfenidone and placebo groups [100, 101]; with more gastrointestinal events [100, 101] and fewer infections [100] in patients receiving pirfenidone. Adverse events judged by blinded adjudication to be attributable to the study drug were more common in the pirfenidone group [100].

Two small additional observational studies (9–11 patients) assessed the role of pirfenidone in lung transplant recipients with CLAD [103, 104]. In Vos et al. median 3-year overall survival following RAS diagnosis was 55% and graft loss occurred in 73% of patients, with a median graft loss–free survival of 1.8 years [103]. In the other study, median overall survival from treatment initiation was 7 months [104].

Across the two studies, a non-significant reduction in the rate of FEV1 decline was observed post- vs. pre-pirfenidone at 3 and 6 months [103, 104], with a significant decrease at 12 months in the study by Vos et al. [103] (−50 to −10 mL/month; p < 0.05). However, only 6/11 (55%) patients could still be evaluated at that time point.

Antifibrotics may cause notable gastrointestinal symptoms, requiring dose reduction or treatment discontinuation. Dose adjustment due to anorexia or nausea was reported in 55% of patients [103], while a single case required treatment interruption for gastrointestinal toxicity in the other study [104]. Additional risks include phototoxicity and hepatotoxicity.

The final results of the Pirfenidone for Restrictive Chronic Lung Allograft Dysfunction (PIRCLAD) study, a single-center study on safety and tolerability of pirfenidone in restrictive CLAD, are not available yet (NCT03359863) [105]. A multicenter RCT evaluating nintedanib in lung transplant recipients with BOS Grade 0p-1–2 (INFINITx BOS) was recently completed, and the results are awaited (NCT03283007) [102]. Other novel antifibrotics, such as nerandomilast [106], may warrant investigation in CLAD. Inhaled antifibrotics, currently studied in interstitial lung diseases, could be explored for future research in CLAD-RAS [107].

Upon review of the current scientific evidence, we do not suggest using pirfenidone for CLAD-BOS, as there is no substantial indication of efficacy. Conversely, data are insufficient to draw conclusions on antifibrotic therapy for CLAD-RAS and further research is warranted.

Limited availability and reimbursement may restrict implementation. In some countries, nintedanib may be prescribed for CLAD-RAS when classified as progressive pulmonary fibrosis and/or as an off-label treatment. Patients should be monitored for adverse effects, including gastrointestinal symptoms, hepatotoxicity, and skin toxicity. Additionally, trough levels of CNI should be assessed due to the potential for drug interactions [103].

Based on the anticipated outcomes from the PIRCLAD study involving patients with restrictive CLAD, further investigation in this patient population might be recommended. Studies with other antifibrotics, such as nerandomilast, could be considered.

One RCT (30 patients; 15 montelukast, 15 placebo) assessed montelukast in lung transplant recipients with BOS and slowly progressive FEV1 decline despite prior azithromycin [108].

Graft loss at 1 and 2 years was similar in montelukast and control groups. Overall, montelukast had no significant effect on FEV1 decline, but a post-hoc subgroup analysis demonstrated a decrease in FEV1 decline in BOS stage 1 patients, which was not seen in BOS stage 2–3 patients.

Serious adverse events were similar between groups, and treatment discontinuation rates did not differ significantly. Rates of respiratory infections were also comparable.

Two additional observational studies assessed montelukast in CLAD patients [109, 110]; all studies were from the same center.

In the largest study (153 patients; 115 BOS, 38 RAS), montelukast stabilized or improved FEV1 in 81% of cases at 3 months, with benefits persisting up to 12 months, and responders showing superior progression-free and overall survival compared with non-responders [110]. A smaller study (n = 22) reported slower FEV1 decline with montelukast compared to standard therapy (13 vs. 114 mL/month) [109].

Overall, these data suggest montelukast may stabilize lung function and delay disease progression in selected CLAD patients. Rapid decliners were less likely to respond [110] and were excluded from the randomized trial [108].

Based on available data on pulmonary chronic graft-versus-host disease (BOS-phenotype) following allogeneic hematopoietic stem cell transplantation, montelukast is recommended as part of the standard first-line “FAM” therapy, which includes inhaled corticosteroids, azithromycin, and montelukast [111]. Nevertheless, the magnitude of montelukast’s therapeutic effect in this context remains uncertain.

No severe adverse events were attributed to montelukast; some patients reported vivid dreams [110]; such sleep disturbances, including nightmares, are known from clinical experience. Rare neuropsychiatric adverse events are recognized from broader use in asthma and allergic disease, leading the U.S. Food and Drug Administration to issue a Boxed Warning for montelukast regarding serious mental health–related adverse effects [112]. Although data largely derive from non-transplant populations, they are relevant to transplant recipients, who experience neuropsychiatric vulnerability. No severe neuropsychiatric events were reported in the study by Vos et al. [110], and such effects appear uncommon from clinical experience.

Overall, data suggest an acceptable safety profile with a low likelihood of serious harm in the transplant population.

Overall, the RCT did not demonstrate an effect of montelukast on FEV1; however, some benefit was observed in patients with early-stage BOS (BOS stage 1). Therefore, montelukast may be considered in this group, with discontinuation advised in the event of disease progression.

The advantage of montelukast compared with other treatments (e.g., ECP or ATG) is its oral administration and low costs. Treatment response should be monitored and discontinuation should be considered in the absence of response. Patients should also be monitored for neurological and psychiatric adverse effects, and changes in sleep patterns.

The Task Force did not formulate specific future research recommendations for montelukast, as they perceive priorities rather lie elsewhere.