Does a patient with checkpoint inhibitor-induced colitis, who developed diarrhea after receiving the first dose of a checkpoint inhibitor (e.g. Pembrolizumab) and was treated with methylprednisolone (20mg every 12 hours), and then experienced shock and hypotension with a low cortisol level (6) after cessation of methylprednisolone, have adrenal insufficiency secondary to immunotherapy rather than an infectious cause?

Checkpoint Inhibitor-Induced Adrenal Insufficiency vs. Infection

This clinical presentation is highly consistent with checkpoint inhibitor-induced secondary adrenal insufficiency unmasked by abrupt cessation of methylprednisolone, rather than infection. The morning cortisol of 6 μg/dL with shock developing after stopping steroids in a patient on pembrolizumab is a classic presentation of iatrogenic adrenal crisis precipitated by withdrawal of exogenous corticosteroids in the setting of underlying immune-related hypophysitis/ACTH deficiency 1.

Why This Fits Checkpoint Inhibitor Adrenal Insufficiency

The clinical scenario demonstrates multiple hallmark features of ICI-induced secondary adrenal insufficiency:

• Timing and context: The patient was receiving methylprednisolone 20 mg q12h (40 mg/day total) for checkpoint inhibitor colitis, which suppresses the HPA axis and masks underlying ACTH deficiency 1, 2. When steroids were abruptly stopped after the morning dose, the patient developed shock overnight—this represents acute adrenal crisis unmasked by steroid withdrawal 1, 3.

• Morning cortisol of 6 μg/dL: This level is diagnostic of adrenal insufficiency in the context of acute illness and shock 1, 3. A morning cortisol <250 nmol/L (<9 μg/dL) with low or inappropriately normal ACTH indicates secondary adrenal insufficiency 1, 4. The cortisol should be >18-20 μg/dL in a patient experiencing shock—a level of 6 μg/dL is profoundly inadequate 3.

• Secondary (not primary) AI pattern: Pembrolizumab-induced adrenal insufficiency is predominantly secondary AI due to isolated ACTH deficiency or hypophysitis 1, 5, 6. Secondary AI presents with hyponatremia WITHOUT hyperkalemia because aldosterone secretion remains intact 4. The absence of hyperkalemia cannot rule out adrenal insufficiency—it's present in only 50% of primary AI cases and typically absent in secondary AI 3, 4.

• Checkpoint inhibitor colitis already present: The patient already had one immune-related adverse event (colitis), which increases the likelihood of additional irAEs including endocrinopathies 1, 5. Pembrolizumab causes secondary AI in 5.4% of NSCLC patients, with isolated ACTH deficiency being the predominant form 6.

Critical Diagnostic Error: Stopping Steroids Abruptly

The development of shock after stopping methylprednisolone represents a preventable iatrogenic adrenal crisis:

• Patients on corticosteroids for management of other irAEs will have low morning cortisol as a result of iatrogenic secondary adrenal insufficiency, and ACTH will also be suppressed—this is expected 1, 3. However, in this patient, the underlying checkpoint inhibitor likely caused true ACTH deficiency that was masked by the therapeutic steroids 7.

• Exogenous steroids suppress the HPA axis and confound diagnostic testing 3, 2. The methylprednisolone was suppressing both the patient's endogenous cortisol production AND masking symptoms of underlying ACTH deficiency 2, 7.

• When steroids are abruptly discontinued in a patient with underlying adrenal insufficiency (whether iatrogenic or immune-mediated), acute adrenal crisis can develop within hours 1, 3. This patient got the morning dose but no further doses, leading to shock overnight as steroid levels dropped 3.

Why Infection is Less Likely

While infection must always be evaluated as a precipitating cause of adrenal crisis, the clinical pattern strongly suggests the primary problem is adrenal insufficiency itself:

• The ASCO guidelines specifically state: "If primary adrenal insufficiency is found biochemically, evaluate for precipitating cause of crisis such as infection" 1. This means you first confirm AI, then look for infection as a trigger—not the other way around 1.

• The temporal relationship (shock developing immediately after stopping steroids) points to steroid withdrawal as the precipitant rather than new infection 3.

• A morning cortisol of 6 μg/dL in a patient with shock is diagnostic of adrenal insufficiency regardless of whether infection is present 3. Even if infection is present, the patient still has inadequate adrenal response and requires stress-dose steroids 1, 3.

Immediate Management Algorithm

Treatment should NEVER be delayed for diagnostic procedures in suspected adrenal crisis 1, 3:

1. Immediate resuscitation (within minutes):

   • IV hydrocortisone 100 mg bolus immediately 1, 3
   • 0.9% normal saline infusion at 1 L/hour (at least 2L total) 1, 3
   • Draw blood for cortisol and ACTH before giving hydrocortisone if possible, but do NOT delay treatment 1, 3

2. Ongoing stress-dose steroids:

   • Continue hydrocortisone 50-100 mg IV q6-8h or 200 mg/24h continuous infusion 1, 3
   • Taper stress-dose corticosteroids down to maintenance doses over 7-14 days after stabilization 1

3. Evaluate for infection (after initiating treatment):

   • Blood cultures, urinalysis, chest X-ray, other cultures as indicated 1
   • Broad-spectrum antibiotics if infection suspected, but this doesn't change the need for stress-dose steroids 1

4. Confirm diagnosis (after stabilization):

   • Measure ACTH with the pre-treatment cortisol sample 1
   • Low ACTH with low cortisol confirms secondary AI 1, 4
   • Consider pituitary MRI to evaluate for hypophysitis 1
   • ACTH stimulation testing can be performed later if diagnosis remains uncertain, but is not needed if morning cortisol <9 μg/dL with shock 1, 3

Long-Term Management Considerations

Once stabilized, this patient will require:

• Maintenance glucocorticoid replacement: Hydrocortisone 15-25 mg daily in divided doses (10-20 mg morning, 5-10 mg early afternoon) OR prednisone 4-5 mg daily 1, 3

• No mineralocorticoid replacement needed: Secondary AI preserves aldosterone secretion, so fludrocortisone is not required 1, 4

• Mandatory patient education: Stress dosing instructions, medical alert bracelet, emergency injectable hydrocortisone 100 mg IM kit with self-injection training 1, 3

• Endocrine consultation: Required for all patients with checkpoint inhibitor-induced adrenal insufficiency 1

• Hold checkpoint inhibitor: Until patient is stabilized on replacement hormone 1

• Start corticosteroids before thyroid hormone: If concurrent hypothyroidism is present, always start corticosteroids several days before initiating thyroid replacement to prevent precipitating adrenal crisis 1, 3

Critical Pitfall to Avoid

Never attempt to "wean" steroids in a patient on checkpoint inhibitors without first confirming intact HPA axis function 3, 7. This patient's steroids should have been tapered gradually while monitoring for symptoms of adrenal insufficiency, with ACTH and cortisol testing performed after sufficient washout time (not while on steroids) 3. The administration of high-dose steroids after ICI administration may mask symptoms of hypoadrenocorticism as irAEs, so clinicians must maintain high suspicion when stopping steroid therapy 7.