Blue Toe Research Articles

Lessons from dermatology about inflammatory responses in Covid-19.

SummaryThe SARS‐Cov‐2 is a single‐stranded RNA virus composed of 16 non‐structural proteins (NSP 1‐16) with specific roles in the replication of coronaviruses. NSP3 has the property to block host innate immune response and to promote cytokine expression. NSP5 can inhibit interferon (IFN) signalling and NSP16 prevents MAD5 recognition, depressing the innate immunity. Dendritic cells, monocytes, and macrophages are the first cell lineage against viruses' infections. The IFN type I is the danger signal for the human body during this clinical setting. Protective immune responses to viral infection are initiated by innate immune sensors that survey extracellular and intracellular space for foreign nucleic acids. In Covid‐19 the pathogenesis is not yet fully understood, but viral and host factors seem to play a key role. Important points in severe Covid‐19 are characterized by an upregulated innate immune response, hypercoagulopathy state, pulmonary tissue damage, neurological and/or gastrointestinal tract involvement, and fatal outcome in severe cases of macrophage activation syndrome, which produce a ‘cytokine storm’. These systemic conditions share polymorphous cutaneous lesions where innate immune system is involved in the histopathological findings with acute respiratory distress syndrome, hypercoagulability, hyperferritinemia, increased serum levels of D‐dimer, lactic dehydrogenase, reactive‐C‐protein and serum A amyloid. It is described that several polymorphous cutaneous lesions similar to erythema pernio, urticarial rashes, diffuse or disseminated erythema, livedo racemosa, blue toe syndrome, retiform purpura, vesicles lesions, and purpuric exanthema or exanthema with clinical aspects of symmetrical drug‐related intertriginous and flexural exanthema. This review describes the complexity of Covid‐19, its pathophysiological and clinical aspects.

Are the cutaneous manifestations during or due to SARS-CoV-2 infection/COVID-19 frequent or not? Revision of possible pathophysiologic mechanisms.

BackgroundSARS-Cov-2 is a single-stranded RNA virus, a Betacoronavirus, composed of 16 non-structural proteins, with specific roles in replication of coronaviruses. The pathogenesis of COVID-19 is not yet fully understood. The virus and host factors interplay among distinct outcomes of infected patients.MethodsUsing MeSH (Medical Subject Headings) in PubMed, authors searched for articles cotaining information on COVID-19 and the skin.ResultsThe pathophysiology of the disease is multifactorial: association with innate immune response, hypercoagulability state, lung tissue damage, neurological and/or gastrointestinal tract involvement, monocytic/macrophage activation syndrome, culminating in exaggerated cytokine secretion, called “cytokine storm”, which leads to worsening and death. These systemic conditions may be associated with cutaneous lesions, that have polymorphic aspects, where at histopathological level show involvement in different skin changes. These lesions may be associated with multisystemic manifestations that could occur due to angiotensin-converting enzyme 2 receptor and transmembrane serine protease action, allowing the pulmonary infection and possibly skin manifestation. Several reports in literature show cutaneous lesions similar to chilblain, urticarial eruptions, diffuse or disseminated erythema, livedo racemosa, blue toe syndrome, retiform purpura, vesicle trunk, purpuric exanthema or exanthema with clinical aspects of symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) and others.ConclusionsThis review describes the complexity of Covid-19, pathophysiological and clinical aspects, dermatological finding and other dermatological conditions associated with SARS-CoV-2 infection or COVID-19.

Blue Toes at High Altitude: Peripheral Cyanosis

At altitudes >2500 m, acute mountain sickness is usually self-limiting, presenting with hypoxia and pulmonary edema.1 Chronic mountain sickness results in pulmonary hypertension and the development of congestive cardiac failure.1,2 Hypoxemia is associated with signs of peripheral cyanosis. Blue toe syndrome is a common presentation of peripheral ischemia as a result of the occlusion of small-caliber peripheral vessels. The differential diagnosis includes atheroembolism, thromboembolism, and vasospastic conditions.

Comparison between direct and indirect revascularization of below-the-knee arterial occlusive diseases based on foot angiosome concept

Objective Ischemic wounds of the foot are the most common cause for major amputations in vascular surgical patients. It can be presumed that revascularization of the artery directly supplying the ischemic angiosome may be superior to indirect revascularization (IR) of the concerned ischemic angiosome. Patients and methods This prospective study enrolled patients with critical limb ischemia due to isolated infrapopliteal disease (stenosis of ≥70% or complete total occlusions of the crural arteries) presented to our Vascular Department between April 2017 and April 2018. We categorized the treatment groups into two main groups: direct revascularization (DR) and IR. We excluded patients with acute limb ischemia, inflow lesions above the knee, sepsis, myocardial infarction during the previous 14 days, blue toe syndrome (microembolization), and patients who cannot ambulate. Results In this study, there were 23 patients with forefoot ischemia, eight patients had ischemic heel, and two patients had mid-foot ischemia. All patients were followed at 1, 6, and 12 months postoperatively for wound healing, major amputation, or death. Wound healing at 1, 6, and 12 months for DR versus IR was 16.6 versus 9.09%, 56.3 versus 33.3%, and 93.75 versus 87.75%, respectively. The limb salvage rate in the DR group was 88.9% and in IR group was 72.7%. The mortality was 10% for DR and 15.4% for IR at 12 months. Conclusion To obtain better wound healing rates, DR of the ischemic angiosome should be considered whenever possible. Revascularization should not be denied to patients with indirect perfusion of the ischemic angiosome, as acceptable rates of limb salvage are obtained.

Blue Toe Syndrome: A Challenging Diagnosis.

Blue Toe Syndrome: A Challenging Diagnosis.

Blue toe syndrome in cutaneous polyarteritis nodosa.

Blue toe syndrome in cutaneous polyarteritis nodosa.

Blue Toe Syndrome due to Mobile Atheromatous Aorto-iliac Plaque Treated Successfully by Endovascular Aortic Repair

Blue Toe Syndrome due to Mobile Atheromatous Aorto-iliac Plaque Treated Successfully by Endovascular Aortic Repair

A woman with purple toes after intrarticular hyaluronic acid administration

Intra-articular injected hyaluronic acid provides pain relief and functional improvements in patients with gonarthrosis. We present a 92-year-old woman with iatrogenic blue toe syndrome after intra-articular in­jection of hyaluronic acid. This is an anecdotally rare complication, which aims to heighten the clinician`s awareness on the possible intervention pitfalls and spectrum of therapeutic indications.

Outcome of surgical and endovascular treatment of popliteal artery aneurysms

Popliteal artery aneurysm is a localized enlargement of lumen of popliteal artery due to atherosclerosis. With incidence of 0.1 – 2.8/100,000 people they are the most common aneurysms of peripheral arteries, affecting mostly male population. In about 50 % of patients aneurysms are found bilaterally and in 78 % of cases patients have them on other arteries, mostly (64 %) on abdominal aorta and iliac arteries. At the beginning, disease is asymptomatic and later it can be presented with pain, compression, rarely rupture and, if embolization of the thrombus occurs distal part of the limb will be ischemic, pale, with blue toes, ulcerations, gangrene and in worse case it will end with amputation. Diagnosis is based on multislice computed tomography (MSCT) angiography but sometimes even palpation of popliteal fossa behind knee articulation is enough. Surgical treatment consists of ligation and bypassing the aneurysm to exclude it from the blood flow. Other option is endovascular treatment in which stent is being embedded inside of the aneurism. The advantages of this treatment are quick recovery and short hospitalization and it is suitable for patients with high operative risk. However, big disadvantages are higher rate of early thrombosis and occlusion with greater number of complications compared with operative method. Operation by medial approach is nowadays the most common operative method in treatment of popliteal artery aneurisms. Most important advantages are great long-term results, low rate of complications, simplicity and short time of intervention which makes it a standard and a first option in treating popliteal artery aneurisms.

The usefulness of Duplex Doppler ultrasound in the angiological and dermatological diagnosis of patients with blue toe syndrome.

IntroductionPeripheral microembolism is one of the most frequent causes of acute limb ischemia. In order to effectively prevent relapses it is essential to localize and eliminate the source of embolism.AimTo evaluate the role of Duplex Doppler ultrasound examination in identifying the causes of blue toe syndrome (BTS).Material and methodsThe group of 165 patients with clinical symptoms of BTS on their upper limbs (n = 16) and lower limbs (n = 149) was investigated. They all underwent Duplex Doppler ultrasound of the major arteries of the extremities, where ischemic changes occurred.ResultsMorphological and functional changes which might be potential sources of microembolism were identified in 146 patients. These changes included significant short-length stenoses or unstable atherosclerotic plaque (n = 73), true aneurysms (n = 42) and pseudoaneurysms (n = 17). In 11 cases, pathology of vascular prostheses in the form of anastomotic aneurysms, infection and residual thrombi after fibrinolysis was detected. In all cases, Duplex diagnosis was confirmed by other imaging and intraoperative tests.ConclusionsDuplex Doppler ultrasound of the arteries in the affected limb with a full length view should be the first-line examination in diagnosing patients with BTS. In the absence of hemodynamic blood flow disturbances in the major arteries in patients with symptoms of BTS, it is advisable to start haematological tests to identify/exclude congenital or acquired thrombophilia.

The Place of Nailfold Capillaroscopy Among Instrumental Methods for Assessment of Some Peripheral Ischaemic Syndromes in Rheumatology.

Micro- and macrovascular pathology is a frequent finding in a number of common rheumatic diseases. Secondary Raynaud's phenomenon (RP) is among the most common symptoms in systemic sclerosis and several other systemic autoimmune diseases including a broad differential diagnosis. It should be also differential from other peripheral vascular syndromes such as embolism, thrombosis, etc., some of which lead to clinical manifestation of the blue toe syndrome. The current review discusses the instrumental methods for vascular assessments. Nailfold capillaroscopy is the only method among the imaging techniques that can be used for morphological assessment of the nutritive capillaries in the nailfold area. Laser-Doppler flowmetry and laser-Doppler imaging are methods for functional assessment of microcirculation, while thermography and plethysmography reflect both blood flow in peripheral arteries and microcirculation. Doppler ultrasound and angiography visualize peripheral arteries. The choice of the appropriate instrumental method is guided by the clinical presentation. The main role of capillaroscopy is to provide differential diagnosis between primary and secondary RP. In rheumatology, capillaroscopic changes in systemic sclerosis have been recently defined as diagnostic. The appearance of abnormal capillaroscopic pattern inherits high positive predictive value for the development of a connective tissue disease that is higher than the predictive value of antinuclear antibodies. In cases of abrupt onset of peripheral ischaemia, clinical signs of critical ischaemia, unilateral or lower limb involvement, Doppler ultrasound and angiography are indicated. The most common causes for such clinical picture that may be referred to rheumatologic consultation are the antiphospholipid syndrome, mimickers of vasculitides such as atherosclerosis with cholesterol emboli, and neoplasms.

Síndrome del dedo azul secundario a ateroembolia por colesterol: reporte de un caso y revisión de la literatura

We describe the case of a 68 year-old woman with very high cardiovascular risk. She consulted because of cyanosis in the toes, associated with transient focal neurological symptoms. Evolution had been 5 days. She was hospitalized with the diagnostic impression of blue toe syndrome and critical arterial ischemia of the lower limbs possibly due to embolic events. After an endovascular procedure, she developed sudden neurological impairment due to multiple strokes, as well as acute renal failure. Biopsy of the affected toes revealed cholesterol crystals inside the blood vessels. Based on the case, a short review about the blue toe syndrome and its main cause, atheroembolism, is presented.

Acute Digital Ischemia In a 30-Year Old Man: A Case Report

Objective: To report a rare case of acute digital ischemia at a young man. Methods: A 30-year old man presented with painful bluish discoloration of the toes and palpable pedal pulses. Results: Physical evaluation and urgent angiography revealed a severe stenosis of the right common iliac artery. Treatment started with a low molecular weight heparin for fifteen days and completed with a bilateral common iliac artery angioplasty after two months. Conclusion: Blue toe syndrome is considered a relatively frequent manifestation of limb ischemia, especially in elderly patients. Treatment is based on surgical or percutaneous elimination of the source of embolisation and restoration of arterial perfusion. In this case report, we present an unusual case of blue toe syndrome caused by a severe common iliac artery stenosis at a 30-year-old male patient. Blue toe syndrome is a rare manifestation of peripheral arterial disease at younger patients, but physicians should be aware of this in order to include it in the differential diagnosis of acute lower limb ischemia.

Blue Toe Syndrome as an Early Sign of Disseminated Intravascular Coagulation.

Dear Editor: Blue toe syndrome (BTS) is often described as painful digits with blue or purple discoloration without direct trauma1. Also it can lead to the amputation of toes and feet and be life threatening. Atheromatous embolism caused by vascular wall injuries from invasive percutaneous procedures or from anticoagulant or fibrinolytic therapy is reported as a common cause of BTS2. However, other causes of decreased blood flow are thrombosis, vasoconstrictive disorders, infectious and noninfectious inflammation, and other vascular obstruction2. The conditions which lead to thrombotic state such as disseminated intravascular coagulation (DIC) can also give rise to BTS. Herein, we report a rare case of BTS that occurred as an early sign of DIC. In our institute, a 69-year-old male complained of non-palpable bluish discoloration on both feet after he was admitted to the ICU ward due to pneumonia (Fig. 1). The physical examination demonstrates symmetric color change with petechiae that had lasted 1 month. The toes felt cold, and the sensation of toes was uncheckable because of his semi-coma status. Also the patient has been treated for pneumonia with history of diabetes mellitus, hypertension, and cerebral infarct. On histological examination from his foot, ischemic necrosis of epidermis and tons of red blood cell extravasation were found (Fig. 2A, B). Also, there were eosinophilic fibrinoid thrombi in the medium- sized vessels and leukocytoclasis (Fig. 2C). The laboratory results were as follows: white blood cell 28,470/mm3, hemoglobin 9.4 g/dl, platelet 37,000/mm3, prothrombin time/activated partial thromboplastin time 18.4/91.7 s, fibrinogen 71 mg/dl, D-dimer 3.75 mg/L. Hence, we could confirm that the causative disease might be DIC. After then, we obtained the result of multi drug resistant acinetobacter baumannii bacteremia from the blood culture. Gram stain and bacterial culture of the skin tissue were not conducted. We concluded that DIC resulted from severe infectious bacteremia. Henceforward, the patient was treated with vancomycin and conservative care for DIC. However, the patient died after 1 month. The possibility of purpura fulminans was ruled out because the patient's lesion was limited to the toes. Fig. 1 Blue to purple discoloration with petechiae on the right foot. Fig. 2 (A) Scanning view (H&E, ×40). (B) Ischemic necrosis of epidermis, and red blood cell extravasation (H&E, ×200). (C) Eosinophilic fibrinoid thrombi in medium-sized vessels (arrow) and leukocytoslasis (H&E, ×400). ... Some conditions that might lead to the slow blood flow or vascular damage that causes BTS are: 1) decreased arterial perfusion, 2) impaired venous outflow, and 3) abnormal circulating blood2,3. Our case corresponds with decreased arterial flow, by thrombosis, not by embolism2. Histologically intravascular fibrin thrombi proved this thrombosis in our case. Besides, this hypercoagulable states can developed diverse cutaneous findings other than BTS2. But if the patient's underlying disease is unclear, we should commit several kinds of work-up such as complete blood count, blood chemistry, urinalysis, culture, antibody, X-ray as well as computerized tomography angio2. DIC is a process which describes widespread abnormal activation of the clotting pathway and generation of excess thrombin2,4. It results in intravascular fibrin formation and thrombotic occlusion of small and larger vessels. Although DIC has to be managed in internal medicine, there are some needs for dermatologists to know it. Because most initial signs of DIC begin with cutaneous findings like BTS, petechiae, purpura fulminans, peripheral gangrene5. In conclusion, we report an instructive case of BTS as an early sign of DIC.

Abstract 15240: Cholesterol Crystal Embolization: The Incidence as a Cardiac Procedural Complication and the Comparison of the Outcomes Between its Causes

Background: Cholesterol crystal embolization (CCE) is very rare, but has a poor prognosis and no proven therapy. Although CCE occurs from various causes, the incidence and outcomes of CCE remain unclear. Purpose: 1) to investigate the incidence of CCE as a complication of percutaneous coronary intervention (PCI), percutaneous transluminal angioplasty (PTA), and cardiovascular surgery; and 2) to investigate patient characteristics and outcomes of CCE on the basis of its causes: idiopathic CCE, catheter-related CCE, and cardiovascular surgery-related CCE. Methods: We registered 75 patients having CCE in the medical records between May 2004 and April 2014 and compared their patient characteristics and outcomes according to the causes of CCE: idiopathic CCE, 31 patients (41%); catheter-related CCE, 32 (43%); and cardiovascular surgery-related CCE, 12 (16%). CCE was diagnosed by clinical findings (blue toe syndrome or livedo) or laboratory findings (elevated serum creatinine level, eosinophil count, or skin biopsy). Results: The incidences of catheter-related CCE were 0.7% in PTA on arteriosclerotic obliterans and 0.17% in PCI. The incidence of CCE after PCI was significantly higher in patients treated with femoral approach than in those treated with nonfemoral approach (0.32% vs. 0.01%, p<0.001). The incidences of cardiovascular surgery-related CCE were relatively high in endovascular aortic repair (1.3%) and in abdominal aortic replacement (0.6%). In the comparison of patient characteristics between idiopathic CCE, catheter-related CCE, and cardiovascular surgery-related CCE, there were significant differences in age and aortic aneurysm. Of the 75 patients, 24 (32%) died, 10 (13%) initiated dialysis, and 7 (9%) underwent leg or toe amputation. There was no significant difference in the outcomes of CCE depending on its causes. Conclusion: The incidences of CCE were significantly high in transfemoral procedures and in surgery for abdominal aortic aneurysm. Between the causes of CCE, there were significant differences in patient characteristics, but no significant differences in the outcomes.

Comparison of posterior and medial approaches for popliteal artery aneurysms

Long-term results of the posterior approach (PA) for the treatment of popliteal artery aneurysms are lacking in the literature. We reviewed our experience during a 13-year period in patients with popliteal artery aneurysms, comparing those treated through a PA with those operated on through a standard medial approach (MA). Clinical data of all patients treated between February 1998 and October 2011 were retrospectively reviewed and outcomes analyzed. The Kaplan-Meier method was used to estimate survival, and χ(2), Wilcoxon, and log-rank tests were used for analysis. A total of 77 aneurysms were treated in 65 patients (64 men). Mean age was 68 years (range, 48-96 years). Thirty-six aneurysms were asymptomatic (47%). Mean sac diameter was 2.8 ± 1 cm. A PA was used in 43 PAAs (55%) and an MA in 34. The PA and MA patients differed significantly in age (median being older), smoking history (more frequent in PA), and renal insufficiency and cerebrovascular disease (higher for MA). In 42 cases the aneurysm was symptomatic (54.5%) for chronic limb ischemia, with intermittent claudication in 18 patients, acute ischemia in 17, blue toe syndrome in 3, compression on adjacent structures in 3, and rupture with severe acute pain in 1. All PA repairs consisted of aneurysmectomy with an interposition graft with end-to-end anastomoses; among MA repairs, 22 interposition grafts and 12 bypasses were performed. A polytetrafluoroethylene graft was used in 54 cases. Five patients had an early thrombosis (two PA and three MA). No perioperative deaths occurred. Two patients sustained a permanent (PA) and a temporary (MA) peroneal nerve lesion. There were no early amputations. The median in-hospital stay was longer for MA (10 days) than for PA (7 days; P = .02). Median follow-up was 58.8 months (range, 5 days-166 months). Nine patients died during follow-up of unrelated causes. The 5-year primary and secondary patency rates were 59.6% ± 8.6% and 96.5% ± 3.4%, respectively, for PA, and 65.1% ± 11.1% and 79.4% ± 9.7%, respectively, for MA (P = .53 for primary patency rate and P = .22 for secondary patency rate). Limb salvage was 100% at 5 years and 93.3% ± 6.4% at 10 years for PA and 91.1% ± 6.3% at both time points for MA (P = .28). PA and MA both achieved satisfactory results in primary and secondary patency rates, as well as limb salvage, during long-term follow-up. The differences between the two groups were small and not statistically significant. PA was burdened by similar postoperative nerve and wound complications compared with MA. The in-hospital stay after PA was significantly lower.

The Case of a Patient with Concomitant Popliteal Artery and Ascending Aortic Aneurysm Who Presented with the Blue Toe Syndrome

Popliteal artery aneurysms (PAAs) are rare though these aneurysms are the most frequently encountered peripheral arterial aneurysms. In this article, we present the treatment of a patient who simultaneously had bilateral popliteal artery and ascending aortic aneurysm but was admitted to the emergency room due to the blue toe syndrome. A 72-old-year female was admitted to the hospital with left lower extremity pain and cyanosis in her toe. Bilateral popliteal artery and ascending aortic aneurysm were observed on computed tomography. Aneurysmectomy and femoropopliteal bypass was performed primarily to the left popliteal artery owing to ischemia. Two months later, we performed valve and ascending aorta replacement followed by right popliteal aneurysmectomy and femoropopliteal bypass 16 months later. In conclusion, since other arterial aneurysms can be simultaneously observed with popliteal artery aneurysm, it is very important to scan whole main arterial system when PAA is evaluated. Key Words: Popliteal Artery; Aorta; Aneurysm; Embolism.

Lečenje sindroma plavih prstiju hiperbaričnom oksigenoterapijom - prikaz slučaja

"Blue toe" syndrome is a relatively rare ischemic disorder produced by occlusion of small blood vessels with fragments of atherosclerotic plaques composed of cholesterol crystals, fatty acids and calcium. It can occur as a complication after endovascular procedures, usually performed on the infra-renal segment of abdominal aorta, as well as in the patients who were under treatment with oral anticoagulant therapy. Hyperbaric oxygen therapy (HBOt) is inhaling 100% oxygen under carefully controlled elevated pressure conditions. In Zemun Clinical Hospital, a patient who presented with "blue toe" syndrome, has been treated with HBOt. After the completion of HBOt course, there was an almost complete regression of ischemic changes.

Blue Toe Sendromu ile Prezente Olan Bilateral Popliteal Arter Anevrizması

Blue Toe Sendromu ile Prezente Olan Bilateral Popliteal Arter Anevrizması

The Pathogenesis and Diagnosis of Thromboangiitis obliterans: Is It Still a Mystery?

Thromboangiitis obliterans (TAO) is a rare disease of unknown etiology that results in the occlusion of limb arteries located distally to the elbow and knee. Despite the fact that more than one hundred years have passed since its first description, knowledge on the pathogenesis of TAO and precipitating factors is still limited. Due to a lack of decisive noninvasive diagnostic methods and geographical differences in the prevalence of this condition, data on TAO epidemiology also remains sparse. This review presents important evidence on the pathogenesis and the course of the condition, as well as diagnostic modalities, with a focus on differential diagnosis. Theories on the pathogenesis of TAO include the theory of an infectious disease, coagulation disorders and injury to vascular endothelium resulting in activation of the inflammatory response. Differential diagnosis should exclude thoracic outlet syndrome, blue toe syndrome, infectious endocarditis, popliteal entrapment syndrome, Takayasu disease, primary and secondary systemic vasculitis, antiphospholipid syndrome, infection with the anaerobic Clostridium sp. bacilli and some less common conditions.