What is the recommended treatment for a patient with suspected mast cell activation syndrome?

Treatment of Mast Cell Activation Syndrome

Initiate non-sedating H1 antihistamines at 2–4 times the standard FDA-approved dose combined with an H2 antihistamine as foundational therapy for all patients with suspected MCAS. 1

First-Line Pharmacologic Therapy

H1 and H2 Antihistamine Combination

• Start with non-sedating H1 antihistamines (cetirizine, fexofenadine, or loratadine) at 2–4 times the standard FDA-approved dose to control histamine-mediated symptoms including flushing, pruritus, urticaria, tachycardia, and abdominal discomfort. 1
• Add an H2 antihistamine (famotidine or ranitidine) to the regimen for enhanced control of gastrointestinal symptoms and overall mediator blockade. 1, 2
• Avoid chronic use of first-generation sedating H1 antihistamines (diphenhydramine, hydroxyzine) in elderly patients due to anticholinergic-related cognitive decline. 1, 2

Mast Cell Stabilizer for Persistent Symptoms

• Add oral cromolyn sodium 200 mg four times daily for patients with persistent gastrointestinal manifestations (diarrhea, abdominal pain, cramping, bloating) or inadequate response to antihistamines. 1
• Titrate cromolyn using divided doses with weekly upward adjustments to the target dose to improve tolerance and adherence. 1
• Allow at least 4–6 weeks at target dose before assessing efficacy, as cromolyn requires at least 1 month for onset of action. 1, 3

Second-Line Therapies Based on Mediator Profiles

Leukotriene-Targeted Therapy

• Add montelukast 10 mg daily (or zafirlukast) when urinary leukotriene E₄ (LTE₄) is elevated or antihistamine response is suboptimal. 1, 2
• This reduces bronchospasm, gastrointestinal symptoms, and synergizes with H1 antihistamines for skin manifestations. 1
• Consider zileuton as an alternative 5-lipoxygenase inhibitor in similar contexts. 1

Aspirin for Prostaglandin-Mediated Symptoms

• Use aspirin 325–650 mg twice daily for patients with flushing and hypotension when urinary 11β-prostaglandin F₂α is elevated. 1, 2
• Aspirin is contraindicated in individuals with NSAID hypersensitivity and must be introduced in a controlled clinical setting because it can paradoxically provoke mast cell degranulation. 1, 3

Additional Pharmacologic Options

Alternative Antihistamines

• Cyproheptadine (sedating H1 antihistamine with antiserotonergic activity) may alleviate gastrointestinal and musculoskeletal symptoms. 1
• Doxepin (potent H1/H2 antihistamine with tricyclic antidepressant properties) can lessen central nervous system manifestations but may cause drowsiness, cognitive decline in older adults, and increased suicidal risk in younger patients with depression. 1, 2

Biologic Therapy

• Omalizumab (anti-IgE monoclonal antibody) has prevented anaphylactic episodes in reported MCAS cases, though evidence is limited to case reports. 1

Corticosteroid Strategy for Refractory Disease

• Reserve systemic corticosteroids for refractory MCAS: start ≈0.5 mg/kg/day prednisone (≈50 mg) and taper slowly over 1–3 months. 1, 2
• For procedures with prior mast cell activation, give 50 mg prednisone at 13 h, 7 h, and 1 h before the intervention to blunt peri-procedural activation. 1
• Long-term corticosteroid use is discouraged due to significant adverse-effect profile. 1

Emergency Preparedness and Acute Management

Mandatory Epinephrine Prescription

• Prescribe two epinephrine auto-injectors (0.3 mg for adults) for every MCAS patient to carry at all times due to heightened anaphylaxis risk; 20–50% of patients with systemic mastocytosis experience systemic anaphylaxis. 1, 2
• Administer intramuscular epinephrine immediately for hypotension, laryngeal angioedema, or severe bronchospasm. 1, 2

Acute Episode Protocol

• Instruct patients to assume a supine position promptly during hypotensive episodes and maintain this position during transport to the emergency department. 1, 2
• Obtain serum tryptase within 30–120 minutes of symptom onset and compare with the patient's baseline level. 1, 3
• Immediately discontinue any suspected triggering medication or exposure. 1
• Provide fluid resuscitation for hypotension and administer intravenous epinephrine for severe reactions. 1
• Give adjunctive corticosteroids and H1/H2 antihistamines. 1

Peri-operative Management

Premedication Protocol

• Premedicate with H1 and H2 antihistamines plus corticosteroids before surgery, invasive procedures, or contrast imaging to prevent anaphylaxis. 1, 2
• Ensure multidisciplinary coordination among surgical, anesthesia, and allergy teams; review prior anesthetic records and avoid known triggers. 1

Preferred and Avoided Anesthetic Agents

• Preferred agents: propofol (induction), sevoflurane/isoflurane (inhalation), fentanyl or remifentanil (analgesia), lidocaine or bupivacaine (local), rocuronium or vecuronium (muscle relaxation). 1, 2
• Agents to avoid: atracurium, mivacurium, succinylcholine, morphine, codeine. 1, 2
• Maintain normothermia and minimize unnecessary trauma in the operating room. 1

Pain Management Considerations

• Do not withhold analgesics; untreated pain itself can trigger mast cell degranulation. 1, 2
• Use fentanyl or remifentanil as safer opioid alternatives to morphine or codeine when opioid analgesia is required. 1, 2

Assessment of Treatment Response

• Therapeutic response should be evaluated over a 2–6-week period before considering escalation of therapy; lack of improvement indicates the need for additional interventions. 3
• Demonstration of clinical improvement with the prescribed mast cell-targeted regimen serves as a diagnostic criterion and confirms that the patient meets MCAS criteria. 3

Trigger Identification and Avoidance

• Identify and avoid common triggers—including insect venoms, extreme temperatures, mechanical irritation, alcohol, aspirin, radiocontrast agents, and certain anesthetic agents—to reduce mast cell activation risk. 1, 2
• For patients with systemic mastocytosis who have a history of systemic anaphylaxis to insect stings, provide lifelong venom immunotherapy; using omalizumab during immunotherapy may lower the risk of anaphylaxis. 1

Critical Pitfalls to Avoid

• Do not eliminate additives in drugs used for anaphylaxis by compounding them; this practice is unsupported by controlled challenge data. 1
• Do not rely on plasma or urine histamine levels as biomarkers; instead, use histamine metabolites (N-methylhistamine) for monitoring mast cell activation. 1, 3
• Do not use heparin or chromogranin A as markers of mast cell activation, as they have not been validated. 1
• Do not diagnose MCAS based solely on nonspecific symptoms, single organ system involvement, or symptoms without documented mediator elevation; MCAS is substantially overdiagnosed. 3

Special Populations

Pregnancy

• Manage MCAS in pregnancy with a multidisciplinary team (high-risk obstetrics, anesthesia, allergy). 1
• Current data indicate no impact on fertility and insufficient evidence of increased maternal or fetal adverse outcomes compared with the general population. 1

Bone Health

• Provide calcium and vitamin D supplementation for patients with osteopenia/osteoporosis. 1
• Use bisphosphonates (alongside antihistamines) to alleviate bone pain and improve vertebral bone mineral density. 1
• For refractory bone pain or worsening BMD on bisphosphonates, consider PEG-interferon-α. 1
• Denosumab (anti-RANKL antibody) is a second-line option for bisphosphonate non-responders or those with renal insufficiency. 1