If not angioedema, what is it? Diagnostic approach to facial edema.

Facial edema is a relatively frequent clinical presentation encountered in patients seen in allergology and dermatology clinics. The differential diagnosis is broad, and sometimes the definitive diagnosis can be a challenge for the clinician. Facial angioedema itself encompasses different etiopathologies (histaminergic, bradykinergic, etc.) that must be distinguished from other causes of facial edema, such as allergic contact dermatitis, granulomatous conditions, inflammatory causes, infections, neoplasms or paraneoplastic syndromes, autoimmune diseases, among other entities hereby referred as miscellanea. A proper diagnostic approach is essential to order the appropriate tests, as well as to prescribe a targeted treatment. This review focuses on entities that present with facial edema and summarize their characteristic clinical features.

Mimicking pneumonia with septic shock: A case report and literature review.

Hydrochlorothiazide (HCTZ) is a commonly used diuretic antihypertensive drug that can cause electrolyte disorders, hyperglycemia and hyperuricemia as well as rare life-threatening adverse drug reactions. These include non-cardiogenic pulmonary edema, interstitial pneumonia, angioedema and aplastic anemia. The present report describes a case of a 59-year-old man who developed a hypersensitivity reaction to HCTZ. Specifically, the patient presented with symptoms of cough, chest tightness and shortness of breath, with pneumonic consolidation on chest CT and elevated levels of white blood cell count, neutrophil percentage, C-reactive protein and procalcitonin. A presumptive diagnosis of severe pneumonia was made initially. However, during the gradual recovery of the patient through treatment, he mistakenly ingested HCTZ containing losartan potassium intended for another patient, which resulted in symptoms similar to those observed upon admission. Upon further inquiry into the medical history, it was revealed that the patient had also taken irbesartan/HCTZ 4 h prior to hospitalization. There was no evidence of a pathogenic infection. Therefore, HCTZ-induced anaphylactic reaction was considered to be the most likely etiology for his severe shock. Treatments including epinephrine, methylprednisolone and respiratory support were administered. After 7 days, the patient was transferred from the Respiratory Intensive Care Unit [The Affiliated Jiangning Hospital of Nanjing Medical University (Nanjing, China)] to a general ward. During the follow-up, 12 months after advising the patient to discontinue HCTZ, there had been no recurrence of the aforementioned symptoms. At the time of publication, the patient is currently alive.

Sorafenib-Induced Capillary Leak Syndrome.

Capillary leak syndrome is a rare life-threatening disorder of acute endothelial hyperpermeability. It consists of initial fluid extravasation resulting in hypotension, hypoalbuminemia, and hemoconcentration, followed by noncardiogenic pulmonary edema from rapid fluid remobilization into intravascular compartment. Drug-induced etiology is an important diagnostic consideration in cancer patients, particularly with use of antimetabolites, immunostimulants, and monoclonal antibodies. Sorafenib-mediated capillary leak syndrome has never been reported. Here, we present the case of a 29-year-old female patient with a desmoid tumor of the thigh, who was admitted for acute hypoxic respiratory failure after recent initiation of sorafenib. She was found to have extensive pulmonary edema, bilateral pleural effusions, and hemoconcentration, all of which stabilized on supportive care with noninvasive mechanical ventilation and intravenous diuresis. Her infectious and cardiac work-up were negative. Given the temporal relationship between sorafenib use and symptom onset as well as a lack of an alternative etiology of her findings, patient was deemed to have sorafenib-induced acute capillary leak syndrome. Importantly, she did not become hypotensive prior to or during this hospitalization. To our knowledge, we reported for the first time an atypical presentation of acute capillary leak syndrome due to sorafenib use without hemodynamic instability.

Systemic Capillary Leak Syndrome as a Rare, Potentially Fatal Complication of COVID-19: A Case Report and Literature Review.

Systemic capillary leak syndrome (SCLS), also known as Clarkson's disease, is a rare and potentially lethal condition characterized by hypotension, hemoconcentration, and hypoalbuminemia; however, the cause of SCLS is still uncertain. We present the case of a 62-year-old male with flu-like symptoms who presented to the emergency department with shock. Initial evaluation revealed hemoconcentration, hypoalbuminemia, acute kidney failure, and positive polymerase chain reaction (PCR) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite aggressive fluid resuscitation, the shock persisted, and the patient's condition deteriorated. After ruling out ischemia and septic shock, the patient was diagnosed with coronavirus disease 2019 (COVID-19)-associated SCLS. Treatment with remdesivir and intravenous immunoglobulin (IVIG), along with the restoration of intravascular volume, led to the gradual improvement of the patient's condition. The patient experienced pulmonary edema, which was managed by correcting the fluid balance through continuous hemodiafiltration. Eventually, the patient recovered without any residual organ complications. SCLS is often misdiagnosed because of its rarity and non-specific symptoms. Accurate diagnosis and understanding of the disease's pathophysiology are crucial for effective management. This report contributes to the existing literature by presenting a case of COVID-19-associated SCLS and emphasizes the need for further research on its occurrence and outcomes.

Idiopathic Systemic Capillary Leak Syndrome: A Clinical Case.

Idiopathic systemic capillary leak syndrome (ISCLS) is a rare condition caused by the extravasation of intravascular fluids and proteins into the interstitial space due to increased vascular endothelium permeability. It is characterized by episodes of hypotension, hypoalbuminemia, and hemoconcentration with generalized edema. Its etiopathogenesis is unknown. However, it is associated with monoclonal gammopathy in more than 80% of cases. There is currently no targeted treatment, and the approach during a crisis is supportive, mainly to control blood pressure, maintain perfusion of vital organs, and prevent complications, such as acute pulmonary edema and organ failure due to ischemia, which are the primary causes of death. We present the case of a 72-year-old man with generalized edema and pleural, pericardial, and peritoneal effusions whose laboratory results showed hypoalbuminemia, hypoproteinemia, and immunoglobulin G kappa monoclonal gammopathy. Other etiologies for severe hypoalbuminemia with anasarca were excluded after an exhaustive complementary study, leading to the diagnosis of ISCLS associated with monoclonal gammopathy. The patient showed progressive clinical improvement with albumin and diuretic therapy. However, they were readmitted to the hospital due to hypotension with multiorgan dysfunction and died a few hours later.

A Rare Case of Idiopathic Systemic Capillary Leak Syndrome.

Idiopathic systemic capillary leak syndrome (SCLS) is characterized by an increased capillary hyperpermeability with subsequent hemoconcentration, hypoproteinemia, and hypovolemia. Patients present with diffuse swelling, weight gain, low blood pressure, and shock. We present our case of idiopathic SCLS in a 50-year-old man presenting with prodromal flu-like illness associated with shock that was complicated by compartment syndrome requiring four limb fasciotomies, disseminated intravascular coagulation, acute kidney injury requiring dialysis, and cardiac arrest.

Intravenous Immunoglobulins Tapering and Withdrawal in Systemic Capillary Leak Syndrome (Clarkson Disease).

BACKGROUND: The systemic capillary leak syndrome (SCLS), also known as Clarkson disease, is a very rare condition characterized by recurrent life-threatening episodes of vascular hyperpermeability in the presence of a monoclonal gammopathy. Extended intravenous immunoglobulin (IVIG) treatment is associated with fewer recurrences and improved survival, but the optimal treatment dosage and duration remain unknown. OBJECTIVE: We aim to evaluate the safety of IVIG tapering and withdrawal in patients with SCLS. METHODS: We conducted a retrospective multicenter study including all adult patients with monoclonal gammopathy-associated SCLS from the EurêClark registry who received at least 1 course of IVIG. The primary end point was overall survival according to IVIG withdrawal. RESULTS: Fifty-nine patients of mean ± SD age 51 ± 13 years were included. Overall cumulative probabilities of 2-, 5-, 10- and 15-year survival were 100%, 85%, 72%, 44%, respectively. The IVIG was withdrawn at least once in 18 patients (31%; W+ group) and never in 41 patients (69%; W- group). Cumulative probabilities of 10-year survival in W+ versus W- groups were 50% and 83% (log rank test, P = .02), respectively. Relapse rate and the median number of relapses in the W+ versus the W- groups were 72% versus 58% (P = 0.3) and 2.5 (0.3-4) versus 1 (0-2) (P = .03), respectively. The IVIG tapering was not statistically associated with increased person-year incidence of attacks using a mixed linear model. CONCLUSIONS: The IVIG withdrawal was associated with increased mortality and higher rate of recurrence in SCLS patients. The IVIG tapering might be cautiously considered in stable SCLS patients.

A deadly capillary leak attack. Clarkson's disease: a narrative review.

A previously 42-year-old healthy man was brought in by an ambulance to the emergency department with symptoms of a distributive shock. He experienced a rapid decline in his clinical state that evolved into a cardiac arrest. Despite all the performed measures and a prolonged resuscitation, the patient died a few hours later without an initial clear diagnosis. Lab results showed an extremely high haemoconcentration leading to further investigations which suggested the possibility of Clarkson's disease, although septic shock as an alternative diagnosis could not be excluded. Nevertheless, because of its presentation, especially emergency and intensive care physicians should be aware of the existence of this condition in the event of an unexplained refractory distributive shock in combination with haemoconcentration and hypoalbuminemia given its possible fatal outcome.

Fatal Systemic Capillary Leak Syndrome after SARS-CoV-2Vaccination in Patient with Multiple Myeloma.

A young man with smoldering multiple myeloma died of hypotensive shock 2.5 days after severe acute respiratory syndrome coronavirus 2 vaccination. Clinical findings suggested systemic capillary leak syndrome (SCLS); the patient had experienced a previous suspected flare episode. History of SCLS may indicate higher risk for SCLS after receiving this vaccine.

Fatal Exacerbations of Systemic Capillary Leak Syndrome Complicating Coronavirus Disease.

We report 2 fatal exacerbations of systemic capillary leak syndrome (SCLS), also known as Clarkson disease, associated with coronavirus disease (COVID-19) in the United States. One patient carried an established diagnosis of SCLS and the other sought treatment for new-onset hypotensive shock, hemoconcentration, and anasarca, classic symptoms indicative of an SCLS flare. Both patients had only mild-to-moderate symptoms of COVID-19. This clinical picture suggests that these patients succumbed to complications of SCLS induced by infection with severe acute respiratory syndrome coronavirus 2. Persons with known or suspected SCLS may be at increased risk for developing a disease flare in the setting of mild-to-moderate COVID-19 infection.

Capillary leak syndrome: State of the art in 2021.

Capillary leak syndrome (CLS) is an increasingly acknowledged multifaceted and potentially lethal disease. Initial nonspecific symptoms are followed by the intriguing CLS hallmark: the double paradox associating diffuse severe edema and hypovolemia, along with hemoconcentration and hypoalbuminemia. Spontaneous resolutive phase is often associated with poor outcome due to iatrogenic fluid overload during leak phase. CLS is mainly triggered by drugs (anti-tumoral therapies), malignancy, infections (mostly viruses) and inflammatory diseases. Its idiopathic form is named after its eponymous finder: Clarkson's disease. CLS pathophysiology involves a severe, transient and multifactorial endothelial disruption which mechanisms are still unclear. Empirical and based-on-experience treatment implies symptomatic care during the acute phase (with the eventual addition of drugs amplifying cAMP levels in the severest cases), and the prophylactic use of monthly polyvalent immunoglobulins to prevent relapses. As CLS literature is scattered, we aimed to collect and summarize the current knowledge on CLS to facilitate its diagnosis, understanding and management.

Nivolumab-induced systemic capillary leak syndrome as an ultra rare life-threatening phenomenon of late toxicity and intravenous immunoglobulin efficacy.

Systemic capillary leak syndrome (SCLS) is a life-threatening disease. It is characterized by severe capillary hyperpermeability to proteins resulting in hemoconcentration, hypoalbuminemia and hypovolemic shock. Its treatment remains supportive, and the prognosis is generally poor. We report on a 51-year old male with melanoma treated with nivolumab for 1 year. 1 month following the completion of the treatment, the patient presented with signs of hypovolemic shock, anasarca, hemoconcentration and hypoalbuminemia. After excluding other diseases, a diagnosis of nivolumab-induced systemic capillary leak syndrome was made. A high dose of intravenous steroid therapy was promptly initiated without any significant clinical improvement. Intravenous immunoglobulin therapy was then administered with normalization of blood pressure, hemoconcentration and complete resolution of anasarca. Intravenous immunoglobulin should be considered a first-line treatment option for this rare phenomenon.

Lay abstract Systemic capillary leak syndrome (SCLS) is a life-threatening disease with a high fatality rate. Patients present with low blood pressure, widespread edema and rapid weight gain. Labs show low albumin levels with highly concentrated blood, seen as high hematocrit and hemoglobin levels. Current treatments aim to support the acute crisis. We are presenting on a 51-year old patient with melanoma, treated with nivolumab for 1 year who developed signs of SCLS 1-month following medication discontinuation. He was first treated with high-dose steroids without symptom resolution. He was then administered immune proteins called intravenous immunoglobulins, resolving all his symptoms. Due to the patient's complete response, we suggest intravenous immunoglobulins as the initial treatment in patients taking nivolumab presenting with SCLS.

[Use of Extracorporeal Membrane Oxygenation in idiopathic capillary leak syndrome: a case report]. / Utilización de membrana de circulación extracorpórea en síndrome de leak capilar idiopático: reporte de un caso.

Introduction: Idiopathic systemic capillary leak syndrome (ISCLS) or Clarkson's disease is unusual but potentially lethal, characterized by recurrent shock incidents and anasarca secondary to idiopathic increase of capillary permeability. In such a context, the use of venoarterial Extracorporeal Membrane Oxygenation (ECMO) as cardiorespiratory support is a rescue action that seeks hemodynamic stability generation until spontaneous disappearance of the capillary occurs with the objective of surpassing the complications of resorption phase. Case Report: A 42 year old patient presented ISCLS and required ECMO as hemodynamic support for 8 days. She remained 20 days in Intensive Care Unit and was given hospital release after 43 days. Conclusions: The use of ECMO in the reported case was a useful strategy in the ISCLS management as a bridge to recovery both in the leak stage and the fluid resorption phase. Notwithstanding its indication is limited to thoroughly selected patients and requires further debate between specialists about its risks and benefits.

Introducción: El Síndrome de Leak Capilar Idiopático (SLCI) o enfermedad de Clarkson es un entidad rara pero potencialmente letal, caracterizada por episodios recurrentes de shock y anasarca secundarios al aumento idiopático de la permeabilidad capilar. En este contexto, el uso de membrana de oxigenación extracorpórea (ECMO) venoarterial como soporte cardiorrespiratorio, es una medida de rescate que busca generar estabilidad hemodinámica a la espera de la desaparición espontánea del leak capilar con el fin de sortear las complicaciones de la fase de reabsorción. Caso Clínico: Se presenta el caso de un paciente un paciente de 42 años de edad que presentó SLCI y requirió ECMO durante 8 días como soporte hemodinámico. Cursó 20 días de internación en la unidad de terapia intensiva y se otorgó el alta hospitalaria luego de 43 días. Conclusiones: El uso de ECMO en el caso reportado significó una estrategia útil para el manejo del SLCI como puente a la recuperación, tanto en la etapa de leak como en la fase de reabsorción de fluidos. Sin embargo, su indicación se ve limitada a pacientes altamente seleccionados, y todavía requiere un mayor debate entre especialistas sobre los posibles riesgos y beneficios.

A case report of capillary leak syndrome with recurrent pericardial and pleural effusions.

BACKGROUND: Capillary leak syndrome (CLS) is a rare connective tissue disease, triggered by the leak of serous fluid into the interstitial spaces, characterized by a hallmark of oedema and effusions in confined spaces. The limiting factor in CLS management appears to be its diagnosis rather than treatment, which is usually to contain the disease progression rather than a cure. CASE SUMMARY: We report a case of a 51-year-old woman with recurrent life-threatening presentations of pericardial effusions, pleural effusions, and generalized swelling of face and extremities. The only notable past medical history was of Type 1 diabetes. Numerous investigations did not lead to specific disease accounting for pericardial effusions and pleural effusions. Eventually, the diagnosis of CLS was made based on hypovolaemic shock, hypoalbuminaemia, and haemoconcentration without the presence of albuminuria. She was managed with steroids to reduce system inflammation and later with immunoglobulins and tumour necrosis factor to contain the disease process. Since her diagnosis and subsequent appropriate management, she has not had further admissions with cardiac tamponade 16 months of follow-up. DISCUSSION: The diagnosis of CLS is difficult to make unless there is a high degree of suspicion and until other causes have been ruled out. It remains a challenging condition to manage as the treatment options are limited and patients recurrently present with emergencies until the correct diagnosis is made and the optimal treatment is provided.

Network-Based Functional Prediction Augments Genetic Association To Predict Candidate Genes for Histamine Hypersensitivity in Mice.

Genetic mapping is a primary tool of genetics in model organisms; however, many quantitative trait loci (QTL) contain tens or hundreds of positional candidate genes. Prioritizing these genes for validation is often ad hoc and biased by previous findings. Here we present a technique for prioritizing positional candidates based on computationally inferred gene function. Our method uses machine learning with functional genomic networks, whose links encode functional associations among genes, to identify network-based signatures of functional association to a trait of interest. We demonstrate the method by functionally ranking positional candidates in a large locus on mouse Chr 6 (45.9 Mb to 127.8 Mb) associated with histamine hypersensitivity (Histh). Histh is characterized by systemic vascular leakage and edema in response to histamine challenge, which can lead to multiple organ failure and death. Although Histh risk is strongly influenced by genetics, little is known about its underlying molecular or genetic causes, due to genetic and physiological complexity of the trait. To dissect this complexity, we ranked genes in the Histh locus by predicting functional association with multiple Histh-related processes. We integrated these predictions with new single nucleotide polymorphism (SNP) association data derived from a survey of 23 inbred mouse strains and congenic mapping data. The top-ranked genes included Cxcl12, Ret, Cacna1c, and Cntn3, all of which had strong functional associations and were proximal to SNPs segregating with Histh. These results demonstrate the power of network-based computational methods to nominate highly plausible quantitative trait genes even in challenging cases involving large QTL and extreme trait complexity.

Chronic idiopathic systemic capillary leak syndrome: a case report.

BACKGROUND: Idiopathic 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 PRESENTATION: Here 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. CONCLUSION: Chronic 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.

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 40 years' experience in treating shock in ISCLS patients to derive a therapeutic algorithm. Records from 12 ISCLS patients (mean follow-up is 6 years, with a mean age at symptoms' onset of 51.5 years) 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 6-12 h and patients should maintain rigorous bed rest. The acute shock phase lasts 24-36 h. Patients should be admitted to ICU, placed on restrictive infusion of fluids favoring cautious boluses of high-molecular-weight plasma expanders when SAP < 70 mmHg; monitored for cerebral/cardiac perfusion, myocardial edema and signs of compartment syndrome. The post-acute (recovery) phase may last from 48 h to 1 week. 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.

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

BACKGROUND: Idiopathic 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 PRESENTATION: A 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. CONCLUSION: ISCLS 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.

Capillary leak syndrome as a complication of antibody-mediated rejection treatment: a case report.

We report a case of capillary leak that developed during treatment of antibody-mediated rejection in a kidney transplant recipient. A 53-year-old female transplant recipient experienced an increase in serum creatinine from 1.1 to 1.8 mg/dL. Antibody-mediated rejection was diagnosed by graft biopsy. She was treated with five plasmapheresis sessions (on alternate days with albumin replacement), five doses of immunoglobulin (5 g/dose at 100 mg/kg), a single dose of rituximab (500 mg), and four doses of bortezomib on days 1, 4, 7, and 10 (1.72 mg/dose at 1.3 mg/m2 body surface area). During treatment, edema, slight diarrhea, pancytopenia, hypoalbuminemia, peripheral neuropathy, and postural hypotension were noted. Despite control of liquids, she presented with edema progressing to an increase of more than 10 kg body weight. Prerenal acute graft dysfunction associated with hypotension was diagnosed on day 12, heart failure or other infectious complications being discounted. On day 13, daily hemodialysis was prescribed, and a stable volume status was reached after five hemodialysis sessions. On day 20, the patient recovered diuresis and the edema and diarrhea abated, but she remained on chronic hemodialysis. After excluding other causes of distributive shock, the diagnosis of capillary leak syndrome was based on the presence of hypotension, generalized edema, and hypoalbuminemia in the absence of significant proteinuria. The concomitant presence of diarrhea, peripheral neuropathy, and pancytopenia, suggest a possible causal role for bortezomib. Awareness by clinicians of capillary leak syndrome associated with bortezomib-based treatment of AMR is paramount, despite its rarity.