Immune Checkpoint Inhibitor Toxicity — Written Clinical Reasoning

Prompt 1 — multisystem immune-related toxicity on combination checkpoint inhibition (15 marks)

Using the clinical stem above, address the following in a structured written answer: ^[1]

(a) Formulate a prioritised problem list and justify your ordering. (4 marks) ^[1]

(b) Outline your immediate and definitive management of the two highest-priority problems, including specific drug doses, monitoring, and the timing of second-line therapy. (8 marks) ^[1]

(c) Explain the investigation strategy for the colitis and the rationale for the order of investigation. (3 marks) ^[1]

Model answer — Prompt 1

(a) Prioritised problem list ^[1]

1. Secondary adrenal insufficiency from checkpoint-inhibitor hypophysitis with evolving adrenal crisis — the immediate life threat. The postural drop, hyponatraemia (126), hyperkalaemia (5.1), and low cortisol with inappropriately low ACTH, in a patient on ipilimumab, are diagnostic. Untreated adrenal crisis is fatal and is the first thing to treat.
2. Grade 3 immunotherapy colitis — the index emergency with perforation risk. Eight bloody stools per day with abdominal pain and a systemic inflammatory response is CTCAE grade 3.
3. Grade 2 immunotherapy hepatitis — the ALT and AST are 5 to 6 times the upper limit of normal with a mildly raised INR; needs exclusion of viral, drug and obstructive causes but is consistent with an irAE.
4. Hypophysitis with central hypothyroidism (low TSH, low free T4) and likely hypogonadism — to be replaced, but only AFTER cortisol replacement.
5. Grade 2 maculopapular skin rash — 25 per cent body surface area without mucosal involvement; manageable alongside the other problems.
6. Metastatic melanoma — the underlying disease; the oncological decision on continuation of therapy follows recovery.
7. Acute kidney injury (pre-renal and possibly interstitial) — likely a combination of hypovolaemia from colitis and adrenal insufficiency; will improve with resuscitation. ^[1]

(b) Immediate and definitive management of the two highest-priority problems ^[1]

Adrenal crisis (problem 1):

• Intravenous hydrocortisone 100 mg stat then 50 mg every 6 hours — do not wait for the pituitary MRI.
• Intravenous fluids: 1 litre normal saline over the first hour, then continue resuscitation guided by haemodynamics and sodium.
• Correct sodium slowly (no more than 8 to 10 mmol/L in 24 hours) to avoid osmotic demyelination.
• Do not give levothyroxine until hydrocortisone is running — thyroid replacement increases cortisol clearance and can precipitate cardiovascular collapse.
• Arrange a pituitary MRI once stable to confirm an enlarged, homogeneously enhancing gland.
• Plan lifelong replacement with hydrocortisone, levothyroxine, and (after a repeat panel) testosterone; involve endocrinology. ^[1]

Grade 3 colitis (problem 2):

• Admit; intravenous fluids and electrolyte correction; thromboprophylaxis (high VTE risk).
• Stool studies MUST be sent before steroids — culture, C. difficile toxin, ova cysts and parasites. (Already done per stem.)
• Once the stool is sent, intravenous methylprednisolone 1 to 2 mg/kg per day (here, around 80 to 100 mg per day).
• Hold both checkpoint inhibitors; plan for permanent discontinuation of the combination after this multisystem grade 3 event.
• Gastroenterology and surgical review at the first opportunity; CT abdomen if peritonism develops or perforation is suspected.
• Infliximab 5 mg/kg at weeks 0, 2 and 6 at 48 to 72 hours if there is no response to steroid — screen with QuantiFERON and hepatitis B surface antigen first (already pending).
• Plan a slow corticosteroid taper over at least 4 to 6 weeks once the colitis has resolved to grade 1. ^[1]

(c) Investigation strategy for the colitis and the rationale ^[1]

The order is: exclude infection first, then confirm the irAE, then assess for complications.

1. Stool culture, C. difficile toxin, ova cysts and parasites — sent before steroids because steroids make interpretation impossible. C. difficile and Campylobacter produce an identical clinical picture.
2. Blood cultures and inflammatory markers — to capture systemic infection.
3. Faecal calprotectin — supports an inflammatory colitis.
4. Flexible sigmoidoscopy or colonoscopy with biopsies — confirms the diagnosis (mucosal oedema, loss of vascular pattern, ulceration; mixed inflammatory infiltrate) and excludes CMV and pseudomembranous colitis. Sigmoidoscopy suffices in the unstable patient.
5. CT abdomen with contrast — if perforation, toxic megacolon or an alternative diagnosis is suspected.
6. Exclusion of coexisting hepatitis — viral serology, autoimmune markers, abdominal ultrasound with Doppler. ^[1]

The rationale for sending stool first is that the management of an infective colitis (antibiotics, no immunosuppression) is the opposite of the management of immunotherapy colitis (immunosuppression). Giving steroids for C. difficile colitis is harmful; withholding steroids for grade 3 immunotherapy colitis risks perforation. The stool result resolves the dilemma, and in a high-probability case steroids are started once the stool is in the lab, not after the result returns. ^[1]