CONTENTS

candidacy for lung transplantation

• General concept of the transplant window
• Contraindications to lung transplantation
• Transplant window for various conditions
  • COPD
  • Interstitial lung disease
  • Cystic fibrosis
  • Pulmonary arterial hypertension

post-transplantation complications

• Chronic immunosuppressive regimens
• PGD (primary graft dysfunction)
• Acute rejection
  • ACR (acute cellular rejection)
  • AMR (antibody-mediated rejection)
• CLAD (chronic lung allograft dysfunction) & RAS (restrictive allograft syndrome)
  • BOS (bronchiolitis obliterans syndrome) ➡️
• Airway complications
• PTLD (post-transplant lymphoproliferative disorder) ➡️
• Infectious complications ➡️

abbreviations used in the pulmonary section: 5

• ABPA: Allergic bronchopulmonary aspergillosis 📖
• AE-ILD: Acute exacerbation of ILD 📖
• AEP: Acute eosinophilic pneumonia 📖
• AFB: Acid Fast Bacilli
• AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
• ANA: Antinuclear antibody 📖
• ANCA: Antineutrophil cytoplasmic antibodies 📖
• ARDS: Acute respiratory distress syndrome 📖
• ASS: Antisynthetase Syndrome 📖
• BAL: Bronchoalveolar lavage 📖
• BiPAP: Bilevel positive airway pressure 📖
• CEP: Chronic eosinophilic pneumonia 📖
• CF: Cystic fibrosis 📖
• COP: Cryptogenic organizing pneumonia 📖
• CPAP: Continuous positive airway pressure 📖
• CPFE: Combined pulmonary fibrosis and emphysema 📖
• CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
• CTEPH: Chronic thromboembolic pulmonary hypertension 📖
• DAD: Diffuse alveolar damage 📖
• DAH: Diffuse alveolar hemorrhage 📖
• DIP: Desquamative interstitial pneumonia 📖
• DLCO: Diffusing capacity for carbon monoxide 📖
• DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
• EGPA: Eosinophilic granulomatosis with polyangiitis 📖
• FEV1: Forced expiratory volume in 1 second 📖
• FVC: Forced vital capacity 📖
• GGO: Ground glass opacity 📖
• GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
• HFNC: High flow nasal cannula 📖
• HP: Hypersensitivity pneumonitis 📖
• IPAF: Interstitial pneumonia with autoimmune features 📖
• IPF: Idiopathic pulmonary fibrosis 📖
• IVIG: Intravenous immunoglobulin 📖
• LAM: Lymphangioleiomyomatosis 📖
• LIP: Lymphocytic interstitial pneumonia 📖
• MAC: Mycobacterium avium complex 📖
• MCTD: Mixed connective tissue disease 📖
• NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
• NSIP: Nonspecific interstitial pneumonia 📖
• NTM: Non-tuberculous mycobacteria 📖
• OHS: Obesity hypoventilation syndrome 📖
• OP: Organizing pneumonia 📖
• OSA: Obstructive sleep apnea 📖
• PAP: Pulmonary alveolar proteinosis 📖
• PE: Pulmonary embolism 📖
• PFT: Pulmonary function test 📖
• PLCH: Pulmonary Langerhans cell histiocytosis 📖
• PPFE: Pleuroparenchymal fibroelastosis 📖
• PPF: Progressive pulmonary fibrosis 📖
• PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
• RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
• RP-ILD: Rapidly progressive interstitial lung disease 📖
• TNF: tumor necrosis factor
• UIP: Usual Interstitial Pneumonia 📖

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transplantation window, general concepts

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patients shouldn't be too well for transplantation

• Lung transplantation outcomes are improving, but post-transplantation morbidity and mortality remain high. Since the lung is continuously exposed to the outside world, it's difficult to strike a balance between providing adequate immunosuppression to prevent graft rejection while avoiding opportunistic infections.
• Median survival after transplantation varies depending on disease: (Murray 2022)
  • Cystic fibrosis: ~9 years.
  • Alpha-1 antitrypsin: ~7 years.
  • COPD, idiopathic pulmonary arterial hypertension: ~6 years.
  • IPF and other idiopathic interstitial pneumonias: ~5 years.
  • Re-transplantation: ~3 years.
• Transplantation should be restricted to patients who have a substantially worse prognosis due to their native lung disease, as compared to that of transplantation. As a general rule of thumb, transplantation should be considered if there is a high risk of death within two years. (Fishman 2023)

patients shouldn't be too sick for transplantation

• Lung transplantation is a challenging surgery to undergo and recover from.
• If patients are too ill prior to transplantation, they are at increased risk of post-procedural complications.

finding the optimal transplantation window

• The optimal transplantation window is the period of time when the patient is sick enough to merit transplantation, but healthy enough to undergo the procedure.
• Finding this window is challenging. Key components are early identification of patients with highly morbid lung disease and careful follow-up to track out their disease trajectory.
• Different transplant centers may vary with regard to their preferences for timing of transplantation. It's probably ideal for patients who are likely to require transplantation to obtain longitudinal follow-up with a transplantation center.
• Below are rough guidelines regarding the optimal transplantation window for different diseases. This is intended only as a rough concept of when patients should be considered for transplantation. When in doubt, consultation with a transplant center or transplant team is recommended.

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general contraindications to lung transplantation

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⚠️ Contraindications to lung transplantation vary substantially across different countries and different transplant centers. When in doubt, consultation with a transplant service should be obtained.

disease processes which may recur in the allograft

• Malignancy (active or recent).
  • Often a 5-year cancer-free interval may be appropriate. (Fishman 2023)
• Chronic infection:
  • HIV is generally considered an absolute contraindication.
  • Chronic infection with highly virulent organisms (e.g., active tuberculosis, Burkholderia cepacia, Mycobacterium abscessus, Lomentospora prolificans).

elevated risk of postoperative respiratory complications

• Significant chest wall or spinal deformity expected to cause severe restriction after transplantation.
• Severe esophageal disease (e.g., esophageal dysmotility, gastroesophageal reflux).
• Body mass index:
  • BMI >30 (especially truncal) may be a relative contraindication.
  • BMI >35 may be considered an absolute contraindication.
  • BMI <16 may be considered as a relative contraindication.

dysfunction of other organs & global fitness

• Untreatable extrapulmonary organ dysfunction:
  • Uncorrectable coagulopathy.
  • Acute renal failure with low likelihood of recovery.
  • Chronic renal failure with GFR <40 ml/min.
  • Cirrhosis with portal hypertension.
  • Stroke within one month.
  • Uncorrected coronary artery disease not amenable to revascularization before or at the time of transplantation.
  • Severe osteoporosis.
  • (Note: Occasional patients with combined cardiac and pulmonary failure may undergo heart-lung transplantation, especially patients with Eisenmenger syndrome.)
• Acute medical instability (e.g., sepsis, MI, liver failure).
• Severe limited premorbid functional status with poor rehability potential.
  • Dementia.
• Older age:
  • Most centers have abandoned hard age cutoffs, with more of a focus on functional status.
  • >75 years old is a soft benchmark beyond which most patients are unlikely to be suitable. (Murray 2022)

barriers to follow-up and adherence

• Smoking, substance abuse, or alcohol abuse (active or recent).
  • Transplant centers vary regarding how they define drug abuse (e.g., marijuana).
• Significant psychiatric illness limiting the ability to cooperate with the medical team and adhere to a complex post-transplantation medical regimen.
• Repeated nonadherence to medical care.
• Absence of an adequate and reliable social support network.

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disease-specific guidelines for listing for lung transplantation

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These aren't actual indications to perform lung transplantation, but rather indications for referral to evaluate for potential transplantation.

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COPD

role of transplantation in COPD?

• Survival benefit for transplantation in COPD has not been proven.
• Determining whether transplantation is beneficial is challenging, because the course of COPD is unpredictable. Many patients can survive a long time despite very poor PFTs.

indications for transplant referral:

• BODE index ≧7
• FEV1 < ~15-20% predicted.
• Three or more severe exacerbations within the preceding year.
• One severe exacerbation with acute hypercapnic respiratory failure.
• Moderate to severe pulmonary hypertension.
• Chronic hypercapnia.

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interstitial lung disease

general indications for transplantation evaluation:

• Decline in FVC >10% during 6 months of follow-up.
• Decline in DLCO >15% during 6 months of follow-up.
• Desaturation to <88% or distance <250 meters on 6-minute walk test, or >50 meter decline in 6-minute walk distance over a 6-month period.
• Pulmonary hypertension on right heart catheterization or echocardiography.
• Hospitalization due to respiratory decline, pneumothorax, or acute exacerbation.

transplantation in IPF (idiopathic pulmonary fibrosis)

• Unfortunately, less than 1/300 patients with IPF actually receive a lung transplant. This reflects that IPF usually affects older patients with comorbidities, who may be suboptimal transplantation candidates. (Shah 2019)

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cystic fibrosis

• Chronic respiratory failure:
  • Hypoxemia (PaO2 <60 mm).
  • Hypercapnia (PaCO2 >50 mm).
• Pulmonary function:
  • FEV1 <25%-30% predicted (United States CF foundation recommends early referral when FEV1 <30% predicted).
  • Rapid lung function decline (>20% drop in FEV1 over a year).
  • 6-minute walk test <1,333 feet (<400 meters).
• Pulmonary hypertension.
• Long-term noninvasive ventilation therapy.
• Frequent hospitalization.
• An exacerbation requiring mechanical ventilation.
• Massive hemoptysis, especially if recurrent despite bronchial artery embolization.
• FEV1 <40% with a pneumothorax.
• WHO functional class IV (symptoms at rest, or severe with any activity).

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pulmonary arterial hypertension

• WHO functional class III-IV despite a trial of at least 3 months of combination therapy including prostanoids.
• Cardiac index <2 L/min/m2.
• Right atrial pressure >15 mm.
• 6-minute walk distance of <350 m.
• Development of significant hemoptysis, pericardial effusion, or signs of progressive right-sided heart failure (renal insufficiency, increasing bilirubin, elevated brain natriuretic peptide, or recurrent ascites).
• Pulmonary capillary hemangiomatosis/pulmonary veno-occlusive disease (PCH/PVOD) should be referred for transplantation evaluation at the time of diagnosis.

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chronic immunosuppressive regimens

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induction immunosuppression

• The goal is to rapidly induce T-cell immunosuppression, thereby avoiding early rejection and facilitating delayed initiation of calcineurin inhibitors. (36774159)
• More aggressive induction might be beneficial among patients with pre-existing sensitization. (36774159)
• Agents utilized:
  • Most often: basiliximab (non-lymphocyte depleting, IL-2 receptor antagonist).
  • Less often: T-cell depleting antibodies:
    • Polyclonal anti-T-cell globulin (ATG).
    • Monoclonal alemtuzumab may suppress T-cell levels for up to three years (whereas B-cell levels usually recover over a few months). (36774159)

maintenance immunosuppression, conventional 3-drug regimen

• (1) Calcineurin inhibitor 💉:
  • Tacrolimus is generally preferred over cyclosporine. Meta-analysis has demonstrated that tacrolimus has superior efficacy against acute rejection and bronchiolitis obliterans syndrome, as compared to cyclosporine. (36774159)
• (2) Antimetabolite:
  • Mycophenolate 💉 is often preferred over azathioprine 💉. In the context of lung transplantation both agents seem to have equal efficacy, but mycophenolate may be better tolerated. (36774159)
• (3) Steroid.

mTOR inhibitors (sirolimus, everolimus) 💉

• Generally these are not front-line agents, due to poor tolerance (with discontinuation rates >60%). (36774159) Common problems include:
  • (a) If utilized in the first three months post-transplantation, these agents may cause airway dehiscence.
  • (b) mTOR inhibitors can cause pneumonitis. (36774159)
• However, mTOR inhibitors may be utilized in some situations: (36116814)
  • (a) Augmentation of immunosuppression in the context of CLAD (chronic lung allograft dysfunction).
  • (b) Inability to tolerate a calcineurin inhibitor (usually due to renal dysfunction). mTOR-inhibitors may be used in place of an antimetabolite, with a goal of dose-reducing the calcineurin inhibitor.

azithromycin

• Some centers may use azithromycin with a goal of preventing BOS (bronchiolitis obliterans syndrome). (36774159)

secondary hypogammaglobulinemia

• Most patients develop secondary hypogammaglobulinemia (e.g., IgG level <700 mg/dL), and about 15% develop severe hypogammaglobulinemia (IgG <400 mg/dL).
• For patients with severe hypogammaglobulinemia and recurrent infections, replacement with intravenous immunoglobulin (IVIG) is routinely utilized. (36774159)

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primary graft dysfunction (PGD)

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basics

• Primary graft dysfunction (PGD) is defined as radiographic opacities in the allograft(s) occurring within <72 hours of transplantation, in the absence of identifiable causes (e.g., pneumonia, rejection, atelectasis, pulmonary venous outflow obstruction). Note that patients with PGD may have fairly good oxygenation (e.g., P/F ratio >300), or they may have ARDS.
• Pathologically, PGD usually correlates with DAD (diffuse alveolar damage), possibly reflective of ischemia-reperfusion injury.

epidemiology

• Severe primary graft dysfunction occurs in ~10% of patients.
• PGD accounts for about half of deaths within the first month after transplantation. (34505059)
• Risk factors include:
  • Donor related:
    • Advanced age.
    • Prolonged mechanical ventilation.
    • Aspiration pneumonitis.
    • Ventilator-associated pneumonia.
    • Hemodynamic instability.
    • Transplantation of undersized lungs (which may lead to proportionately high tidal volumes).
  • Recipient related:
    • Pulmonary hypertension
    • Idiopathic pulmonary fibrosis
    • BMI > 25 kg/m2
    • Cardiac dysfunction, including diastolic dysfunction.
  • Surgery related:
    • Prolonged ischemic time
    • Single lung transplant
    • Blood transfusions
    • Cardiopulmonary bypass
  • Post-transplant risk factors:
    • Aspiration.
    • Volume overload.
    • Ventilation with large tidal volumes. (34505059, 36774158)

clinical presentation

• Most patients may have mild hypoxemia, but ~10% of patients experience ARDS.
• PGD usually begins within <48 hours, whereas alternative diagnostic processes (e.g., acute rejection or infection) usually occur later on. (36774158)
• Primary graft dysfunction has grades of severity:
  • Grade 1: P/F ratio >300 or SaO2/FiO2 >315.
  • Grade 2: P/F ratio 200-300 or SaO2/FiO2 235 – 315.
  • Grade 3: P/F ratio <200 or SaO2/FiO2 <235.

radiology

• Radiologically this may look like DAD.
• Middle and lower lobes are often predominantly involved. (34505059)
• Findings typically include: (34505059)
  • Diffuse ground-glass opacities.
  • Interlobular septal thickening.
  • Bronchial wall thickening.

differential diagnosis

• Cardiogenic pulmonary edema (e.g., post-operative MI, volume overload).
• Pulmonary venous outflow tract obstruction (anastomotic stricture or thrombosis).
• Rejection:
  • Acute cellular rejection (although unlikely to occur this early).
  • Antibody-mediated rejection.
• Pneumonia.
• Aspiration.
• Other causes of ARDS.

evaluation

• Usual evaluations for a patient with ARDS.
• Consider transesophageal echocardiogram to exclude venous anastomotic obstruction.

management

• Treatment is essentially the same as for ARDS.
• Retransplantation has poor outcomes and is usually avoided.

prognosis

• Severe primary graft dysfunction carries a mortality of ~25%.
• Primary graft dysfunction is a risk factor for subsequent BOS (bronchiolitis obliterans syndrome).

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acute cellular rejection (ACR)

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epidemiology

• Overall risk:
  • ~25% of patients may have one or more episodes within the first year. (Murray 2022)
  • Acute cellular rejection is more common than antibody-mediated rejection (AMR, section below).
• Timing: Acute rejection usually occurs within 3-6 months post-transplantation, but late episodes can occur after the first year. (Fishman 2023)
• Risk factors: Nonadherence to anti-rejection therapies.

symptoms

• ⚠️ Occasionally, acute rejection may be asymptomatic (which is why some centers perform routine surveillance bronchoscopy with transbronchial biopsies).
• Symptoms may include:
  • Dyspnea.
  • Dry cough.
  • Hypoxia.
  • Malaise, low-grade fever.
• The exam may disclose rales, wheezing, and/or exertional desaturation.

imaging

• The chest radiograph is usually unremarkable or only mildly abnormal. Findings may vary (e.g., alveolar or interstitial infiltrates, localized or diffuse).
• CT scan:
  • It commonly shows ground-glass opacification and consolidative opacities in a peribronchovascular distribution. (34505059) An absence of ground-glass opacities strongly suggests an alternative diagnosis. (de Moraes 2024)
  • Septal thickening may be seen. (36774160)
  • Pleural effusion and/or pleural thickening may occur.

pulmonary function tests (PFTs)

• FEV1 may deteriorate by >10-15%.
• FVC may decrease by >10-15%.

bronchoscopy with transbronchial biopsy is the diagnostic gold standard

• Some centers perform routine bronchoscopy to evaluate for subclinical ACR, but this remains controversial.
• Transbronchial biopsy has a sensitivity of ~75% and specificity of ~95%. However, there is considerable inter-observer variability between pathologists, with only 50-80% concordance rates. (36774160) Inflammation may be irregularly scattered throughout the lungs, causing transbronchial biopsies to be falsely negative. 
• At least five samples of well-expanded alveolated lung parenchyma are required for adequate assessment of ACR. Cryobiopsy is another option. (de Moraes 2024)
• Viral infection may cause mononuclear inflammation, so inflammation should be attributed to ACR only after the exclusion of acute infection. (36774160) 

histologic grading of ACR

• General comments on the histology of ACR:
  • An A-grade and a B-grade are assigned based on the amount of perivascular inflammation and lymphocytic bronchiolitis, respectively.
  • A-grade is generally more reliable due to the paucity of bronchial tissue sampled.
  • Diagnosis is based predominantly on the A-grade. Lymphocytic bronchiolitis (B-grade) inflammation is more commonly seen accompanying higher grades of A-grade rejection (>A2). (36774160) 
• A-grade = Perivascular inflammation:
  • A0= Normal lung parenchyma.
  • A1 (minimal) =
    • Scattered, small mononuclear perivascular cellular infiltrates.
    • May be 2-3 layers thick.
  • A2 (mild) =
    • More frequent perivascular mononuclear cellular infiltrates.
    • >3 layers of mononuclear cells present.
    • Eosinophils may be present.
  • A3 (moderate)
    • Extension into interstitial space (alveolar septa).
    • Dense perivascular mononuclear cellular infiltrates.
    • Eosinophils are usually present.
    • Neutrophils may be present.
    • It can involve endotheliitis.
  • A4 (severe)
    • Diffuse perivascular, interstitial, and airspace infiltrates of mononuclear cells. There is often evidence of acute lung injury (organizing pneumonia, fibrinous pneumonia, and/or diffuse alveolar damage).
    • Eosinophils are usually present.
    • Neutrophils and/or endotheliitis may be present.
• B-grade = Lymphocytic bronchiolitis:
  • B0 = No bronchiolar inflammation.
  • B1R (low grade) = Infrequent, scattered, or single-layer mononuclear cells in bronchiolar submucosa (predominantly lymphocytes).
  • B2R (high grade) = Larger infiltrates of larger and activated lymphocytes in bronchiolar submucosa, can involve eosinophils and plasmacytoid cells, epithelial damage with necrosis, metaplasia, and intra-epithelial lymphocyte infiltration.

differential diagnosis: discussed in the section below on CLAD: ⚡️

treatment

• Indication for treatment?
  • It's unclear whether asymptomatic grade-A1 ACR requires treatment.
  • Clinical symptoms and/or higher grades warrant therapy. (36774160) 
• ACR usually responds well to steroids. Pulse dose IV methylprednisolone at 10-15 mg/kg/day for three days is the initial therapy. This may be followed by an increase in steroid dose to 0.5-1 mg/kg/day, with a gradual taper. Clinical improvement is expected within 24-48 hours. (de Moraes 2024)
• Maintenance immunosuppressive medications should be augmented.
• Follow-up bronchoscopy with transbronchial biopsy should be done after 3-6 weeks to evaluate for persistent acute cellular rejection (which may be seen in about 25% of cases). (Fishman 2023)

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antibody-mediated rejection (AMR)

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basics

• Antibody-mediated rejection (AMR) is due to antibodies against donor antigens (usually Class I or especially Class II HLA antigens). Antibody binding triggers the complement cascade.

clinical presentation

• AMR usually occurs within the first few months after transplantation.
• Symptoms vary widely:
  • Asymptomatic impairment in spirometry.
  • Mild dyspnea.
  • May be clinically indistinguishable from acute cellular rejection.
  • May cause fulminant hypoxemic respiratory failure. (36774172)
• Patients can experience dyspnea, cough, fever, hemoptysis, and respiratory failure.

radiology

• Imaging may reveal diffuse ground glass opacities and air trapping. (34505059)

diagnostic features of AMR include:

• Depending on how many of the following features are present, a diagnosis of definite/probable/possible AMR might be appropriate: 
• (1) Clinically apparent graft dysfunction.
• (2) Lung injury pathology:
  • Histologic patterns in AMR are variable (including organizing lung injury, diffuse alveolar damage, and capillaritis).
  • Neutrophilic capillaritis may be the most suggestive pattern for AMR, but it is not seen in most cases of confirmed AMR. (36774172)
• (3) Capillary C4d deposition:
  • This is often considered the most conclusive evidence of AMR. (36774172)
  • Unfortunately, other causes of C4d deposition may include ischemia-reperfusion injury, infection, or ACR (acute cellular rejection). (36774172)
• (4) Circulating donor-specific antibodies (DSA):
  • Mean fluorescence intensity >3000 correlates with higher risk of AMR. (36774172)
  • Some patients with antibodies don't develop AMR, so merely the presence of antibodies doesn't indicate the presence of clinical disease.
• (5) Clinical exclusion of other possible causes of allograft dysfunction.

management

• The optimal approach to AMR remains undefined (largely extrapolated from antibody-mediated rejection other organs).
• Treatment involves combined, aggressive therapies to remove antibody and prevent additional antibody formation, for example:
  • Plasmapheresis and/or IVIG may be utilized to remove or neutralize donor-specific antibodies.
  • Reduced donor-specific antibody synthesis may be achieved with the use of pulse-dose steroid, rituximab, and/or proteasome inhibitors (bortezomib or carfilzomib, which cause plasma cell apoptosis).
  • Complement cascade activation may be impaired by the use of eculizumab.

prognosis

• 1-year survival is ~60%. (36774172)
• Survivors are likely to progress to CLAD. (36774172)

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CLAD (chronic lung allograft dysfunction) and RAS (restrictive allograft syndrome)

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definition & staging of CLAD

• CLAD: chronic allograft dysfunction that cannot be attributed to an alternative diagnosis, causing a >20% reduction in FEV1 from the post-transplant baseline value. (36774160) CLAD includes BOS (an obstructive process) and RAS (a restrictive process).
  • ~75% is BOS (bronchiolitis obliterans syndrome) 📖.
  • ~25% is RAS (restrictive allograft syndrome).
  • Occasional patients may have features of both BOS and RAS.
• Staging of CLAD:
  • CLAD 0: FEV1 80-100% of post-transplant baseline.
  • CLAD 1: FEV1 65-80% of post-transplant baseline.
  • CLAD 2: FEV1 50-65% of post-transplant baseline.
  • CLAD 3: FEV1 35-50% of post-transplant baseline.
  • CLAD 4: FEV1 <35% of post-transplant baseline.
• Restrictive allograft syndrome (RAS) is defined in terms of both of the following:
  • [1] Restrictive physiology (e.g., FEV1 reduction by >20% and total lung capacity reduction by >10%).
  • [2] Persistent opacities on chest radiograph or CT scan.

differential diagnosis for respiratory failure post-transplantation

• Infection.
• Rejection:
  • Acute rejection.
  • Chronic rejection (i.e., CLAD).
• Airway complication (e.g., anastomotic stricture).
• Drug toxicity.
• Pulmonary embolism.
• Re-emergence of primary disease.
• Aspiration.
• PTLD (post-transplant lymphoproliferative disorder).
• Diaphragmatic dysfunction.  (de Moraes 2024)

evaluation for delayed respiratory failure post-transplantation

• CT scan including inspiratory and expiratory images: (36774160)
  • Lack of infiltrates combined with mosaic air trapping would favor BOS (bronchiolitis obliterans syndrome). 📖
  • Infiltrates could suggest infection, acute cellular rejection, antibody-mediated rejection, or RAS (restrictive allograft syndrome).
• Infectious evaluation.
• Testing for anti-HLA antibodies.
• Bronchoscopy with bronchoalveolar lavage and transbronchial biopsy.
• Responsiveness to azithromycin: Improvement following 2-3 months of therapy with azithromycin suggests ARAD (azithromycin-responsive allograft dysfunction; previously known as neutrophil reversible allograft dysfunction). Radiologically, ARAD may appear similar to BOS (bronchiolitis obliterans syndrome), although tree-in-bud opacities may be more prominent. (34505059)

radiology-pathology of RAS

• Radiology:
  • RAS may present with upper lobe fibrotic changes consistent with a diagnosis of PPFE (pleuroparenchymal elastosis) 📖.
• Pathology:
  • Histology is extremely variable, including the following:
  • PPFE (pleuroparenchymal fibroelastosis).
  • DAD (diffuse alveolar damage).
  • Fibrotic NSIP (nonspecific interstitial pneumonitis).
  • AFOP (acute fibrinous organizing pneumonia).
  • OP (organizing pneumonia). (Murray 2022)

management of CLAD

• General treatment options for CLAD may include:
  • Modification of the immunosuppressive regimen.
  • Therapeutic trial of azithromycin.
  • Treatment of gastroesophageal reflux disease.
• Management of BOS: 📖
• Management of RAS:
  • Antifibrotic agents have been used with mixed results. (Fishman 2023)
  • Retransplant has worse outcomes after RAS, as compared to BOS. (ERS handbook 3rd ed.)

prognosis

• The prognosis for RAS:
  • The survival rate for RAS is much worse than for BOS (bronchiolitis obliterans syndrome).
  • Median survival of ~1 year. (Murray 2022; Walker 2019)

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airway complications

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introduction to airway complications

• Airway complications occur in ~15% of patients, usually within the first couple of  months following transplantation.
• Diagnostics:
  • CT scan (may help evaluate for mediastinitis, pneumomediastinum).
  • Bronchoscopy (definitive diagnostic test which allows for visualization of the lesion and microbiological sampling, if indicated).

dehiscence

• Basics:
  • Major dehiscence is highly lethal, but now rare. Partial dehiscence is more common.
  • Dehiscence usually occurs 2-4 weeks after transplantation. (34505059)
• Clinical presentation may include:
  • Pneumothorax (which may be bilateral).
  • Pneumomediastinum.
  • Mediastinitis.
  • Sepsis.
• CT scan is highly sensitive and specific for more severe dehiscence, but it may miss more subtle, partial dehiscence.
  • Direct evidence: airway wall irregularity and wall defects. (34505059)
  • Indirect evidence:
    • Extraluminal air (e.g., pneumothorax or pneumomediastinum) is ~100% sensitive, but ~72% specific. (Walker 2019)
    • Atelectasis may occur beyond the dehiscence.
• Bronchoscopy may reveal the earliest stages of ischemia and dehiscence, so flexible bronchoscopy is still required.
• Differential diagnosis: Other causes of pneumothorax may include parenchymal infection or rejection.
• Management of partial dehiscence:
  • Conservative management may be successful. However, in more severe cases surgery or stenting may be needed to stabilize the airway.
  • Antibiotics may be considered for possible infection.
  • If pneumothorax is present, chest tube insertion may promote lung expansion.
  • Steroid dose reduction may be used to promote wound healing.

anastomotic stenosis

• Basics:
  • Stenosis may result from granulation tissue or fibrosis.
  • Most common airway complication (~10-15% incidence). (Murray 2022)
  • Usually occurs ~2-9 months after transplantation. (34505059)
• Risk factors include:
  • History of PGD (primary graft dysfunction).
  • History of acute rejection.
  • History of anastomotic infection or dehiscence. (34505059)
• Clinical presentation:
  • Dyspnea and worsening of pulmonary function tests.
  • Wheezing that may be focal.
  • Recurrent postobstructive pneumonia.
• Diagnosis:
  • Stenosis may be visualized using CT scan or bronchoscopy.
  • Stenosis of >50% of the lumen is felt to be clinically significant. (34505059)
• Treatment may include dilation, stenting, and/or laser treatment of granulation tissue.

non-anastomotic stenosis (vanishing bronchus intermedius syndrome)

• Complete luminal obliteration may occur.
• This usually occurs 2-6 months after surgery, but can occur up to one year afterwards.
• Risk factors include ischemic injury to the donor bronchus and acute cellular rejection. (30382785)

tracheobronchomalacia (TBM)

• Tracheobronchomalacia may be localized to the anastomosis, or it may occur anywhere in the allograft. (36774163, 34505059)
• Tracheobronchomalacia typically develops 2-4 months after surgery. (34505059)
• Symptoms may include: (34505059)
  • Cough.
  • Dyspnea, stridor, and wheezing.
  • Mucus plugging and infection.
• Treatments may include:
  • Airway clearance.
  • Nocturnal noninvasive positive pressure ventilation.
  • Occasionally, silicone stenting.
• Further discussion of tracheobronchomalacia here: 📖

infection

• Various pathogens may be involved:
  • Fungal anastomotic infection (usually Aspergillus or Candida).
  • Bacterial anastomotic infection (usually Pseudomonas or Staph.).
• Treatment depends on the causative pathogen.

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Guide to emoji hyperlinks 

•  = Link to online calculator.
•  = Link to Medscape monograph about a drug.
•  = Link to IBCC section about a drug.
•  = Link to IBCC section covering that topic.
•  = Link to FOAMed site with related information.
• 📄 = Link to open-access journal article.
• = Link to supplemental media.