Red flags
- Graft tenderness + fever + rising creatinine -> pyelonephritis of the graft, or rejection
- Fever with no localising signs in the first 6 months -> CMV until proven otherwise
- Neutropenia (valganciclovir, mycophenolate, trimethoprim, CMV, parvovirus) - removes the usual inflammatory signs
- Steroids blunt fever and peritonism - a soft abdomen does not exclude perforation or an intra-abdominal collection
- Recent ATG or rituximab -> profound and prolonged T- or B-cell depletion
- Hypotension, lactate, new confusion - sepsis in a patient who cannot mount a normal response
- Diarrhoea + fever + rising tacrolimus level -> CMV colitis or C. difficile, with drug accumulation
- Headache or any neurology -> cryptococcus, listeria, nocardia, toxoplasma, PTLD, PML - low threshold for CT and LP
- Dyspnoea with a clear chest X-ray -> PJP (do not wait for radiological change)
- Travel or residence in an endemic area -> TB, strongyloides hyperinfection, melioidosis, endemic mycoses
Differential by mechanism1 exam ›
By time since transplant - the single most useful framework
<1 month - the same infections as any post-surgical patient
- Nosocomial and surgical: wound infection, UTI/graft pyelonephritis, line sepsis, pneumonia, C. difficile
- Donor-derived infection (rare, but consider bacteraemia, HSV, LCMV, tuberculosis)
- Recipient-derived colonisation (MRSA, VRE, candida)
- *Opportunistic infection is uncommon this early - the immunosuppression has not had time to work*
- Non-infective: DVT/PE, drug fever, acute rejection, haematoma, urinoma
1-6 months - the opportunistic window
- CMV - classically the most important opportunistic infection in this period
- Fever + malaise + leucopenia and thrombocytopenia; tissue-invasive: colitis, oesophagitis, hepatitis, pneumonitis, retinitis
- BK virus (usually afebrile - creatinine rise)
- PJP, nocardia, listeria, toxoplasma, cryptococcus, aspergillus
- TB reactivation, strongyloides hyperinfection
- EBV -> PTLD (fever, night sweats, lymphadenopathy, tonsillar mass)
- HSV/VZV reactivation, hepatitis B reactivation
- Prophylaxis shifts this window - the patient on valganciclovir and trimethoprim gets CMV and PJP later, after it stops
>6 months - mostly community-acquired
- Community respiratory viruses, influenza, COVID, community-acquired pneumonia, UTI
- Late CMV after prophylaxis ceases (especially D+/R-)
- PTLD, malignancy-related fever
- Chronic viral: hepatitis B/C, BK, JC virus (PML)
- Patients requiring intensified immunosuppression for rejection reset to the 1-6 month risk profile
Non-infective causes of fever - do not forget
- Acute rejection, drug fever (ATG, rituximab, trimethoprim, mTOR inhibitors), PTLD/malignancy, VTE, gout flare, adrenal insufficiency
Focused history
Establish the risk profile
- Time since transplant - drives the entire differential
- Donor and recipient CMV and EBV serostatus (D+/R-?)
- Induction agent - ATG or alemtuzumab means much deeper immunosuppression
- Current immunosuppression and any recent intensification for rejection
- What prophylaxis is she on, and when did it stop? (valganciclovir, trimethoprim-sulfamethoxazole, nystatin)
- Vaccination status
The exposure history
- Country of birth and travel - TB, strongyloides, melioidosis, endemic mycoses, malaria
- Contacts - respiratory viruses, TB, varicella
- Gardening/soil (nocardia, legionella, aspergillus), building works, unpasteurised dairy and deli meats (listeria), pets, birds
- Recent instrumentation, dental work, endoscopy
Localising symptoms - ask actively, they are often absent
- Dysuria, graft pain, diarrhoea, cough, dyspnoea, headache, visual change, rash, mouth ulcers, sore throat, night sweats, weight loss
Focused examination
- Vital signs, and expect them to under-call the severity
- Graft: tenderness, swelling, bruit - graft pyelonephritis and acute rejection both give a tender graft
- Wound, exit sites, vascular access, indwelling lines
- Chest - often normal in PJP; hypoxia on exertion is the clue
- Mouth and skin - candida, HSV, VZV, Kaposi sarcoma, nocardia nodules, disseminated fungal lesions, cellulitis
- Lymph nodes and tonsils - PTLD
- Fundoscopy - CMV retinitis
- Abdomen - peritonism is blunted by steroids
- Full neurological examination - listeria, cryptococcus, toxoplasma, nocardia, PML
Investigation strategy
First-line, in everyone
- Blood cultures x2 (before antibiotics), urine microscopy and culture
- FBE with differential (leucopenia -> CMV, drugs), UEC, LFT, CRP, lactate, VBG
- CMV PCR (quantitative) and BK PCR
- Tacrolimus/ciclosporin trough - diarrhoea and azoles raise it, rifampicin drops it
- CXR; CT chest with a low threshold (plain film misses PJP, nodules and early fungal disease)
- Respiratory virus PCR panel, COVID and influenza
- Stool: *culture, C. difficile toxin, viral PCR*
- Ultrasound of the graft: hydronephrosis, collection, flow
Second-line, directed
- Sputum/BAL - PJP PCR, galactomannan, AFB, nocardia (modified acid-fast), fungal culture
- Serum beta-D-glucan and galactomannan
- Cryptococcal antigen (serum and CSF)
- LP for any neurological feature - cell count, culture, cryptococcal antigen, PCR panel (HSV, VZV, enterovirus, JC), toxoplasma PCR
- Blood EBV viral load if PTLD suspected -> CT neck/chest/abdomen/pelvis, tissue biopsy
- Interferon-gamma release assay (may be falsely negative under immunosuppression)
- Strongyloides serology if from an endemic region
- Graft biopsy if the creatinine is rising and infection does not explain it
Management
1. Resuscitate and treat empirically - do not wait
- Broad-spectrum antibiotics within 1 hour if septic, guided by local ecology and prior isolates
- Cover Gram-negatives including Pseudomonas; add vancomycin if line-associated or MRSA risk
- Fluids, source control (remove an infected line, drain a collection, relieve obstruction)
2. Adjust the immunosuppression - the decision unique to this patient
- Reduce or hold the antimetabolite (mycophenolate/azathioprine) in severe infection
- Continue the CNI where possible - stopping everything risks rejection
- Never stop corticosteroids abruptly - give stress-dose hydrocortisone in septic shock; these patients are adrenally suppressed
- Restore immunosuppression as the infection resolves, and monitor the creatinine
3. Pathogen-directed
- CMV - IV ganciclovir (or oral valganciclovir for non-severe disease), reduce immunosuppression; letermovir or maribavir for resistant disease; treat until PCR negative x2 and >=2 weeks
- PJP - high-dose trimethoprim-sulfamethoxazole 21 days + adjunctive corticosteroid if PaO2 <70 mmHg or A-a gradient >35
- Nocardia - trimethoprim-sulfamethoxazole, long course; image the brain (abscesses are common)
- Listeria - benzylpenicillin or amoxicillin (+/- gentamicin); cephalosporins do not cover it
- Cryptococcus - liposomal amphotericin + flucytosine, then fluconazole; manage raised intracranial pressure with serial LPs; watch for IRIS as immunosuppression is reduced
- Aspergillus - voriconazole or isavuconazole; *azoles raise CNI levels dramatically - reduce the tacrolimus dose by ~two-thirds and monitor*
- TB - *rifampicin induces CYP3A4 and collapses CNI levels -> rejection.* Use rifabutin, or increase the CNI dose with close monitoring; discuss with ID
- PTLD - reduce immunosuppression first, then rituximab +/- chemotherapy
- Graft pyelonephritis - 14-21 days of antibiotics, image for obstruction and abscess
4. Prevent the next episode
- Reinstate or extend prophylaxis; inactivated vaccines only (influenza, COVID, pneumococcal) - no live vaccines
- Food, soil, water and travel advice
- Review whether the immunosuppression burden is right for this patient
Traps
- *Fever may be absent or minimal* - steroids, and calcineurin inhibitors, blunt it. Take a low-grade temperature seriously
- CRP and white cell count are unreliable - leucopenia in this context suggests CMV or drug toxicity, not the absence of infection
- A normal chest X-ray does not exclude PJP or invasive fungal disease - get a CT
- *Azoles (voriconazole, posaconazole, fluconazole) and macrolides raise tacrolimus levels catastrophically; rifampicin collapses them.* Every new antimicrobial needs an interaction check and a CNI level
- Diarrhoea raises tacrolimus levels (loss of gut CYP3A4/P-glycoprotein) - the creatinine rise may be drug toxicity, not rejection
- Rejection and infection can coexist, and the treatments are opposite. Biopsy rather than guess
- Do not reduce immunosuppression to zero - rejection while septic is a disaster
- Ceftriaxone does not cover listeria; ampicillin/amoxicillin does
- *A patient recently treated for rejection has reset to the highest-risk period* whatever the calendar date
- Interferon-gamma release assays and tuberculin testing are frequently falsely negative in this population
- Trimethoprim raises creatinine without changing GFR - and also causes hyperkalaemia and neutropenia
- Adrenal insufficiency presents as unexplained fever and hypotension in a steroid-dependent patient
Talk track
1. Frame by the timeline
- "My first question is how long since the transplant - under a month I'm thinking nosocomial and surgical, one to six months opportunistic with CMV at the top, and beyond six months mostly community-acquired unless she's had recent rejection treatment."
2. State the modifiers
- "Then the CMV and EBV donor-recipient serostatus, what induction she had, and what prophylaxis she's on and when it stopped."
3. Acknowledge the blunted signs
- "I'd take a low-grade fever seriously - steroids blunt fever and peritonism, and a normal white cell count and CRP don't reassure me."
4. Investigate broadly and early
- "Blood and urine cultures, CMV and BK PCR, a tacrolimus level, and a CT chest rather than a plain film if there's any respiratory symptom."
5. Treat, then tune the immunosuppression
- "Empirical broad-spectrum antibiotics within the hour, then I'd reduce or hold the mycophenolate, keep the calcineurin inhibitor, and never stop the steroid - stress-dose it if she's shocked."
6. Flag the interaction
- "If she needs an azole or rifampicin I'd adjust the tacrolimus dose immediately and monitor levels - that interaction causes both toxicity and rejection."
7. Keep rejection in the differential
- "If the creatinine is rising and the infection doesn't explain it, I'd biopsy - rejection and infection coexist and the treatments pull in opposite directions."
8 of 8 sections written · drafted 2026-09-04