A woman with Addison's disease walks into an emergency room with nausea, low blood pressure, and confusion. She hands the triage nurse a card explaining her condition and the need for immediate intravenous steroids. The nurse files the card. The physician orders standard IV fluids and a metabolic panel. Two hours pass. Her blood pressure keeps dropping. Someone finally reads the card. By then, the window for preventing cardiovascular collapse has narrowed considerably.
This scenario plays out in emergency departments across the country, across dozens of rare diseases, every day. The details change. The pattern doesn't. A patient arrives knowing exactly what they need. The ER team, trained to recognize the 50 most common presentations, doesn't know what to do with the 51st. The standard protocol gets applied to a nonstandard body. Things go wrong.
An AHRQ systematic review of emergency department diagnostic errors found that 1 in 18 ED patients receives an incorrect diagnosis. That translates to 7.4 million misdiagnosed patients per year in the U.S., with an estimated 350,000 suffering permanent disability or death from those errors (AHRQ, 2022). The error rates for individual conditions ranged from 1.5% for heart attacks to 56% for spinal abscesses. Rare diseases weren't included in the analysis. They didn't need to be. If a condition that every medical student learns about gets missed 17% of the time (stroke), imagine the odds for a disease the ER doctor last encountered in a textbook 15 years ago.
“7.4 million patients misdiagnosed in U.S. emergency departments every year. 350,000 left with permanent disability or death.”
AHRQ Systematic Review, 2022
A multinational clinician survey published in the Orphanet Journal of Rare Diseases found that 98.2% of physicians felt their knowledge about rare diseases was insufficient. Only 19% were mostly or very confident in making a rare disease diagnosis. These aren't bad doctors. Emergency medicine residency covers roughly 15,000 disease presentations in 3 to 4 years. Rare diseases number over 7,000. The math doesn't work.
Sickle cell disease and the 178-minute wait
Sickle cell disease affects approximately 100,000 people in the United States, predominantly Black Americans. A vaso-occlusive crisis, the hallmark emergency, occurs when sickled red blood cells block small blood vessels, causing pain so severe that patients describe it as worse than surgical recovery. The NHLBI guidelines are clear. Sickle cell pain crises should be triaged as ESI level 2 (emergent), and the first dose of analgesic should be administered within 30 minutes of arrival.
That's not what happens. A 2025 study in Blood Advances examined triage patterns for sickle cell patients presenting with vaso-occlusive crises and found that most were not triaged appropriately according to national guidelines (Abu Haimed et al., 2025). Patients correctly assigned ESI 2 waited a median of 65 minutes for their first pain medication. Patients downgraded to ESI 3 waited 178 minutes. That's nearly 3 hours of documented crisis-level pain before receiving any treatment at all.
4 patients assigned ESI 3 left the emergency department without ever receiving pain medication, after waiting a median of 349 minutes. Nearly 6 hours. No patient in the study fell within the recommended 30-minute treatment window outlined by NHLBI.
“A patient with [sickle cell disease](/trials/sickle-cell-disease) assigned an ESI 2 compared to ESI 3 is about six times more likely to receive pain medication quicker.”
Abu Haimed et al., Blood Advances, 2025
The racial dimension is unavoidable. A 2024 study in the Journal of Racial and Ethnic Health Disparities found that pediatric providers harbor implicit racial bias at rates comparable to the general population. Research published in the North Carolina Medical Journal in 2024 documented instances of ER physicians denying pain medication during vaso-occlusive crises. 75% of ED providers were unaware of NHLBI sickle cell guidelines.
A predominantly Black patient population. Subjective pain as the primary complaint. Providers who don't know the guidelines and carry measurable bias. The 178-minute wait is the predictable result.
Addison's disease and the $2 injection that saves lives
Addison's disease (primary adrenal insufficiency) affects roughly 1 in 10,000 people. The adrenal glands don't produce enough cortisol, the hormone that regulates blood pressure, blood sugar, and the body's stress response. Daily replacement steroids keep patients stable. Physical stress, an infection, a car accident, surgery, even severe dehydration, can tip them into adrenal crisis, where the body cannot mount a cortisol response and blood pressure free-falls toward circulatory collapse.
The treatment is simple and well-established. 100 mg of intravenous hydrocortisone, given immediately, followed by additional doses every 6 to 8 hours. The StatPearls clinical reference on adrenal crisis is explicit: when adrenal crisis is suspected, lab results should not delay treatment. Mortality rates for adrenal crisis range from 0.5% to 6% depending on the population studied, with delays in steroid administration being the primary contributor to deaths that should have been preventable (Dineen et al., 2019).
Patients know this. Many carry emergency injection kits and medical ID cards or bracelets. Multiple surveys of adrenal insufficiency patients have documented that a substantial proportion report suboptimal treatment during emergency department visits, even when presenting with established diagnoses and carrying emergency documentation. Hydrocortisone is cheap, available in every ER, and takes seconds to administer. The problem is recognition. An ER doctor who sees low blood pressure and confusion runs through the standard differential (sepsis, cardiac event, stroke, diabetic emergency) and adrenal crisis may not appear on that list until the patient is already crashing.
[Mastocytosis](/trials/mastocytosis), or when the ER's own drugs cause the emergency
Mastocytosis involves an abnormal accumulation of mast cells in the skin, bone marrow, liver, spleen, or gastrointestinal tract. Mast cells release histamine and other inflammatory mediators. In systemic mastocytosis, triggers that would cause a mild reaction in a healthy person, a bee sting, a temperature change, physical pressure, certain foods, can provoke severe anaphylaxis. The Mast Cell Disease Society estimates that systemic mastocytosis affects fewer than 200,000 people in the U.S., though the related condition mast cell activation syndrome (MCAS) may be significantly more common and is increasingly diagnosed.
The danger in the ER comes from the ER's own medicine cabinet. Morphine and codeine are potent mast cell degranulators, meaning they trigger mast cells to dump their contents directly, bypassing the normal immune pathway. For a mastocytosis patient arriving in pain, the standard ER response of administering an opioid can itself trigger anaphylaxis.
NSAIDs are more complicated. A study in Allergy found that 87% of adults with mastocytosis tolerated them, but the remaining 13% experienced reactions severe enough that most specialists recommend NSAIDs only in patients with a documented history of tolerating them.
The Mast Cell Disease Society publishes an ER protocol document specifically designed for emergency physicians who have never encountered the condition. It lists safe and unsafe medications, anaphylaxis management steps (epinephrine dosing, IV fluid protocols), and pre-medication strategies for any procedure. The document exists because the standard ER formulary contains multiple drugs that are dangerous for these patients, and the ER physician has no reason to know that unless the patient tells them.
[Ehlers-Danlos syndrome](/trials/ehlers-danlos-syndrome), where 58% say the numbing doesn't work
Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders affecting collagen structure throughout the body. The hypermobile type (hEDS) is the most common, and it brings patients to the ER frequently for joint dislocations, chronic pain flares, gastroparesis episodes, and injuries from falls caused by joint instability. Vascular EDS, the rarest and most dangerous type, carries a risk of spontaneous arterial dissection and organ rupture.
The anesthesia problem is well-documented but poorly known in emergency medicine. When hypermobile EDS patients were asked about local anesthetic effectiveness, 58% reported that local anesthetics were ineffective compared to 21% of control subjects. Dental anesthetic failure is a widely recognized problem in this population. A clinical trial at Stanford (NCT05603741) is actively studying local anesthetic response in EDS to better characterize the mechanism. The leading theory is that altered connective tissue changes how local anesthetics diffuse to nerve fibers, reducing their concentration at the target site.
In the ER, this means a patient who needs a laceration sutured, a dislocated joint reduced, or an abscess drained may report that the local anesthetic isn't working, and the provider may not believe them. An Orphanet Journal of Rare Diseases review noted that no established anesthesia guidelines exist for EDS patients, and that increased rates of cervical spine instability in the hypermobile population create additional risks during intubation and procedural sedation that most ER physicians aren't trained to anticipate.
Vascular EDS patients face a different set of risks entirely. Arterial walls are fragile. Standard procedures like central line placement, arterial blood gas draws, and even aggressive blood pressure cuff inflation can cause vessel tears. A 2014 review in the Orphanet Journal recommended that vascular EDS patients avoid invasive vascular procedures whenever possible and that emergency teams be explicitly informed of the diagnosis before any procedure.
The antibiotics that can paralyze a [myasthenia gravis](/trials/myasthenia-gravis) patient
Myasthenia gravis (MG) is an autoimmune disease where antibodies attack the acetylcholine receptors at the neuromuscular junction, the connection point between nerves and muscles. The result is fluctuating muscle weakness that worsens with activity and improves with rest. Current U.S. prevalence data from 2021 puts the rate at roughly 37 per 100,000 people. Myasthenic crisis, where respiratory muscles weaken to the point of requiring mechanical ventilation, occurs in 15 to 20% of MG patients at some point in their disease course.
Several categories of medications commonly used in emergency departments can worsen myasthenia gravis or precipitate crisis. Aminoglycoside antibiotics (gentamicin, tobramycin, neomycin) impair neuromuscular transmission and have triggered respiratory failure in MG patients across numerous case reports, almost always when given alongside other neuromuscular-affecting drugs. Fluoroquinolone antibiotics (ciprofloxacin, levofloxacin, moxifloxacin) carry FDA black box warnings for neuromuscular effects. Beta-blockers, IV magnesium, and macrolide antibiotics (azithromycin, erythromycin) are all on the Myasthenia Gravis Foundation of America's cautionary drug list.
The muscle relaxant situation is counterintuitive. Succinylcholine, a depolarizing agent used for rapid-sequence intubation, isn't contraindicated in MG, but it behaves unpredictably. Because MG patients have fewer functioning acetylcholine receptors, they're resistant to succinylcholine (the dose may need to be 2 to 2.6 times higher than normal) while being extremely sensitive to nondepolarizing agents like rocuronium and vecuronium. An ER physician who doesn't know the patient has MG and uses standard dosing of a nondepolarizing agent can cause prolonged paralysis that outlasts the ventilatory support plan.
Why rare disease patients keep getting hurt in the ER
Sickle cell patients wait 3 hours for pain medication because triage protocols don't match guidelines. Addison's patients go into crisis because a $2 steroid injection gets delayed by a lab panel. Mastocytosis patients receive the exact drug that triggers their anaphylaxis. EDS patients are told the anesthetic is working when it isn't. MG patients get an antibiotic that shuts down their ability to breathe. Different diseases, same failure mode.
Emergency medicine is built on protocols, algorithms, and pattern recognition. That system works remarkably well for common conditions. For the estimated 25 to 30 million Americans living with a rare disease, the system has a structural gap. There are over 7,000 known rare diseases. No ER physician can memorize the contraindications, crisis protocols, and drug interactions for all of them. The question is whether the system can be designed to catch what the physician's memory can't hold.
Some hospitals are trying. The Undiagnosed Diseases Program at the NIH maintains detailed emergency protocols for patients in their program. The Mast Cell Disease Society, the Myasthenia Gravis Foundation, the Adrenal Insufficiency United, and the Ehlers-Danlos Society all publish emergency department guides. NORD launched the Living Rare Study in October 2024, a multi-year research initiative designed to document the real-world experiences of rare disease patients across all aspects of care, including emergency encounters. The data from that study, once published, may be the first large-scale U.S. evidence base for how rare disease patients actually fare in emergency settings.
How to prepare for an ER visit with a rare disease
The research is consistent on one point. Rare disease patients who arrive at the ER with written documentation of their condition, including crisis protocols, contraindicated medications, and emergency contact information for their specialist, have better outcomes than those who rely on verbal communication alone. The ER is loud, fast, and understaffed. A laminated card or a letter from your specialist cuts through the noise in a way that a verbal explanation during triage cannot.
Carry a one-page emergency protocol signed by your specialist. Include your diagnosis, your daily medications, the specific crisis you're most likely to present with, the treatment that crisis requires, and the drugs that are contraindicated. List your specialist's name and after-hours number. Hand it to the treating physician, not the triage nurse and not the medical assistant. Ask them to read it before ordering anything. This is not being difficult. It's being safe.
Wear a medical ID bracelet or necklace that names your condition. MedicAlert and similar services allow ER staff to call a hotline and retrieve your full medical profile, including medication lists and emergency instructions. For conditions where specific drugs are dangerous (mastocytosis, MG), this can be the difference between a safe ER visit and an iatrogenic crisis (a medical problem caused by the treatment itself).
If you're able, ask a family member or friend who understands your condition to come with you. Patients in crisis are not always able to advocate for themselves. A person who can say "she has Addison's disease and needs IV hydrocortisone now, here's the letter from her endocrinologist" changes the trajectory of the visit. The Ehlers-Danlos Society, MGFA, and NADF all provide printable ER guides. Trial Friend tracks clinical trials for many of the diseases discussed here, and each disease page includes a medication conflict checker that can help you identify drugs to flag with your ER team.