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Rej Flashcards

1
Q

Acute Cellular Rejection

A

T lymphocytes recognition of donor mhc (hla) or other antigen in donor lung. Predominant type of rejection.
Risk of death and significant risk factor for CLAD

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2
Q

Antibody Mediated Rejection

A

Antibodies against donor hla epitopes or other antigens. May be preformed or develop post-transplant (de novo).

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3
Q

Clad phenotypes

A 
Based on obstruction, restriction (TLC decline >10% from baseline), CT opacities
BOS
RAS
Mixed
Undefined
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4
Q

RAS presentation

A

Upper lobe fibrotic changes. Pulmonary restriction.

If have lower lobe or diffuse opacities and blood eosinophilia have poor prognosis.

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5
Q

BO Pathology

A

1) submucosal lymphocytic inflammation and disruption of the epithelium of small airway
2) ingrowth of fibromyxoid granulation tissue to airway lumen with partial or completer obstruction
3) Granulation tissue organises in cicatricial pattern with obliteration of airway lumen

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6
Q

Risk Factors CLAD

A 
Primary Graft Dysfunction
Acute Cellular Rejection
Antibody Mediated Rejection
Viral Infection
Bacterial and fungal infection / colonisation
GORD
Single > Double
Autoimmunity
Lymphocytic Bronchiolitis
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7
Q

CLAD Clinical Presentation

A

Non-specific symptoms early - SOBOE, non-productive cough.
Often asymptomatic (decline in FEV1).
Clear imaging early.
Late can mimic bronchiectasis - productive cough + end inspiratory squeaks

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8
Q

BO / BOS Evaluation

A

Hyperinflation, bronchiectasis on imaging

Bronchoscopy +/- transbronchial

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9
Q

BO vs BOS Diagnosis

A

BO - dense fibrous scar tissue affecting small airways

BOS - Graft deterioration secondary to progressive airways disease for which there is no other cause

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10
Q

Ddx CLAD

A

Airway complications - bronchial stenosis. tracheobronchomalacia
Infection
Acute cellular rejection
Acute Antibody Mediated Rejection
Progression or recurrence of underlying disease
Restrictive lung disease - Obesity, muscular weakness, pleural effusion, infection…

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11
Q

CLAD Prevention

A

aggressive initial immunosuppression to eliminate early episodes of acute cellular rejection, prophylaxis against cytomegalovirus (CMV) with oral valganciclovir in recipients who are at risk for CMV infection, vaccination against influenza and pneumococcus, reduction in cold ischemia time and other methods to reduce primary graft dysfunction, treatment of gastroesophageal reflux to reduce acid and alkaline aspiration, and long-term azithromycin.

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12
Q

CLAD Treatment

A 
Early
Azithromycin
Change immunosuppression
Late
Everolimus
Montelukast
Trials - ECP, Antithymocyte globulin
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13
Q

Hyperacute rejection

A

A rare form of humoral rejection that occurs within first 24 hours due to pre-formed HLA antibodies

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14
Q

Histopathological Features of Acute Rejection

A

Vascular: Perivascular mononuclear infiltrates that may extend to subendothelium. Can spread to involve the alveolar walls.
Airway: Lymphocytic response initially in submucosa and the extending through basement membrane. Ulceration of airway epithelium in advanced.

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15
Q

Risk Factors Acute Rejection

A 
HLA mismatching
Genetic variants  - Il-10, CCL4L, TLR4
Immunosuppression
Younger age  - probably
? Vit D deficiency
Infection
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16
Q

Acute Rejection Clinical

A

One third of patients will have an episode in first 12 months.
Often asymptomatic and diagnosed on surveillance TBBx
Nonspecific symptoms -low-grade temp, cough, sob
Crackles or effusion

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17
Q

Acute Rejection Investigations

A

Acute rejection vs airway stenosis vs infection
Bloods - Can have high eo, Lymphocytosis, basophilic. CMV viral load
Spiro - reduced fev1 not sensitive or specific but always done
HRCT - bilateral ggo, lower lobe predominance, septal thickening without cardiomegaly/consolidation/atelectasis has high PPV
Pleural tap - lymphocytic
Bronch + transbronchiial

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18
Q

Treatment Acute Rejection

A
  1. A1 (Spirometrically Stable): Consider PO prednisolone 0.5mg/kg/day tapering by 5mg every 5 days until at baseline dose.
  2. Treat A1 rejection with IV Methylpred if there is a significant decline in graft function, tissue/BAL eosinophilia or recurrent A1 biopsies.
  3. A2 or greater: Methylprednisolone 10-15mg/kg/day for 3 days followed by PO prednisolone 0.5mg/kg/day tapering by 5mg every 5 days until at baseline dose.
  4. Consider CMV and antifungal prophylaxis in high risk patients.
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19
Q

Hyperacute Rejection Pathology

A

Acute lung injury with neutrophilic infiltration and platelet and fibrin thrombi in alveolar septae with concomitant fibrinoid necrosis and hemorrhage

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20
Q

Hyperacute rejection Evaluation

A

The evaluation includes assessment for AMR, fluid overload, aspiration, primary lung graft dysfunction, and vascular anastomotic complications.

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21
Q

Luminex

A

Recipient screened for pre-existing HLA Antibodies
Recipients serum tested against beads coated with single or multiple purified HLA antigens.
Fluorescent antihuman IgG added
Mean Fluorescent Intensity (MFI) for any HLA antibody that is detected provides a measure of the antibody’s avidity to its respective HLA molecule.
cPRA % gives risk of positive cross match with any randomly selected aussie

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22
Q

Direct Crossmatch

1) CDC
2) Flow cytometry

A

Fresh recipient serum and donor lymphocytes

1) CDC = Complement detected cytotoxicity
2) Detects both complement binding and non-complement binding HLA antibodies

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23
Q

Class I MHC

A
  • Present cytoplasm-derived peptides (eg viruses) to CD8 positive T cells.
  • Found on almost all cell types (except red blood cells) with high levels on APC
  • APC – dendritic cells, macrophages, B lymphocytes and vascular endothelial cells
  • HLA-A, HLA-B, HLA-C
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24
Q

Class II MHC

A
  • Bind peptides from extracellular (exogenous) proteins and present mainly to CD4 T cells
  • Found on Interstitial dendritic cells, macrophages and B cells
  • Epithelial cell and vascular endothelial cell MHC class II expression is upregulated with exposure to proinflammatory cytokines (IL-2, IFN-g)
  • HLA-DP, HLA-DQ, and HLA-DR
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25
Leukocyte Migration
Leukocyte migration from the circulation to a site of inflammation involves four steps including selectin-mediated rolling, chemokine-mediated triggering, integrin-mediated firm adhesion, and platelet endothelial cell adhesion molecule (PECAM)- and chemokine-mediated transmigration. Chemokine-regulated attraction of leukocytes to sites of tissue injury, infection, or allotransplantation is essential for the induction of the acute inflammatory response.
26
Direct vs Indirect
Direct pathway - recipient T cells recognise intact donor MHC complexes on donor APCs Indirect - presentation of processed donor alloantigen by recipient APCs.
27
Virtual Cross Match
The presence or absence of Donor Specific Antibodies | Recipient HLA Ab history (from luminex) is compared against donor HLA profile to see if they will react
28
CLAD Diagnosis (spirometry)
1. Baseline graft function is established as the average of the two best FEV1 values measured at least 3 weeks apart. 2. Significant declines in graft function are defined as FEV1 value > 12% below the baseline as defined above. These may be reversible or irreversible. 3. CLAD is diagnosed when the FEV1 declines irreversibly below 80% of the baseline FEV1. Two lung function tests are required to confirm this
29
CLAD Staging
``` 0 > 80% 1 - 65-80% 2 - 50-65% 3 - 35-50% 4 - <35% ```
30
Primary Graft Dysfunction
Diffuse pulmonary opacities on thoracic imaging and hypoxemia without other identifiable cause, developing in the first 72 hours after lung allograft implantation. The typical histopathologic pattern of PGD is diffuse alveolar damage. Assessed at four time points, starting at the time of reperfusion of the second lung (T0), and then at 24, 48, and 72 hours
31
Primary Graft Dysfunction Grade
PGD grade 0 (no PGD): no opacities on chest radiograph •PGD grade 1:P/F ratio >300 or S/F ratio >315 •PGD grade 2:P/F ratio = 200 to 300 or S/F ratio = 235 to 315 •PGD grade 3: P/F ratio <200 or S/F ratio <235
32
Primary Graft Dysfunction Differential
``` Hyperacute rejection APO Pneumonia Occlusion of venous anastomosis Pleural effusion/ haemothorax TRALI Aspiration ```
33
Primary Graft Dysfunction Assessment
``` Review crossmatch, new screen for DSA Assess volume status TTE TOE (venus anastomosis) CT Chest Bronchoscopy - infections, anastomotic issues ```
34
Primary Graft Dysfunction Treatment
Supportive Restrictive fluid management, lung protection ventilation, empiric antibiotics, no role for changing immunosuppression, ECMO at grade 3
35
Acute Rejection Grade - A
A1 - Minimal - Scattered, infrequent perivascular mononuclear infiltrates 2-3 cells thick A2 - Mild - More frequent perivascular mononuclear infiltrates readily seen on low-powered magnification. Infiltrates may include lymphocytes, macrophages, eo A3 - Moderate - dense perivascular mononuclear infiltrates commonly associated with endothelialitis. Extension of infiltrate into alveolar septa and airspaces. Eo and neutrophils common. A4 - Severe - Diffuses perivascular, interstitial and air-space infiltrates of mononuclear cells, alveolarpneumocyte damage and endothelialitis.
36
Acute Rejection Grade - B
B1R - Low grade - Mononuclear cells within the sub-mucosa of the bronchioles with occasional sub-mucosal eo B2R - High grade - Large and activated mononuclear cells, eo and plasmacytoid cells in the submucosa; evidence of epithelial damage with necrosis, metaplasia and intra-epithelial lymphocytic infiltration BO - none X - ungradable
37
Antibody Mediated Rejection Diagnosis
Acute allograft dysfunction ●Circulating DSA in the recipient's serum ●Histologic evidence of acute lung injury ●Sub-endothelial C4d deposition in alveolar capillaries ●Exclusion of other potential causes of allograft dysfunction
38
Antibody Mediated Rejection Treatment
1. Methylpred pulse 3 days 2. High dose IVIG or Total Plasma exchange and low dose IVIG 3. Rituxumab (1 dose on last day IVIG) 4. Alter immunosuppression (ensure drug levels)
39
EBUS - lymph node malignant characteristics
``` Round shape Distinct margin Heterogenous Central necrosis sign Size ```
40
EBUS - L4
Upper border Ao, lower PA
41
Aspergillus syndromes
Colonisation Tracheobronchitis - positive BAL, abnormal secretions and airways. Normal CT. Bronchial anastomotic infection Probable Pulmonary IA - positive micro with ct changes Proven Pulmonary IA - positive histology or culture from sterile tissue Disseminated IA
42
Absolute Contraindications
Untreatable other organ dysfunction Malignancy < 2 years Non-curable infection (Cepacia, abscesses if no treatment available) Non-adherence / inability to comply with complex therapy Morbid obesity (BMI > 35kgm2) Substance abuse Severe limitation of function with poor rehab potential Severe progressive malnutrition
43
Relative Contraindications
``` Age > 65 Critical/unstable condition Poor rehab potential Colonisation with highly virulent organsims HBV, HCV, HIV Severe osteoporosis Absence of an adequate and reliable social support system Scleroderma Obesity ```
44
Tacrolimus mechanism
Is a macrolide antibiotic which forms complexes with cytoplasmic immunophilins which block action of calcineurin in activated T cells. Mainly T helper Prevents production of IL-2 and other cytokines which stimulate t cell proliferation and differentiation
45
Tacrolimus AEs
Nephrotoxicity (acute is dose dependent and reversible). Neurotoxicity - tremor and headache + other Alopecia Prolonged QT HT, Cholesterol, LFTs, low MG, high K, DM, diarrhoea
46
Tac XL
Same time each day Ideally on empty stomach Beware interactions Don't crush or chew XL
47
Calcineurin Drug Interactions
Prolong QT interval Increase K Metabolised by CYP3A4 (inhibitors will increase level) Drugs that increase tac levels - azoles, amiodarone, carbamazepine, diltiazem, clarithromycin, erythromycin, esomeprazole/lansoprazole can increase levels, omeprazole can cause increase or decreased levels
48
Lignocaine
Risk of toxicity increases in those with hepatic and cardiac dysfunction, and significant renal impairment. Doses up to 15.4 mg/kg may be used without serious adverse events, but subjective symptoms of lidocaine toxicity (eg, dizziness, euphoria) were reported in studies using ≥9.6 mg/kg lidocaine. (Evidence level 2+) Low total doses of lidocaine <160 mg may be associated with effective cough suppression. (Evidence level 1+) 1% = 1000 mg/100 mL = 10 mg/mL of solution.
49
Bleeding
5-10mL 1 in 10000 adrenaline Cold saline Bleeding side down
50
Aspergillus Treatment 1) Invasive/ tracheobronchitis 2) Colonisation 3) Prophylaxis 4) REMEMBER
1) Voriconazole 6mg/kg iv for 2 doses then 4mg/kg po/iv for 6 weeks (200mg po bd)then consider change to itraconazole of posaconazole for another 6 weeks then repeat CT and BAL 2) Itraconazole - 200mg po bd for 3 months at least 3) Amphotericin 10mg bd nebs in hospital. Consider IV pre-transplant if colonised and then ? itra for 3 months 4) CHECK TAC LEVELS with azoles!!!! Reduce dose by 50%.
51
COPD Criteria
Forced expiratory volume in one second (FEV1) <20% of predicted • Body-mass, airflow obstruction, dyspnea and exercise (BODE) index >7 • Severe exacerbation with hypercapnoic respiratory failure or recurrent exacerbations • Moderate to severe pulmonary hypertension • PCO2 >50 mmHg and/or PO2 <60 mmHg.
52
CF Criteria
* Frequent hospitalisation * FEV1 <30% of predicted especially if a rapid downward trajectory is observed * Increasing antibiotic dependence or resistance * Life threatening haemoptysis or pneumothorax * Requirement for non-invasive ventilation * Development of pulmonary hypertension * PCO2 >50 mmHg and/or PO2 <60 mmHg.
53
Pulmonary Fibrosis Criteria
* Decline in forced vital capacity (FVC) of 10% or more and in diffusing capacity of the lungs for carbon monoxide (DLCO) of 15% or more within the prior 6 months * Development of pulmonary hypertension * Hospitalisation because of respiratory decline, acute exacerbation or pneumothorax * Significant exercise-associated desaturation or requirement for oxygen.
54
PAH Criteria
* NYHA Functional class III or IV despite escalation of pulmonary vasodilator therapy * Refractory or progressive right heart failure * Right heart catheter measurements of mean right atrial pressure >15 mmHg, cardiac index of <2 litres/ minute/m2 and mean pulmonary artery pressure (PAP) >50 mmHg.
55
Suitability criteria for lung donation
General organ donor criteria No significant untreatable lung disease abg on 100% FiO2 and PEEP 5 > 250mmHg
56
Information required from donor
Accurate lung disease and treatment history - smoking, aspiration, asthma, TB Height and race - TLC Investigations - ABO, abs, CXR and lung field measurements, cross match, CMV/ EBV serology, Bronchoscopy and CT selected patients.
57
CMV syndrome / symptomatic viraemia
``` CMC PCR +'ve + 2 of Fever New malaise or increased fatigue Leukopaenia or neutropaenia Atypical lymphocytosis > 5% Thrombocytopaenia (<100) Elevation of transaminases > 2 x upper limit normal ```
58
CMV Disease
``` Pneumonitis Enteritis Hepatitis Retinitis Indirect effects - rejection, OI, EBV associated lymphoproliferative disease ```
59
CMV Diagnosis
PCR - >500 sig if low risk, > 1000 if high risk Can have tissue invasive infection with negative peripheral PCR BAL PCR doesn't mean invasive disease Ideally see CMV inclusion bodies on biopsy or CMV IHC on tissue
60
CMV Treatment
``` Asymptomatic viraemia Valganciclovir 900mg po bd Severe and/or colitis Ganciclovir IV 5mg/kg/ bd CMV Hyperimmunoglobulin 1.5 million units (D1, 2,3, 7, 14, 21) Treat for at least 2 weeks until clinical resolution and CMV PCR <713 on 2 consecutive PCR one week apart Then prophylaxis for at least 12 weeks Consider reduction of immunosuppression ```
61
CMV Prophylaxis
CMV R+ Ganciclovir 5mg/kg IV daily. Switch to Valganciclovir 900mg po daily for 6-9months Mismatch Consider Hyperimmune globulin Ganciclovir 5mg/kg iv daily until absorbing then switch to valganciclovir 900mg po daily for minimum 24 months Monitor CMV PCR weekly for 2-4 weeks after cessation of prophylaxis CMV -/- valaciclovir 500mg po bd for 3 months (continue indefinitely if EBV mismatch) Prophylaxis for 8-12 weeks after any treatment for rejection and monitor PCR once stopped.
62
General Donor Info
``` PMH - surgery and CVS risks Smoking, ETOH, drugs Malignancy Risks of infection - hepatitis, HIV (history of STIs) Risk of TSE Birth place and prior travel and residence Course of illness and cause of death Cardiorespiratory status Medications BMI Skin exam and examine for masses ```
63
Donor Infection Screen
``` BAL / Sputum MC+S HIV Ag/Ab + PCR HBsAb, HBsAg, HBcAb. HBV PCR HCV Ab + PCR CMV IgG EBV IgG Syphilis serology Toxoplasmosis IgG HTLV1/2 Ab SARS-CoV-2 PCR Urine MC+S Beware haemodilution ```
64
Perilymphatic nodules
Subpleural, interlobular septa, interlobar fissures, along bronchovascular bundles. Sarcoidosis, silicosis, lymphangitis carcinmatosis
65
Random, perivascular
Subpleural, don't cluster, may have basal predominance. | Miliary tb or fungus, septic emboli, mets.
66
Centrilobular nodules
Spare the sub pleural regions and found 5-10mm from pleural surfaces. Surround small vessels and can be diffuse or patchy. HP, LCH, bronchiolitis Can look like tree in bud sometimes
67
Airspace nodules
"Tree in bud". Usually larger than centrilobular. Bronchogenic spread. TB, aspiration, bronchiolitis, diffuse panbronchiolitis.
68
High REM
DQA1*05 (DQA5) AND DQB1*02 (DQB2) or DQB1*03:01 (DQB7) in the donor and not the recipient
69
Individual patient allocation criteria for donor lungs
1. ABO compatibility 2. Size (CXR measurements / TLC) 3. Absence of a positive T cell cross match and acceptable HLA Antibody profile 4. If more than 1 fulfil above - clinical urgency, logistics, long-term outcome benefit, CMV status 5. Recipient waiting time
70
Pre-capillary PAH pressures RHC
mPAP 20mmHg PCWP < 15mmHg PVR 3

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