Immune Checkpoint Inhibitor Adverse Event Management — Part 3: Endocrine and Pulmonary irAEs

Endocrine Immune-Related Adverse Events

Endocrine irAEs are among the most common irAEs and are unique in that they often result in permanent glandular destruction requiring lifelong hormone replacement. Importantly, well-controlled endocrine irAEs on appropriate hormone replacement do not typically require ICI discontinuation. Endocrine irAEs are frequently underrecognized because their symptoms (fatigue, nausea, weakness, weight changes) overlap with those of cancer, chemotherapy, and general illness.^{1 2 3}

Overview of Endocrine irAE Incidence

Thyroid Disorders

Thyroiditis and Hypothyroidism

ICI-induced thyroid dysfunction is the most common endocrine irAE. The typical course is an initial thyrotoxic phase (painless thyroiditis with release of preformed thyroid hormone) followed by hypothyroidism due to thyroid gland destruction. Some patients present with isolated hypothyroidism without a preceding thyrotoxic phase.^{1 4}

Workup for suspected thyroid irAE:

• TSH, free T4, free T3
• If thyrotoxicosis: TSH receptor antibodies (TRAb) to distinguish Graves disease from destructive thyroiditis (TRAb negative in ICI thyroiditis); consider thyroid uptake scan if diagnosis uncertain (low uptake in destructive thyroiditis, elevated in Graves)
• TPO antibodies (may be positive, suggesting autoimmune predisposition)
• Thyroglobulin (may be elevated in destructive thyroiditis)

Hypothyroidism: Grading and Management

Thyrotoxicosis (Hyperthyroidism)

The thyrotoxic phase of ICI thyroiditis is typically transient (2–6 weeks) and self-limited, followed by hypothyroidism. True Graves disease is rare but can occur.

Key point: After the thyrotoxic phase resolves, monitor for development of hypothyroidism – this occurs in the majority of patients within weeks to months and requires levothyroxine replacement.^{1 4}

Adrenal Insufficiency

Primary Adrenal Insufficiency (Adrenalitis)

Primary adrenal insufficiency from ICI-mediated destruction of the adrenal cortex is rare (< 1%–2%) but potentially life-threatening if unrecognized. It should be suspected in patients with fatigue, hypotension, hyponatremia, hyperkalemia, and hyperpigmentation.^{1 2}

Workup:

• Morning cortisol (8 AM): < 3 mcg/dL is diagnostic; 3–15 mcg/dL is indeterminate and warrants ACTH stimulation test
• ACTH stimulation test (cosyntropin 250 mcg IV; cortisol at 0 and 60 minutes): peak cortisol < 18 mcg/dL confirms adrenal insufficiency
• ACTH level: elevated (> 2x ULN) in primary adrenal insufficiency; low or inappropriately normal in secondary (pituitary-mediated)
• Basic metabolic panel (hyponatremia, hyperkalemia)
• Renin and aldosterone (both affected in primary AI)
• CT adrenal glands (may show bilateral enlargement acutely or atrophy later; rule out metastases or hemorrhage)
• 21-hydroxylase antibodies (may be positive)

Management:

Stress dosing for illness/procedures: Patients on maintenance hydrocortisone should double or triple their dose during febrile illness, major stress, or procedures. For surgery or severe illness: hydrocortisone 50–100 mg IV bolus, then 50 mg every 8 hrs, tapering back to maintenance over 1–3 days.

Primary adrenal insufficiency is typically permanent and requires lifelong glucocorticoid and mineralocorticoid replacement.¹

Secondary Adrenal Insufficiency (from Hypophysitis)

Secondary adrenal insufficiency results from loss of ACTH production due to pituitary inflammation (hypophysitis). Unlike primary AI, it does not affect aldosterone production (which is regulated by the renin-angiotensin system), so fludrocortisone is generally not needed. See Hypophysitis section below.

Hypophysitis

Hypophysitis is inflammation of the pituitary gland and is more common with anti-CTLA-4 agents (5%–10% with ipilimumab) than anti-PD-1/PD-L1 agents (< 1%). It typically presents at 6–12 weeks of therapy. The anterior pituitary is most commonly affected, with the ACTH and TSH axes being the most frequently impaired. Posterior pituitary involvement (diabetes insipidus) is uncommon.^{1 2 3 5}

Clinical presentation:

• Headache (most common presenting symptom, present in 60%–80% of cases)
• Fatigue, weakness, anorexia, nausea
• Visual field defects (if pituitary enlargement compresses the optic chiasm – uncommon)
• Symptoms of hormone deficiencies: adrenal insufficiency (fatigue, hypotension, hyponatremia), hypothyroidism, hypogonadism

Workup:

• Anterior pituitary hormone panel: morning cortisol, ACTH, TSH, free T4, FSH, LH, estradiol or testosterone, prolactin, IGF-1
• Basic metabolic panel: hyponatremia (from cortisol deficiency or hypothyroidism)
• Brain MRI with pituitary protocol (with gadolinium): may show pituitary enlargement, stalk thickening, or heterogeneous enhancement; normal MRI does not exclude hypophysitis

Management:

Key principles:

• ACTH deficiency (secondary adrenal insufficiency) is the most common and most dangerous component – always replace cortisol before thyroid hormone
• Fludrocortisone is typically NOT needed for secondary adrenal insufficiency (aldosterone is regulated by renin-angiotensin, not ACTH)
• High-dose corticosteroids are used for mass effect symptoms only; physiologic-dose hydrocortisone is the standard replacement
• Recovery of pituitary axes: TSH and gonadotropin axes may recover in 30%–50% of cases; ACTH axis recovers in < 10%–most patients require lifelong cortisol replacement⁵
• Once stable on hormone replacement, ICI can typically be resumed

Type 1 Diabetes Mellitus (ICI-Induced)

ICI-induced type 1 diabetes is rare (< 1%) but can present fulminantly with diabetic ketoacidosis (DKA) as the initial manifestation. It is more common with anti-PD-1/PD-L1 agents and results from autoimmune destruction of pancreatic beta cells.^{1 2 6}

Clinical presentation:

• Polyuria, polydipsia, weight loss, nausea, vomiting
• Hyperglycemia (often markedly elevated, > 300–500 mg/dL)
• DKA at presentation in approximately 70% of reported cases
• May develop rapidly over days

Workup:

• Blood glucose, hemoglobin A1c
• Serum bicarbonate, anion gap, serum ketones (beta-hydroxybutyrate)
• C-peptide level (low, indicating insulin deficiency)
• Islet cell antibodies: GAD65, IA-2, ZnT8 (positive in approximately 50%–70% of cases; can be negative)
• Lipase (exclude concurrent pancreatitis)

Management:

Key principles:

• ICI-induced type 1 diabetes is permanent in the vast majority of cases; patients require lifelong insulin therapy
• Corticosteroids are NOT effective for ICI-induced type 1 diabetes (the beta cell destruction is typically complete by the time of diagnosis)
• ICI can usually be resumed once glucose is controlled on insulin
• Monitor all ICI patients for hyperglycemia; consider baseline HbA1c and fasting glucose
• Distinguish from steroid-induced hyperglycemia (which is dose-dependent and reversible with steroid taper)

Pulmonary Immune-Related Adverse Events: Pneumonitis

Immune-mediated pneumonitis is one of the most clinically significant irAEs due to its potential severity and the significant mortality associated with grade 3 or higher disease. It occurs in approximately 2% to 5% of patients on anti-PD-1/PD-L1 monotherapy and 7% to 10% on combination regimens, with grade 3 or higher events in 1% to 2% on monotherapy and 3% to 5% on combination. Pneumonitis is among the leading causes of irAE-related death.^{1 2 3 7}

Risk Factors for ICI Pneumonitis

• Prior or concurrent thoracic radiation (radiation recall pneumonitis)
• Preexisting lung disease (COPD, pulmonary fibrosis, ILD)
• Lung cancer (higher rate than in extrathoracic malignancies)
• Combination immunotherapy
• Anti-PD-1/PD-L1 agents (higher rate than anti-CTLA-4 alone)
• Prior lung surgery

Clinical Presentation

Symptoms include dyspnea (most common), nonproductive cough, chest pain, and hypoxia. Onset is typically 8 to 14 weeks after initiation but can occur at any time. Fever may be present but suggests concurrent infection until proven otherwise.

Imaging Patterns

ICI pneumonitis has variable radiographic presentations:⁷

Grading

Differential Diagnosis

The differential for ICI-associated pulmonary infiltrates is broad, and alternative diagnoses must be excluded before attributing findings to immune-mediated pneumonitis:

• Infection: Bacterial pneumonia, PJP (especially if on corticosteroids), viral pneumonia (influenza, COVID-19, CMV, RSV), fungal pneumonia
• Pulmonary embolism
• Disease progression: lymphangitic carcinomatosis, new parenchymal metastases
• Radiation pneumonitis (if prior thoracic radiation)
• Drug-induced pneumonitis from other agents (bleomycin, methotrexate, TKIs)
• Heart failure / fluid overload
• Diffuse alveolar hemorrhage

Workup

Grade-Based Management of ICI Pneumonitis

Pneumonitis Corticosteroid Taper Schedule (After Grade 2–3)

Starting from prednisone 1–2 mg/kg/day (e.g., 80 mg/day for an 80 kg patient):

• If symptoms recur during taper: return to last effective dose for at least 1 week, then reattempt slower taper
• Obtain follow-up CT chest at 4 weeks and before any ICI rechallenge
• PJP prophylaxis throughout corticosteroid course if >/= 20 mg/day for >/= 4 weeks

References