Annals of B-Pod: Hereditary Angioedema
/History of Present Illness
The patient is a male in his early twenties with a past medical history notable for hereditary angioedema and opioid abuse who presents to the emergency department (ED) complaining of tongue swelling. He was found by EMS providers on the morning of presentation after reportedly using heroin. He received naloxone, became alert and oriented, and was taken to an outside hospital for evaluation. After a reassuring examination and a normal head CT were performed, he was discharged to a correctional facility in police custody. Soon after discharge, the patient began complaining of tongue swelling and dysphagia. The swelling then progressed to include his left eye, so he was taken to the ED for further evaluation. On arrival, the patient reports significant swelling of his tongue and left eye as well as vision changes in that eye. He denies shortness of breath, voice changes, nausea, vomiting, abdominal pain, and rash.
Past Medical History: Hereditary angioedema, heroin use disorder
Past Surgical History: None
Medications: None
Allergies: None
Vitals: T 37° HR 57 BP 122/82 RR 14 SaO2 100% on room air
Physical Exam: The patient is a young adult male who appears his stated age and is in no apparent respiratory distress. There is a small abrasion to the left forehead. The tongue is moderately edematous, both anteriorly and posteriorly, occluding the majority of the posterior oropharynx from view. The left upper and lower eyelids both exhibit significant edema extending beyond the orbit, which is tender to palpation, but not warm to touch. There is no erythema. Cardiovascular, pulmonary, abdominal, and neurologic exams are within normal limits.
Diagnostics
Na:137 K: 4.0 Cl: 104 CO2: 27 BUN: 8 Cr: 0.79 Glucose: 81
WBC: 6.2 Hgb: 14.1 Hct: 41.6 Plt: 177 CK: 464
Hospital Course
Upon presentation to the ED, the primary concern was for an acute exacerbation of the patient’s known hereditary angioedema. Initially he was protecting his airway and handling his secretions appropriately. He was given oral diphenhydramine, famotidine, and intravenous dexamethasone. An infusion of a C1 esterase inhibitor was administered. After a short period of observation, he began complaining of dyspnea at rest and difficulty swallowing. For this reason, he was electively intubated due to concerns for impending airway occlusion. The patient was fiberoptically intubated and no glottic or laryngeal edema was noted during the intubation. He was subsequently admitted to the medical intensive care unit (MICU) for further monitoring and management of his angioedema.
The patient had a prolonged MICU stay after developing ventilator associated pneumonia, and he was ultimately extubated. At his outpatient appointment with allergy and immunology he was provided with a prescription for icatibant to self-administer in the event of future acute attacks.
DIscussion
Angioedema is a physical exam sign defined as non-pitting edema that is transient and confined to a specific anatomic region.[1] Hereditary angioedema (HAE) is a diverse group of rare inherited disorders resulting from a mutation in the C1-inhibitor gene. This disease classically presents with intermittent eruptions of deep dermal swelling.
The pathophysiology underlying HAE is complex.[2] The problem stems from a mutation in the sequence of C1 esterase inhibitor. This leads to a dysfunctional endogenous enzyme, which in turn results in a surge of bradykinin. Bradykinin increases endothelial cell activation, resulting in an efflux of fluid into the interstitium.[3] Factor XII is also involved in this process by activating kallikrein and prompting release of bradykinin from the HK-B complex.
It is unclear why HAE attacks occur, but they often occur following “triggers” specific to the affected individual. The most common trigger of an HAE attack is mental stress, followed by menstruation, physical exertion, infection, and occasionally narcotic abuse. Patients will usually be cognizant of their specific triggers and try to avoid them if possible. Patients with HAE usually have a care plan in place when they are exposed to a trigger and will usually present to the nearest ED for treatment. Emergency physicians should therefore be familiar and comfortable managing these patients when they present following an acute HAE attack.
In the patient described above, the primary concern was for airway compromise due to laryngeal edema. However, gastrointestinal and cutaneous symptoms are much more common than laryngeal involvement in HAE.[2] Gastrointestinal attacks generally produce crampy, severe abdominal pain accompanied by nausea, vomiting, and diarrhea. Management focuses on analgesia and investigation of other emergent causes of the abdominal pain. Unfortunately, many unnecessary procedures are performed on undiagnosed HAE patients with abdominal pain due to the severity of their symptoms.3 These attacks may be accompanied by hypotension due to fluid efflux into the bowel wall that can mimic intra-abdominal sepsis. Cutaneous attacks may lead to edema in many parts of the body including the face, distal extremities, or genitalia. Management in these cases focuses on early administration of the therapeutic agents discussed below.
On initial presentation, HAE may be easily confused with anaphylaxis, particularly if there is no personal or family history. Anaphylaxis is due to the massive release of pre-made granules from mast cells and basophils. The biologically active components of these granules are histamine and tryptase. These compounds cause urticaria, bronchoconstriction, nausea, vomiting, and circulatory collapse.[4] Morbidity and mortality is reduced with early administration of intramuscular epinephrine. Adjunctive treatment with antihistamines and glucocorticoids reduces symptom burden and prevent theoretical late-phase effects of anaphylaxis. The symptoms of HAE are caused by binding of the bradykinin receptor, which is unaffected by antihistamines or epinephrine. There is no published data examining the effect of epinephrine in acute attacks of HAE, although anecdotally some authors report transient benefit.[1,6] Despite the lack of evidence for epinephrine in HAE, clinicians should strongly consider early epinephrine for patients in distress presenting with angioedema. Both conditions present with significant overlap and anaphylaxis is much more common than HAE. Epinephrine and antihistamines are readily available in the ED. Therefore, it is generally recommended to administer epinephrine and antihistamines to patients with undifferentiated angioedema in the ED.
Diagnostics
The primary focus in most cases of HAE will be on airway management. However, obtaining C4 and tryptase levels during an acute event can be very helpful for the admitting team or for outpatient follow up with an allergist.[7] C4 levels help inpatient teams confirm the diagnosis of HAE when the clinical picture is not entirely clear. Tryptase is useful to differentiate anaphylaxis from HAE.
Management
Airway protection is a common concern in HAE patients. It is difficult to separate which patients may experience simple facial swelling from those who may go on to develop laryngeal edema and airway compromise. In a retrospective review of 123 patients with HAE, laryngeal edema was preceded by facial swelling in only a small minority of patients.[8] Only six patients in this cohort required definitive airway management, with four patients requiring cricothyrotomy. In a second retrospective review examining 58 patients with known HAE, 23 deaths were attributed to asphyxiation secondary to airway edema.[9] Long term follow up of known HAE families in Hungary suggested that edema of the face and lips preceded 15-30% of clinical events of upper airway compromise.[10]
There are currently no published guidelines for definitive airway management of the patient with HAE and this decision is primarily based on the provider’s clinical judgment. While physical exam is unreliable at determining who is at high risk of developing airway obstruction, adjunctive techniques can provide greater clarity. Nasopharyngoscopy is an essential tool for evaluating patients presenting with HAE. A consensus statement published by both emergency and allergy physicians recommends visualization of the supraglottic structures in patients with voice changes, hoarseness, angioedema of intraoral structures, or stridor on examination.[1] Intubation is recommended if the swelling extends to any airway structures or the base of the tongue. It is important to remember that intubation will not address the patient’s underlying pathophysiology. Adjunctive pharmacotherapy is still required in order to counteract ongoing edema.
C1 Esterase Inhibitor
Molecular therapies for HAE were first described in 1980, when C1 esterase inhibitor (C1INH) was used to treat acute attacks.[11] C1INH is administered as an infusion of 20 units per kilogram over 10 minutes. C1INH has been found to be superior to placebo for treating acute attacks in a number of studies. The largest of these was a randomized, double-blinded, placebo-controlled study of 125 patients. The primary outcome was time from administration to onset of symptom relief. Symptom relief occurred within 30 minutes in the treatment group versus 1.5 hours in the placebo group.[12] In a 2001 case series of 95 patients with known HAE, 193 episodes of laryngeal edema were treated with C1INH. Clinical response was documented within 30-60 minutes of receiving the treatment in 192 of these cases.[13]
When C1INH was originally approved in the US, the inhibitor was pooled from donated plasma, coalesced, and administered as a collective dose. Recombinant C1INH became available in the US in 2014 and has demonstrated similar efficacy when compared to plasma-derived C1INH. The recombinant form minimizes potential transmission of blood borne infectious vectors.[14] One minor drawback is that the half-life of recombinant C1INH is only 3 hours compared to over 20 hours in plasma-derived C1INH. Despite this, there have been no associated relapses of symptoms with recombinant treatment compared to plasma-derived C1INH. No head-to-head trials exist to suggest that one option outperforms the other, although the recombinant drug avoids the issues associated with administration of plasma-based products.
Bradykinin Receptor Antagonist
The bradykinin receptor can also be targeted by pharmacotherapy in acute HAE attacks. Icatibant is a synthetic peptide that blocks bradykinin from binding to its receptor. This medication is administered as a subcutaneous injection of 30 milligrams. Several multi-center, randomized, placebo-controlled trials have examined icatibant. These studies were published in succession known as the FAST (For Angioedema Subcutaneous Treatment) series. FAST-1 compared icatibant to placebo and showed no difference between the two groups. FAST-2 compared icatibant and tranexamicacid, and showed that icatibant significantly reduced time to initial onset of symptom relief.[15] FAST-3 attempted to settle the score by randomizing patients with moderate to severe cutaneous or abdominal symptoms to icatibant or placebo. Patients who received icatibant had quicker onset of symptom relief and reached 50% symptom reduction sooner than the placebo group.[16] Adverse effects were minimal and included injection site pain, nausea, dizziness, and headache. It is important to note that patients with known ischemic heart disease were excluded from these trials because icatibant has been observed to reduce coronary blood flow in animal models. Based on the most recent evidence, icatibant should be administered if available to help reduce symptoms, in addition to C1INH.
Kallikrein Inhibitor
Ecallantide is a recombinant protein approved by the FDA in 2009 for treatment of acute HAE exacerbations. This molecule interferes with production of bradykinin via inhibition of kallikrein. Decreased bradykinin decreases edema by preventing migration of fluid into surrounding tissue. Ecallantide is administered intramuscularly in a single dose of 30 milligrams. In the 2010 EDEMA3 trial, patients receiving ecallantide reported significant improvement of their symptoms at a higher rate than patients in the placebo arm after 4 hours.[17] Ecallantide can be re-dosed within one hour of the initial injection in the case of suboptimal symptom reduction.
Plasma
The therapies discussed above are expensive and may not be immediately available in all emergency departments. Plasma has long been utilized to manage acute presentations of HAE. Assuming the donors are not affected by HAE, plasma will contain normal C1INH and improve symptoms. Fresh frozen plasma (FFP) is most commonly available in the ED. No controlled trials have demonstrated FFP’s efficacy despite the fact that FFP had been the only treatment for acute HAE for years in the United States. A review of 12 case reports found that patients who received plasma all experienced some relief, although the response was highly variable.[18] Providers can initially transfuse one to three units of FFP and repeat this every four hours if improvement is not observed. With the advent of targeted therapies, the risks of blood product transfusion such as transfusion related acute lung injury (TRALI), transfusion associated cardiac overload (TACO), and infection, coupled with the lack of quality data demonstrating efficacy make FFP a second line agent in management of acute attacks.[1]
While there are several agents available to treat acute HAE, no single treatment has been proven to be clearly superior. One review article attempted to quantify differences between treatment options specifically in laryngeal attacks.[19] Of the 12 eligible studies included in the review, plasma-derived C1INH conferred the shortest time to onset of symptom relief, followed by icatibant, ecallantide, and recombinant C1INH. The authors did note that the heterogeneity of the studies included limited their conclusions and no recommendation could be given based on this data. The latest guidelines from the World Allergy Organization strongly recommend administration of plasma-derived C1INH, ecallantide, or icatibant for any acute HAE attack.[20] If these therapies are not readily available, then plasma can be considered.
These medications are unlikely to be readily available in most EDs in the United States. Most of these medications require reconstitution and often need to be transported from a central pharmacy. As such, coordination with a dedicated emergency pharmacist or with the central pharmacy early in the patient’s course is essential.
Disposition
Many emergency physicians may feel uncomfortable determining a safe disposition for non-intubated HAE patients, and with good reason. Patients who do not initially require intubation still need high level monitoring in an airway capable unit.[1] One otolaryngology study sought to create a risk stratification tool based on airway assessment that can help determine appropriate disposition for patients with angioedema.[21] These recommendations are based on a retrospective review of HAE patients over a ten-year period. Patients are classified in different stages depending on their physical exam findings. Stage I patients have a facial rash, lip swelling, or other facial edema. Soft palate edema placed patients in stage II while lingual swelling constitutes stage III. Finally, stage IV patients demonstrated laryngeal edema. Based on their findings, patients in stage I or II can likely be managed in an outpatient or floor setting. Stage III and IV patients should strongly be considered for ICU admission as airway intervention was required in 7% of stage III and 24% of stage IV patients.[21]
Early consultation with an allergist or immunologist can help facilitate administration of the appropriate treatments, establish a follow-up plan, and allow physicians to feel comfortable discharging otherwise well patients. In summary, HAE is a rare hereditary disease that can present with a wide variety of patient complaints. While uncommon, HAE can be life-threatening, and emergency providers should recognize when airway intervention may be required and be familiar with the available treatment options.
AUTHORED by Christopher shaw, m.d.
POSTED By Matthew Scanlon, m.D.
References
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