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Transplantation, Immunosuppression, AIDS & Universal Precautions
PART I: TRANSPLANTATION
A. Definitions & Types of Grafts
| Term | Definition |
|---|
| Autograft | Graft from same individual (e.g., skin graft, saphenous vein CABG) |
| Isograft (Syngeneic) | Graft between genetically identical individuals (identical twins) |
| Allograft | Graft between members of the same species but different genotype (most transplants) |
| Xenograft | Graft between different species (e.g., porcine heart valves, pig-to-human) |
B. The Immunological Basis of Rejection
Major Histocompatibility Complex (MHC) / HLA System
- HLA antigens (Human Leukocyte Antigens) are the main alloantigens responsible for rejection
- Encoded on chromosome 6 (short arm)
- Class I (HLA-A, B, C): expressed on all nucleated cells; recognised by CD8+ cytotoxic T cells
- Class II (HLA-DR, DP, DQ): expressed on APCs (dendritic cells, B cells, macrophages); recognised by CD4+ helper T cells
- ABO blood group antigens: also expressed on endothelium; mismatch → hyperacute rejection
Allorecognition Pathways
| Pathway | Mechanism |
|---|
| Direct | Recipient T cells recognise intact donor MHC on donor APCs (early; acute rejection) |
| Indirect | Recipient APCs process donor peptides → present to recipient T cells (chronic rejection) |
| Semi-direct | Recipient T cells acquire donor MHC from donor APCs |
C. Types of Rejection
| Type | Timing | Mechanism | Histology | Treatment |
|---|
| Hyperacute | Minutes to hours | Pre-formed antibodies against ABO or HLA class I antigens → complement activation → thrombosis | Fibrin thrombi, neutrophil infiltration, haemorrhagic necrosis | None effective; organ must be removed; prevented by cross-matching |
| Accelerated Acute | 2–5 days | Reactivation of sensitised T cells (previously sensitised recipient) | Similar to acute | High-dose steroids; may reverse |
| Acute | Days to 3 months | T cell-mediated (cellular) or antibody-mediated (humoral) | Lymphocytic infiltration, tubulitis (kidney); endothelialitis | Pulse IV methylprednisolone; anti-thymocyte globulin (ATG); plasmapheresis for humoral |
| Chronic | Months to years | Indirect allorecognition; fibrosis; intimal smooth muscle proliferation | Obliterative vasculopathy; fibrosis; tubular atrophy | No effective reversal; optimise immunosuppression |
Graft-versus-Host Disease (GvHD):
- Occurs when donor immunocompetent T cells attack a relatively immunocompromised host
- Seen in: bone marrow / haematopoietic stem cell transplantation (HSCT), small bowel transplant, blood transfusion in immunocompromised
- Acute GvHD (<100 days): skin rash, diarrhoea, hepatitis
- Chronic GvHD (>100 days): resembles autoimmune disease (scleroderma-like)
- Treatment: high-dose corticosteroids, ciclosporin, mycophenolate
D. Tissue Matching / Pre-Transplant Workup
| Test | Purpose |
|---|
| ABO typing | Compatibility essential to prevent hyperacute rejection |
| HLA typing | Match at HLA-A, B, DR reduces rejection risk (especially renal) |
| Crossmatch | Recipient serum + donor lymphocytes → if +ve (pre-formed antibodies present) → contraindication (hyperacute rejection risk) |
| Panel Reactive Antibody (PRA) | % of panel cell population against which recipient has antibodies; high PRA = highly sensitised |
| Mixed lymphocyte reaction (MLR) | In vitro test of T cell response; used mainly in bone marrow transplant |
E. Brain Death & Organ Donation
Brain Death Criteria (UK/most guidelines):
- Irreversible structural brain damage from known cause
- No sedatives/metabolic cause
- Tests performed by 2 senior doctors on 2 separate occasions:
- Absent brainstem reflexes (pupillary, corneal, oculovestibular/caloric, gag, cough, oculocephalic)
- Apnoea test: PaCO₂ rises to ≥6.65 kPa with no respiratory effort
Types of donors:
- DBD (Donation after Brain Death): heart-beating donor; optimal oxygenation of organs
- DCD (Donation after Circulatory Death): controlled (Maastricht III) or uncontrolled; higher rates of primary non-function (ischaemia)
Cold Ischaemia Times (approximate maximums):
| Organ | Maximum Cold Ischaemia Time |
|---|
| Heart | 4–6 hours |
| Lung | 6–8 hours |
| Liver | 12–24 hours |
| Pancreas | 12–18 hours |
| Kidney | 24–36 hours |
| Small bowel | 8–12 hours |
F. Individual Organ Transplants
1. Renal Transplantation
- Most common solid organ transplant
- Recipient's native kidneys NOT removed (unless symptomatic - hypertension, recurrent infection, polycystic disease)
- Site: Heterotopic - iliac fossa (extraperitoneal)
- Anastomoses: Renal artery to external iliac artery; renal vein to external iliac vein; ureter to bladder (ureteroneocystostomy)
- Early complications: acute tubular necrosis (ATN), acute rejection, renal artery thrombosis, ureteric obstruction/fistula
- Late complications: chronic rejection, calcineurin inhibitor nephrotoxicity, opportunistic infections, post-transplant lymphoproliferative disorder (PTLD), recurrent original disease
2. Liver Transplantation
- Indications: cirrhosis (alcoholic, viral, NAFLD), acute liver failure, cholestatic disease (PBC, PSC), hepatocellular carcinoma (Milan criteria: 1 lesion ≤5 cm or 3 lesions ≤3 cm, no vascular invasion, no extrahepatic spread)
- Orthotopic (native liver removed); caval replacement or piggy-back technique
- MELD score used to prioritise allocation
- Split liver / living donor (right lobe)
- Complications: primary non-function, hepatic artery thrombosis (most feared early complication), biliary leak/stricture, acute/chronic rejection
3. Heart Transplantation
- Indications: end-stage heart failure (NYHA class IV), ischaemic/dilated cardiomyopathy, refractory arrhythmias
- Orthotopic; bicaval technique now preferred
- Denervated heart: resting HR ~100 bpm; no angina with ischaemia; relies on Frank-Starling and circulating catecholamines
- Complications: primary graft failure, acute rejection (Rx: OKT3/ATG), cardiac allograft vasculopathy (chronic rejection - obliterative coronary disease; diagnosed by annual coronary angiography), accelerated atherosclerosis
4. Lung Transplantation
- Indications: COPD, IPF, cystic fibrosis, pulmonary hypertension
- Single or bilateral sequential
- Primary graft dysfunction (reperfusion injury): most common early cause of death
- Bronchiolitis obliterans syndrome (BOS): manifestation of chronic rejection; progressive airflow obstruction; azithromycin may slow progression
5. Pancreas Transplantation
- Usually combined with kidney (SPK - simultaneous pancreas kidney)
- Indications: Type 1 diabetes with end-stage renal disease
- Exocrine drainage: bladder (older) or enteric (newer preferred)
- Monitoring rejection: serum amylase/lipase rise indicates graft pancreatitis; urinary amylase (if bladder drainage)
PART II: IMMUNOSUPPRESSION
A. Goals
- Prevent acute rejection
- Prevent chronic rejection
- Maintain adequate immune function to fight infections
- Minimise drug toxicity
B. Immunosuppressive Drugs - Mechanism & Side Effects
1. Calcineurin Inhibitors (CNIs)
| Drug | Ciclosporin (Cyclosporine) | Tacrolimus (FK506) |
|---|
| Mechanism | Binds cyclophilin → inhibits calcineurin → blocks IL-2 gene transcription → T cell suppression | Binds FKBP-12 → inhibits calcineurin → same IL-2 blockade; 10-100× more potent |
| Key toxicity | Nephrotoxicity, hypertension, hyperlipidaemia, hirsutism, gingival hyperplasia, neurotoxicity | Nephrotoxicity, neurotoxicity, diabetes mellitus (new onset), alopecia, hyperkalaemia |
| Monitoring | Trough blood levels | Trough blood levels |
| Interactions | CYP3A4 substrate: azole antifungals ↑ levels; rifampicin ↓ levels | Same |
2. Antiproliferative Agents
| Drug | Azathioprine | Mycophenolate Mofetil (MMF) |
|---|
| Mechanism | Purine analogue → inhibits DNA synthesis in rapidly dividing cells (T & B cells) | Inhibits inosine monophosphate dehydrogenase (IMPDH) → blocks de novo purine synthesis → selective T and B cell inhibition |
| Key toxicity | Bone marrow suppression, hepatotoxicity; do NOT use with allopurinol (xanthine oxidase inhibition → azathioprine toxicity) | GI upset, diarrhoea, bone marrow suppression; teratogenic |
| Use | Being replaced by MMF | Preferred antiproliferative today |
3. mTOR Inhibitors
| Drug | Sirolimus (Rapamycin) | Everolimus |
|---|
| Mechanism | Binds FKBP-12 → inhibits mTOR → blocks IL-2-driven T cell proliferation (G1→S phase block) | Same |
| Key toxicity | Hyperlipidaemia, mouth ulcers, impaired wound healing, pneumonitis, not nephrotoxic | Same |
| Advantage | CNI-sparing (useful in CNI nephrotoxicity); anti-proliferative (reduces PTLD, HCC recurrence) | Same |
4. Corticosteroids
- Mechanism: Broad anti-inflammatory and immunosuppressive; inhibit NF-κB, reduce cytokine production (IL-1, IL-2, IL-6, TNF-α), impair APC function
- Uses: Maintenance (low dose prednisolone), acute rejection (IV methylprednisolone 500 mg–1 g/day × 3 days)
- Side effects: Diabetes, osteoporosis, hypertension, weight gain, adrenal suppression, cataracts, avascular necrosis of hip, poor wound healing, susceptibility to infection
5. Biological Agents
| Agent | Class | Mechanism | Use |
|---|
| Basiliximab | Anti-CD25 mAb (IL-2R blocker) | Blocks IL-2 receptor on T cells | Induction immunosuppression |
| ATG (Anti-thymocyte globulin) | Polyclonal antibody | Depletes T cells | Induction; acute steroid-resistant rejection |
| Rituximab | Anti-CD20 mAb | Depletes B cells | Antibody-mediated rejection |
| Belatacept | CTLA4-Ig fusion protein | Blocks CD28-B7 co-stimulation | CNI-free maintenance |
| OKT3 (Muromonab) | Anti-CD3 mAb | Depletes/inactivates T cells | Steroid-resistant rejection (largely replaced) |
| Eculizumab | Anti-C5 mAb | Blocks complement activation | Antibody-mediated rejection; thrombotic microangiopathy |
6. Standard Triple Therapy Protocol
CNI + Antiproliferative + Corticosteroid
e.g., Tacrolimus + MMF + Prednisolone
Induction: Basiliximab or ATG at time of transplant
Maintenance: taper steroids over time; CNI doses reduced per trough levels
C. Complications of Immunosuppression
| Complication | Details |
|---|
| Opportunistic infections | CMV (most common; Rx ganciclovir), PCP (Pneumocystis jirovecii; Rx co-trimoxazole prophylaxis), candida, aspergillus, TB reactivation, BK virus nephropathy (renal transplant) |
| Malignancy | 3× increased cancer risk; PTLD (EBV-driven B-cell lymphoma), skin cancers (SCC > BCC - reversed from general population), Kaposi sarcoma, cervical/anal cancer (HPV-driven) |
| Cardiovascular disease | Accelerated atherosclerosis; hypertension (CNIs); hyperlipidaemia |
| Metabolic | NODAT (New Onset Diabetes After Transplant; tacrolimus > ciclosporin); osteoporosis (steroids) |
| Drug nephrotoxicity | CNI nephrotoxicity → chronic allograft nephropathy |
PART III: AIDS IN SURGICAL CONTEXT
A. Pathophysiology Review
- HIV (Human Immunodeficiency Virus) - RNA retrovirus; predominantly HIV-1
- Targets CD4+ T cells (also macrophages, dendritic cells) via gp120-CD4 binding + co-receptor (CCR5 or CXCR4)
- Reverse transcriptase converts RNA → DNA → integrates into host genome
- Progressive CD4+ depletion → AIDS when CD4 count <200 cells/μL (or AIDS-defining illness)
B. AIDS-Defining Conditions (Surgical Relevance)
| Category | Examples |
|---|
| Opportunistic infections | PCP, CMV retinitis/colitis, MAC, toxoplasmosis, cryptococcal meningitis, oesophageal candidiasis |
| AIDS-defining malignancies | Kaposi sarcoma, CNS lymphoma, invasive cervical cancer |
| Anorectal disease | Anal condylomata (HPV), anal SCC (HPV-16), anal fissure, anal ulcers (primary HIV), perianal abscess/fistula |
| GI disease | CMV colitis (bloody diarrhoea), HIV enteropathy, cryptosporidiosis |
C. Surgical Considerations in HIV/AIDS Patients
Pre-operative assessment:
- CD4 count and viral load (guide surgical risk)
- Full medication history (ARTs, interactions)
- CD4 >200/μL: most elective surgery safe
- CD4 <50/μL: high perioperative risk; consider deferring elective surgery
Surgical complications more common in HIV/AIDS:
- Poor wound healing
- Higher rates of infection (including resistant organisms)
- Higher recurrence of anorectal conditions
- Increased risk of post-op opportunistic infections
- Drug interactions between ARTs and anaesthetic agents
Common surgical indications in HIV:
- Anorectal surgery (most common): condylomata, fissures, abscesses, fistulae
- Surgery not significantly different but expect impaired healing and higher recurrence
- Splenomegaly/hypersplenism: splenectomy may be required
- Kaposi sarcoma: intestinal (bleeding, obstruction, perforation)
- Lymphoma: abdominal (obstruction, perforation, staging)
- CMV colitis: perforation → emergency surgery (high mortality)
PART IV: UNIVERSAL PRECAUTIONS
A. Definition
Universal Precautions (introduced by the CDC, 1987) - the principle that all blood and body fluids from every patient should be treated as potentially infectious for HIV, HBV, HCV and other bloodborne pathogens, regardless of the patient's known or presumed infection status.
Expanded to "Standard Precautions" (1996) - includes blood, all body fluids, secretions, excretions (except sweat), non-intact skin, and mucous membranes.
B. Components of Standard/Universal Precautions
| Precaution | Detail |
|---|
| Hand hygiene | Most important single measure; soap + water or alcohol gel before and after patient contact |
| Gloves | When touching blood, body fluids, mucous membranes, non-intact skin |
| Mask + eye protection | When there is a risk of splashing blood/body fluids |
| Gown/apron | When clothing may be contaminated |
| Safe sharps handling | Never re-sheath needles by hand; use sharps bin immediately; use blunt needles where possible |
| Safe waste disposal | Yellow bags (clinical waste), sharps containers, pharmaceutical waste |
| Decontamination | Instruments: cleaning → disinfection → sterilisation (autoclave 134°C for prions) |
C. Bloodborne Pathogen Risks to Healthcare Workers
| Pathogen | Risk per Needlestick | Prevention | Post-Exposure Prophylaxis |
|---|
| HBV | 6–30% | Hepatitis B vaccination (3 doses) | HBIG + vaccine booster within 48 hrs |
| HCV | 0.5–2% (1.8% average) | No vaccine | No proven PEP; monitor LFTs + HCV RNA; treat if seroconversion (SOF-based DAAs) |
| HIV | 0.3% (percutaneous); 0.09% (mucous membrane) | No vaccine; ARV PEP | PEP within 1 hour (ideally) and no later than 72 hours; 28-day course |
HIV Risk by route of exposure:
- Needlestick: 0.3%
- Mucous membrane splash: 0.09%
- Intact skin: negligible
- Risk increased by: hollow bore needle, deep puncture, visible blood on device, terminal illness in source patient (high viral load)
D. Post-Exposure Protocol (Needlestick)
IMMEDIATE actions:
- Encourage bleeding from wound; wash thoroughly with soap and water (do NOT suck wound)
- Splash to eyes/mouth: irrigate copiously with water
- Report immediately to occupational health / A&E
- Risk-assess the source patient (HIV, HBV, HCV status; consent for urgent testing)
- Assess baseline serology of exposed worker (HIV, HBV, HCV)
If HIV risk (source HIV+ve or unknown high-risk):
- Start PEP within 1 hour, no later than 72 hrs
- Standard PEP regimen: Truvada (tenofovir + emtricitabine) + raltegravir (or dolutegravir) × 28 days
- Follow-up HIV test at 6 weeks and 3 months
If HBV risk:
- If worker vaccinated and known responder → no action needed
- If unvaccinated or non-responder: HBIG + vaccine within 48 hours
E. Additional Precaution Categories (Beyond Standard)
| Category | Indications | Additional Measures |
|---|
| Contact precautions | MRSA, VRE, C. difficile, scabies, wound infections | Gloves + gown for all contact; dedicated equipment |
| Droplet precautions | Influenza, meningococcal disease, mumps, pertussis | Surgical mask within 1 metre; single room if possible |
| Airborne precautions | TB, measles, chickenpox, COVID-19 (aerosolised) | FFP3 respirator, negative pressure room, HEPA filtration |
F. Surgical Team Protection - Theatre Precautions
| Risk | Precaution |
|---|
| Sharps injury | No-touch technique for passing sharps; "neutral zone" on instrument trolley; blunt suture needles for fascia closure |
| Blood splash | Double gloving (reduces needlestick by 25%), face shields/visor |
| Bone fragments | Eye protection during orthopaedic / thoracic procedures |
| Electrocautery aerosol/plume | Smoke evacuators; N95 masks during laparoscopy (especially HPV/HIV patients) |
| High-risk list patients | HIV, HBV, HCV → no change in standard precautions; same care for all; Universal Precautions apply to ALL patients regardless |
G. Sterilisation & Disinfection
| Level | Method | Kills | Used for |
|---|
| Sterilisation | Autoclave (steam, 121°C/134°C), ethylene oxide gas, gamma radiation | All organisms including spores and prions (134°C) | Surgical instruments, implants |
| High-level disinfection | Glutaraldehyde, peracetic acid, chlorine dioxide | All except prions | Endoscopes |
| Intermediate disinfection | 70% alcohol, chlorhexidine + alcohol | Bacteria, most viruses, mycobacteria | Skin prep, surfaces |
| Low-level disinfection | Quaternary ammonium compounds | Most bacteria, some viruses | General surface cleaning |
Creutzfeldt-Jakob Disease (CJD/vCJD): prion diseases require autoclave at 134°C × 18 min or 1M NaOH/sodium hypochlorite; disposable instruments used where possible for high-risk patients.
Sources: Bailey and Love's Short Practice of Surgery 28th Ed; Mulholland and Greenfield's Surgery 7e (HIV and AIDS, p. 3589); Cellular and Molecular Immunology (Abbas); Harrison's Principles of Internal Medicine 22e; Brenner & Rector's The Kidney; CDC Standard Precautions guidelines