Idiopathic Systemic Capillary Leak Syndrome Research Articles

Genesis of Antibiotic Resistance LIII: “Virchow’s Triad” of Capillary (Vascular) Leak Syndrome (CLS) tethered Adverse Pressure Gradient exacerbated mortality rate in NCT01663701: A critical appraisal

Based on adverse effects of biosimilar(s), for oncological treatment modalities (radiation/chemotherapy), posted in FAERS and VigiBase, an effort has been made to derive a temporal correlation between CLS and hemodynamic (Fluid dynamic/mechanics properties) dysregulation lead exacerbated mortality rate in NCT01663701. Idiopathic (unknown etiology) systemic capillary leak syndrome (SCLS) or Capillary leak syndrome (CLS), also known as vascular leak syndrome (VLS), with clinical features such as leakage of the plasma (reversible plasma extravasation with fluid resuscitation), vascular collapse accompanied by a classic triad of hypoalbuminemia, hemoconcentration, and hypotension in the absence of secondary causes of shock with edema. Fluid management is an effective clinical management strategy for an improved prognosis (verbatim in part and modified from J Clin Med. 2018; seven (11); J Clin Med. 2019; 8(2)). The clinical presentation of CLS with a corollary of Virchow’s triad ( https://www.ncbi.nlm.nih.gov/books/NBK539697/) and the critical events for a laminar to turbulence transition ( ELTT) is systematically correlated. Virchow’s triad I ‐ Endothelial damage:ELTT 1. Region of instability of small wavy disturbances called Tollmien‐Schlichting wave ELTT 2. Periodicity accompanied by the appearance of vortices ELTT 3. Peak‐Valley development in vortices, ELTT 4. Vorticity concentration and shear layer development with inflectional profile appearance and disappearance in Tollmien‐Schlichting wave pattern, Virchow’s triad II ‐ Venous stasis: ELTT 5. Breakdown: evolution of a staggered vortex pattern twice the wavelength of Tollmien‐Schlichting waves ( a high frequency fluctuations of hairpin eddies ‐ eddy currents, disrupts the laminar flow of blood, bringing platelets in close contact with the vascular wallVirchow’s triad III ‐ Hypercoagulability: ELTT 6. Cascading of vortices and turbulent‐spot development, (spots of thrombus lead to increased turbulence thus reduction in blood flow. Infarction and ischemia Thrombi often result in reduced blood flow to tissue (ischemia) or complete obstruction (absolute irreversible stasis NFP=0 mmHG, ?) of blood flow leading to cell death(infarction) with concurrent impairment of global net filtration pressure (NFP) in mark transition of laminar to turbulent flow pattern. Taken together, herewith it is suggested that a better understanding of the components of multifactorial mode of turbulence modelling in particular on time scale, blood viscosity, velocity profile, NFP gradient, and structural integrity of blood vessels (endothelial damage) of the capillary bed in the context of thromboembolic events [DDx: ischemic stroke(CVA), disseminated intravascular coagulation (DIC), deep vein thrombosis (DVT), pulmonary embolism and CLS], would enable better stratification of clinical risk factors, precision in clinical decision making amalgamating differential diagnosis for an accurate prognosis in early resuscitation protocol on sepsis such as NCT01663701.Support or Funding InformationSupported by professional development funds by SWTJC to Subburaj Kannan

The effects of severe hemoconcentration on acid-base equilibrium in critically ill patients: the forgotten role of buffers in whole blood.

Idiopathic Systemic Capillary Leak Syndrome (ISCLS) is a paroxysmal permeability disorder characterized by abrupt onset of shock and hemoconcentration due to massive shift of fluids and proteins from the intravascular to the interstitial compartment. We hypothesize that increased hemoglobin concentration has a pivotal role in the acid-base imbalance during life-threatening crises. Analysis of the acid-base balance fluctuations during six severe ISCLS flares admitted to ICU of a referral center for ISCLS. Acid-base equilibrium was assessed for plasma and the whole blood by single and multicompartmental models. The acute phase of ISCLS was characterized by shock, hypoalbuminemia, severe hemoconcentration, and acidosis. The physical-chemical approach for plasma found a remarkable component of unmeasured anions (SIG) during the acute phase. After correction of the physical-chemical model for the whole blood, the SIG variations disappeared because the buffer role of hemoglobin was relevant. Hemoglobin has a remarkable role in buffering metabolic acidosis during the shock phase of ISCLS. In these circumstances, the assessment of acid-base equilibrium in plasma alone may overestimate unmeasured anions. On the contrary, the physical-chemical model corrected for whole blood better explains the metabolic component of acid-base imbalance when marked shift of hemoglobin concentration occurs.

Myocardial edema in paroxysmal permeability disorders: The paradigm of Clarkson's disease

PurposeParoxysmal Permeability Disorders (PPDs) comprise a variety of diseases characterized by recurrent and transitory increase of endothelial permeability. Idiopathic Systemic Capillary Leak Syndrome (ISCLS) is a rare PPD that leads to an abrupt massive shift of fluids and proteins from the intravascular to the interstitial compartment. In some cases, tissue edema may involve the myocardium, but its role in the development of shock has not been elucidated so far. Materials and methodsAssessment of cardiac involvement during ten life-threatening ISCLS episodes admitted to ICU. ResultsTransthoracic echocardiographic examination was performed in eight episodes, whereas a poor acoustic window prevented cardiac ultrasound assessment in two episodes. Myocardial edema was detected by echocardiography in eight episodes and marked pericardial effusion in one-episode. Cardiac magnetic resonance showed diffuse myocardial edema in another episode. In one case, myocardial edema caused fulminant left ventricular dysfunction, which required extracorporeal life support. The mean septum thickness was higher during the shock phase compared to the recovery phase [15.5 mm (13.1–21 mm) vs. 9.9 mm (9–11.3 mm), p = .0003]. Myocardial edema resolved within 72 h. ConclusionsDuring early phases of ISCLS, myocardial edema commonly occurs and can induce transient myocardial dysfunction, potentially contributing to the pathogenesis of shock.

Immunoglobulin Treatment in Severe Ovarian Hyperstimulation Syndrome.

A 32-year-old woman undergoing an in vitro fertilization program was admitted to our hospital with the diagnosis of severe ovarian hyperstimulation syndrome (OHSS). Transvaginal ultrasonography showed two gestational sacs. Treatment with fluid restriction, serum albumin and intravenous furosemide was started, and repeated thoracentesis and paracenteses were performed. In the absence of clinical improvement, the patient was transferred to the intensive care unit and a therapeutic abortion was suggested. Due to the similarities between OHSS and idiopathic systemic capillary leak syndrome, we offered the patient compassionate treatment with intravenous immunoglobulins. After administration, the patient showed rapid improvement and we were able to suspend intravenous furosemide and serum albumin. She was discharged, and pregnancy has continued normally to date.LEARNING POINTSOHSS is an infrequent yet serious complication of assisted reproductive treatment that involves increased capillary permeability.In severe refractory cases, immunoglobulins may be a useful and safe treatment to reverse this syndrome.

ABNORMAL PRESENTATION OF INFLUENZA A-RELATED SYSTEMIC CAPILLARY LEAK SYNDROME

SESSION TITLE: Case Report Semifinalists 9 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: Systemic Capillary Leak Syndrome (SCLS) is a rare and life threatening disorder that can present as fluid-resistant shock in the presence of hemoconcentration, hypotension, and hypoalbuminemia. To date, no cause of SCLS has been confirmed, and mainstays of therapy have been supportive care and IVIG based on limited case reports. CASE PRESENTATION: A 41 year-old man presented with lower extremity swelling and malaise and profound hypotension after a three day viral prodrome. This patient was hospitalized within the past year for similar symptoms of shock with hemoconcentration and hypoalbuminemia without clear etiology. Upon arrival, patient had hypotension resistant to aggressive fluid resuscitation, followed by rapidly progressing renal and cardiac failure and eventually requiring endotracheal intubation due to laryngeal edema. Patient received intravenous immunoglobulin (IVIG) shortly thereafter for possible SCLS. During resuscitation, patient had increasingly tight muscular compartments concerning for compartment syndrome; patient was evaluated by orthopedics and was taken to operating theatre where he received bilateral upper and lower extremity fasciotomies of legs, thighs, forearms. It is known that SCLS presents with a “leak phase” during which extravasation and shock is common, followed by a “post-leak phase” during which extravasated fluid rapidly moves intravascularly. To avoid further compartment syndrome and post-leak volume overload, a goal of normotension with a central venous pressure of 4-8 mmHg was successfully used to guide resuscitation. Due to association of SCLS with oncologic processes, urgent hematology and oncology consult was obtained. Patient underwent evaluation for leukemia and lymphoma without any evidence of malignancy. During this time, patient tested positive for influenza A via PCR. Patient was noted upon workup to have elevated levels of IL-6. The patient was discharged on hospital day 15 to sub-acute rehab with instructions to receive tocilizumab, a biologic targeted at IL-6, if they experienced similar edema and malaise. DISCUSSION: There are scant case reports suggesting influenza A as the inciting factor for SCLS exacerbation. However, this is the first reported case of influenza-associated SCLS with an elevated interleukin-6 level, suggesting a clinical hypothesis that IL-6 may play a role in SCLS. Furthermore, very few of influenza-related SCLS have presented with such acuity, making this a very unusual case. CONCLUSIONS: Difficult to diagnose and manage, SCLS remains poorly understood. Little is known about best management, although IVIG and guided resuscitation may have a role. In this patient, early diagnosis and intervention led to a favorable outcome. Furthermore, an elevated in IL-6 in this patient invokes speculation towards a possible therapy. Reference #1: Ebdrup L, Druey K, Mogensen TH Severe capillary leak syndrome with cardiac arrest triggered by influenza virus infection Case Reports 2018;2018:bcr-2018-226108. Reference #2: Kapoor P, Greipp PT, Schaefer EW, Mandrekar SJ, Kamal AH, Gonzalez-Paz NC, Kumar S, Greipp PR. Idiopathic systemic capillary leak syndrome (Clarkson's disease): the Mayo clinic experience. Mayo Clin Proc. 2010 Oct;85(10):905-12. https://doi.org/10.4065/mcp.2010.0159. Epub 2010 Jul 15. PubMed PMID: 20634497; PubMed Central PMCID: PMC2947962. DISCLOSURES: No relevant relationships by Alexander Croft, source=Web Response No relevant relationships by Rajat Kapoor, source=Web Response

Non-occlusive Mesenteric Ischaemia and Acute Kidney Injury: A Case Report of Severe Idiopathic Systemic Capillary Leak Syndrome.

Systemic capillary leak syndrome is a rare, underdiagnosed and life-threatening disease characterized by periodic episodes of hypovolaemic shock due to leakage of plasma from the intravascular to the extravascular space. It is associated with haemoconcentration, hypoalbuminaemia and generalized oedema.We report the case of a patient with a history of emergent extensive small and large bowel resection and several episodes of hypovolaemic shock with acute renal injury, who presented with abdominal pain, headache and generalized oedema. Severe systemic capillary leak syndrome was diagnosed after a complex diagnostic approach. This case report describes the acute and prophylactic treatment administered to the patient and the 4-year follow-up. We highlight the importance of timely recognition and prompt treatment, as well as the need for new investigations to prevent the serious and unusual complications seen in this case.LEARNING POINTSIdiopathic systemic capillary leak syndrome (ISCLS) should be suspected in the presence of the triad of hypotension, haemoconcentration and hypoalbuminaemia; the diagnostic work-up is challenging and requires exclusion of several causes of hypotension and shock of uncertain aetiology.Acute mesenteric ischaemia leading to extensive and emergent bowel resection is an irreversible but atypical complication of ISCLS; other complications include myocardial oedema and deep vein thrombosis.ISCLS is characterized by three phases; supportive as well as prophylactic treatment adapted to each phase is crucial for prognosis and to avoid end-organ damage.

Handling shock in idiopathic systemic capillary leak syndrome (Clarkson's disease): less is more.

Idiopathic systemic capillary leak syndrome (ISCLS) presents with recurrent potentially life-threatening episodes of hypovolemic shock associated with severe hemoconcentration and hypoproteinemia. Timely recognition is of paramount importance because ISCLS, despite resembling other kinds of hypovolemic shock, requires a peculiar approach, to prevent life-threatening iatrogenic damage. Due to the rarity of this condition with only scattered cases described worldwide, evidence-based recommendations are still lacking. Here, we summarize our 40years' experience in treating shock in ISCLS patients to derive a therapeutic algorithm. Records from 12 ISCLS patients (mean follow-up is 6years, with a mean age at symptoms' onset of 51.5years) were informative for treatment modalities and outcome of 66 episodes of shock. Episodes are divided in three phases and treatment recommendations are the following: prodromal symptoms-signs (growing malaise, oligo-anuria, orthostatic dizziness) last 6-12h and patients should maintain rigorous bed rest. The acute shock phase lasts 24-36h. Patients should be admitted to ICU, placed on restrictive infusion of fluids favoring cautious boluses of high-molecular-weight plasma expanders when SAP < 70mmHg; monitored for cerebral/cardiac perfusion, myocardial edema and signs of compartment syndrome. The post-acute (recovery) phase may last from 48h to 1week. Monitor for cardiac overload to prevent cardiac failure; in case of persistent renal failure, hemodialysis may be necessary; consider albumin infusion. Complications listed by frequency in our patients were acute renal failure, compartment syndrome and neuropathy, rhabdomyolysis, myocardial edema, pericardial-pleural-abdominal effusion, cerebral involvement, acute pulmonary edema and deep vein thrombosis.

Chronic idiopathic systemic capillary leak syndrome: a case report

BackgroundIdiopathic systemic capillary leak syndrome (ISCLS), is a rare disorder characterized by recurrent attacks of varying severity of hypovolemic shock and generalized edema in association with hemoconcentration and hypoalbuminemia in the absence of albuminuria. The chronic form of ISCLS is extremely rare with only a few cases reported in the literature.Case presentationHere we report the case of a young woman who developed chronic ISCLS characterized by massive, generalized and persistent edema. The work up confirmed the presence of monoclonal gammopathy. She was treated with several agents with no response.ConclusionChronic ISCLS is a very rare disease of unknown etiology and results in devastating complications. The medical community should be aware of this disease with the hope that targeted therapy will become available in the future.

Paroxysmal Permeability Disorders: Development of a Microfluidic Device to Assess Endothelial Barrier Function.

Background: Paroxysmal Permeability Disorders (PPDs) are pathological conditions caused by periodic short lasting increase of endothelial permeability, in the absence of inflammatory, degenerative, ischemic vascular injury. PPDs include primary angioedema, idiopathic systemic capillary leak syndrome and some rare forms of localized retroperitoneal-mediastinal edema.Aim: to validate a microfluidic device to study endothelial permeability in flow conditions.Materials and Methods: we designed a microchannel network (the smallest channel is 30μm square section). Human Umbilical Vein Endothelial Cells (HUVECs) were cultured under constant shear stress in the networks. Endothelial permeability assessment was based on interaction of biotinylated fibronectin used as a matrix for HUVECs and FITC-conjugated avidin. The increase in endothelial permeability was identified as changes in fluorescence intensity detected by confocal fluorescent microscopy.Results: The microchannels were constantly perfused with a steady flow of culture medium, ensuring a physiologically relevant level of shear stress at the wall of ~0.2 Pa. Our preliminary results demonstrated that circulation of culture medium or plasma from healthy volunteers was associated with low fluorescence of fibronectin matrix. When bradykinin diluted in culture medium was perfused, an increase in average fluorescence was detected.Conclusion: Our microvasculature model is suitable to study endothelial functions in physiological flow conditions and in the presence of factors like bradykinin known as mediator of several PPDs. Therefore, it can be a promising tool to better understand the mechanisms underlying disorders of endothelial permeability.

Myocardial oedema in an 8-year-old Chinese boy with Idiopathic systemic capillary leak syndrome

BackgroundIdiopathic systemic capillary leak syndrome (ISCLS) is rare, and there has been about 32 cases reported in children worldwide since this disorder was first described in 1960. Clinical guidelines on the management approach stemming from robust scientific evidence are lacking. This case report presents the first reported paediatric case of severe ISCLS with significant myocardial oedema and emphasizes this disease’s impact on a child’s cardiac function.Case presentationA Chinese boy had his first attack of severe hypovolaemic shock that responded to fluid resuscitation when he was 6 years of age. His second attack developed at 8 years of age. He was then transferred to our cardiac unit for refractory hypotensive shock. The patient’s echocardiogram revealed ventricular wall thickening with significant cardiac dysfunction requiring extracorporeal membrane oxygenation support. Subsequently, he made a full recovery, including his myocardial wall thickness and function. The echocardiographic findings suggested myocardial oedema that was transient in nature. Clinical and laboratory investigation from both episodes were compatible with ISCLS.ConclusionISCLS is rare, and therefore there is only a limited understanding on the pathophysiology of this disorder. The current treatment approach is based on a few case reports and series. During the acute phase, optimal supportive management is paramount. Our case highlights the importance of early recognition and consideration for extracorporeal membrane oxygenation support in patients with a life-threatening presentation, as it was lifesaving for this child who suffered myocardial oedema and ventricular dysfunction.

Characterizing drug-induced capillary leak syndromes using the World Health Organization VigiBase

Characterizing drug-induced capillary leak syndromes using the World Health Organization VigiBase

Idiopathic systemic capillary leak syndrome (Clarkson syndrome) in childhood: systematic literature review.

Approximately 500 cases of idiopathic systemic capillary leak syndrome (Clarkson syndrome) have been reported worldwide. This life-threatening condition is characterized by episodes of increase in vascular permeability with loss of fluid into the interstitium and presents with acute onset of edema, signs of tissue hypoperfusion, hemoconcentration, and low blood protein level. It has been diagnosed mainly in middle-aged adults with a monoclonal gammopathy. We performed a systematic review of the literature on Clarkson syndrome in subjects ≤ 18years of age. We identified 24 reports, published since 1989, providing data on 32 otherwise healthy subjects, who experienced 67 well-documented episodes of Clarkson syndrome. The condition affected more frequently girls (21, 66%) than boys, presented throughout childhood, and was preceded by a mostly viral illness in 75% of cases. A monoclonal gammopathy was never reported. Uncompensated circulatory shock, muscle compartment syndrome, acute kidney injury, pulmonary edema, and either pleural or pericardial effusion were, in decreasing order of frequency, the most common complications. Four patients died.Conclusion: Clarkson syndrome develops not only in adulthood but also in childhood. In this age group, this condition is not linked to a monoclonal gammopathy. What is Known: • Clarkson syndrome is a rare condition that has been diagnosed mainly in middle-aged adults and is mostly linked to a monoclonal gammopathy. What is New: • In subjects ≤ 18years of age, Clarkson syndrome is not linked to a monoclonal gammopathy.

A rare cause of pericardial tamponade- Idiopathic systemic capillary leak syndrome

A rare cause of pericardial tamponade- Idiopathic systemic capillary leak syndrome

Clinical Presentation, Management, and Prognostic Factors of Idiopathic Systemic Capillary Leak Syndrome: A Systematic Review

The idiopathic systemic capillary leak syndrome is a rare disease characterized by unexplained recurrent shock caused by capillary hyperpermeability. Because of the rarity of the disease, this disease has easily been misdiagnosed and evidence of efficacious agents used empirically is lacking. To analyze the clinical and laboratory data, treatment modalities, and mortality rate of patients and to find contributing factors leading to mortality. We searched MEDLINE (inception to December 2016) and reviewed reference lists of previous systematic reviews. A total of 133 case reports (161 patients) and 5 case series (102patients) of idiopathic systemic capillary leak syndrome were included. Patients had hypotension (81.4%), edema (64.6%), and previous flu-like illness (34.2%). This disease was misdiagnosed as hypovolemic shock, septic shock, polycythemia vera, or angioedema. Thirty-seven patients died (23%) mainly because of systemic capillary leak syndrome itself (78.4%). There were significant differences in the survival rates between patients who were treated with prophylactic β2 agonists, methylxanthines, and intravenous immunoglobulins and those who were not. The estimated 1-, 5-, and 10-year survival rate of patients treated with intravenous immunoglobulins was 100%, 94%, and 94%, respectively. We systematically analyzed in detail clinical presentations of all reported patients and identified various factors associated with mortality and effects of prophylactic treatment in idiopathic systemic capillary leak syndrome. The findings of this review will facilitate diagnostic approaches of idiopathic systemic capillary leak syndrome and aid in the selection of treatment.

Mimicker of hereditary angioedema: Idiopathic systemic capillary leak syndrome successfully treated with intravenous immunoglobulin

Mimicker of hereditary angioedema: Idiopathic systemic capillary leak syndrome successfully treated with intravenous immunoglobulin

Idiopathic Systemic Capillary Leak Syndrome: A Diagnostic Challenge and Its Management

Idiopathic Systemic Capillary Leak Syndrome: A Diagnostic Challenge and Its Management

Idiopathic systemic capillary leak syndrome in childhood: A Literature Review

Idiopathic systemic capillary leak syndrome in childhood: A Literature Review

Idiopathic systemic capillary leak syndrome (Clarkson disease)

In 1960, Dr Bayard Clarkson described a woman experiencing sporadic recurrent episodes of shock and anasarca. Plasma from an acute attack induced a shock-like syndrome when injected into rats. The enigmatic systemic capillary leak syndrome (SCLS) named for Dr Clarkson is characterized by transient and severe but reversible hemoconcentration and hypoalbuminemia caused by leakage of fluids and macromolecules into tissues. Although less than 500 cases of SCLS have been reported in the literature since 1960, the condition is probably underdiagnosed because of a lack of awareness and a high mortality without treatment. Allergists should be vigilant of this diagnosis because its presentation can resemble more common plasma leakage syndromes, including angioedema or systemic anaphylaxis. Although the precise molecular cause of SCLS remains unknown, substantial advances over the last 5years have increased our understandingof SCLS pathogenesis.

Angioedema and the role of bradykinins: new treatments and implications in patients with heart failure

The definition of angioedema is an edema of subcutaneous and submucosal tissues due to increased vascular permeability and fluid extravasation. It can affect different areas, including extremities, genitals, upper airways and intestinal mucosa. The symptoms are disabling and this condition can be fatal if it involves the larynx. We can distinguish different forms of angioedema (hereditary and acquired) with different pathogenetic mechanisms, therefore responding to different treatments. Bradykinin-mediated angioedema (such as hereditary angioedema due to C1-inhibitor deficiency) does not respond to the standard therapy used for histamine-mediated angioedema. These forms should be immediately recognized and specific treatment should be used. In addition, when a patient manifests hypotension not responding to fluid replacement and associated with diffuse edema, hypoalbuminemia and hemoconcentration, we should consider the diagnosis of idiopathic systemic capillary leak syndrome, a very rare but fatal condition.

A Case of Idiopathic Systemic Capillary Leak Syndrome: Masquerader of Anaphylaxis – an Emblematic Case from a Cohort of 21 Patients

S A T U R D A Y Mike Tankersley, MD, FAAAAI, Alan DeJarnatt, MD, Ross DeJarnatt; University of Tennessee Health Sciences Center, Allergy and Asthma Care. RATIONALE: Galactose-alpha-1,3-galactose hypersensitivity (alphagal) is a recently reported condition associated with the production of specific IgE to this oligosaccharide found in mammalian meat. A registry was maintained of alpha-gal patients to more fully understand this condition in our patient population. METHODS: A retrospective chart review of a single-site Allergy practice in Tennessee was conducted of the clinic’s alpha-gal registry of patients seen from 2010-2015. RESULTS: There were 38 patients diagnosed with alpha-gal hypersensitivity over a five-year period (2010-2015). Patient characteristics included: mean age at diagnosis 50.7 years (range 14-74 years), 44.7% were male (17/38), mean alpha-gal IgE 29.7 kU/L (range 1.1-97.3; two patients excluded from mean with levels >100). Four patients had followup alpha-gal levels which had all decreased: patient 1 (6.2 to 1.9 kU/L after 42 months), patient 2 (23.2 to 8.7 kU/L after 42 months), patient 3 (82.3 to 58.7 kU/L after 34 months) and patient 4 (95.2 to 1.3 kU/L after 48 months). Signs and symptoms included cutaneous pruritus, urticaria, angioedema, hoarseness, dyspnea, nausea, vomiting, diarrhea, lightheadedness, hypotension, and syncope. Culprit foods included beef, pork, venison, cow’smilk, and lamb. Time between onset of signs and symptoms to diagnosis was 1 month-15 years. Time between ingestion and signs/ symptoms was 1-6 hours. CONCLUSIONS: Alpha-gal hypersensitivity is not an uncommon food hypersensitivity as demonstrated by the 38 patients diagnosed in this single-site clinic in Tennessee over a 5-year period. All medical care providers should maintain a high index of suspicion of this condition in patients presenting with anaphylaxis in the absence of an immediate allergen association.